Daniela Traini

A Safe-by-Design Approach for the Synthesis of a Novel Cross-Linked Hyaluronic Acid with Improved Biological and Physical Properties

Publisher: MDPI AG

Date: 11-03-2023

DOI: 10.3390/PH16030431

Abstract: Hyaluronic acid (HA) is a polymer with unique biological properties that has gained in interest over the years, with applications in pharmaceutical, cosmetic, and biomedical fields however, its widespread use has been limited by its short half-life. Therefore, a new cross-linked hyaluronic acid was designed and characterized using a natural and safe cross-linking agent, such as arginine methyl ester, which provided improved resistance to enzymatic action, as compared to the corresponding linear polymer. The antibacterial profile of the new derivative was shown to be effective against S. aureus and P. acnes, making it a promising candidate for use in cosmetic formulations and skin applications. Its effect on S. pneumoniae, combined with its excellent tolerability profile on lung cells, also makes this new product suitable for applications involving the respiratory tract.

Polymer coating of carrier excipients modify aerosol performance of adhered drugs used in dry powder inhalation therapy

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1016/J.IJPHARM.2012.08.036

Abstract: The potential of excipient coating to enhance aerosol performance of micronized drugs in carrier excipient-drug blends, used in dry powder inhalers, was investigated. Both EC (ethyl cellulose) and PVP (polyvinylpyrrolidone) were used as coating agents. Carriers were prepared via sieve fractioning followed by spray drying, with and without polymer additive. Each uncoated and coated carrier salbutamol sulphate (SS) blended systems were evaluated for particle size, morphology, drug carrier adhesion and aerosolisation performance, after blending and storage for 24h. All carrier-based systems prepared had similar particle sizes and morphologies. The surface chemistries of the carriers were significantly different, as was drug-carrier adhesion and aerosolisation performance. Particle adhesion between SS and aerosol performance (fine particle fraction FPF) followed the rank: PVP coated>un-coated>EC coated lactose. This rank order could be attributed to the surface energy measured by contact goniometry and related to the chemistry of lactose and each polymer. Storage did not significantly affect aerosol performance, however a rank increase in mean FPF value was observed for uncoated and EC coated lactose. Finally, the net electrostatic charge across the aerosol cloud indicated that the EC coated lactose transferred less charge to SS particles. The performance of each carrier system could be attributed to the carrier surface chemistry and, in general, by careful selection of the coating polymer, drug-carrier adhesion, electrostatic charge and aerosol performance could be controlled.

Determination of physical and chemical stability in pressurised metered dose inhalers: potential new techniques

Publisher: Informa Healthcare

Date: 12-06-2015

DOI: 10.1517/17425247.2015.1046834

Abstract: Pressurised metered dose inhalers (pMDIs) are subject to rigorous physical and chemical stability tests during formulation. Due to the time and cost associated with product development studies, there is a need for online techniques to fast screen new formulations in terms of physical and chemical (physico-chemical) stability. The problem with achieving this is that pMDIs are by their definition, pressurised, making the direct observation of physico-chemical properties in situ difficult. This review highlights the characterisation tools that can enhance the product development process for pMDIs. Techniques investigated include: laser diffraction, Raman spectroscopy, isothermal oule calorimetry, titration calorimetry and gas perfusion calorimetry. The operational principles behind each technique are discussed and complemented with ex les from the literature. Laser diffraction is well placed to analyse real-time physical stability as a function of particle size however, its use is restricted to suspension pMDIs. Raman spectroscopy can be potentially used to attain both suspension and solution pMDI spectra in real time however, the majority of experiments are ex-valve chemical composition mapping. Calorimetry is an effective technique in capturing both chemical and physical degradations of APIs in real time but requires redevelopment to withstand pressure for the purposes of pMDI screening.

Isothermal calorimetry: A predictive tool to model drug-propellant interactions in pressurized metered dose systems

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.IJPHARM.2013.11.055

Abstract: The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried s les of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.

Micronized drug powders in binary mixtures and the effect of physical properties on aerosolization from combination drug dry powder inhalers

Publisher: Informa UK Limited

Date: 16-02-2012

DOI: 10.3109/03639045.2012.654793

Abstract: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. The median SS particle diameter was larger than BDP (4.33 ± 0.37 µm compared to 2.99 ± 0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested in idually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the in idual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.

Evolved gas analysis during thermal degradation of salbutamol sulphate

Publisher: Springer Science and Business Media LLC

Date: 22-07-2015

DOI: 10.1007/S10973-014-3935-8

The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.IJPHARM.2011.06.020

Abstract: Previous studies have reported that carrier:drug ratio and carrier size influence the aerosol performance of dry powder inhalation systems. These previous studies were complicated by the heterogeneous nature of the carriers used, making it difficult to define an explicit relationship between parameters and performance. Here, the authors studied the influence of drug loading and carrier size on drug aerosol performance using homogeneous spherical model carriers. Different formulations containing drug (salbutamol sulphate) and carriers (polystyrene beads with median diameters of 82.8μm, 277.5μm and 582.9μm, respectively) were prepared by varying the ratio of carrier to drug (from ∼5:1 to ∼85:1). The surface morphology of the carrier particles and force of adhesion were investigated using atomic force microscopy, while the aerosol performance was evaluated using a multi-stage liquid impinger. The carrier surface morphology for all carrier sizes was homogenous with root-mean square roughness values ≤112nm. No significant difference in the force of adhesion between salbutamol sulphate and the three carrier sizes was observed. Significant differences in aerosol performance of salbutamol sulphate (measured as fine particle dose (FPD) and fraction (FPF)≤5μm) from the carriers were observed. Specifically, as carrier size increased FPF decreased. In comparison, as drug loading increased there was no change in FPF until a critical threshold was exceeded. Such observations suggest that: (A) aerosolisation performance is governed by carrier collisions and (B) when homogeneous carriers are used, the aerosol performance remains constant with respect to drug concentration, until the formulation transitions from an ordered mix to an agglomerated and/or segregated powder bed.

Overcoming dose limitations using the orbital^® multi-breath dry powder inhaler

Publisher: Mary Ann Liebert Inc

Date: 04-2014

DOI: 10.1089/JAMP.2013.1080

Abstract: A new approach to delivering high doses of dry powder medicaments to the lung is presented. The Orbital(®) dry powder device is designed to deliver high doses of drugs to the respiratory tract in a single dosing unit, via multiple inhalation maneuvers, overcoming the need to prime or insert multiple capsules. The Orbital was tested in its prototype configuration and compared with a conventional RS01 capsule device. Three formulations were evaluated: 200 mg of spray-dried ciprofloxacin formulation for respiratory infection, 200 mg of spray-dried mannitol formulation for mucus clearance, and 100, 200, and 400 mg of co-spray-dried 1:8 formulations containing ciprofloxacin and mannitol as combination therapy. The systems were evaluated in terms of physicochemical properties and tested using a multistage liquid impinger at 60 L/min. Emptying rates were evaluated, and the aerosolization performance compared with 10 capsules used sequentially in the RS01. The systems were different in terms of morphology, thermal response, moisture sorption, and stability however, they had similar sizes when measured by laser diffraction, making them suitable for comparison in the Orbital and RS01 devices. The aerosolization performance from the Orbital device and RS01 was dependent on the formulation type however, the fine particle fraction (FPF) produced by the Orbital device was higher than that by the RS01. The FPFs for ciprofloxacin, mannitol, and co-spray-dried formulation were 67.1±1.8, 47.1±2.2, and 42.0±1.8, respectively. For the Orbital, 90% of the loaded dose was delivered within 10 inhalation maneuvers, with the profile being dependent on the formulation type. The Orbital provides a means of delivering high doses of medicine to the respiratory tract through multiple breath maneuvers after a single actuation. This approach will allow the delivery of a wide range of high-payload formulations (>100 mg) for the treatment of a variety of lung disorders. To date, no such passive device exists that meets these crucial criteria.

Micro-particle corrugation, adhesion and inhalation aerosol efficiency

Publisher: Elsevier BV

Date: 09-2008

DOI: 10.1016/J.EJPS.2008.05.009

Abstract: Atomic force microscopy (AFM) was used to evaluate the particle adhesion and surface morphology of engineered particles for dry powder inhaler (DPI) respiratory therapy to gain a greater understanding of interparticle forces and the aerosolisation process. A series of spherical model drug particles of bovine serum albumin (BSA) was prepared with different degrees of surface corrugation. The particles were evaluated in terms of particle size (laser diffraction) and microscopic morphology (scanning electron microscopy). Conventional tapping mode AFM was used to evaluate the nanoscopic morphology and derive specific roughness parameters, while AFM colloid probe microscopy was used to directly measure the interaction of functionalised probes. The physical characterisation and AFM measurements were evaluated in terms of in vitro aerosolisation performance, using a conventional Rotahaler((R)) DPI and multistage liquid impinger. A direct relationship between the root mean square roughness, particle adhesion and in vitro aerosol performance (measured as fine particle fraction, FPF) was observed suggesting that as the degree of corrugation increased, particle adhesion was reduced which, resulted in a concomitant increase in FPF. This study demonstrates that AFM may be used to predict the aerosolisation performance micron sized particles for inhalation based on their morphological properties.

Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/J.EJPHAR.2021.174098

Recent Advances in Controlled Release Pulmonary Therapy

Publisher: Bentham Science Publishers Ltd.

Date: 08-2009

DOI: 10.2174/156720109789000546

Abstract: Delivering therapeutic agents to the airways maximizes their concentration in lung tissue, decreasing systemic exposure or facilitating systemic absorption as desired. Many formulations exist for the treatment of respiratory illnesses however, no controlled release inhalation formulation exists to-date. This review is an update of the current advances in controlled release inhalation formulations and evaluation. The major successful particle engineering strategies are discussed along with potential in vitro and in vivo methodologies required for their characterisation. Controlled release formulation has many challenges to overcome, specific to this kind of medicament for inhalation. With small particle size and thus an increase in surface area, it becomes more difficult to achieve an effective controlled release profile. In addition, the physiology of the lung and its impact on resident particles need to be considered. An important issue when developing controlled release inhalation formulation is the toxic, inflammatory and accumulation effects of the release modifying agents used. These effects will need to be scrutinized in much greater detail in order to bring these formulations to the market. Currently, strategies for controlling the release of inhalation therapy include molecular dispersions (liposomal-based systems), solid lipid microparticles, coating or encapsulating drug particles in a lipid outer shield, solid biodegradable (synthetic and natural excipient-based matrices), conjugates and viscous semisolid vehicles. However, the availability of standardized pharmacopoeia methodologies to test the in vitro release rates or in vivo methodologies to evaluate deposition, pharmacokinetics and clearance of controlled release systems are not available. These methodologies are presented and discussed in this review.

Development and Evaluation of Paclitaxel and Curcumin Dry Powder for Inhalation Lung Cancer Treatment

Publisher: MDPI AG

Date: 22-12-2020

DOI: 10.3390/PHARMACEUTICS13010009

Abstract: Despite the effort to develop efficient targeted drug delivery for lung cancer treatment, the outcome remains unsatisfactory with a survival rate of 15% after 5 years of diagnosis. Inhalation formulation is an ideal alternative that could ensure the direct deposition of chemotherapeutics to the lungs. However, the design of an inhalable formulation that could simultaneously achieve a high local chemotherapeutic dose to the solid tumor and exert low pulmonary toxicities is a challenge, as the presence of 10–30% of chemotherapeutics in the lung is sufficient to induce toxicity. Therefore, this study aimed to develop a simple dry powder inhalation (DPI) formulation containing a model chemotherapeutic agent (paclitaxel, PTX) and a natural antioxidant (curcumin, CUR) that acts to protect healthy lung cells from injury during direct lung delivery. The co-jet-milling of CUR and PTX resulted in formulations with suitable aerosol performance, as indicated in the high fine particle fractions (FPF) ( %) and adequate mass median aerodynamic diameter (MMAD). The CUR/PTX combination showed a more potent cytotoxic effect against lung cancer cells. This is evident from the induction of apoptosis/necrotic cell death and G2/M cell cycle arrests in both A549 and Calu-3 cells. The increased intracellular ROS, mitochondrial depolarization and reduced ATP content in A549 and Calu-3 cells indicated that the actions of CUR and PTX were associated with mitochondrial oxidative stress. Interestingly, the presence of CUR is crucial to neutralize the cytotoxic effects of PTX against healthy cells (Beas-2B), and this is dose-dependent. This study presents a simple approach to formulating an effective DPI formulation with preferential cytotoxicity towards lung cancer.

Motion representation of ciliated cell images with contour-alignment for automated CBF estimation

Publisher: Springer International Publishing

Date: 2015

DOI: 10.1007/978-3-319-24574-4_36

Novel nano-cellulose excipient for generating non-Newtonian droplets for targeted nasal drug delivery.

Publisher: Informa UK Limited

Date: 21-06-2017

DOI: 10.1080/03639045.2017.1339078

Abstract: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips. Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient. The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray. Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.

Themed issue: Inhalation pharmaceutics - Current technologies and approaches to respiratory drug delivery

Publisher: Oxford University Press (OUP)

Date: 06-08-2012

DOI: 10.1111/J.2042-7158.2012.01581.X

Paclitaxel-eluting silicone airway stent for preventing granulation tissue growth and lung cancer relapse in central airway pathologies

Publisher: Informa UK Limited

Date: 31-08-2020

DOI: 10.1080/17425247.2020.1811224

Concurrent oral and inhalation drug delivery using a dual formulation system: the use of oral theophylline carrier with combined inhalable budesonide and terbutaline

Publisher: Springer Science and Business Media LLC

Date: 02-03-2013

DOI: 10.1007/S13346-013-0137-Z

Abstract: A novel approach to concurrently deliver oral and inhaled drugs as a single formulation is presented. A triple therapy containing theophylline (THEO orally delivered) with budesonide (BUD) and terbutaline (TERB as single and co-spray-dried inhaled powders) was prepared as an ordered mix, with THEO acting as a carrier. The aerosolisation performance of THEO formulations containing BUD and TERB alone, physical mix and co-spray-dried powder was evaluated using a next-generation impactor (NGI). Physicochemical properties were investigated using electron microscopy, laser diffraction, dynamic vapour sorption and thermal analysis. NGI analysis indicated that >99 % of the THEO powder was >4.46 μm, with >90 % dissolved within 5 min. Particle size analysis showed TEB and BUD s les were of a suitable size for inhalation. Thermal and moisture analysis suggested powders to be stable at room temperature up to 70 % RH. Aerosol studies indicated a different performance of BUD and TERB depending on the mixing procedure. The co-spray-dried formulation showed the highest performance, with a fine particle fraction (≤4.46 μm) of BUD and TERB of 34.39 ± 3.56 and 33.61 ± 5.67 %, respectively. Such observations suggest that this multicomponent drug delivery system could be developed to concomitantly deliver oral and inhaled drugs, an approach that, to date, does not exist. Ultimately, this technology potentially reduces the requirement for multiple therapies and increases patient compliance.

Co-spray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.EJPS.2010.03.020

Abstract: The aim of this study was to assess the potential of delivering a combination therapy, containing mannitol (a sugar alcohol with osmotic characteristics), and ciprofloxacin hydrochloride (an antibacterial fluoroquinolone), as a dry powder inhaler (DPI) formulation for inhalation. Single and combination powders were produced by spray drying ciprofloxacin and mannitol, from aqueous solution, at different ratios and under controlled conditions, as to obtain similar particle size distributions. Each formulation was characterised using laser diffraction, scanning electron microscopy, differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and colloidal force microscopy. The in vitro aerosol performance of each formulation was studied using an Aerolizer DPI device and a multi-stage liquid impinger (analysed using high performance liquid chromatography). In addition, a disk diffusion test was performed to assess the in vitro antimicrobial activity of each formulation and starting materials. All formulations had similar particle size distributions, however, the morphology, thermal properties and moisture sorption was dependent on the relative percentages of each component. In general, the combination formulation containing 50% (w/w) mannitol appeared to have the best aerosol performance, good stability and lowest particle cohesion (as measured by colloid probe microscopy). Furthermore, of the formulations tested, mannitol did not appear to alter the effectiveness of the ciprofloxacin antimicrobial activity to Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes. The combination of co-spray-dried mannitol and ciprofloxacin from a DPI is an attractive approach to promote mucous clearance in the respiratory tract while simultaneously treating local chronic infection, such as chronic obstructive pulmonary disease and cystic fibrosis.

The formulation, chemical and physical characterisation of clarithromycin-based macrolide solution pressurised metered dose inhaler

Publisher: Oxford University Press (OUP)

Date: 11-12-2013

DOI: 10.1111/JPHP.12190

Abstract: The formulation of a clarithromycin (CLA) pressurised metered dose inhalers (pMDIs) solution formulation opens up exciting therapeutic opportunities for the treatment of inflammation in chronic obstructive lung diseases. In this study, we have formulated and tested a low dose macrolide formulation of CLA for treatment of inflammation and studied its physicochemical and aerosol properties. The system was characterised for in-vitro aerosol performance using an Andersen cascade impactor. Short-term chemical and physical stability was assessed by dose content uniformity over a range of temperatures. Standard physicochemical characteristics were also investigated using scanning electron microscopy, thermo analysis and laser diffraction techniques. The formulation had a relatively high fine particle fraction (47%) and produced a particle size distribution suitable for inhalation drug delivery. Particles had an irregular morphology and were predominately amorphous. Furthermore, the short-term stability showed the formulation to be stable from 4 to 37°C. This study demonstrated the feasibility of formulating a solution-based pMDI containing CLA for the treatment of lung inflammatory diseases.

In vitro and in vivo applications of a universal and synthetic thermo-responsive drug delivery hydrogel platform

Publisher: Elsevier BV

Date: 03-2023

DOI: 10.1016/J.IJPHARM.2023.122777

Advances in drug delivery: is triple therapy the future for the treatment of chronic obstructive pulmonary disease?

Publisher: Informa UK Limited

Date: 30-06-2011

DOI: 10.1517/14656566.2011.589837

Abstract: Current therapies for chronic obstructive pulmonary disease (COPD) focus on the improvement of clinical symptoms via the use of bronchodilators: β(2)-adrenoreceptor agonists and muscarinic (M3) acetylcholine receptor antagonists. The combination of inhaled corticosteroids (ICSs) and long-acting β(2) agonists (LABAs), or LABAs and anticholinergics has become an efficient alternative to single therapies. These combinations consist of a LABA and an ICS together with an anticholinergic, such as ipratropium or tiotropium. This review summarizes the latest thinking and findings on the usefulness of triple therapy in the treatment and management of COPD. Drawing on commercial, clinical, scientific and intellectual property data and publications, it aims to provide an overview to understand the efficacy and need for COPD triple therapy. The reader will gain an in-depth view of the triple therapy approach in managing COPD, existing molecules in the market or in development as well as new chemical entities. Clinical evidence in support of triple therapy, formulations and products are also discussed. There is limited documented clinical evidence for the use of triple therapy in COPD, reflected in the lack of commercial activity in the field. The future for the management of COPD may lie with triple therapy, but may equally rest on a better understanding of the disease and subsequent development of new chemical entities, such as dimer molecules, longer-acting β-agonists and antimuscarinics.

A ‘soft spot’ for drug transport: modulation of cell stiffness using fatty acids and its impact on drug transport in lung model

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C4TB01928H

Abstract: The impact of a polyunsaturated fatty acid, arachidonic acid (AA), on membrane fluidity of epithelial cells and subsequent modulation of the drug transport was investigated.

Magnetised Thermo Responsive Lipid Vehicles for Targeted and Controlled Lung Drug Delivery

Publisher: Springer Science and Business Media LLC

Date: 15-05-2012

DOI: 10.1007/S11095-012-0774-9

Abstract: Conditions such as lung cancer currently lack non-invasively targetable and controlled release topical inhalational therapies. Superparamagnetic iron-oxide nanoparticles (SPIONs) have shown promising results as a targetable therapy. We aimed to fabricate and test the in-vitro performance of particles with SPION and drug within a lipid matrix as a potentially targetable and thermo-sensitive inhalable drug-delivery system. Budesonide and SPIONs were incorporated into lipid particles using oil-in-water emulsification. Particles size, chemical composition, responsiveness to magnetic field, thermosensitiveness and inhalation performance in-vitro were investigated. Particles of average diameter 2-4 μm with budesonide and SPIONs inside the lipid matrix responded to a magnetic field with 100% extraction at a distance of 5 mm. Formulations were shown to have accelerated rate of drug release at hyperthermic temperatures (45°C)--controlled release. The produced inhalation dry powder presented promising inhalation performance, with an inhalable fine particle fraction of 30%. The lipid system presented thermo-sensitive characteristics, suitable for controlled delivery, the model drug and SPION loaded lipid system was magnetically active and movable using simple permanent magnets, and the system demonstrates promise as an effective drug vehicle in targeted and controlled inhalation therapy.

The use of inverse gas chromatography for the study of lactose and pharmaceutical materials used in dry powder inhalers

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.ADDR.2011.12.015

Abstract: Inverse gas chromatography (IGC) is a sensitive technique for the measurement of powder surface properties, especially surface energetics. Given the importance of these characteristics to the performance of dry powder inhaler formulations (DPIs), it is unsurprising that IGC has been applied to the study of these systems. Monitoring batch-to-batch variation and the effects of processing steps are established uses of IGC in this field and the relevant studies are discussed. A less established use of IGC is for the prediction of DPI performance. Although some groups have found a negative relationship between the dispersive surface energy of one formulation component and fine particle delivery, such studies often have a number of limitations. More complex approaches have failed to produce consistent results. Further, more carefully designed, studies are required in this area. In the final section of this article, some areas for on-going research are discussed, including the need to critically assess the best method for the calculation of the specific free energy of adsorption with pharmaceutical materials.

The formation of aerosol particles from solution-based pressurized metered dose inhalers and implications of incomplete droplet drying

Publisher: Informa UK Limited

Date: 30-09-2015

DOI: 10.1080/02786826.2015.1096897

Preparation and Evaluation of Controlled Release Microparticles for Respiratory Protein Therapy

Publisher: Elsevier BV

Date: 08-2009

DOI: 10.1002/JPS.21653

A varying-swirl design concept for dry powder inhalers

Publisher: Elsevier BV

Date: 06-2023

DOI: 10.1016/J.JAEROSCI.2023.106162

Introduction of the electrical Next Generation Impactor (eNGI) and investigation of its capabilities for the study of pressurized metered dose inhalers

Publisher: Springer Science and Business Media LLC

Date: 31-10-2009

DOI: 10.1007/S11095-008-9761-6

Abstract: To introduce the design of the electrical next generation impactor (eNGI), and validate its proposed function as a method of electrostatic characterization for pressurized metered dose inhaler (pMDI) formulations. Flixotide (fluticasone propionate), ventolin (salbutamol sulphate), and qvar (beclomethasone dipropionate) were used as model pMDIs in this study. At an airflow rate of 30 l/min, five in idual actuations of each pMDI were introduced into the electrical low-pressure impactor (ELPI), Next Generation Impactor (NGI), and the eNGI. Charge profiles for each actuation were measured by the ELPI and eNGI, while mass profiles were recorded by the all three impactors. The difference in estimated mass median aerodynamic diameters and geometric standard deviations for all pMDIs using the NGI and eNGI were not found to be statistically significant (p<0.05). The mean charge profiles from the ELPI and eNGI overlap well between 0.54 and 6.61 microm (flixotide and ventolin), and between 0.615 and 11.72 microm (qvar), where the majority of the impacted doses were collected. For the analysis of pMDIs, the eNGI is comparable to the NGI in measuring particle size distribution, while still being comparable to the ELPI in measuring charge distribution.

Time- and passage-dependent characteristics of a Calu-3 respiratory epithelial cell model

Publisher: Informa UK Limited

Date: 08-04-2010

DOI: 10.3109/03639041003695113

Abstract: Although standard protocols for the study of drug delivery in the upper airways using the sub-bronchial epithelial cell line Calu-3 model, particularly that of the air-liquid interface configuration, are readily available, the model remains un-validated with respect to culture conditions, barrier integrity, mucous secretion, and transporter function. With respect to the latter, the significance of functional P-glycoprotein (P-gp) activity in Calu-3 cells has recently been questioned, despite previous reports demonstrating a significant contribution by the same transporter in limiting drug uptake across the pulmonary epithelium. Therefore, the aim of this study was the standardization of this model as a tool for drug discovery. Calu-3 cells were grown using air-interfaced condition (AIC) on polyester cell culture supports. Monolayers were evaluated for transepithelial electrical resistance (TEER), permeability to the paracellular marker fluorescein sodium (flu-Na), surface P-gp expression, and functionality. Mucous secretion was also identified by alcian blue staining. TEER and permeability values obtained for Calu-3 monolayers were shown to plateau between day 5 and day 21 in culture with values reaching 474 +/- 44 omega cm(2) and 2.33 +/- 0.36 x 10(-7) cm/s, respectively, irrespective of the passage number examined. 32.7 +/- 1.49% of Calu-3 cells cultured under these conditions detected positive for cell surface P-gp expression from day 7 onwards. Functional cell surface expression was established by rhodamine 123 drug extrusion assays. This study establishes a clear dependence on culture time and passage number for optimal barrier integrity, mucous secretion, and cell-surface P-gp expression and function in Calu-3 cells. Furthermore it provides initial guidelines for the optimization of this model for high throughput screening applications.

Nano- and micro-based inhaled drug delivery systems for targeting alveolar macrophages

Publisher: Informa UK Limited

Date: 26-04-2015

DOI: 10.1517/17425247.2015.1039509

Abstract: Macrophages are the most versatile cells in the hematopoietic system and are strategically distributed in tissues to fight pathogens or other foreign particles. In the lung, however, for intracellular infections such as tuberculosis, pneumonia and aspergillosis, bacteria and fungi utilize the alveolar macrophage as a breeding ground. This has become a challenge for the treatment of these infections, as most drugs do not effectively reach the macrophages at therapeutic levels. Alveolar macrophages also play an important role to initiative adaptive immunity toward combating inflammation and cancer in the lung. This review focuses on the development of micro- and nanotechnology-based drug delivery systems to target alveolar macrophages in association with intracellular infections, cancer and lung inflammation. Aspects of nanoparticle and micron-sized particle engineering through exploitation of particles' physicochemical characteristics such as particle size, surface charge and geometry of particles are discussed. In addition, the application of nanocarriers such as liposomes, polymeric nanoparticles and dendrimers are covered with respect to macrophage targeting. Drug delivery targeted to alveolar macrophages in the lung is becoming a reality thanks to micro- and nanotechnology breakthrough. The literature review shows that regulation of physicochemical parameters of particles could be a recipe to enhance macrophage targeting and uptake. However, there is still a need to identify more target-specific receptors in order to facilitate drug targeting. Besides that, the toxicity of nanocarriers arising from prolonged residence in the lung should be taken into consideration during formulation.

Particle aerosolisation and break-up in dry powder inhalers: Evaluation and modelling of impaction effects for agglomerated systems

Publisher: Elsevier BV

Date: 07-2011

DOI: 10.1002/JPS.22503

Toxicity of curcumin nanoparticles towards alveolar macrophage: Effects of surface charges

Publisher: Elsevier BV

Date: 05-2022

DOI: 10.1016/J.FCT.2022.112976

Abstract: Curcumin has been used for chronic lung diseases management due to its ersified molecular actions. However, the potential cytotoxicity which occurs in cells following the exposure to high concentrations of curcumin has been overlooked. This study evaluated the toxic events of curcumin nanoparticles (Cur-NPs) with alterable surface polarity in alveolar macrophages (NR8383). We aimed to establish the correlation between the toxicity of Cur-NPs with different surface charges and the internalization mechanisms of the NPs. Toxicity data showed that positively charged Cur-NPs (IC

Aerosol particle generation from solution-based pressurized metered dose inhalers: A technical overview of parameters that influence respiratory deposition

Publisher: Informa UK Limited

Date: 22-09-2015

DOI: 10.3109/10837450.2014.959176

Abstract: There are a multitude of formulation factors to consider when developing a solution-based pressurized metered dose inhaler (pMDI). Evaluation of these variables and their underpinning driving force has been performed over the years. Key components, including formulation composition and device design, play significant roles in determining the aerosol performance of these solution-based formulations. This review outlines research efforts that have focused on these essential governing factors, how the aerosol performance changes when these variables are modified and fundamental mechanisms affecting the delivery efficiency of such formulations.

The Development and Validation of anIn VitroAirway Model to Assess Realistic Airway Deposition and Drug Permeation Behavior of Orally Inhaled Products Across Synthetic Membranes

Publisher: Mary Ann Liebert Inc

Date: 04-2018

DOI: 10.1089/JAMP.2017.1400

Abstract: Current in vitro approaches to assess lung deposition, dissolution, and cellular transport behavior of orally inhaled products (OIPs) have relied on compendial impactors to collect drug particles that are likely to deposit in the airway however, the main drawback with this approach is that these impactors do not reflect the airway and may not necessarily represent drug deposition behavior in vivo. The aim of this article is to describe the development and method validation of a novel hybrid in vitro approach to assess drug deposition and permeation behavior in a more representative airway model. The medium-sized Virginia Commonwealth University (VCU) mouth-throat (MT) and tracheal-bronchial (TB) realistic upper airway models were used in this study as representative models of the upper airway. The TB model was modified to accommodate two Snapwell The Snapwell test system demonstrated reproducible and discriminatory drug permeation profiles for already dissolved and nebulized CIP-HCL droplets through a range of synthetic permeable membranes under different test conditions. The rate and extent of drug permeation depended on the permeable membrane material used, presence of a stirrer in the receptor compartment, and, most importantly, the drug collection method. This novel hybrid in vitro approach, which incorporates a modified version of a realistic upper airway model, coupled with the Snapwell test system holds great potential to evaluate postairway deposition characteristics, such as drug permeation and particle dissolution behavior of OIPs. Future studies will expand this approach using a cell culture-based setup instead of synthetic membranes, within a humidified chamber, to assess airway epithelia transport behavior in a more representative manner.

The effect of non-specific tight junction modulators on the transepithelial transport of poorly permeable drugs across airway epithelial cells

Publisher: Informa UK Limited

Date: 24-11-2017

DOI: 10.1080/1061186X.2016.1258703

Pharmacopeial methodologies for determining aerodynamic mass distributions of ultra-high dose inhaler medicines

Publisher: Elsevier BV

Date: 03-2010

DOI: 10.1016/J.JPBA.2009.10.011

Abstract: Three different impactor methodologies, the Andersen cascade impactor (ACI), next-generation impactor (NGI) and multistage-liquid impinger (MSLI) were studied to determine their performance when testing ultra-high dose dry powder formulations. Cumulative doses of spray-dried mannitol (Aridol) were delivered to each impactor at a flow rate of 60Lmin(-1) (up to a max dose of 800mg delivering 20 sequential 40mg capsules). In general, total drug collected in both the ACI and NGI falls below the range 85-115% of label claim criteria recommended by the United States of America Food and Drug Administration (FDA) at nominal mannitol doses exceeding 20mg and 200mg, respectively. In comparison analysis of the MSLI data, over a 5-800mg cumulative dosing range, indicated that the percentage of nominal dose recovered from the MSLI was within the +/-15% limits set in this study. Furthermore all s les, apart from the 5mg and 10mg analysis were within 5% of the nominal cumulative dose. While the MSLI is not routinely used for regulatory submission, the use of this impinger when studying ultra-high dose formulations should be considered as a complementary and comparative source of aerosol deposition data.

Spray freeze drying for protein encapsulation: Impact of the formulation to morphology and stability

Publisher: Informa UK Limited

Date: 25-06-2023

DOI: 10.1080/07373937.2022.2089162

Engineered dry powders for the nose-to-brain delivery of transforming growth factor-beta

Publisher: Elsevier BV

Date: 08-2023

DOI: 10.1016/J.EJPB.2023.06.015

Development and in vitro characterization of a novel pMDI diclofenac formulation as an inhalable anti-inflammatory therapy for cystic fibrosis

Publisher: Elsevier BV

Date: 03-2021

DOI: 10.1016/J.IJPHARM.2021.120319

Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection

Publisher: Springer Science and Business Media LLC

Date: 07-02-2018

DOI: 10.1007/S11095-018-2350-4

Abstract: The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm. Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy. Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone. The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.

Advances in the use of cell penetrating peptides for respiratory drug delivery

Publisher: Informa UK Limited

Date: 19-03-2020

DOI: 10.1080/17425247.2020.1739646

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery

Publisher: Informa UK Limited

Date: 07-05-2017

DOI: 10.1080/03639045.2017.1321659

Abstract: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray. The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus-BUD formulation. The freeze-dried Soluplus-BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334 ± 0.0178 m Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.

In vitro and ex vivo methods predict the enhanced lung residence time of liposomal ciprofloxacin formulations for nebulisation

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.EJPB.2013.06.024

Abstract: Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily administration due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study, three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air interface Calu-3 cells and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank order of drug release/transport from the different formulations was consistent across the in vitro and ex vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex vivo methodologies provided a robust analysis of formulation behaviour, including mechanistic insights, and predicted in vivo pharmacokinetics.

Fabrication of polyphenol nanoparticles co-stabilized with different polyvinylpyrrolidone concentrations: Effects on particle stability, drug release and cellular uptake

Publisher: Elsevier BV

Date: 08-2023

DOI: 10.1016/J.JDDST.2023.104575

Multiple dosing of simvastatin inhibits airway mucus production of epithelial cells: implications in the treatment of chronic obstructive airway pathologies.

Publisher: Elsevier BV

Date: 08-2013

DOI: 10.1016/J.EJPB.2013.01.021

Abstract: Chronic obstructive pulmonary disease (COPD) is characterised by mucus hyper-production. This pathology, together with other inflammatory contributions, leads to airway obstruction and breathing complications. Newer therapeutic approaches are of increased interest, including the use of HMG-CoA reductase inhibitors. Retrospective studies have shown that statins are effective in reducing patient mortality and blood cytokines levels. These findings suggest statins may also provide a new therapeutic approach in COPD treatment. The aim of the present work was to study the transport of simvastatin (SV) across Calu-3 epithelial cells and to investigate its pharmacological action with respect to reduction in mucus production. Calu-3 cells were grown under liquid covered culture (LCC) conditions for transport studies in order to demonstrate the ability of SV to transport across the monolayer. For mucus detection, cells were grown under air interface culture (AIC) conditions. S les collected for microscope analysis were stained with alcian blue images of the stained cell surface were acquired and the mucus was quantified as the RGBB ratio. SV was transported through the cell monolayer and 'retained' inside the Calu-3 cells. Colour analysis of stained Calu-3 monolayers microscope-images showed that chronic administration of SV for 14 days caused a significant inhibition in mucus production. These findings suggest that local delivery of SV directly to the lungs may provide a promising treatment and potential disease management approach of COPD, with significant effects on mucus reduction.

Limitations of high dose carrier based formulations

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.IJPHARM.2018.04.012

Abstract: This study was performed to investigate how increasing the active pharmaceutical ingredient (API) content within a formulation affects the dispersion of particles and the aerosol performance efficiency of a carrier based dry powder inhalable (DPI) formulation, using a custom dry powder inhaler (DPI) development rig. Five formulations with varying concentrations of API beclomethasone dipropionate (BDP) between 1% and 30% (w/w) were formulated as a multi-component carrier system containing coarse lactose and fine lactose with magnesium stearate. The morphology of the formulation and each component were investigated using scanning electron micrographs while the particle size was measured by laser diffraction. The aerosol performance, in terms of aerodynamic diameter, was assessed using the British pharmacopeia Apparatus E cascade impactor (Next generation impactor). Chemical analysis of the API was observed by high performance liquid chromatography (HPLC). Increasing the concentration of BDP in the blend resulted in increasing numbers and size of in idual agglomerates and densely packed BDP multi-layers on the surface of the lactose carrier. BDP present within the multi-layer did not disperse as in idual primary particles but as dense agglomerates, which led to a decrease in aerosol performance and increased percentage of BDP deposition within the Apparatus E induction port and pre-separator. As the BDP concentration in the blends increases, aerosol performance of the formulation decreases, in an inversely proportional manner. Concurrently, the percentage of API deposition in the induction port and pre-separator could also be linked to the amount of micronized particles (BDP and Micronized composite carrier) present in the formulation. The effect of such dose increase on the behaviour of aerosol dispersion was investigated to gain greater insight in the development and optimisation of higher dosed carrier-based formulations.

Pulmonary Spray Dried Powders of Tobramycin Containing Sodium Stearate to Improve Aerosolization Efficiency

Publisher: Springer Science and Business Media LLC

Date: 31-01-2009

DOI: 10.1007/S11095-009-9825-2

Abstract: Tobramycin microparticulate powders containing the hydrophobic adjunct sodium stearate were studied for their use as pulmonary formulations in dry powder inhalers. Spray-dried powders were characterized in terms of particle size distribution, morphology, crystallinity, drug dissolution rate, toxicity on epithelial lung cells and aerosol efficiency. The presence of the sodium stearate had a direct influence on the aerosol performance of tobramycin spray-dried powders. Powders containing 1% w/w sodium stearate had fine particle fraction FPF of 84.3 +/- 2.0% compared to 27.1 +/- 1.9% for powders containing no adjunct. This was attributed to the accumulation of sodium stearate at the particle surface. Powders with higher sodium stearate concentrations (2% w/w) showed significantly lower FPF (66.4 +/- 0.9%) and less accumulation of sodium stearate at the particle surface. This was attributed to the formation of adjunct micelles, which remained internalised in the particle structure due to their reduced tropism toward the drying drop surface and molecular mobility. Preliminary analysis of the toxicity effect of sodium stearate on A549 cell lines showed that the adjunct, in the concentration used, had no effect on cell viability over a 24-h period compared to particles of pure tobramycin. Tobramycin pulmonary powders with low level of sodium stearate, presenting high respiration performances and no overt toxicity on lung cells, could be used to improve therapeutic outcomes of patient with Cystic Fibrosis (CF).

Generic dry powder inhalers bioequivalence

Publisher: Elsevier BV

Date: 11-2022

DOI: 10.1016/J.DRUDIS.2022.103350

Abstract: Active pharmaceutical ingredient(s) [API(s)] of dry powder inhalers (DPIs) deposition and their fate in the respiratory system are influenced by a complex matrix of formulation, device, manufacturing and physiological variations. DPIs on the market have shown bioinequivalence between batches of the same product. Despite being clinically insignificant, they affect bioequivalence studies when a generic product is compared with the originator. This review discusses implications of batch-to-batch variability on bioequivalence study outcomes and shortcomings of current regulatory requirements. Possible formulation and manufacturing factors resulting in batch-to-batch variability highlight the inherent nature of this issue. Despite scholarly investigations and official regulatory guidance, there remains a need for reliable and realistic in vitro tests that accurately guide a representative reference product batch selection.

The influence of drug morphology on the aerosolisation efficiency of dry powder inhaler formulations

Publisher: Elsevier BV

Date: 07-2008

DOI: 10.1002/JPS.21195

Strategies to enhance drug absorption via nasal and pulmonary routes

Publisher: MDPI AG

Date: 11-03-2019

DOI: 10.3390/PHARMACEUTICS11030113

Abstract: New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their administration. However, a major concern for some of these newly developed therapeutic agents is their poor absorption. Therefore, absorption enhancers have been investigated to address this major administration problem. This paper describes the basic concepts of transmucosal administration of drugs, and in particular the use of the pulmonary or nasal routes for administration of drugs with poor absorption. Strategies for the exploitation of absorption enhancers for the improvement of pulmonary or nasal administration are discussed, including use of surfactants, cyclodextrins, protease inhibitors, and tight junction modulators, as well as application of carriers such as liposomes and nanoparticles.

Development of ciprofloxacin-loaded poly(vinyl alcohol) dry powder formulations for lung delivery

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.IJPHARM.2018.05.060

Abstract: Polymeric microparticles are micro carriers for the sustained drug delivery of drugs in the lungs, used as alternatives to the use of established excipients. This study aims to develop and characterize inhalable ciprofloxacin (CPx)-loaded poly(vinyl alcohol) (PVA) microparticles by a single-step spray-drying procedure. The optimization of the processing parameters was achieved by an orthogonal design of the most relevant processing parameters (polymer concentration, feed rate and inlet temperature). The obtained spray-dried particles showed a drug encapsulation efficiency higher than 90%. Furthermore, PVA-CPx formulations, with drug contents up to 10 wt%, showed a morphology and size suitable for inhalation, with a sustained release profile over 24 h. Data from Fourier transformed infra-red spectroscopy and differential scanning calorimetry indicated absence of interaction between the polymer matrix and the drug. Aerodynamic assessment of PVA-CPx 10 wt% was determined by the next generation impactor (NGI), using spray-dried CPx as a control. The results showed improved values of mass median aerodynamic diameter (5.06±0.10μm) and a fine particle fraction (39.78±0.98%) when comparing with the CPx alone (5.33±0.39μm and 30.43±1.38%). This study highlights the potential of spray-dried PVA microparticles as drug carriers for lung local delivery of antibiotics.

The ability of people with intellectual disability to use inhalers

Publisher: Informa UK Limited

Date: 12-09-2016

DOI: 10.3109/02770903.2015.1065423

Abstract: This aim of this study was to assess inhaler technique of people with intellectual disability (ID), and evaluate the effectiveness of teaching with respect to their in idual ability to adopt correct technique. Seventeen people with ID were recruited through existing networks of general practitioners and disability support organisations. Inhaler technique was assessed using validated checklists and placebo devices, followed by provision of in idualised training. The educational interaction between participant and researcher was captured via video recording and analysed qualitatively. Seventeen people with ID participated females comprised 65%. At baseline, no participants correctly used any device. Pressurised metered dose inhalers, with or without accessory devices, were the most poorly used devices. Inhalation steps were poorly performed across all devices. Following training, the proportions of assessed participants that were able to master inhaler technique were 100% of Accuhaler users, 40% of Turbuhaler users, 25% of pressurised metered dose inhaler users and 0% of Handihaler users. Barriers identified included poor comprehension of breathing processes, the lack of attentiveness and poor dexterity. Facilitators for educator delivery of inhaler technique education included the use of analogies and being patient. This is the first study to examine inhaler technique mastery in people with ID. Results show that with education that addresses the unique patient barriers inherent in this group, some in iduals can be trained to mastery. Structured modules of inhaler technique training tailored for people with ID, but which can be in idualised, are recommended.

Does electrostatic charge affect powder aerosolisation?

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1002/JPS.21996

Aerosol tribocharging and its relation to the deposition of Oxis™ Turbuhaler® in the electrical next generation impactor

Publisher: Elsevier BV

Date: 12-2011

DOI: 10.1002/JPS.22721

Microfluidic production of endoskeleton droplets with controlled size and shape

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.POWTEC.2018.01.050

In vitro biological activity of resveratrol using a novel inhalable resveratrol spray-dried formulation

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1016/J.IJPHARM.2015.06.033

Abstract: The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5 μm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9 ± 1.1% and 3.7 ± 0.1 μm, respectively, when assessed with an Andersen cascade impactor (ACI) at 60 l/min. The cytotoxicity results of resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 μM). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD.

A Simple and Rapid Method for Deposition and Measurement of Drug Transport Across Air Interface Respiratory Epithelia.

Publisher: Springer Science and Business Media LLC

Date: 12-09-2018

DOI: 10.1208/S12249-018-1170-5

Abstract: The purpose of this study was to present a novel and simple drug deposition method to evaluate drug transport of aerosol microparticles across airway epithelial cells. Microparticles containing ciprofloxacin HCl (Cip) and doxycycline (Dox), alone or in a 50:50% w/w ratio, were spray dried and suspended using 2H, 3H-perfluoropentane, model propellant. The suspension was then used to assess deposition, and transport of these drug microparticles across sub-bronchial epithelial Calu-3 cells was also studied. In comparison with other methods of depositing microparticles, this proposed method, using drug suspended in HPFP, provides control over the amount of drugs applied on the surface of the cells. Therefore, cell permeability studies could be conducted with considerably smaller and more reproducible doses, without the physicochemical characteristics of the drugs being compromised or the use of modified pharmacopeia impactors. The suspension of microparticles in HPFP as presented in this study has provided a non-toxic, simple, and reproducible novel method to deliver and study the permeability of specific quantity of drugs across respiratory epithelial cells in vitro.

An automated segmentation framework for nasal computational fluid dynamics analysis in computed tomography

Publisher: Elsevier BV

Date: 12-2019

DOI: 10.1016/J.COMPBIOMED.2019.103505

Abstract: The use of computational fluid dynamics (CFD) to model and predict surgical outcomes in the nasal cavity is becoming increasingly popular. Despite a number of well-known nasal segmentation methods being available, there is currently a lack of an automated, CFD targeted segmentation framework to reliably compute accurate patient-specific nasal models. This paper demonstrates the potential of a robust nasal cavity segmentation framework to automatically segment and produce nasal models for CFD. The framework was evaluated on a clinical dataset of 30 head Computer Tomography (CT) scans, and the outputs of the segmented nasal models were further compared with ground truth models in CFD simulations on pressure drop and particle deposition efficiency. The developed framework achieved a segmentation accuracy of 90.9 DSC, and an average distance error of 0.3 mm. Preliminary CFD simulations revealed similar outcomes between using ground truth and segmented models. Additional analysis still needs to be conducted to verify the accuracy of using segmented models for CFD purposes.

Combination of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate for the treatment of inflammatory lung diseases: An in vitro study

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.EJPS.2018.04.042

Abstract: This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL - SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL - SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) - SAP and the single SAP, HA and HA-CL components. S le solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL - SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA - SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent.

An update on the use of rifapentine for tuberculosis therapy

Publisher: Informa Healthcare

Date: 08-01-2014

DOI: 10.1517/17425247.2014.877886

Abstract: Tuberculosis (TB) remains r ant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial. This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented. Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial.

HOXA13 in etiology and oncogenic potential of Barrett’s esophagus

Publisher: Springer Science and Business Media LLC

Date: 07-06-2021

DOI: 10.1038/S41467-021-23641-8

Abstract: Barrett’s esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma. HOX genes are known mediators of position-dependent morphology. Here we show HOX collinearity in the adult gut while Barrett’s esophagus shows high HOXA13 expression in stem cells and their progeny. HOXA13 overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett’s esophagus. Intriguingly, employing a mouse model that contains a reporter coupled to the HOXA13 promotor we identify single HOXA13-positive cells distally from the physiological esophagus, which is mirrored in human physiology, but increased in Barrett’s esophagus. Additionally, we observe that HOXA13 expression confers a competitive advantage to cells. We thus propose that Barrett’s esophagus and associated esophageal adenocarcinoma is the consequence of expansion of this gastro-esophageal HOXA13 -expressing compartment following epithelial injury.

Selective shape-change response by anisotropic endoskeletal droplets

Publisher: Elsevier BV

Date: 02-2020

DOI: 10.1016/J.EML.2019.100618

Delivery of pDNA Polyplexes to Bronchial and Alveolar Epithelial Cells Using a Mesh Nebulizer

Publisher: Springer Science and Business Media LLC

Date: 15-11-2019

DOI: 10.1007/S11095-018-2542-Y

Abstract: In this study, a cell penetrating peptide was used as an uptake enhancer for pDNA delivery to the lungs. Polyplexes were prepared between pDNA and CPP. Intracellular delivery of pDNA was assessed in both alveolar (A549) and bronchial (Calu-3) epithelial cells. Aerosol delivery was investigated using a mesh nebulizer. Efficient intracellular delivery of pDNA occurs in both A549 and Calu-3 cells when delivered as polyplexes. Protection against nucleases and endosomal escape mechanism occurs when pDNA is formulated within the polyplexes. For aerosol delivery, 1% (w/v) mannitol was able to protect naked DNA structure during nebulization with a significant increase in fine particle fraction (particles <5 μm). The structure of polyplexes when delivered via a mesh nebulizer using 1% (w/v) mannitol could partially withstand the shear forces involved in aerosolization. Although some loss in functionality occurred after nebulization, membrane-associated fluorescence was observed in A549 cells. In Calu-3 cells mucus entrapment was a limiting factor for polyplex delivery. The presence of CPP is essential for efficient intracellular delivery of pDNA. The polyplexes can be delivered to lung epithelial cells using mesh nebulizer. The use of different excipients is essential for further optimization of these delivery systems.

Ciprofloxacin is actively transported across bronchial lung epithelial cells using a calu-3 air interface cell model

Publisher: American Society for Microbiology

Date: 06-2013

DOI: 10.1128/AAC.00306-13

Abstract: Ciprofloxacin is a well-established broad-spectrum fluoroquinolone antibiotic that penetrates well into the lung tissues still, the mechanisms of its transepithelial transport are unknown. The contributions of specific transporters, including multidrug efflux transporters, organic cation transporters, and organic anion-transporting polypeptide transporters, to the uptake of ciprofloxacin were investigated in vitro using an air interface bronchial epithelial model. Our results demonstrate that ciprofloxacin is subject to predominantly active influx and a slight efflux component.

Inhalation Drug Delivery

Publisher: Wiley

Date: 11-01-2013

DOI: 10.1002/9781118397145

The Effects of Mannitol on the Transport of Ciprofloxacin across Respiratory Epithelia

Publisher: American Chemical Society (ACS)

Date: 11-07-2013

DOI: 10.1021/MP400030N

Abstract: Inhalation of antibiotics and mucolytics is the most important combination of inhaled drugs for chronic obstructive lung diseases and has become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using a Calu-3 air-interface cell model. Transport studies of ciprofloxacin HCl were performed using different configurations including single spray-dried ciprofloxacin alone, co-spray-dried ciprofloxacin with mannitol, and deposition of mannitol prior to ciprofloxacin deposition. To understand the mechanism of transport and interactions between the drugs, pH measurements of apical surface liquid (ASL) and further transport studies were performed with ciprofloxacin base, with and without the presence of ion channel/transport inhibitors such as disodium cromoglycate and furosemide. Mannitol was found to delay absorption of ciprofloxacin HCl through the increase in ASL volume and subsequent reduction in pH. Conversely, ciprofloxacin base had a higher transport rate after mannitol deposition. This study clearly demonstrates that the deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model has an effect on its transport rate. This was also dependent on the salt form of the drug and the timing and sequence of formulations administered.

Simvastatin Nanoparticles Reduce Inflammation in LPS-Stimulated Alveolar Macrophages

Publisher: Elsevier BV

Date: 12-2019

DOI: 10.1016/J.XPHS.2019.08.029

Abstract: Simvastatin (SV) is widely used as a lipid-lowering medication that has also been found to have beneficial immunomodulatory effects for treatment of chronic lung diseases. Although its anti-inflammatory activity has been investigated, its underlying mechanisms have not yet been clearly elucidated. In this study, the anti-inflammatory and antioxidant effects and mechanism of simvastatin nanoparticles (SV-NPs) on lipopolysaccharide-stimulated alveolar macrophages (AMs) NR8383 cells were investigated. Quantitative cellular uptake of SV-NPs, the production of inflammatory mediators (interleukin-6, tumor necrosis factor, and monocyte chemoattractant protein-1), and oxidative stress (nitric oxide) were tested. Furthermore, the involvement of the nuclear factor κB (NF-κB) signaling pathway in activation of inflammation in AMs and the efficacy of SV were visualized using immunofluorescence. Results indicated that SV-NPs exhibit a potent inhibitory effect on nitric oxide production and secretion of inflammatory cytokine in inflamed AM, without affecting cell viability. The enhanced anti-inflammatory activity of SV-NPs is likely due to SV-improved chemical-physical stability and higher cellular uptake into AM. The study also indicates that SV targets the inflammatory and oxidative response of AM, through inactivation of the NF-κB signaling pathway, supporting the pharmacological basis of SV for treatment of chronic inflammatory lung diseases.

Tuning aerosol performance using the multibreath Orbital® dry powder inhaler device: controlling delivery parameters and aerosol performance via modification of puck orifice geometry.

Publisher: Elsevier BV

Date: 07-2015

DOI: 10.1002/JPS.24458

In vitro evaluation of nebulized eucalyptol nano-emulsion formulation as a potential COVID-19 treatment

Publisher: Elsevier BV

Date: 12-2022

DOI: 10.1016/J.JSPS.2022.09.014

Investigation into physical-chemical variables affecting the manufacture and dissolution of wet-milled clarithromycin nanoparticles

Publisher: Informa UK Limited

Date: 04-10-2014

DOI: 10.3109/10837450.2013.840844

Abstract: A critical problem associated with poor water-soluble drugs is their low and variable bioavailability, which is derived from the slow dissolution and erratic absorption. Nano-formulation has been identified as one approach to enhance the rate and extent of drug absorption for compounds that demonstrate limited water solubility. This study aimed to investigate the physico-chemical variables that affect the manufacture, dissolution and consequent bioavailability of wet-milled clarithromycin (CLA) nanoparticles, a macrolide antibiotic. CLA nanoparticles were prepared using wet milling method followed by freeze-drying. Different stabilizer systems, consisting of surfactants and polymers alone or their combinations were studied to determine the optimum conditions for producing nano-sized CLA particles. In vitro characterizations of the CLA nanoparticles were performed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry and dissolution efficiency test. Results showed that in general the wet milling process did not modify the crystallinity of the CLA nanoparticles. The poloxamers and polyvinyl alcohol (PVA) stabilizers resulted in nanoparticles with the smallest particle size and best dissolution rates. Furthermore, poloxamers F68 and F127, and PVA stabilizers demonstrated the best performance in increasing dissolution efficacy.

Advances in pulmonary therapy

Publisher: CRC Press

Date: 25-09-2008

DOI: 10.3109/9781420043884-4

A rifapentine-containing inhaled triple antibiotic formulation for rapid treatment of tubercular infection

Publisher: Springer Science and Business Media LLC

Date: 16-11-2014

DOI: 10.1007/S11095-013-1245-7

Abstract: The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection. A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity. The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 ± 0.08 μm and 2.51 ± 0.06 μm, with a relatively high fine particle fraction of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified. Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.

Recent advances in understanding the influence of composite-formulation properties on the performance of dry powder inhalers

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1016/J.PHYSB.2006.12.058

Measuring charge and mass distributions in dry powder inhalers using the electrical Next Generation Impactor (eNGI)

Publisher: Elsevier BV

Date: 09-2009

DOI: 10.1016/J.EJPS.2009.06.003

Abstract: The electrical Next Generation Impactor (eNGI) was assessed against the electrical low-pressure impactor (ELPI) and next generation impactor (NGI) for its capability to characterise particle size and electrostatic charge properties of dry powder inhaler (DPI) formulations. Following assessment, the relationship between inhalational air flow rate and drug powder charge was explored using the eNGI. At a vacuum flow rate of 30L/min, doses of Pulmicort (budesonide 400 microg) and Bricanyl (terbutaline 500 microg) were dispersed into the ELPI, NGI and eNGI, from which particle size profiles and charge profiles were ascertained. Further doses of Pulmicort and Bricanyl were fired into the eNGI at vacuum air flow rates of 45, 60, 75 and 90 L/min, and the resultant size and charge profiles were determined. Particle size profiles at 30 L/min were found to be comparable between the NGI and eNGI, while charge profiles were comparable between the eNGI and ELPI. As air flow rate increased from 30 to 90 L/min, in vitro aerosol performance improved before reaching a peak at 45 L/min (Pulmicort) and 60 L/min (Bricanyl). Net charge also increased with flow rate, the cause of which may be a combination of increased turbulence and aerosol performance. This study demonstrates that the eNGI is capable of electrostatic and particle size characterization of commercial drug-only DPI products.

Exploring the impact of sample flowrate on in vitro measurements of metered dose inhaler performance

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.IJPHARM.2016.05.025

Abstract: Pharmacopoeial methods for measurement of the aerodynamic particle size distribution (APSD) of metered dose inhalers (MDIs) by cascade impaction specify a s ling flow rate of 28.3L/min. However, there is little data within the literature to rationalize this figure, or to support its clinical relevance. In addition, the standard United States Pharmacopoeia Induction Port (USP IP) used for testing is known to inaccurately reflect deposition behavior in the upper airway, further compromising the relevance of testing, for product development. This article describes experimental studies of the effect of s ling flow rate on APSD data gathered using an Andersen Cascade Impactor (ACI). Tests were carried out using two different formulations to assess the influence of formulation composition. In addition, comparative testing with an Alberta Idealised Throat, in place of the USP IP, to ensure more realistic representation of the upper airway. The results show how measured APSD and fine particle dose, the dose than on the basis of size would be expected to deposit in the lung, vary as a function of test methodology, providing insight as to how the testing can be modified towards greater clinical relevance.

Is the cellular uptake of respiratory aerosols delivered from different devices equivalent?

Publisher: Elsevier BV

Date: 06-2015

DOI: 10.1016/J.EJPB.2015.04.012

Abstract: The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols' behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions.

Antibiotic transport across bronchial epithelial cells: Effects of molecular weight, LogP and apparent permeability.

Publisher: Elsevier BV

Date: 02-2016

DOI: 10.1016/J.EJPS.2015.12.010

Abstract: The first step in developing a new inhalable formulation for the treatment of respiratory diseases is to understand the mechanisms involved in the absorption of drugs after lung deposition. This information could be important for the treatment of bacterial infection in the lung, where low permeability would probably be beneficial, or a systemic infection, where high permeability would be desirable. The goal of this study was to evaluate the transport of several antibiotics (ciprofloxacin, azithromycin, moxifloxacin, rif icin, doxycycline and tobramycin) across human bronchial airway epithelium and to study the influence of molecular weight and LogP on the apparent permeability. The experiments were conducted using Calu-3 cells seeded in the apical compartment of 24-well Transwell® inserts. The antibiotics transport was measured in both apical to basolateral (A-B) and basolateral to apical (B-A) directions and the apparent permeability of each antibiotic was calculated. The A-B transport of ciprofloxacin and rif icin was independent of the initial concentration in the donor compartment, suggesting the involvement of active transporters in their absorption. Moxifloxacin, doxycycline, azithromycin and tobramycin presented a low absorptive permeation in the A-B direction, indicating that these substances could be substrate for efflux pumps. Generally, all antibiotics studied showed low permeabilities in the B-A direction. These findings suggest that the inhalation route would be favorable for delivering these specific antibiotics for the treatment of respiratory infection, compared with present oral or intravenous administration.

Inhalable tranexamic acid for haemoptysis treatment.

Publisher: Elsevier BV

Date: 06-2015

DOI: 10.1016/J.EJPB.2015.04.015

Abstract: An inhalable dry powder formulation of tranexamic acid (TA) was developed and tested in a novel high-dose Orbital® multi-breath inhaler. The formulation was specifically intended for the treatment of pulmonary haemorrhage and wound healing associated with haemoptysis. Inhalable TA particles were prepared by spray drying and the powder characterised using laser diffraction, electron microscopy, thermal analysis, moisture sorption and X-ray powder diffraction. The aerosol performance was evaluated using cascade impaction and inline laser diffraction and interaction with epithelia cells and wound healing capacity investigated using Calu-3 air interface model. The spray dried TA particles were crystalline and spherical with a D0.5 of 3.35 μm. The powders were stable and had limited moisture sorption (0.307%w/w at 90%RH). The Orbital device delivered ca. 38 mg powder per 'inhalation' at 60 l · min(-1) across four sequential shots with an overall fine particle fraction (⩽ 6.4 μm) of 59.3 ± 3.5% based on the emitted mass of ca. 150 mg. The TA particles were well tolerated by Calu-3 bronchial epithelia cells across a wide range of doses (from 1 nM to 10nM) and no increase in inflammatory mediators was observed after deposition of the particles (a decrease in IL-1β, IL-8 and INFγ was observed). Time lapse microscopy of a damaged confluent epithelia indicated that wound closure was significantly greater in TA treated cells compared to control. A stable, high performance aerosol of TA has been developed in a multi-breath DPI device that can be used for the treatment of pulmonary lesions and haemoptysis.

Delivery of high solubility polyols by vibrating mesh nebulizer to enhance mucociliary clearance

Publisher: Mary Ann Liebert Inc

Date: 10-2012

DOI: 10.1089/JAMP.2011.0961

Abstract: Inhaled dry powder mannitol has established in vivo therapeutic efficacy for enhancing mucociliary function. However, a single dose necessitates multiple inhalations of a sizeable powder mass. Nebulization of mannitol by vibrating mesh devices has recently been shown in vitro to impart similar dosing in a comparable or lesser treatment time. Nevertheless, the limited solubility of mannitol restricted fluid concentrations to 150 mg/mL. The present study examines the feasibility of higher solubility polyols that presumably possess similar therapeutic properties to mannitol but deliverable at higher concentrations to shorten treatment time. A secondary aim is to compare delivery by two commercially available mesh nebulizers-the Aeroneb® Go and PARI eFlow Rapid. A series of formulations containing three polyols (mannitol, sorbitol, and xylitol) of increasing concentration in 1% w/v sodium chloride were nebulized. Aerosol characteristics and treatment times were determined primarily by laser diffraction. RESULTS indicate viscosity is the primary determinant of vibrating mesh nebulizer performance. For both nebulizers, xylitol 334 mg/mL exhibits the greatest osmolar output-double that of 150 mg/mL mannitol. A nebulized xylitol solution has potential clinical application for promoting rapid mucociliary clearance. Both vibrating mesh nebulizers facilitate quick treatment times. Future in vivo studies would compare the efficacy of nebulized xylitol to commercial hyperosmolar agents and establish any potential polyol-associated antibacterial activity.

Combination of Silver Nanoparticles and Curcumin Nanoparticles for Enhanced Anti-biofilm Activities

Publisher: American Chemical Society (ACS)

Date: 03-12-2015

DOI: 10.1021/ACS.JAFC.5B04559

Abstract: Biofilm tolerance has become a serious clinical concern in the treatment of nosocomial pneumonia owing to the resistance to various antibiotics. There is an urgent need to develop alternative antimicrobial agents or combination drug therapies that are effective via different mechanisms. Silver nanoparticles (AgNPs) have been developed as an anti-biofilm agent for the treatment of infections associated with the use of mechanical ventilations, such as endotracheal intubation. Meanwhile curcumin, a phenolic plant extract, has displayed natural anti-biofilm properties through the inhibition of bacterial quorum sensing systems. The aim of this study was to investigate the possible synergistic/additive interactions of AgNPs and curcumin nanoparticles (Cur-NPs) against both Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) microorganisms. The combination of AgNPs and Cur-NPs (termed Cur-SNPs) at 100 μg/mL disrupted 50% of established bacterial biofilms (formed on microtiter plates). However, further increase in the concentration of Cur-SNPs failed to effectively eliminate the biofilms. To achieve the same effect, at least 500 μg/mL Cur-NP alone was needed. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) revealed that combination therapy (Cur-SNPs) was the most potent to eradicate preformed biofilm compared to monodrug therapy. These agents are also nontoxic to healthy human bronchial epithelial cells (BEAS2B).

Synthesis and Characterization of Inhalable Flavonoid Nanoparticle for Lung Cancer Cell Targeting

Publisher: American Scientific Publishers

Date: 02-2016

DOI: 10.1166/JBN.2016.2162

Abstract: Current cancer treatments are not adequate to cure cancer disease, as most chemotherapeutic drugs do not differentiate between cancerous and non-cancerous cells which lead to systemic toxicity and adverse effects. We have developed a promising approach to deliver a potential anti-cancer compound (curcumin) for lung cancer treatment through pulmonary delivery. Three different sizes of curcumin micellar nanoparticles (Cur-NPs) were fabricated and their cytotoxicity effects (proliferation, apoptosis, cell cycle progression) were evaluated against non-small-cell lung cancer, human lung carcinoma (A549) and human lung adenocarcinoma (Calu-3). The in vitro cytotoxicity assay showed that Cur-NPs were more effective to kill lung cancer cells compared to DMSO-solubilised raw curcumin. The potency of the anti-cancer killing activities was size-dependent. Both raw curcumin and Cur-NPs were not toxic to healthy lung cells (BEAS-2B). Smaller Cur-NPs accumulated within nucleus, membrane and cytoplasm. Cur-NPs also induced apoptosis and caused G2/M arrest in both A549 and Calu-3 cell lines. Compared to raw curcumin, Cur-NPs were more effective in suppressing the expression of the inflammatory marker, Interleukin-8 (IL8). The aerosol performance of Cur-NPs was characterized using the next generation impactor (NGI). All Cur-NPs showed promising aerosolization property with mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) ranging between 4.8-5.2 and 2.0-2.1, respectively. This study suggests that inhaled curcumin nanoparticles could potentially be used for lung cancer treatment with minimal side effects.

Effect of polyunsaturated fatty acids (PUFAs) on airway epithelial cells' tight junction

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.PUPT.2016.07.004

A review of electrostatic measurement techniques for aerosol drug delivery to the lung

Publisher: Informa UK Limited

Date: 2011

DOI: 10.1163/016942410X525632

In vitro cell integrated impactor deposition methodology for the study of aerodynamically relevant size fractions from commercial pressurised metered dose inhalers.

Publisher: Springer Science and Business Media LLC

Date: 19-02-2014

DOI: 10.1007/S11095-013-1282-2

Abstract: The purpose of this study was to present a modified Andersen cascade impactor (ACI) as a platform to evaluate the deposition and subsequent transport of aerosol micropaticles across airway epithelial cells. The impaction plate of an ACI was modified to accommodate up to eight Snapwells. Aerodynamic particle size distribution of the modified ACI was investigated with two commercially available formulations of Ventolin® (salbutamol sulphate) and QVAR® (beclomethasone dipropionate). Deposition and transport of these drug microparticles across sub-bronchial epithelial Calu-3 cells were also studied. The modified ACI demonstrated reproducible deposition patterns of the commercially available pressurised metered dose inhalers compared to the standard ACI. Furthermore, the Calu-3 cells could be placed in different stages of the modified ACI. No significant effect was observed among the transport rate of different particle sizes deposited on Calu-3 cells within the range of 3.3 to 0.4 μm. The use of the cell compatible ACI to assess the fate of microparticles after deposition on the respiratory epithelia may allow for better understanding of deposited microparticles in vivo.

Anti‐androgens may protect against severe COVID‐19 outcomes: results from a prospective cohort study of 77 hospitalized men

Publisher: Wiley

Date: 21-10-2020

DOI: 10.1111/JDV.16953

Engineered nasal dry powder for the encapsulation of bioactive compounds

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.DRUDIS.2022.04.012

Abstract: In this review, we present the potential of nasal dry powders to deliver stable bioactive compounds and their manufacture using spray-drying (SD) techniques to achieve encapsulation. We also review currently approved and experimental excipients used for powder manufacturing for specific target drugs. Polymers, sugars, and amino acids are recommended for specific actions, such as mucoadhesive interactions, to increase residence time on the nasal mucosa for ex le, high-molecular weight polymers, such as hydroxypropyl methylcellulose, or mannitol, which protect the bioactive compounds, increase their stability, and enhance drug absorption in the nasal mucosa and leucine, which promotes particle formation and improves aerosol performance.

Modifying and Integrating in vitro and ex vivo Respiratory Models for Inhalation Drug Screening.

Publisher: Frontiers Media SA

Date: 23-10-2020

DOI: 10.3389/FBIOE.2020.581995

On the Use of Computational Fluid Dynamics (CFD) Modelling to Design Improved Dry Powder Inhalers

Publisher: Springer Science and Business Media LLC

Date: 02-2021

DOI: 10.1007/S11095-020-02981-Y

Comparison of spray congealing and melt emulsification methods for the incorporation of the water-soluble salbutamol sulphate in lipid microparticles

Publisher: Informa UK Limited

Date: 24-09-2013

DOI: 10.3109/10837450.2012.717947

Abstract: Salbutamol sulphate is widely used as bronchodilator for the treatment of asthma. Its use is limited by the relatively short duration of action and hence sustained delivery of salbutamol sulphate offers potential benefits to patients. This study explores the preparation of lipid microparticles (LMs) as biocompatible carrier for the prolonged release of salbutamol sulphate. The LMs were produced using different lipidic materials and surfactants, by classical melt emulsification-based methods (oil-in-water and water-in-oil-in-water emulsions) and the spray congealing technique. For the LMs obtained by melt emulsification a lack of release modulation was observed. On the other hand, the sustained release of salbutamol sulphate was achieved with glyceryl behenate microparticles prepared by spray congealing. These LMs were characterized by scanning electron microscopy, X-ray diffractometry and differential scanning calorimetry. The drug loading was 4.72% (w/w). The particle size distribution measured by laser diffraction and electrical zone sensing was represented by a volume median diameter (Dv(50)) of 51.7-71.4 µm. Increasing the atomization air pressure from 4 to 8 bar produced a decrease of the Dv(50) to 12.7-17.5 µm. Incorporation of the hydrophilic salbutamol sulphate into LMs with sustained release characteristics was achieved by spray congealing.

Sulfotransferase activity in plucked hair follicles predicts response to topical minoxidil treatment in Brazilian female pattern hair loss patients

Publisher: Hindawi Limited

Date: 27-12-2020

DOI: 10.1111/DTH.13195

A novel inhalable form of rifapentine

Publisher: Elsevier BV

Date: 05-2014

DOI: 10.1002/JPS.23911

In vitro interactions of aerosol formulations with human nasal epithelium using real-time monitoring of drug transport in a nasal mucosa-on-a-chip

Publisher: Elsevier BV

Date: 03-2023

DOI: 10.1016/J.BIOS.2022.115010

Mono- and Cocultures of Bronchial and Alveolar Epithelial Cells Respond Differently to Proinflammatory Stimuli and Their Modulation by Salbutamol and Budesonide

Publisher: American Chemical Society (ACS)

Date: 06-07-2015

DOI: 10.1021/ACS.MOLPHARMACEUT.5B00124

Abstract: The aim of this study was to investigate the changes in transport and effectiveness of salbutamol sulfate (SAL) and budesonide (BD) following stimulation with transforming growth factor-β (TGF-β) in mono- and coculture models of bronchial and alveolar epithelium. Primary bronchial and alveolar epithelial cells, grown at air interface on filters, either as monocultures or in coculture with airway smooth muscle cells or alveolar macrophages, respectively, were stimulated with TGF-β. The biological response was modulated by depositing aerosolized SAL and BD on bronchial and alveolar models, respectively. Barrier integrity, permeability to fluorescein-Na, transport of the deposited drug, and the pharmacological response to SAL (cAMP and IL-8 levels) or BD (IL-6 and -8 levels) were measured. While stimulation with TGF-β did not have any significant effect on the transepithelial electrical resistance and permeability to fluorescein-Na in mono- and coculture models, transport of SAL and BD were affected in cultures from some of the patients (6 out of 12 for bronchial and 2 out of 4 for alveolar cells). The bronchial coculture showed a better responsiveness to SAL in terms of cAMP release than the monoculture. In contrast, the difference between alveolar mono- and cocultures to TGF-β mediated interleukin release and its modulation by BD was less pronounced. Our data point to intrinsic differences in the transport of, and responsiveness to, SAL and BD when epithelial cell cultures originate from different patients. Moreover, if the biological responses (e.g., IL-8, cAMP) involve communication between different cell types, coculture models are more relevant to measure such effects than monocultures.

Surface energy and interparticle forces correlations in model pMDI formulations

Publisher: Springer Science and Business Media LLC

Date: 05-2005

DOI: 10.1007/S11095-005-2599-2

Abstract: To compare experimental measurements of particle cohesion and adhesion forces in a model propellant with theoretical measurements of the interfacial free energy of particulate interactions with the aim of characterizing suspension stability of pressurized metered dose inhalers (pMDIs). Interparticulate forces of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H,3H perfluoropentane. The surface thermodynamic properties were determined by contact angle (CA) and inverse gas chromatography (IGC). Experimental data were compared with theoretical work of adhesion/cohesion using a surface component approach (SCA), taking into account both dispersive and polar contributions of the surface free energy. Results indicated that the measured forces of interaction between particles in model propellant could not be accounted for by theoretical treatment of the dispersive surface free energies via CA and IGC. A correlation between theoretical work of adhesion/cohesion and AFM measurements was observed upon the introduction of the polar interfacial interactions within the SCA model. It is suggested that the polar contributions of the surface free energy measurements of particles may play a crucial role in particle interaction within propellant-based systems. Together with the application of a SCA model, this approach may be capable of predicting suspension stability of pMDI formulations.

Investigating potential TRPV1 positive feedback to explain TRPV1 upregulation in airway disease states

Publisher: Informa UK Limited

Date: 02-12-2021

DOI: 10.1080/03639045.2022.2070759

Abstract: The airway epithelium is a potential source of pathophysiology through activation of transient potential receptor vallinoid type 1 (TRPV1) channel. A positive feedback cycle caused by TRPV1 activity is hypothesized to induce upregulation and production of inflammatory cytokines, leading to exacerbations of chronic airway diseases. These cytokine and protein regulation effects were investigated in this study. Healthy (BEAS-2B) and cancer-derived (Calu-3) airway epithelial cell lines were assessed for changes to TRPV1 protein expression and mRNA expression following exposure to capsaicin (5-50 µM), and TRPV1 modulators including heat (43 °C), and hydrochloric acid (pH 3.4 to pH 6.4). Cytotoxicity was measured to determine the working concentration ranges of treatment. Subsequent bronchoconstriction by TRPV1 activation with capsaicin was measured on guinea pig airway tissue to confirm locally mediated activity without the action of known neuronal inputs. TRPV1 protein expression was not different for all capsaicin, acidity, and heat exposures ( TRPV1 expression was present in airway epithelial cells but its expression was not changed after activation by TRPV1 activators. Thus, it was not apparent the reason for reported TRPV1 upregulation in patients with airway disease states. More complex mechanisms are likely involved and will require further investigation.

Across the pulmonary epithelial barrier: Integration of physicochemical properties and human cell models to study pulmonary drug formulations.

Publisher: Elsevier BV

Date: 12-2014

DOI: 10.1016/J.PHARMTHERA.2014.05.003

Abstract: During the process of inhalable formulation development a deep knowledge of the physicochemical characteristics of the drug and formulation components and the biological properties of the airways is necessary. For ex le, the solubility and lipophilicity of a drug may affect therapeutic efficacy by changing the residence time of the microparticles at the airway surface. Furthermore, the properties of microparticles, such as shape, size and density, as well as the diseases of the respiratory tract, delivery device and inhalation manoeuvre will have an impact on where these microparticles are deposited. The airway epithelium is involved in the pathogenesis and treatment of respiratory diseases. Epithelial cells are directly exposed to the environment and respond to xenobiotics. In some cases, they are the site of action for drug molecules or the drug molecules might need to be transported across the epithelium to arrive at the site of action. The drug particles deposited on the respiratory epithelia have to interact with the mucus lining, dissolve and get transported through this layer. Despite advances in in vitro testing of respiratory epithelial permeability, there is little known about how and where drugs are absorbed at a cellular level and how long they reside in the lung. Therefore, pulmonary permeability assessment of drugs may provide insights that will allow formulations to be developed with optimised therapeutic outcomes. This review focuses on the integration of these physicochemical characteristics with the biological factors to provide a better understanding of the fate of microparticles after deposition on the epithelial cells.

Using individualized three-dimensional printed airway models to guide airway stent implantation

Publisher: Oxford University Press (OUP)

Date: 05-11-2020

DOI: 10.1093/ICVTS/IVAA206

Abstract: Airway stents are used to manage central airway obstructions by restoring airway patency. Current manufactured stents are limited in shape and size, which pose issues in stent fenestrations needed to be manually created to allow collateral ventilation to airway branches. The precise location to place these fenestrations can be difficult to predict based on 2-dimensional computed tomography images. Inspiratory computed tomography scans were obtained from 3 patients and analysed using 3D-Slicer™, Blender™ and AutoDesk® Meshmixer™ programmes to obtain working 3D-airway models, which were 3D printed. Stent customizations were made based on 3D-model dimensions, and fenestrations into the stent were cut. The modified stents were then inserted as per usual technique. Two patients reported improved airway performance however, stents were later removed due to symptoms related to in-stent sputum retention. In a third patient, the stent was removed a few weeks later due to the persistence of fistula leakage. The use of a 3D-printed personalized airway model allowed for more precise stent customization, optimizing stent fit and allowing for cross-ventilation of branching airways. We determine that an airway model is a beneficial tool for stent optimization but does not prevent the development of some stent-related complications such as airway secretions.

Mannitol delivery by vibrating mesh nebulisation for enhancing mucociliary clearance

Publisher: Elsevier BV

Date: 07-2011

DOI: 10.1002/JPS.22494

The development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of cystic fibrosis

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.IJPHARM.2016.04.009

Abstract: The aerosol performance and delivery characteristics of tobramycin for the treatment of respiratory infection were evaluated using the Orbital™, a multi-breath, high dose, dry powder inhaler (DPI). Micronised tobramycin was prepared and tested in the Orbital and in the commercially available TOBI Podhaler (Novartis AG). Furthermore, the TOBI Podhaler formulation containing tobramycin as Pulmospheres was tested in both the commercial Podhaler device (T-326) and Orbital for comparison. By varying the puck geometry of the Orbital, it was possible to deliver equivalent doses of micronised tobramycin (114.09±5.86mg) to that of the Podhaler Pulmosphere product (116.01±2.59mg) over 4 sequential simulated breaths (60Lmin

Understanding the effects of aerodynamic and hydrodynamic shear forces on Pseudomonas aeruginosa biofilm growth

Publisher: Wiley

Date: 21-03-2022

DOI: 10.1002/BIT.28077

Abstract: Biofilms are communities of bacterial cells encased in a self‐produced polymeric matrix and exhibit high tolerance towards environmental stress. Despite the plethora of research on biofilms, most biofilm models are produced using mono‐interface culture in static flow conditions, and knowledge of the effects of interfaces and mechanical forces on biofilm development remains fragmentary. This study elucidated the effects of air–liquid (ALI) or liquid–liquid (LLI) interfaces and mechanical shear forces induced by airflow and hydrodynamic flow on biofilm growing using a custom‐designed dual‐channel microfluidic platform. Results from this study showed that comparing biofilms developed under continuous nutrient supply and shear stresses free condition to those developed with limited nutrient supply, ALI biofilms were four times thicker, 60% less permeable, and 100 times more resistant to antibiotics, while LLI biofilms were two times thicker, 20% less permeable, and 100 times more resistant to antibiotics. Subjecting the biofilms to mechanical shear stresses affected the biofilm structure across the biofilm thickness significantly, resulting in generally thinner and denser biofilm compared to their controlled biofilm cultured in the absence of shear stresses, and the ALI and LLI biofilm's morphology was vastly different. Biofilms developed under hydrodynamic shear stress also showed increased antibiotic resistance. These findings highlight the importance of investigating biofilm growth and its mechanisms in realistic environmental conditions and demonstrate a feasible approach to undertake this study using a novel platform.

Dynamic electrostatic charge of lactose-salbutamol sulphate powder blends dispersed from a Cyclohaler®

Publisher: Informa UK Limited

Date: 10-05-2011

DOI: 10.3109/03639045.2011.576679

Abstract: Electrostatic forces have been claimed to be a mechanism for aerosol deposition in the lungs. However, the extent of its influence on aerosol performance is not clear, particularly for carrier-drug formulations. To prepare lactose-salbutamol powder blends, varying in blend ratio, and identify any relationships between salbutamol dose, electrostatic characteristics and in vitro aerosol performance. Decanted lactose and micronized salbutamol sulfate was mixed to produce five blends (equivalent to 50, 100, 200, 300 and 400 µg salbutamol per 33 mg of powder). 33 ± 1 mg of a blend was loaded into a Cyclohaler™ and dispersed into the electrical Next Generation Impactor (eNGI) at an air flow rate of 60 L/min. This was conducted in triplicate for all five lactose-salbutamol blends. Fine particle fraction increased with salbutamol dose, from 5.89 ± 1.42 to 21.35 ± 2.91%. Specific charge (charge ided by mass) distributions for each blend were greatest in magnitude for the 50 µg blend and similar in magnitude between all other blends. However, in eNGI Stage 1 (>8.06 µm), specific charge decreased from 100 µg (-170.4 ± 45.8 pC/µg) to 400 µg (-10.0 ± 9.1 pC/µg). The improvement in fine particle fraction with increased salbutamol dose was indicative of fine drug binding to high and low energy sites on the lactose carrier surface. This finding was supported by electrostatic charge results, but the aerosol charge itself was not found to influence aerosol performance by electrostatic forces.

Deposition, Diffusion and Transport Mechanism of Dry Powder Microparticulate Salbutamol, at the Respiratory Epithelia

Publisher: American Chemical Society (ACS)

Date: 23-05-2012

DOI: 10.1021/MP200620M

Abstract: The deposition, dissolution and transport of salbutamol base (SB) and salbutamol sulfate (SS) inhalation powders were investigated using the Calu-3 air interface cell culture model and Franz diffusion cell. Drug uptake by cells was studied with respect to deposited dose, drug solubility and hydrophobicity. Furthermore, the role of active transport via organic cationic transporters (OCTs) was studied. SB and SS were processed to have similar diameters (3.09 ± 0.06 μm and 3.07 ± 0.03 μm, respectively) and were crystalline in nature. Analysis of drug wetting, dissolution and diffusion using a conventional in vitro Franz cell (incorporating a cell culture support Transwell polyester membrane) showed diffusion of SB to be slower than that of SS (98.57 ± 4.23 μg after 4 h for SB compared to 98.57 ± 4.01 μg after 15 min for SS). Such observations suggest dissolution to be the rate-limiting step. In comparison, the percentage transfer rate using the air interface Calu-3 cell model suggested SB transport to be significantly faster than SS transport (92.02 ± 4.47 μg of SB compared to 63.76 ± 8.84 μg of SS transported over 4 h), indicating that passive diffusion through the cell plays a role in transport. Furthermore, analysis of SB and SS transport, over a range of deposited doses, suggested the transport rate in the Franz diffusion cell to be limited by wetting of the particle and dissolution into the medium. However, for the cell monolayer, the cell membrane properties regulate the diffusion and transport rate. Analysis of the drug transport in the presence of triethylamine (TEA), a known inhibitor of OCTs, resulted in a significant decrease in drug transport, suggesting an active transport mechanism. The presence of OCTs in this cell line was further validated by Western blot analysis. Finally, the transport of SS from a commercial product (Ventolin Rotacaps) was studied and showed good agreement with the model SS system studied here.

The nanoscale in pulmonary delivery. Part 1: deposition, fate, toxicology and effects

Publisher: Informa Healthcare

Date: 31-10-2007

DOI: 10.1517/17425247.4.6.595

Abstract: This two-part review explores the nanoscale in inhalation delivery. The first part covers the deposition, fate, toxicity and effects of nanoparticles delivered via inhalation. The second part analyses the potential of major inhalation delivery routes. Efficient particle deposition in the lung can be achieved with nanoparticles (50 - 100 nm). However, this particle range has hardly been exploited in a medical setting. Thus, formulation scientists have a rare opportunity to develop new concepts in inhalation delivery. The delivery of nanoparticles raises concern over increased toxicity, but also opens up the possibility for enhanced therapeutic effects and reduced dosage. Toxicity data available so far concerns mainly non-therapeutic molecules, and it remains a moot point as to whether these apply to drug molecules.

Computational and visualization approaches in respiratory delivery

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.ADDR.2012.02.001

Delivery of antibiotics to the respiratory tract

Publisher: Informa UK Limited

Date: 29-07-2009

DOI: 10.1517/17425240903110710

Abstract: The use of inhaled medications for the treatment of pulmonary diseases has become an increasingly popular drug delivery route over the past few decades. This delivery route allows for a drug to be delivered directly to the site of the disease, with a lower dose than more conventional oral or intravenous delivery methods, with reduced systemic absorption and consequently reduced risk of adverse effects. For asthma this delivery route has become the 'golden standard' of therapy. It is not unexpected therefore, that there has been great interest in the prospect of using inhaled antibiotics for the treatment of both chronic and recurrent respiratory infections. Since the early 1980s, several investigations have demonstrated that antibiotics could be delivered safely by means of inhalation, using nebulisers as their delivery systems. Lately, antibiotics delivery via inhalation have seen a 'revival' in interest and most of these studies have focused on delivering antibiotics to the lungs by means of a dry powder format. This review focuses on recent advances in antibiotic inhalation therapy.

Microstructural analysis of porous composite materials: Dynamic imaging of drug dissolution and diffusion through porous matrices

Publisher: Springer Science and Business Media LLC

Date: 14-11-2008

DOI: 10.1208/S12248-008-9063-2

Timothy Grass Pollen Induces Spatial Reorganisation of F-Actin and Loss of Junctional Integrity in Respiratory Cells

Publisher: Springer Science and Business Media LLC

Date: 29-01-2022

DOI: 10.1007/S10753-021-01614-9

Abstract: Grass pollens have been identified as mediators of respiratory distress, capable of exacerbating respiratory diseases including epidemic thunderstorm asthma (ETSA). It is hypothesised that during thunderstorms, grass pollen grains swell to absorb atmospheric water, rupture, and release internal protein content to the atmosphere. The inhalation of atmospheric grass pollen proteins results in deadly ETSA events. We sought to identify the underlying cellular mechanisms that may contribute towards the severity of ETSA in temperate climates using Timothy grass (Phleum pratense). Respiratory cells exposed to Timothy grass pollen protein extract (PPE) caused cells to undergo hypoxia ultimately triggering the subcellular re-organisation of F-actin from the peri junctional belt to cytoplasmic fibre assembly traversing the cell body. This change in actin configuration coincided with the spatial reorganisation of microtubules and importantly, decreased cell compressibility specifically at the cell centre. Further to this, we find that the pollen-induced reorganisation of the actin cytoskeleton prompting secretion of the pro-inflammatory cytokine, interleukin-8. In addition, the loss of peri-junctional actin following exposure to pollen proteins was accompanied by the release of epithelial transmembrane protein, E-cadherin from cell-cell junctions resulting in a decrease in epithelial barrier integrity. We demonstrate that Timothy grass pollen regulates F-actin dynamics and E-cadherin localisation in respiratory cells to mediate cell-cell junctional integrity highlighting a possible molecular pathway underpinning ETSA events.

The effects of loaded carrier mass and formulation mass on aerosolization efficiency in dry powder inhaler devices

Publisher: Bentham Science Publishers Ltd.

Date: 10-03-2015

DOI: 10.2174/1567201811666140822113207

Abstract: Previous studies have suggested that particle-particle impaction may influence aerosolization properties in carrier-based dry powder inhalers, through transfer of kinetic energy from large carriers to surface-deposited active drug. The importance of particle-particle collision has yet to be compared against other mechanisms that could lead to drug liberation, such as particle-wall impaction and turbulence. In particular, particle-particle collisions are difficult to model in silico due to computational restrictions. This study investigated the effects of dry powder inhaler particle-particle collisions in vitro using an established carrier-drug model dry powder inhalation formulation. Spherical polystyrene beads of median size 82.80 μm were chosen as a model carrier as they were of uniform size, shape, surface area, density, porosity and hardness and thus eliminated potential variables that would have conflicted with the study. This model carrier was geometrically blended with micronized salbutamol sulphate (loaded blend). The correlation between the mass of loaded blend (5-40 mg) in the Rotahaler® DPI device and resulting fine particle fraction (FPF) was examined at a constant flow rate of 60 L.min(-1). In a second experiment, the mass of loaded blend was kept constant and a variable amount of blank carrier particles were added to the Rotahaler® device to ascertain if additional "blank" carrier particles affected the final FPF. The efficiency of aerosolization remained constant with varying amounts of blank carrier particles as determined by the fine particle fraction of the emitted dose (FPFED) and fine particle fraction of the loaded dose (FPFLD). No statistical difference in FPFED and FPFLD values were observed for increasing masses of blank carrier. In addition, no statistical difference in FPFED and FPFLD between the two experiments was obtained. These observations suggest that particle-particle collisions are not a driving mechanism responsible for deaggregation of drug from carrier-based systems.

Curcumin Nanoparticles Attenuate Production of Pro-inflammatory Markers in Lipopolysaccharide-Induced Macrophages

Publisher: Springer Science and Business Media LLC

Date: 09-09-2015

DOI: 10.1007/S11095-015-1789-9

Abstract: The surface charge of nanoparticles is an important factor that controls efficiency and cellular uptake. The aim of this study was to investigate the efficacy of curcumin nanoparticles (Cur-NPs) with different surface charges, in terms of toxicity, internalization, anti-inflammatory and anti-oxidant activities towards alveolar macrophages cells. The surface charge of curcumin nanoparticles (positive, negative and neutral), with an average diameter of 30 nm, were synthesized and characterized. Polyvinyl-alcohol, polyvinylpyrrolidone and dextran were used as coatings to confer negative, positive and neutral charges. The synthesized Cur-NPs were evaluated for particle size, encapsulation efficiency, surface charge, qualitative and quantitative cellular uptakes, anti-oxidant and anti-inflammatory activities. Positively charged nanoparticles showed higher cytotoxicity effects compared to negative and neutral particles. The same trend was observed in antioxidant activity, which included radical scavenging and nitric oxide production. In addition, the anti-inflammatory activity (interleukin-1β, IL-6 and TNF-α) depleted in the order: positive>negative>neutral. The void neutral-, positively- and negatively-charged nanoparticles did not show any cytotoxic effects. The difference in activity for different surface charges of Cur-NPs may be due to the internalization rate of the particles by alveolar macrophages. Intracellular uptake measurements demonstrated that Cur-NPs with positive surface charges possessed the strongest interaction with alveolar macrophages.

The potential to treat lung cancer via inhalation of repurposed drugs

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.ADDR.2018.08.012

Abstract: Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative to improve lung cancer therapy. This review describes the rationale and development of repositioning of drugs for lung cancer treatment with emphasis on inhalation. The review includes the current progress of repurposing non-cancer drugs, as well as current chemotherapeutics for lung malignancies via inhalation. Several potential non-cancer drugs such as statins, itraconazole and clarithromycin, that have demonstrated preclinical anti-cancer activity, are also presented. Furthermore, the potential challenges and limitations that might h er the clinical translation of repurposed oncology drugs are described.

The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer

Publisher: Informa UK Limited

Date: 27-10-2016

DOI: 10.1080/17425247.2017.1247804

Abstract: The effectiveness of conventional cancer chemotherapy is h ered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle-based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer. Areas covered: This review focuses on the recent advances in the functionalization of nanocarriers with specific ligands, including antibodies, transferrin, folate, and peptides to overcome MDR cancer. The limitations of effective ligand-functionalized nanoparticles as well as therapeutic successes in ligand targeting are covered in the review. Expert opinion: Targeting MDR tumors with ligand-functionalized nanoparticles is a promising approach to improve the treatment of cancer. With this approach, higher drug concentrations at targeted sites would be achieved with lower dosage frequencies and reduced side effects in comparison to existing formulations of chemotherapeutic drugs. However, potential toxicities and immunological responses to ligands should be carefully reviewed for viable options in for future MDR cancer treatment.

Does carrier size matter? A fundamental study of drug aerosolisation from carrier based dry powder inhalation systems

Publisher: Elsevier BV

Date: 07-2011

DOI: 10.1016/J.IJPHARM.2011.04.002

Abstract: There is plenty of evidence supporting the notion that the size of the carrier influences the aerosolisation performance of drug from a drug-carrier blend. Interestingly, that evidence is contradictory in places and the study of such mechanisms is fraught by the compounding variables associated with comparing crystalline powders (e.g. as size is varied so may the shape, surface chemistry, roughness and the amount of fine excipients). To overcome these limitations, a series of model polystyrene spheres were used to study the influence of size on aerosol performance. Three polystyrene sphere carriers (TS-80, TS-250 and TS-500, describing their approximate diameters) were characterised using laser diffraction, atomic force microscopy, colloid probe microscopy, electron microscopy, true density and dynamic vapour sorption. The model carriers were blended with micronized salbutamol sulphate (67.5:1 ratios) and the aerosolisation performance was tested using a multistage liquid impinger at a range of flow rates (40-100 lmin(-1)). Physico-chemical analysis of the carriers indicated that all carriers were spherical with similar roughness and densities. Furthermore, the adhesion force of drug to the carrier surfaces was independent of carrier size. Significant differences in drug aerosolisation were observed with both flow rate and carrier size. In general, as carrier size was increased, aerosol performance decreased. Furthermore, as flow rate was increased so did performance. Such observations suggest that higher energy processes drive aerosolisation, however this is likely to be due to the number of impaction events (and associated frictional and rotational forces) rather than the actual collision velocity (since the larger carriers had increased momentum and drag forces). This study shows that, in isolation of other variables, as carrier size increases, a concurrent decrease in drug aerosolisation performance is observed.

Modification of Disodium Cromoglycate Passage Across Lung Epithelium In Vitro Via Incorporation into Polymeric Microparticles

Publisher: Springer Science and Business Media LLC

Date: 28-12-2011

DOI: 10.1208/S12248-011-9317-2

The application of in vitro cellular assays for analysis of electronic cigarettes impact on the airway

Publisher: Elsevier BV

Date: 06-2022

DOI: 10.1016/J.LFS.2022.120487

Abstract: Electronic (e)-cigarettes have been marketed for more than a decade as an alternative to conventional cigarettes. Their popularity and use among adolescents have grown significantly during recent years. While e-cigarettes do not release carcinogenic aromatic hydrocarbons, they can generate reactive carbonyls and radicals during the heating process in vitro. Emphasis has been placed in recent studies to introduce more rigorous and physiologically relevant in vitro models to characterise the toxicological profile of e-cigarettes. However, significant challenges are present due to difficulties for the developed systems to fully represent the in vivo inhalation settings. Furthermore, research protocols that fail to simulate the characteristics of e-cigarettes can affect the findings of in vitro studies. This review will illustrate the status quo of e-cigarette assays in vitro, discussing the various cellular assays used for evaluating the safety profile of e-cigarettes. Future directions will also be provided to better assist the scientific community in interpreting the health risks of e-cigarettes.

Dosing challenges in respiratory therapies

Publisher: Elsevier BV

Date: 03-2018

DOI: 10.1016/J.IJPHARM.2018.07.007

Abstract: The pulmonary route of administration has been commonly used for local lung conditions such as asthma and chronic obstructive pulmonary disease (COPD). Recently, with the advent of new technologies available for both formulation and device design, molecules usually delivered at high doses, such as antibiotics and insulin to treat cystic fibrosis (CF) and diabetes, respectively, can now be delivered by inhalation as a dry powder. These molecules are generally delivered in milligrams instead of traditional microgram quantities. High dose delivery is most commonly achieved via dry powder inhalers (DPIs), breath activated devices designed with a formulated powder containing micronized drug with aerodynamic diameters between 1 and 5 µm. The powder formulation may also contain other excipients and/or carrier particles to improve the flowability and aerosol dispersion of the powder. A drawback with high doses is that the formulation contains a great number of fine particles, leading to a greater degree of cohesive forces, producing strongly bound agglomerates. With greater cohesive forces holding fine particles together, higher dispersion forces are needed for efficient de-agglomeration and aerosolisation. This requirement of greater dispersion forces has led to different dry powder formulations and vastly different inhaler designs. The purpose of this review is to evaluate the different formulation types, various DPI devices currently available, and how these affect the aerosolisation process and delivery of high dosed inhalable dry powder formulations to the lungs.

Twenty years of HFA pMDI patents: Facts and perspectives

Publisher: Oxford University Press (OUP)

Date: 10-11-2012

DOI: 10.1111/J.2042-7158.2011.01387.X

Abstract: Over the past 20 years, the inhalation drug delivery industry has undergone a quiet revolution after the phasing out of the chlorofluorocarbon propellants used to formulate pressure-metered dose inhalers (pMDIs). This review looks back to the creative landscape of those 20 years through a study of patent application trends. To this end, an analysis of the hydrofluoroalkane pMDIs patent landscape was undertaken. A statistical analysis demonstrates that 20 years after the introduction of hydrofluoroalkanes in the inhalation delivery field, the original patent applications are coming to the end of their legal life. Detailed analysis revealed that, from a total of 971 of the patents identified, up to 2.3% will expire within the next 5 years, rising to up to 7.3% in the next 10 years. The UK and USA were the main patent destinations and locations of inventive activity, as measured by patent filing location. Interestingly, the UK was the first destination and location of inventive activity in Europe, largely due to the activity of GlaxoSmithKline, followed by Italy, thanks to the work of Trinity-Chiesi. The analysis also showed that patent assignees are not always major pharmaceutical companies, with suppliers of propellants, as well as companies without major inhalation activity (such as Novadel), making substantial contributions to the landscape. These developments may have a significant impact on innovation trends and key company activity around novel pMDI formulations, in particular for generics manufacturers.

Protective abilities of an inhaled DPI formulation based on sodium hyaluronate against environmental hazards targeting the upper respiratory tract

Publisher: MDPI AG

Date: 22-06-2022

DOI: 10.3390/PHARMACEUTICS14071323

Abstract: The exposure of lung epithelium to environmental hazards is linked to several chronic respiratory diseases. We assessed the ability of an inhaled dry powder (DPI) medical device product (PolmonYDEFENCE/DYFESATM, SOFAR SpA, Trezzano Rosa, Italy), using a formulation of sodium hyaluronate (Na-Hya) as the key ingredient as a defensive barrier to protect the upper respiratory tract. Specifically, it was evaluated if the presence of the barrier formed by sodium hyaluronate present on the cells, reducing direct contact of the urban dust (UD) with the surface of cells can protect them in an indirect manner by the inflammatory and oxidative process started in the presence of the UD. Cytotoxicity and the protection capability against the oxidative stress of the product were tested in vitro using Calu-3 cells exposure to UD as a trigger for oxidative stress. Inflammation and wound healing were assessed using an air-liquid interface (ALI) culture model of the Calu-3 cells. Deposition studies of the formulation were conducted using a modified Anderson cascade impactor (ACI) and the monodose PillHaler® dry powder inhaler (DPI) device, Na-Hya was detected and quantified using high-performance-liquid-chromatography (HPLC). Solubilised PolmonYDEFENCE/DYFESATM gives protection against oxidative stress in Calu-3 cells in the short term (2 h) without any cytotoxic effects. ALI culture experiments, testing the barrier-forming (non-solubilised) capabilities of PolmonYDEFENCE/DYFESATM, showed that the barrier layer reduced inflammation triggered by UD and the time for wound closure compared to Na-Hya alone. Deposition experiments using the ACI and the PillHaler® DPI device showed that the majority of the product was deposited in the upper part of the respiratory tract. Finally, the protective effect of the product was efficacious for up to 24 h without affecting mucus production. We demonstrated the potential of PolmonYDEFENCE/DYFESATM as a preventative barrier against UD, which may aid in protecting the upper respiratory tract against environmental hazards and help with chronic respiratory diseases.

Pulmonary delivery of curcumin and quercetin nanoparticles for lung cancer–Part 1

Publisher: Elsevier BV

Date: 09-2023

DOI: 10.1016/J.JDDST.2023.104646

Effect of dosing cup size on the aerosol performance of high-dose carrier-based formulations in a novel dry powder inhaler

Publisher: Elsevier BV

Date: 02-2019

DOI: 10.1016/J.XPHS.2018.09.033

Abstract: This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm

Beating cilia identification in fluorescence microscope images for accurate CBF measurement

Publisher: IEEE

Date: 09-2015

DOI: 10.1109/ICIP.2015.7351657

A novel apparatus for the determination of solubility in pressurized metered dose inhalers

Publisher: Informa UK Limited

Date: 2006

DOI: 10.1080/03639040600920325

Abstract: The accurate solubility of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate in hydrofluoroalkane propellant 134a at 25 degrees C for 24 h, are reported. The authors describe a novel reusable in-line pressurized solubility apparatus containing an integral filter holder and a continuous decrimpable valve for the determination of drug/excipients solubility in pressurized metered dose inhalers. The solubility was determined by high-performance liquid chromatography. Solubility of salbutamol sulfate was determined as being below the detection limits while budesonide and formoterol fumarate dihydrate solubility were 23.136 +/- 2.951 microg x g(-1) and 0.776 +/- 1.023 microg x g(-1), respectively (n = 3). This novel solubility apparatus offers an improved ease of use and potential higher analytical throughput.

Controlled release antibiotics for dry powder lung delivery

Publisher: Informa UK Limited

Date: 2010

DOI: 10.3109/03639040903099769

Abstract: Two controlled release (CR) antibiotics intended for inhalation therapy were evaluated. Ciprofloxacin and doxycycline (both hydrochlorides) were selected as model drugs. Microparticles containing 90:10 ratio of polyvinyl alcohol (PVA) and single antibiotics or combinations were obtained via spray drying. The microparticles were evaluated in terms of particle size, morphology, thermal properties, aerosol performance, and in vitro release. Analysis of the microparticle morphology indicated comparable size distributions (2.04 ± 0.06, 2.15 ± 0.01, and 2.21 ± 0.01 μm for ciprofloxacin, doxycycline, and co-spray-dried antibiotic formulations, respectively). Thermal analysis of the microparticles suggested similar responses, which were dominated by the endothermic peaks observed for PVA alone. Analysis of the aerosol performance suggested that the in idual antibiotic formulations had different aerosol profiles that were dependent on the antibiotic used. In comparison, the combination CR antibiotics had identical aerosol profiles, suggesting that the microparticles were homogeneous. The release of antibiotics from the CR microparticles showed that ≤ 50% was released over a 6-hour period in comparison to ≥ 90% being released in the first hour for microparticles containing no PVA. The potential for antibiotic therapy, and specifically CR antibiotic therapy using dry powder inhalers, provides a promising route for the treatment of pulmonary infection.

Use of the International Classification of Functioning, Disability and Health (ICF) to identify preliminary comprehensive and brief core sets for multiple sclerosis

Publisher: Informa UK Limited

Date: 2007

DOI: 10.1080/09638280600756141

Abstract: To identify the preliminary comprehensive and brief core sets for multiple sclerosis (MS), in a Delphi process using the International Classification of Functioning, Disability and Health (ICF). Focus groups and a consensus process were used to identify ICF core sets for MS. This included: preliminary ICF studies empirical patient data collection for 101 MS participants review of the evidence base and treatment in MS literature followed by a Delphi exercise with 23 physicians and allied health professionals in Melbourne, Australia. One hundred and forty-four (40%) second level ICF categories were selected by 23 participants in three rounds. The comprehensive MS ICF core set includes 34 (24%) categories from the component 'body function', six (4%) categories from 'body structures', 68 (47%) from 'activities and participation' and 36 (25%) from the component 'environmental' factors. Ten categories in 'personal factors' in MS were also suggested by the participants after intensive discussions. The brief set comprises 30 categories, 21% of categories in the comprehensive core set. Consensus expert opinion can use ICF categories to identify the core set for MS which reflects disease complexity and care burden for persons' with MS. Further research is needed to identify ICF categories of relevant personal factors to improve our understanding of the large social and cultural variance associated with them.

The Effect of Actuator Nozzle Designs on the Electrostatic Charge Generated in Pressurised Metered Dose Inhaler Aerosols

Publisher: Springer Science and Business Media LLC

Date: 10-2014

DOI: 10.1007/S11095-014-1529-6

Abstract: To investigate the influence of different actuator nozzle designs on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs). Four actuator nozzle designs (flat, curved flat, cone and curved cone) were manufactured using insulating thermoplastics (PET and PTFE) and conducting metal (aluminium) materials. Aerosol electrostatic profiles of solution pMDI formulations containing propellant HFA 134a with different ethanol concentration and/or model drug beclomethasone dipropionate (BDP) were studied using a modified electrical low-pressure impactor (ELPI) for all actuator designs and materials. The mass of the deposited drug was analysed using high performance liquid chromatography (HPLC). Both curved nozzle designs for insulating PET and PTFE actuators significantly influenced aerosol electrostatics and aerosol performance compared with conducting aluminium actuator, where reversed charge polarity and higher throat deposition were observed with pMDI formulation containing BDP. Results are likely due to the changes in plume geometry caused by the curved edge nozzle designs and the bipolar charging nature of insulating materials. This study demonstrated that actuator nozzle designs could significantly influence the electrostatic charges profiles and aerosol drug deposition pattern of pMDI aerosols, especially when using insulating thermoplastic materials where bipolar charging is more dominant.

Advances in soft mist inhalers

Publisher: Informa UK Limited

Date: 10-07-2023

DOI: 10.1080/17425247.2023.2231850

Liposomal nanoparticles control the uptake of ciprofloxacin across respiratory epithelia.

Publisher: Springer Science and Business Media LLC

Date: 26-07-2012

DOI: 10.1007/S11095-012-0827-0

Abstract: Liposomal ciprofloxacin nanoparticles were developed to overcome the rapid clearance of antibiotics from the lungs. The formulation was evaluated for its release profile using an air interface Calu-3 cell model and further characterised for aerosol performance and antimicrobial activity. Liposomal and free ciprofloxacin formulations were nebulised directly onto Calu-3 bronchial epithelial cells placed in an in vitro twin-stage impinger (TSI) to assess the kinetics of release. The aerosol performance of both the liposomal and free ciprofloxacin formulation was characterised using the next generation impactor. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined and compared between formulations to evaluate the antibacterial activity. The liposomal formulation successfully controlled the release of ciprofloxacin in the cell model and showed enhanced antibacterial activity against Pseudomonas aeruginosa. In addition, the formulation displayed a respirable aerosol fraction of 70.5 ± 2.03% of the emitted dose. Results indicate that the in vitro TSI air interface Calu-3 model is capable of evaluating the fate of nebulised liposomal nanoparticle formulations and support the potential for inhaled liposomal ciprofloxacin to provide a promising treatment for respiratory infections.

Development of Inhalable Spray Dried Nitrofurantoin Formulations for the Treatment of Emphysema

Publisher: MDPI AG

Date: 31-12-2022

DOI: 10.3390/PHARMACEUTICS15010146

Abstract: A central characteristic of emphysematous progression is the continuous destruction of the lung extracellular matrix (ECM). Current treatments for emphysema have only addressed symptoms rather than preventing or reversing the loss of lung ECM. Nitrofurantoin (NF) is an antibiotic that has the potential to induce lung fibrosis as a side effect upon oral administration. Our study aims to repurpose NF as an inhalable therapeutic strategy to upregulate ECM expression, thereby reversing the disease progression within the emphysematous lung. Spray-dried (SD) formulations of NF were prepared in conjunction with a two-fluid nozzle (2FN) and three-fluid nozzle (3FN) using hydroxypropyl methylcellulose (HPMC) and NF at 1:1 w/w. The formulations were characterized for their physicochemical properties (particle size, morphology, solid-state characteristics, aerodynamic behaviour, and dissolution properties) and characterized in vitro with efficacy studies on human lung fibroblasts. The 2FN formulation displayed a mass mean aerodynamic diameter (MMAD) of 1.8 ± 0.05 µm and fine particle fraction (FPF) of 87.4 ± 2.8% with significantly greater deposition predicted in the lower lung region compared to the 3FN formulation (MMAD: 4.4 ± 0.4 µm FPF: 40 ± 5.8%). Furthermore, drug dissolution studies showed that NF released from the 2FN formulation after 3 h was significantly higher (55.7%) as compared to the 3FN formulation (42.4%). Importantly, efficacy studies in human lung fibroblasts showed that the 2FN formulation induced significantly enhanced ECM protein expression levels of periostin and Type IV Collagen (203.2% and 84.2% increase, respectively) compared to untreated cells, while 3FN formulations induced only a 172.5% increase in periostin and a 38.1% increase in type IV collagen. In conclusion, our study highlights the influence of nozzle choice in inhalable spray-dried formulations and supports the feasibility of using SD NF prepared using 2FN as a potential inhalable therapeutic agent to upregulate ECM protein production.

An investigation of surface properties, local elastic modulus and interaction with simulated pulmonary surfactant of surface modified inhalable voriconazole dry powders using atomic force microscopy

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C6RA01154C

Abstract: l -Leucine modified voriconazole spray dried micropartcles.

The influence of micronised particulates on the aerosolisation properties of pressurised metered dose inhalers

Publisher: Elsevier BV

Date: 04-2009

DOI: 10.1016/J.JAEROSCI.2008.12.006

The contribution of different formulation components on the aerosol charge in carrier-based dry powder inhaler systems

Publisher: Springer Science and Business Media LLC

Date: 31-03-2010

DOI: 10.1007/S11095-010-0115-9

Abstract: To measure aerosol performance of a lactose carrier/salbutamol sulphate powder blend and identify contributions of non-formulation and formulation components on the resulting aerosol charge. A 67.5:1 (%w/w) blend of 63-90 microm lactose with salbutamol sulphate, and lactose alone (with and without the blending process), was dispersed from a Cyclohaler into the electrical Next Generation Impactor at 30, 60 and 90 L/min. Mass and charge profiles were measured from each dispersion, as a function of impactor stage. The charge profile from an empty capsule in the Cyclohaler was also studied. Lactose deposition from the blend was significantly greater, and net charge/mass ratios were smaller, in the pre-separator compared to formulations without drug. Fine particle fraction of salbutamol sulphate increased with flow rate (9.2 +/- 2.5% to 14.7 +/- 2.7%), but there was no change in net charge/mass ratio. The empty capsule produced a cycle of alternating net positive and negative discharges ( approximately 200 pC to 4 nC). Capsule charge can ionize surrounding air and influence net charge measurements. Detachment of fine drug during aerosolisation may reduce net specific charge and lead to increased lactose deposition in the pre-separator. Increase in FPF may be due to increased force of detachment rather than electrostatic forces.

Biological Effects of Simvastatin Formulated as pMDI on Pulmonary Epithelial Cells

Publisher: Springer Science and Business Media LLC

Date: 04-08-2015

DOI: 10.1007/S11095-015-1766-3

Abstract: The aim of this study is to evaluate the biological effects of Calu-3 epithelial cells in response to the delivery of simvastatin (SV) via solution pressurized metered dose inhaler (pMDI). SV pMDI was aerosolised onto Calu-3 air-interface epithelial cells using a modified glass twin stage impinger. The transport of SV across Calu-3 cells, mucus production, inflammatory cytokines production i.e., interleukin (IL) 6, 8 and tumour necrosis factor alpha (TNF- α) and oxidative stress from Calu-3 cells following treatment with SV pMDI was investigated and compared to untreated cells. It was found that SV had the ability to penetrate into the respiratory epithelium and convert into its active SV hydroxy acid (SVA) metabolite. Furthermore, the amount of mucus produced was significantly reduced when SV was deposited on Calu-3 compared to untreated cells. Additionally, SV delivered by pMDI reduces production of IL-6, 8 and TNF-α from Calu-3 following stimulation with lipopolysaccharide (LPS). SV also showed equivalent antioxidant property to vitamin E. Treatment with SV solution pMDI formulation on Calu-3 cells reduces mucus production, inflammatory cytokines and oxidative stress. This formulation could potentially be used clinically as muco-inhibitory and anti-inflammatory therapy for treatment of chronic lung diseases.

Co-delivery of inhalable therapies: Controlling active ingredients spatial distribution and temporal release

Publisher: Elsevier BV

Date: 03-2021

DOI: 10.1016/J.MSEC.2020.111831

Dry powder formulation of simvastatin

Publisher: Informa Healthcare

Date: 22-09-2015

DOI: 10.1517/17425247.2015.963054

Abstract: This study focuses on the development of a dry powder inhaler (DPI) formulation of simvastatin (SV), and the effects of SV on the respiratory epithelium. Micronised SV s les were prepared by dry jet-milling. The long-term chemical stability and physicochemical properties of the formulations were characterised in terms of particles size, morphology, thermal and moisture responses. Furthermore, in vitro aerosol depositions were performed. The formulation was evaluated for cell viability and its effect on cilia beat activity, using ciliated nasal epithelial cells in vitro. The formulation transport across an established air interface Calu-3 bronchial epithelial cells and its ability to reduce mucus secretion was also investigated. The particle size of the SV formulation and its aerosol performance were appropriate for inhalation therapy. Moreover, the formulation was found to be non-toxic to pulmonary epithelia cells and cilia beat activity up to a concentration of 10(-6) M. Transport studies revealed that SV has the ability to penetrate into airway epithelial cells and is converted into its active SV hydroxy acid metabolite. Single dose of SV DPI also decreased mucus production after 4 days of dosing. This therapy could potentially be used for the local treatment of diseases like chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis given its anti-inflammatory effects and ability to reduce mucus production.

An Investigation into the Powder Release Behavior from Capsule-Based Dry Powder Inhalers

Publisher: Informa UK Limited

Date: 20-08-2015

DOI: 10.1080/02786826.2015.1082532

Influence of humidity on the electrostatic charge and aerosol performance of dry powder inhaler carrier based systems

Publisher: Springer Science and Business Media LLC

Date: 22-03-2007

DOI: 10.1007/S11095-006-9218-8

Abstract: To investigate the influence of storage relative humidity (RH) on the aerosolisation efficiency and tribo-electrification of carrier based dry powder inhaler (DPI) formulations using the next generation impactor (NGI) in vitro methodology and the electrostatic low pressure impactor (ELPI). Micronised salbutamol (d (0.5) 1.48 +/- 0.03 microm) was blended with 63-90 microm sieve fractioned alpha-lactose monohydrate carrier and stored at a range of humidities (0-84% RH). The aerosolisation efficiency after storage for 24 h periods was investigated using the NGI. The same experiment was conducted using the ELPI, with corona charger switched off, to measure the net charge vs. mass deposition profile. Significant variations in the aerosolisation efficiency of the formulation were observed with respect to storage RH. In general, the fine particle fraction aerosol performance measured by NGI and ELPI (fraction with mass median aerodynamic diameter 60% RH. Analysis of the ELPI charge data suggested that the micronised salbutamol sulphate had an electronegative charge when aerosolised from lactose based carriers, which was most electronegative at low RH. Increased storage RH resulted in a reduction in net charge to mass ratio with the greatest reduction at RH >60%. The aerosol performance of this binary system is dependent on both electrostatic and capillary forces. The use of the ELPI allows a degree of insight into how these forces affect formulation performances after storage at different RH.

Particle synergy and aerosol performance in non-aqueous liquid of two combinations metered dose inhalation formulations: An AFM and Raman investigation

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.JCIS.2011.05.073

Abstract: The drug-drug interaction of two pMDI (pressure metered dose inhaler) combination products budesonide-formoterol fumarate dihydrate and salmeterol xinafoate-fluticasone propionate were investigated using in situ atomic force microscopy (AFM), equipped with a liquid cell filled with model a propellant, and Raman spectroscopy. Electron microscopy images of the budesonide-formoterol formulation suggested discrete particulates while the salmeterol-fluticasone formulation appeared agglomerated. Based on the analysis of the AFM curves, it is proposed that interactions in the budesonide-formoterol system (cohesion and adhesion) are dominated by van der Waals forces while interactions between salmeterol and fluticasone are of a chemical nature. Such observations are further substantiated by analysis of the Raman maps produced from pMDI actuations deposited on Andersen cascade impactor plates. The relevance of such synergy between particulates of different chemical nature is discussed. In particular, it is anticipated that strong interactions between particles could lead to heteroflocculation, increase aerosol particle size and consequently reduction of the respirable fine particle fraction.

Epithelial profiling of antibiotic controlled release respiratory formulations.

Publisher: Springer Science and Business Media LLC

Date: 26-05-2011

DOI: 10.1007/S11095-011-0462-1

Abstract: Release profiles of two ciprofloxacin hydrochloride formulations for the treatment of respiratory infection were evaluated using different in vitro methodologies and characterised for aerosol performance and toxicity. Spray-dried ciprofloxacin and ciprofloxacin spray-dried with polyvinyl alcohol as a controlled release (CR) agent at a 50:50 w/w ratio were formulated and physico-chemically characterised. Aerosol performances were assessed in vitro using a liquid impinger. Drug release was performed using a modified Franz cell and a validated air interface Calu-3-modified twin stage impinger (TSI). Ciprofloxacin toxicity was also established in vitro. Both formulations had a similar size distribution, while CR ciprofloxacin had superior aerosol performance and stability. The release profiles showed the CR formulation to have a higher transport rate compared to ciprofloxacin alone in the cell model. Contrary results were observed using the diffusion cell. Results suggest that the air interface cell model provides a more physiologically relevant model than the modified Franz cell. Toxicity analysis showed that the lung epithelial cells could tolerate a wide range of ciprofloxacin concentrations. This study establishes that the in vitro modified TSI air interface Calu-3 model is capable of evaluating the fate of inhaled powder formulations.

Composite carriers improve the aerosolisation efficiency of drugs for respiratory delivery

Publisher: Elsevier BV

Date: 2008

DOI: 10.1016/J.JAEROSCI.2007.10.003

The use of atomic force microscopy to study the conditioning of micronised budesonide

Publisher: Elsevier BV

Date: 05-06-2008

DOI: 10.1016/J.IJPHARM.2008.01.042

Abstract: Patent literature describes "conditioning" techniques which employ organic vapours to recrystallise amorphous regions in micronised particles, with the aim of improving their processability and physico-chemical stability. This report describes a preliminary study investigating the efficacy of PhaseImaging atomic force microscopy (AFM) for the investigation of such processes. AFM phase images demonstrated variation in mechanical properties across the surface of milled budesonide particles, which diminished upon exposure to ethanol vapour. No variation was seen in phase images of unmilled budesonide. Dynamic vapour sorption confirmed the presence amorphous material in the milled s le and its subsequent recrystallisation following exposure to ethanol vapour under the same conditions as those used in the AFM experiment. It was therefore hypothesised that variation in the phase images indicated the presence of amorphous regions which were subsequently conditioned. PhaseImaging AFM may therefore be a useful method for the study of conditioning techniques, enabling the efficacy and kinetics of the process to be observed.

Respiratory medication use in an Australian developmental disability clinic population

Publisher: CSIRO Publishing

Date: 2014

DOI: 10.1071/PY12153

Abstract: Australian data suggest up to 15% of people with intellectual disability (ID) have asthma. The inhaled route of administration is optimal for the management of obstructive airways diseases however, correct inhaler use requires dexterity and particular breathing patterns and potentially represents a problem in this population due to physical and cognitive deficits. Understanding the nature and extent of inhaler use in persons with ID is important, as correct inhaler technique is imperative for optimal clinical outcomes however, currently no evidence base exists to inform health professionals. This study describes respiratory medication use, reported prevalence of asthma, and asthma management practices undertaken in a clinic s le of Australian adults with ID. Results showed a prevalence of retrospectively reported asthma of 6%, with 86% of asthma patients prescribed inhaled medication. A review of patient records also indicated omission of some recommended asthma management strategies.

Investigation into the influence of polymeric stabilizing excipients on inter-particulate forces in pressurised metered dose inhalers

Publisher: Elsevier BV

Date: 31-08-2006

DOI: 10.1016/J.IJPHARM.2006.04.016

Abstract: Colloid probe atomic force microscopy (AFM) was utilised to quantify the cohesive forces of salbutamol sulphate in a model non-pressurised fluorinated liquid (mHFA), in the presence of increasing concentrations of poly(ethylene glycol) (PEG molecular weight (MW) 200, 400 and 600). In addition, s les of PEG 400 (0.05-0.5%, v/w), were analysed in the presence of 0.001% (w/w) of poly(vinyl pyrrolidone) (PVP). In the absence of any stabilizing agents, strong attractive forces were present between particles. Increasing the concentration of the different MW PEG solutions in the mHFA system (up to 0.5%, v/w), significantly decreased the force of interaction (ANOVA, p<0.05). The decrease in cohesion was particularly evident at very low concentrations of PEG (0.05-0.1%, v/w). Further data analysis (p 0.05). Clearly, an understanding of the conformation of polymer molecules at interfaces is of vital importance when controlling the stability/flocculation behaviour of sterically stabilized pMDI suspensions. In this context, the use of the colloid probe AFM technique has provided a quantitative insight into the interactions of these complex systems and may be an invaluable asset during the early phase of formulation product development.

The influence of dose on the performance of dry powder inhalation systems

Publisher: Elsevier BV

Date: 30-05-2005

DOI: 10.1016/J.IJPHARM.2005.02.004

Abstract: The relationship between drug/lactose ratio and aerosolisation performance of conventional carrier based formulations was investigated using the twin stage impinger. A dose range of approximately 10-450 microg of drug in a 50 mg lactose carrier formulation was studied. Statistical differences in both the fine particle dose and fine particle fraction were observed across the dosage range (ANOVA, p<0.05). In general, no statistically significant difference (Fishers Pairwise, p<0.05) in fine particle dose was observed between drug levels of approximately 10 microg and 135 microg, whereas a linear decrease in fine particle fraction was observed across the same drug level range (R2=0.977). Increasing the dose from approximately 135 microg to 450 microg resulted in a statistically significant increase in both fine particle dose and fraction (ANOVA p<0.05). Such observations may be attributed to the occupation of 'active' carrier sites by drug particles at low drug concentration, since the quantity of drug particles liberated from the carrier during aerosolisation remains constant at the lower dosing regimes.

Under pressure

Publisher: Elsevier BV

Date: 06-2003

DOI: 10.1016/S0021-9797(03)00032-8

Chronic obstructive pulmonary disease: Patho-physiology, current methods of treatment and the potential for simvastatin in disease management

Publisher: Informa Healthcare

Date: 26-05-2011

DOI: 10.1517/17425247.2011.588697

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is a severe disease that leads to a non-reversible obstruction of the small airways. The prevalence of this disease is rapidly increasing in developed countries, and in 2020 it has been predicted that this disease will reach the third cause of mortality worldwide. COPD patients do not respond well to current treatment modalities, such as bronchodilators and corticosteroids. This review article focuses on the patho-physiology of COPD, explores current approaches to alleviate and treat the disease, and discusses the potential use of statins for treatment. Specifically, the mechanism of action and metabolism of simvastatin, the most known and studied molecule among the statin family, are critically reviewed. Various cellular pathways have been implicated in COPD, with alveolar macrophages emerging as pivotal inflammatory mediators in the COPD patho-physiology. Recently, emerging anti-cytokine therapies, such as PDE4 inhibitors and ACE inhibitors, have shown good anti-inflammatory properties that can be useful in COPD treatment. Recently, statins as a drug class have gained much interest with respect to COPD management, following studies which show simvastatin to exert effective anti-inflammatory effects, via inhibition of the mevalonic acid cascade in alveolar macrophages.

Real-time quantitative monitoring of in vitro nasal drug delivery by a nasal epithelial mucosa-on-a-chip model.

Publisher: Informa UK Limited

Date: 19-01-2021

DOI: 10.1080/17425247.2021.1873274

Delivery of theophylline as dry powder for inhalation

Publisher: Elsevier BV

Date: 12-2015

DOI: 10.1016/J.AJPS.2015.08.005

Quercetin solid lipid microparticles: a flavonoid for inhalation lung delivery.

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.EJPS.2013.03.009

Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges

Publisher: Elsevier BV

Date: 12-2015

DOI: 10.1016/J.AJPS.2015.08.009

Androgenetic alopecia may be associated with weaker COVID-19 T-cell immune response: An insight into a potential COVID-19 vaccine booster

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.MEHY.2020.110439

Immunomodulatory Effects of a Low-Dose Clarithromycin-Based Macrolide Solution Pressurised Metered Dose Inhaler

Publisher: Springer Science and Business Media LLC

Date: 24-12-2014

DOI: 10.1007/S11095-014-1605-Y

Abstract: The aim of this study was to assess the effects of low-dose clarithromycin, formulated as solution pressurized metered dose inhaler, following deposition on the Calu-3 respiratory epithelial cells. Clarithromycin was deposited on the air-interface culture of Calu-3 cells using a modified Andersen cascade impactor. Transport of fluorescein-Na, production of mucus and interleukin-8 release from Calu-3 cells following stimulation with transforming growth factor-β and treatment with clarithromycin was investigated. The deposition of clarithromycin had significant effect on the permeability of fluorescein-Na, suggesting that the barrier integrity was improved following a short-term treatment with clarithromycin (apparent permeability values were reduced to 3.57 × 10(-9) ± 2.32 × 10(-9) cm.s(-1), compared to 1.14 × 10(-8) ± 4.30 × 10(-8) cm.s(-1) for control). Furthermore, the amount of mucus produced was significantly reduced during the course of clarithromycin treatment. The concentration of interleukin-8 secreted from Calu-3 cells following stimulation with transforming growth factor-β resulted in significantly lower level of interleukin-8 released from the cells pre-treated with clarithromycin (5.2 ± 0.5 ng.ml(-1) clarithromycin treated vs. 7.7 ± 0.8 ng.ml(-1) control, respectively). Our data demonstrate that treatment with clarithromycin decreases the paracellular permeability of epithelial cells, mucus secretion and interleukin-8 release and therefore, inhaled clarithromycin holds potential as an anti-inflammatory therapy.

Inhalation and Nasal Products

Publisher: Wiley

Date: 11-01-2013

DOI: 10.1002/9781118397145.CH2

Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 2: Evaluation of in vitro release profiling methodologies for controlled release respir

Publisher: Elsevier BV

Date: 09-2008

DOI: 10.1016/J.EJPB.2008.04.009

Abstract: Three in vitro methodologies were evaluated as models for the analysis of drug release from controlled release (CR) microparticulates for inhalation. USP Apparatus 2 (dissolution model), USP Apparatus 4 (flow through model) and a modified Franz cell (diffusion model), were investigated using identical sink volumes and temperatures (1000 ml and 37 degrees C). Microparticulates containing DSCG and different percentages of PVA (0%, 30%, 50%, 70% and 90%) were used as model CR formulations. Evaluation of the release profiles of DSCG from the modified PVA formulations, suggested that all data fitted a Weibull distribution model with R2 > or =0.942. Statistical analysis of the t(d) (time for 63.2% drug release) indicated that all methodologies could distinguish between microparticles that did or did not contain PVA (Students t-test, p or =0.862 for the diffusion methodology data set). Due to the relatively low water content in the respiratory tract and the lack of differentiation between formulations for USP Apparatus 2 and 4, it is concluded that the diffusion model is more applicable for the evaluation of CR inhalation medicines.

Delivery of pDNA to lung epithelial cells using PLGA nanoparticles formulated with a cell-penetrating peptide

Publisher: Informa UK Limited

Date: 18-02-2020

DOI: 10.1080/03639045.2020.1724134

Formulation of Inhalation Medicines

Publisher: Wiley

Date: 11-01-2013

DOI: 10.1002/9781118397145.CH3

Inhalation Drug Delivery

Publisher: Wiley

Date: 11-01-2013

DOI: 10.1002/9781118397145.CH1

Recent advances in curcumin nanoformulation for cancer therapy

Publisher: Informa Healthcare

Date: 24-05-2014

DOI: 10.1517/17425247.2014.916686

Abstract: Natural compounds are emerging as effective agents for the treatment of malignant diseases. Curcumin (diferuloylmethane), the active constituent of turmeric extract, has gained significant interest as a plant-based compound with anti-cancer properties. Curcumin is physiologically very well tolerated, with negligible systemic toxicity observed even after high oral doses administration. Despite curcumin's superior properties as an anti-cancer agent its applications are limited due to its low solubility and physico-chemical stability, rapid systemic clearance and low cellular uptake. This review focuses on the development of curcumin nano-particle formulation to improve its therapeutic index through enhanced cellular uptake, localization to targeted areas and improved bioavailability. The feasibility of nano-formulation in delivering curcumin and the limitations and challenges in designing and administrating the nano-sized curcumin particles are also covered in this review. Nanotechnology is a promising tool to enhance efficacy and delivery of drugs. In this context, formulation of curcumin as nano-sized particles could reduce the required therapeutic dosages and subsequently reduced its cell toxicity. These nanoparticles are capable to provide local delivery of curcumin targeted to specific areas and thereby preventing systemic clearance. In addition, using specific coating, better pharmacokinetic and internalization of nano-curcumin could be achieved. However, the potential toxicity of nano-carriers for curcumin delivery is an important issue, which should be taken into account in curcumin nano-formulation.

Image-based ciliary beating frequency estimation for therapeutic assessment on defective mucociliary clearance diseases

Publisher: IEEE

Date: 04-2014

DOI: 10.1109/ISBI.2014.6867842

Thermoresponsive and Injectable Hydrogel for Tissue Agnostic Regeneration

Publisher: Wiley

Date: 17-10-2022

DOI: 10.1002/ADHM.202201714

Abstract: Injectable hydrogels can support the body's innate healing capability by providing a temporary matrix for host cell ingrowth and neovascularization. The clinical adoption of current injectable systems remains low due to their cumbersome preparation requirements, device malfunction, product dislodgment during administration, and uncontrolled biological responses at the treatment site. To address these challenges, a fully synthetic and ready‐to‐use injectable biomaterial is engineered that forms an adhesive hydrogel that remains at the administration site regardless of defect anatomy. The product elicits a negligible local inflammatory response and fully resorbs into nontoxic components with minimal impact on internal organs. Preclinical animal studies confirm that the engineered hydrogel upregulates the regeneration of both soft and hard tissues by providing a temporary matrix to support host cell ingrowth and neovascularization. In a pilot clinical trial, the engineered hydrogel is successfully administered to a socket site post tooth extraction and forms adhesive hydrogel that stabilizes blood clot and supports soft and hard tissue regeneration. Accordingly, this injectable hydrogel exhibits high therapeutic potential and can be adopted to address multiple unmet needs in different clinical settings.

Salbutamol Sulfate Absorption Across Calu-3 Bronchial Epithelia Cell Monolayer is Inhibited in the Presence of Common Anionic NSAIDs

Publisher: Informa UK Limited

Date: 18-03-2013

DOI: 10.3109/02770903.2013.773518

Abstract: The aim of this study was to characterize the permeability kinetics of salbutamol sulfate, a commonly used β2-agonist in the treatment of asthma exacerbation, across Calu-3 respiratory epithelial cell monolayers in the presence of non-steroidal anti-inflammatory drugs (NSAIDs), as they have been implicated to be able to modulate organic cation transporters (OCTs). Calu-3 cell monolayers were grown in a liquid covered culture (LCC) configuration on 0.33 cm(2) Transwell polyester cell culture supports. Monolayers, cultured between 11 and 14 days were evaluated for epithelial resistance, tight junction integrity, and expression of OCT using Western blot analysis. The transport of salbutamol across the monolayer was studied as a function of concentration. Directional transport was investigated by assessing apical-basal (a-b) and basal-apical (b-a) directions. The influence of a non-specific OCT inhibitor (tetraethylammonium, TEA) and three NSAIDs (aspirin, ibuprofen, and indomethacin) on the uptake of salbutamol was studied. The flux of salbutamol sulfate increased with increasing concentration before reaching a plateau, suggesting the involvement of a transport-mediated uptake mechanism. Western blot analysis detected the presence of OCT1-3 and N1 and N2 sub-types, suggesting the presence of functioning transporters. The apparent permeability (P(app)) of 0.1 mM salbutamol across the epithelial monolayer displayed directional transport in the a-b direction which was inhibited by ˜70% in the presence of TEA, suggesting OCT-mediated uptake. Likewise, the uptake of 0.1 mM salbutamol was decreased in the presence of all the three NSAIDs, supporting a mechanism whereby NSAIDs inhibit absorption of salbutamol across the bronchial epithelium via effects on the OCT transporters. This study demonstrates that NSAIDs influence the uptake kinetics of salbutamol in an in vitro Calu-3 cell system.

The future of inhalers: how can we improve drug delivery in asthma and COPD?

Publisher: Informa UK Limited

Date: 29-08-2016

DOI: 10.1080/17476348.2016.1227246

Unique location but similar issues

Publisher: Wiley

Date: 09-2015

DOI: 10.1002/JPPR.1110

Challenges and current advances in in vitro biofilm characterization

Publisher: Wiley

Date: 31-07-2023

DOI: 10.1002/BIOT.202300074

Abstract: Biofilms are structured communities of bacterial cells encased in a self‐produced polymeric matrix, which develop over time and exhibit temporal responses to stimuli from internal biological processes or external environmental changes. They can be detrimental, threatening public health and causing economic loss, while they also play beneficial roles in ecosystem health, biotechnology processes, and industrial settings. Biofilms express extreme heterogeneity in their physical properties and structural composition, resulting in critical challenges in understanding them comprehensively. The lack of detailed knowledge of biofilms and their phenotypes has deterred significant progress in developing strategies to control their negative impacts and take advantage of their beneficial applications. A range of in vitro models and characterization tools have been developed and used to study biofilm growth and, specifically, to investigate the impact of environmental and growth factors on their development. This review article discusses the existing knowledge of biofilm properties and explains how external factors, such as flow condition, surface, interface, and host factor, may impact biofilm growth. The limitations of current tools, techniques, and in vitro models that are currently used for biofilms are also presented.

Preparation and Evaluation of Single and Co-Engineered Combination Inhalation Carrier Formulations for the Treatment of Asthma

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1002/JPS.23304

Development and in vitro-in vivo performances of an inhalable indole-3-carboxaldehyde dry powder to target pulmonary inflammation and infection

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/J.IJPHARM.2021.121004

5‐alpha‐reductase inhibitors are associated with reduced frequency of COVID‐19 symptoms in males with androgenetic alopecia

Publisher: Wiley

Date: 22-11-2020

DOI: 10.1111/JDV.17021

Design, Synthesis, Characterization, and In Vitro Evaluation of a New Cross-Linked Hyaluronic Acid for Pharmaceutical and Cosmetic Applications

Publisher: MDPI AG

Date: 13-10-2021

DOI: 10.3390/PHARMACEUTICS13101672

Abstract: Hyaluronic acid (HA), an excellent biomaterial with unique bio properties, is currently one of the most interesting polymers for many biomedical and cosmetic applications. However, several of its potential benefits are limited as it is rapidly degraded by hyaluronidase enzymes. To improve the half-life and consequently increase performance, native HA has been modified through cross-linking reactions with a natural and biocompatible amino acid, Ornithine, to overcome the potential toxicity commonly associated with traditional linkers. 2-chloro-dimethoxy-1,3,5-triazine/4-methylmorpholine (CDMT/NMM) was used as an activating agent. The new product (HA–Orn) was extensively characterized to confirm the chemical modification, and rheological analysis showed a gel-like profile. In vitro degradation experiments showed an improved resistance profile against enzymatic digestions. Furthermore, in vitro cytotoxicity studies were performed on lung cell lines (Calu-3 and H441), which showed no cytotoxicity.

Nasal Powder Formulation of Tranexamic Acid and Hyaluronic Acid for the Treatment of Epistaxis

Publisher: Springer Science and Business Media LLC

Date: 04-09-2020

DOI: 10.1007/S11095-020-02913-W

Comparative study of erythritol and lactose monohydrate as carriers for inhalation: Atomic force microscopy and in vitro correlation

Publisher: Elsevier BV

Date: 02-2006

DOI: 10.1016/J.EJPS.2005.10.005

Abstract: The adhesion of micronised salbutamol sulphate to two carrier excipients, lactose monohydrate and erythritol, was investigated using the atomic force microscope (AFM) colloid probe technique and correlated with their respective physico-mechanical properties and aerosolisation performance. The particle size, morphology and moisture sorption properties of the carriers were similar thereby allowing direct comparison of functionality. AFM force measurements (n = 1024 force curves) were obtained between salbutamol sulphate drug probes (n = 4) and the excipients, as 63-90 microm sieve fractions and atomically smooth crystals. In general, significant differences in drug adhesion to lactose monohydrate and erythritol were observed (ANOVA, p<0.05), with erythritol exhibiting relatively greater adhesiveness. A linear relationship between drug probe adhesion to lactose monohydrate and drug probe adhesion to erythritol was established with salbutamol sulphate-lactose monohydrate adhesion being 60-70% of that of the erythritol system. In vitro analysis suggested good correlation with the adhesion measurements. The aerosolisation of salbutamol sulphate from erythritol carrier particles was significantly less (ANOVA, p<0.05) than from lactose monohydrate, with a fine particle dose (<6.4 microm) of 41.9 +/- 7.4 microg and 24.9 +/- 3.1 microg for the lactose monohydrate and erythritol carriers, respectively (n = 3).

Novel Simvastatin Inhalation Formulation and Characterisation

Publisher: Springer Science and Business Media LLC

Date: 08-05-2014

DOI: 10.1208/S12249-014-0127-6

The influence of lactose pseudopolymorphic form on salbutamol sulfate-lactose interactions in DPI formulations

Publisher: Informa UK Limited

Date: 2008

DOI: 10.1080/03639040802154889

Abstract: A series of 63- to 90-microm sieve-fractioned lactose pseudopolymorphs were investigated in terms of carrier functionality for dry powder inhaler (DPI) formulations. Stable alpha-anhydrous, alpha-monohydrate, and beta-anhydrous were chosen as model pseudopolymorphs. In addition, the beta-anhydrous was further purified to remove residual alpha-monohydrate content (beta-treated). The carriers were investigated in terms of morphology, particle size, crystallinity, and surface energy using inverse gas chromatography. Furthermore, the lactose s les carrier performance was evaluated by studying the aerosolization efficiency of the model drug, micronized salbutamol sulfate, from drug-carrier blends using a next generation impactor (NGI). In general, the aerosol performance of drug from carrier followed the rank order alpha-monohydrate > beta-anhydrous > beta-treated > alpha-anhydrous. Significant difference in carrier size was observed, specifically with relation to the amount of fines (where a rank order of beta-treated > beta-anhydrous > alpha-monohydrate > alpha-anhydrous. No direct relationship between fine content and particle morphology was observed. In comparison, an inverse relationship between surface energy and aerosolization efficiency was found, where a plot of fine particle fraction (aerodynamic diameter < 4.46 microm) against total surface energy resulted in R(2) = .977. Such observations are most likely due to increased particle carrier adhesion and reduced drug liberation during the aerosolization process, indicating surface chemistry (in this case due to the existence of different pseudopolymorphs) to play a dominating role in DPI systems.

Incorporation of quercetin in respirable lipid microparticles: Effect on stability and cellular uptake on A549 pulmonary alveolar epithelial cells

Publisher: Elsevier BV

Date: 12-2013

DOI: 10.1016/J.COLSURFB.2013.07.067

Abstract: The aim of the present study was to develop controlled release inhalable lipid microparticles (LMs) loaded with the antioxidant flavonoid, quercetin and to investigate the interaction of these microparticles with A549 pulmonary alveolar epithelial cells. The LMs were produced using different lipidic materials and surfactants, by melt emulsification followed by a sonication step. The most efficient modulation of the in vitro release of quercetin was achieved by the LMs prepared with tristearin and hydrogenated phosphatidylcholine, which were used for subsequent studies. These LMs exhibited a quercetin loading of 11.8±0.3%, and a volume median diameter, determined by laser diffraction, of 4.1±0.2μm. Moreover, their mass median aerodynamic diameter (4.82±0.15μm) and fine particle fraction (27.2±3.9%), as measured by multi-stage liquid impinger, were suitable for pulmonary delivery. Quercetin was found to be highly unstable (complete decomposition within 6-h incubation) in Ham's F-12 medium used for A549 cell culture. Degradation was markedly reduced (16.4% of the initial quercetin content still present after 24-h incubation) after encapsulation in the lipid particle system. Viability studies performed by lactate dehydrogenase assay, demonstrated that quercetin LMs showed no significant cytotoxicity on the A549 cells, over the concentration 0.1-5μM. The uptake of quercetin by the A549 lung alveolar cells was also investigated. After 4-h incubation, the accumulation of quercetin in the A549 cells was significantly higher (2.3-fold increase) for the microparticle entrapped flavonoid when compare to non-encapsulated quercetin. The enhanced intracellular delivery of quercetin achieved by the LMs is likely due to the flavonoid stabilization after encapsulation.

Solid lipid budesonide microparticles for controlled release inhalation therapy

Publisher: Springer Science and Business Media LLC

Date: 12-11-2009

DOI: 10.1208/S12248-009-9148-6

Properties of rapamycin solid lipid nanoparticles for lymphatic access through the lungs & part I: the effect of size.

Publisher: Future Medicine Ltd

Date: 08-2020

DOI: 10.2217/NNM-2020-0077

Abstract: Background: Lymphangioleiomyomatosis (LAM) is characterized by growth of smooth muscle-like cells in the lungs that spread to other organs via lymphatic vessels. Current oral rapamycin treatment is limited by low bioavailability of approximately 15%. Aim: The effect of inhaled rapamycin solid lipid nanoparticles (Rapa-SLNs) size on its penetration through the lymphatics. Method: Three Rapa-SLN formulations (200–1000 nm) were produced and assessed for particle characteristics and further for toxicity and performance in vitro. Results: Rapa-SLNs of 200 nm inhibited proliferation in TSC2-negative mouse embryonic fibroblast cells and penetrated the respiratory epithelium and lymphatic endothelium significantly faster compared with free rapamycin and larger Rapa-SLNs. Conclusion: Rapa-SLN approximately 200 nm allows efficient entry of rapamycin into the lymphatic system and is therefore a promising treatment for LAM patients.

The use of computational approaches in inhaler development

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.ADDR.2011.10.004

Abstract: Computational Fluid Dynamics (CFD) and Discrete Element Modelling (DEM) studies relevant to inhaled drug delivery are reviewed. CFD is widely used in device design to determine airflow patterns and turbulence levels. CFD is also used to simulate particles and droplets, which are subjected to various forces, turbulence and wall interactions. These studies can now be performed routinely because of the availability of commercial software containing high quality turbulence and particle models. DEM allows for the modelling of agglomerate break-up upon interaction with a wall or due to shear in the flow. However, the computational cost is high and the number of particles that can be simulated is minimal compared with the number present in typical inhaled formulations. Therefore DEM is currently limited to fundamental studies of break-up mechanisms. With decreasing computational limitations, simulations combining CFD and DEM that can address outstanding issues in agglomerate break-up and dispersion will be possible.

Properties of rapamycin solid lipid nanoparticles for lymphatic access through the lungs

Publisher: Future Medicine Ltd

Date: 08-2020

DOI: 10.2217/NNM-2020-0192

Abstract: Aim: Lymphangioleiomyomatosis is characterized by smooth muscle-like cells in the lungs that spread to other organs via lymphatic vessels. Oral rapamycin is restricted by low bioavailability approximately 15%. The aim of the present study is to systematically investigate the effect of inhaled rapamycin solid lipid nanoparticles (Rapa-SLN) surface charge on efficacy and penetration into the lymphatics. Materials & methods: Rapa-SLN formulations with different charge: neutral, positive and negative, were produced and assessed for their physicochemical particle characteristics and efficacy in vitro. Results: Negative Rapa-SLNs were significantly faster at entering the lymphatic endothelium and more potent at inhibiting lymphanigiogenesis compared with neutral and positive Rapa-SLNs. Conclusion: Negative Rapa-SLNs showed efficient lymphatic access and should therefore be investigated further as a treatment for targeting extrapulmonary lymphangioleiomyomatosis.

Temporally and Spatially Resolved x-ray Fluorescence Measurements of in-situ Drug Concentration in Metered-Dose Inhaler Sprays

Publisher: Springer Science and Business Media LLC

Date: 12-11-2016

DOI: 10.1007/S11095-015-1828-6

Abstract: Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution. In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 [Formula: see text] / [Formula: see text] IPBr. Instantaneous concentration measurements were obtained with 1 ms temporal resolution and 5 [Formula: see text] spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo. Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.

Inhaled rapamycin solid lipid nano particles for the treatment of Lymphangioleiomyomatosis

Publisher: Elsevier BV

Date: 2020

DOI: 10.1016/J.EJPS.2019.105098

Abstract: Lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by uncontrolled growth of smooth muscle -like cells in the lungs that can spread via the lymphatic system to other parts of the body. The current treatment for LAM, oral rapamycin, is limited by its low oral bioavailability and side effects. This study aims to develop an inhaled formulation of rapamycin solid lipid nanoparticles (Rapa-SLNs) to avoid first-pass metabolism, increase invivo half-life and facilitate entry into the lymphatic system through the lungs. Rapa-SLNs were manufactured using a hot evaporation technique and freeze-dried overnight with 5% (w/v) mannitol and before being assessed further for particle characteristics and in vitro aerosol performance and release. The formulation's ability to penetrate through bronchial epithelial layer was evaluated using a Calu-3 cell model, while its ability to interfere with the LAM intracellular cascade was evaluated using Mouse Embryonic fibroblast (MEF) cells deficient for the tuberous sclerosis complex 2 (TSC2) and compared with rapamycin solution. Results showed that the Rapa- SLNs had the appropriate size (237.5 ± 1.8 nm), charge (-11.2), in vitro aerosol performance (MMAD=5.4 ± 0.4 μm) and sustained release profile suitable for entry into the lymphatic system via the pulmonary route. Additionally, the nanoparticles were transported at a faster rate across the bronchial epithelial layer compared to free rapamycin solution. The formulation also showed similar mTOR (mammalian target of Rapamycin) inhibition properties compared to free rapamycin, and was able to significantly decrease the amount of proliferation in TSC2 negative MEF cells. This formulation is therefore a promising alternative treatment for LAM patients, as it could potentially reduce problems associated with low bioavailability and side effects of current oral treatment.

Inhaled gene delivery: a formulation and delivery approach

Publisher: Informa UK Limited

Date: 05-08-2017

DOI: 10.1080/17425247.2016.1214569

Abstract: Gene therapy is a potential alternative to treat a number of diseases. Different hurdles are associated with aerosol gene delivery due to the susceptibility of plasmid DNA (pDNA) structure to be degraded during the aerosolization process. Different strategies have been investigated in order to protect and efficiently deliver pDNA to the lungs using non-viral vectors. To date, no successful therapy involving non-viral vectors has been marketed, highlighting the need for further investigation in this field. Areas covered: This review is focused on the formulation and delivery of DNA to the lungs, using non-viral vectors. Aerosol gene formulations are ided according to the current delivery systems for the lung: nebulizers, dry powder inhalers and pressurized metered dose inhalers highlighting its benefits, challenges and potential application. Expert opinion: Successful aerosol delivery is achieved when the supercoiled DNA structure is protected during aerosolization. A formulation strategy or compounds that can protect, stabilize and efficiently transfect DNA into the cells is desired in order to produce an effective, low-cost and safe formulation. Nebulizers and dry powder inhalers are the most promising approaches to be used for aerosol delivery, due to the lower shear forces involved. In this context it is also important to highlight the importance of considering the 'pDNA-formulation-device system' as an integral part of the formulation development for a successful nucleic acid delivery.

Real-time in-situ electrochemical monitoring of Pseudomonas aeruginosa biofilms grown on air-liquid interface and its antibiotic susceptibility using a novel dual-chamber microfluidic device

Publisher: Wiley

Date: 05-12-2023

DOI: 10.1002/BIT.28288

Abstract: Biofilms are communities of bacterial cells encased in a self‐produced polymeric matrix that exhibit high tolerance toward environmental stress. Despite the plethora of research on biofilms, most P. aeruginosa biofilm models are cultured on a solid–liquid interface, and the longitudinal growth characteristics of P. aeruginosa biofilm are unclear. This study demonstrates the real‐time and noninvasive monitoring of biofilm growth using a novel dual‐chamber microfluidic device integrated with electrochemical detection capabilities to monitor pyocyanin (PYO). The growth of P. aeruginosa biofilms on the air–liquid interface (ALI) was monitored over 48 h, and its antibiotic susceptibility to 6 h exposure of 50, 400, and 1600 µg/ml of ciprofloxacin solutions was analyzed. The biofilm was treated directly on its surface and indirectly from the substratum by delivering the CIP solution to the top or bottom chamber of the microfluidic device. Results showed that P. aeruginosa biofilm developed on ALI produces PYO continuously, with the PYO production rate varying longitudinally and peak production observed between 24 and 30 h. In addition, this current study shows that the amount of PYO produced by the ALI biofilm is proportional to its viable cell numbers, which has not been previously demonstrated. Biofilm treated with ciprofloxacin solution above 400 µg/ml showed significant PYO reduction, with biofilms being killed more effectively when treatment was applied to their surfaces. The electrochemical measurement results have been verified with colony‐forming unit count results, and the strong correlation between the PYO electrical signal and the viable cell number highlights the usefulness of this approach for fast and low‐cost ALI biofilm study and antimicrobial tests.

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research

Publisher: MDPI AG

Date: 05-08-2021

DOI: 10.3390/BIOENGINEERING8080110

Abstract: The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.

High-Speed Laser Image Analysis of Plume Angles for Pressurised Metered Dose Inhalers: The Effect of Nozzle Geometry

Publisher: Springer Science and Business Media LLC

Date: 17-06-2016

DOI: 10.1208/S12249-016-0564-5

Abstract: The aim of this study is to investigate aerosol plume geometries of pressurised metered dose inhalers (pMDIs) using a high-speed laser image system with different actuator nozzle materials and designs. Actuators made from aluminium, PET and PTFE were manufactured with four different nozzle designs: cone, flat, curved cone and curved flat. Plume angles and spans generated using the designed actuator nozzles with four solution-based pMDI formulations were imaged using Oxford Lasers EnVision system and analysed using EnVision Patternate software. Reduced plume angles for all actuator materials and nozzle designs were observed with pMDI formulations containing drug with high co-solvent concentration (ethanol) due to the reduced vapour pressure. Significantly higher plume angles were observed with the PTFE flat nozzle across all formulations, which could be a result of the nozzle geometry and material's hydrophobicity. The plume geometry of pMDI aerosols can be influenced by the vapour pressure of the formulation, nozzle geometries and actuator material physiochemical properties.

Knowing Pedagogical Praxis in Twenty-First Century Education

Publisher: Springer Singapore

Date: 2018

DOI: 10.1007/978-981-13-2053-8_10

Spatial reorganization of F-actin in respiratory cells as measured by Brillouin microscopy

Publisher: SPIE

Date: 11-08-2023

DOI: 10.1117/12.2672413

Co-spray dried resveratrol and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/J.EJPS.2016.02.018

Abstract: Oxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroid responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratios of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages. This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages.

The use of fatty acids as absorption enhancer for pulmonary drug delivery

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.IJPHARM.2018.02.027

Abstract: A limitation in the systemic uptake of many inhalable drugs is the restricted permeation through the pulmonary epithelial layer barrier. One strategy to bypass the epithelial layer when delivering non-permeable drugs is to alter the paracellular transport, allowing the uptake of drugs into the systemic circulation. In this study, the potential of sodium decanoate (Na dec), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as absorption enhancers has been investigated to increase pulmonary paracellular permeability by modulating epithelial cells' tight junctions. By incorporating Na dec, DHA and EPA, separately, into a nebulising formulation, the aim was to enhance the absorption of a fluorescent marker (flu-Na, used as model drug) across pulmonary epithelial cells (Calu-3). Results indicate that the aerosol performance of all the nebulizing formulations containing absorption enhancers was significantly better than control. Furthermore, the in vitro cell assays demonstrated a significant increase in paracellular transport of the fluorescent marker with Na dec and DHA formulations. This finding supports the potential use ofDHA and Na dec to enhance epithelial transport of poorly permeable drugs delivered via inhalation.

The nanoscale in pulmonary delivery. Part 2: formulation platforms

Publisher: Informa Healthcare

Date: 31-10-2007

DOI: 10.1517/17425247.4.6.607

Abstract: This article is the second part of a review on the nanoscale in pulmonary drug delivery. Specifically it summarises and analyses the potential of the different inhalation delivery routes: nebulisers, dry powder inhalers, pressurised metered-dose inhalers, for the delivery of nanoparticles or nanodroplets. Few products and experimental studies have managed to fully exploit the nanoscale in inhalation delivery, although some may unknowingly benefit from it. Nebulisers are the most advanced in using the nanoscale, pressurised metered-dose inhalers require further developments to realise its full potential, and dry powder inhalers are specifically in need of a dry solid nanoparticle generation technique to make it a reality.

A novel dry powder inhalable formulation incorporating three first-line anti-tubercular antibiotics

Publisher: Elsevier BV

Date: 02-2012

DOI: 10.1016/J.EJPB.2012.08.007

Abstract: Treatment for tuberculosis (TB) using the standard oral antibiotic regimen is effective but inefficient, requiring high drug dosing and lengthy treatment times. Three concurrent first-line antibiotics recommended by the World Health Organization (WHO) guidelines are pyrazinamide, rif icin and isoniazid. Combining these antibiotics in a novel formulation for dry powder inhalation (DPI) may facilitate rapid and efficient resolution of local and systemic infection. However, spray-dried in idually, these antibiotics were found to be physically unstable. A solution of the three antibiotics, at the WHO-recommended ratio, was spray-dried. The collected powder was assessed by a series of in vitro methods to investigate aerosol performance, particle physico-chemical characteristics and dissolution profile. Particles obtained were spherical with a surface composed primarily of rif icin, as identified by TOF-SIMS. A mass median aerodynamic diameter of 3.5 ± 0.1 μm and fine particle fraction (<5 μm) of 45 ± 3% indicated excellent aerosol performance. The combination powder was differentiated by the presence of rif icin dihydrate and the delta polymorph of pyrazinamide. Quantitative analysis indicated in idual particles contained the three antibiotics at the expected proportions (400:150:75 w/w). This excipient-free triple antibiotic DPI formulation could be used as a significant enhanced treatment for TB.

Racial variations in COVID‐19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti‐androgens a potential treatment for COVID‐19?

Publisher: Wiley

Date: 14-06-2020

DOI: 10.1111/JOCD.13455

Investigation into the Manufacture and Properties of Inhalable High-Dose Dry Powders Produced by Comilling API and Lactose with Magnesium Stearate

Publisher: Springer Science and Business Media LLC

Date: 09-01-2017

DOI: 10.1208/S12249-016-0708-7

Abstract: The aim of the study was to understand the impact of different concentrations of the additive material, magnesium stearate (MGST), and the active pharmaceutical ingredient (API), respectively, on the physicochemical properties and aerosol performance of comilled formulations for high-dose delivery. Initially, blends of API/lactose with different concentrations of MGST (1-7.5% w/w) were prepared and comilled by the jet-mill apparatus. The optimal concentration of MGST in comilled formulations was investigated, specifically for agglomerate structure and strength, particle size, uniformity of content, surface coverage, and aerosol performance. Secondly, comilled formulations with different API (1-40% w/w) concentrations were prepared and similarly analyzed. Comilled 5% MGST (w/w) formulation resulted in a significant improvement in in vitro aerosol performance due to the reduction in agglomerate size and strength compared to the formulation comilled without MGST. Higher concentrations of MGST (7.5% w/w) led to reduction in aerosol performance likely due to excessive surface coverage of the micronized particles by MGST, which led to failure in uniformity of content and an increase in agglomerate strength and size. Generally, comilled formulations with higher concentrations of API increased the agglomerate strength and size, which subsequently caused a reduction in aerosol performance. High-dose delivery was achieved at API concentration of >20% (w/w). The study provided a platform for the investigation of aerosol performance and physicochemical properties of other API and additive materials in comilled formulations for the emerging field of high-dose delivery by dry powder inhalation.

The use of AFM and surface energy measurements to investigate drug-canister material interactions in a model pressurized metered dose inhaler formulation

Publisher: Informa UK Limited

Date: 04-2006

DOI: 10.1080/02786820500543316

Oral minoxidil bio‐activation by hair follicle outer root sheath cell sulfotransferase enzymes predicts clinical efficacy in female pattern hair loss

Publisher: Wiley

Date: 11-09-2019

DOI: 10.1111/JDV.15891

Particle aerosolisation and break-up in dry powder inhalers 1: Evaluation and modelling of venturi effects for agglomerated systems

Publisher: Springer Science and Business Media LLC

Date: 06-04-2010

DOI: 10.1007/S11095-010-0128-4

Abstract: This study utilized a combination of computational fluid dynamics (CFD) and standardized entrainment tubes to investigate the influence of turbulence on the break-up and aerosol performance of a model inhalation formulation. Agglomerates (642.8 mum mean diameter) containing 3.91 mum median diameter primary spherical mannitol particles were prepared by spheronisation. A series of entrainment tubes with different Venturi sections were constructed in silico, and the flow pattern and turbulence/impaction parameters were predicted using CFD. The entrainment models were constructed from the in silico model using three-dimensional printing. The aerosol performance of the mannitol was assessed by entraining the agglomerates into the experimental tubes at a series of flow rates and assessing the size distribution downstream of the venturi via in-line laser diffraction. A series of parameters (including Reynolds number (Re), turbulence kinetic energy, turbulence eddy frequency, turbulence length-scale, velocity and pressure drop) were calculated from the CFD simulation. The venturi diameter and volumetric flow rate were varied systematically. The particle size data of the agglomerated powders were then correlated with the CFD measurements. No correlation between turbulence and aerosol performance could be made (i.e. at a Reynolds number of 8,570, the d(0.1) was 52.5 mum +/- 19.7 mum, yet at a Reynolds number of 12,000, the d(0.1) was 429.1 mum +/- 14.8 mum). Lagrangian particle tracking indicated an increase in the number of impactions and the normal velocity component at the wall, with increased volumetric airflow and reduced venturi diameter. Chemical analysis of the mannitol deposited on the walls showed a linear relationship with respect to the theoretical number of impactions (R(2) = 0.9620). Analysis of the relationship between the CFD results and the experimental size data indicated a critical impact velocity was required to initiate agglomerate break-up ( approximately 0.4 m.s(-1)). While this study focussed on the effect of turbulence on agglomerate break-up, the small amount of impaction, which inevitably occurs in the venturi assembly, appeared to dominate agglomerate break-up in this dry powder system.

Murine pharmacokinetics of rifapentine delivered as an inhalable dry powder

Publisher: Elsevier BV

Date: 03-2015

DOI: 10.1016/J.IJANTIMICAG.2014.11.009

Abstract: A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue s les were collected and drug levels were quantified at time points up to 24h. Concentration-time data were analysed using a mixed-effects modelling approach to provide model-based estimates of area under the concentration-time curve from time 0 to infinity (AUC0-∞). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0-∞ compared with IP delivery. The plasma AUC0-∞ following IT dry powder delivery was ca. four-fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity.

Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 28-10-2020

DOI: 10.1124/JPET.120.000281

Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography

Publisher: Springer Science and Business Media LLC

Date: 17-02-2016

DOI: 10.1007/S11095-016-1869-5

Abstract: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques. We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays. Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 μm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow. Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.

Preparation andin vitroevaluation of salbutamol-loaded lipid microparticles for sustained release pulmonary therapy

Publisher: Informa UK Limited

Date: 30-12-2011

DOI: 10.3109/02652048.2011.646326

Abstract: The aim of this study was to prepare lipid microparticles (LMs) loaded with the polar bronchodilator agent salbutamol, and designed for sustained release pulmonary delivery. The microparticles were produced by melt emulsification followed by a sonication step, using different biocompatible lipid carriers (tristearin, stearic acid and glyceryl behenate) and phosphatidylcholine as the surfactant. The use of salbutamol free base, rather than salbutamol sulphate, was necessary to obtain the incorporation of the drug in the lipid particle matrix. The prolonged release of salbutamol base was achieved only by the glyceryl behenate microparticles (40.9% of encapsulated drug being released after 8 h). The salbutamol loading was 4.2% ± 0.1 and the mass median diameter, determined by laser diffraction, ranged from 4.8 to 5.4 µm. The sustained release of LMs were formulated as a carrier-free dry powder for inhalation and exhibited a fine particle fraction of 17.3% ± 2.2, as measured by multi-stage liquid impinger.

In vitro characterization of physico-chemical properties, cytotoxicity, bioactivity of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate nasal powder formulation

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.IJPHARM.2019.01.012

Abstract: An innovative lyophilized dry powder formulation consisting of urea-crosslinked hyaluronic acid (HA-CL) and sodium ascorbyl phosphate (SAP) - LYO HA-CL - SAP- was prepared and characterized in vitro for physico-chemical and biological properties. The aim was to understand if LYO HA-CL - SAP could be used as adjuvant treatment for nasal inflammatory diseases. LYO HA-CL - SAP was suitable for nasal delivery and showed to be not toxic on human nasal septum carcinoma-derived cells (RPMI 2650 cells) at the investigated concentrations. It displayed porous, polygonal particles with unimodal, narrow size distribution, mean geometric diameter of 328.3 ± 27.5 µm, that is appropriate for nasal deposition with no respirable fraction and 88.7% of particles with aerodynamic diameter >14.1 µm. Additionally, the formulation showed wound healing ability on RPMI 2650 cells, and reduced interleukin-8 (IL-8) level in primary nasal epithelial cells pre-induced with lipopolysaccharide (LPS). Transport study across RPMI 2650 cells showed that HA-CL could act not only as carrier for SAP and active ingredient itself, but potentially also as mucoadhesive agent. In conclusion, these results suggest that HA-CL and SAP had anti-inflammatory activity and acted in combination to accelerate wound healing. Therefore, LYO HA-CL - SAP could be a potential adjuvant in nasal anti-inflammatory formulations.

Cospray dried antibiotics for dry powder lung delivery

Publisher: Elsevier BV

Date: 08-2008

DOI: 10.1002/JPS.21239

Nanotoxicologic effects of PLGA nanoparticles formulated with a cell-penetrating peptide

Publisher: MDPI AG

Date: 03-01-2019

DOI: 10.3390/PHARMACEUTICS11010012

Abstract: The use of cell-penetrating peptides (CPPs) in combination with nanoparticles (NPs) shows great potential for intracellular delivery of DNA. Currently, its application is limited due to the potential toxicity and unknown long-term side effects. In this study NPs prepared using a biodegradable polymer, poly(lactic–co–glycolic acid (PLGA) in association with a CPP, was assessed on two lung epithelial cell lines (adenocarcinomic human alveolar basal epithelial cells (A549) and normal bronchial epithelial cells (Beas-2B cells)). Addition of CPP was essential for intracellular internalization. No effects were observed on the mitochondrial activity and membrane integrity. Cells exposed to the NPs–DNA–CPP showed low inflammatory response, low levels of apoptosis and no activation of caspase-3. Increase in necrotic cells (between 10%–15%) after 24 h of incubation and increase in autophagy, induced by NPs–DNA–CPP, are likely to be related to the lysosomal escape mechanism. Although oxidative stress is one of the main toxic mechanisms of NPs, NPs–DNA–CPP showed decreased reactive oxygen species (ROS) production on Beas-2B cells, with potential antioxidant effect of CPP and no effect on A549 cells. This NP system appears to be safe for intracellular delivery of plasmid DNA to the lung epithelial cells. Further investigations should be conducted in other lung-related systems to better understand its potential effects on the lungs.

An in vitro model for assessing drug transport in cystic fibrosis treatment: Characterisation of the CuFi-1 cell line

Publisher: Elsevier BV

Date: 11-2020

DOI: 10.1016/J.EJPB.2020.09.002

Effect of continuous positive airway pressure treatment on permeability, inflammation and mucus production of human epithelial cells

Publisher: European Respiratory Society (ERS)

Date: 04-2020

DOI: 10.1183/23120541.00327-2019

Abstract: Continuous positive airway pressure (CPAP) therapy is the gold standard treatment for obstructive sleep apnoea, which affects millions of people worldwide. However, this therapy normally results in symptoms such as dryness, sneezing, rhinorrhoea, post-nasal drip, nasal congestion and epistaxis in the upper airways. Using bronchial epithelial (Calu-3) and nasal epithelial (RPMI 2650) cells in an in vitro respiratory model, this study, for the first time, investigates the effect of CPAP positive pressure on the human respiratory epithelial mechanisms that regulate upper airways lubrication characteristics. To understand how the epithelium and mucus are affected by this therapy, several parameters were determined before and after positive pressure application. This work demonstrates that the positive pressure not only compresses the cells, but also reduces their permeability and mucus secretion rate, thus drying the airway surface liquid layer and altering the mucus/water ratio. It is also observed that the respiratory epithelia is equally inflamed without or with external humidification during CPAP application. These findings clearly identify the causes of the side-effects reported by patients under CPAP therapy.

Is there a role for inhaled anti-inflammatory drugs in cystic fibrosis treatment?

Publisher: Informa UK Limited

Date: 28-11-2018

DOI: 10.1080/21678707.2018.1409110

The formulation of a pressurized metered dose inhaler containing theophylline for inhalation

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1016/J.EJPS.2015.04.016

Abstract: Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP. Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells. The mass deposition profile of the formulation showed an emitted dose of 250.04±14.48μg per 5 actuations, achieving the designed nominal dose (50μg/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-α (TNF-α) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92±0.77ng·ml(-1) TP treated vs. 8.83±2.05ng·ml(-1) TNF-α stimulated, respectively). The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.

Revealing pMDI Spray Initial Conditions

Publisher: Springer Science and Business Media LLC

Date: 17-01-2017

DOI: 10.1007/S11095-017-2098-2

Abstract: Sprays from pressurised metered-dose inhalers are produced by a transient discharge of a multiphase mixture. Small length and short time scales have made the investigation of the governing processes difficult. Consequently, a deep understanding of the physical processes that govern atomisation and drug particle formation has been elusive. X-ray phase contrast imaging and quantitative radiography were used to reveal the internal flow structure and measure the time-variant nozzle exit mass density of 50 µL metered sprays of HFA134a, with and without ethanol cosolvent. Internal flow patterns were imaged at a magnification of 194 pixels/mm and 7759 frames per second with 150 ps temporal resolution. Spray projected mass was measured with temporal resolution of 1 ms and spatial resolution 6 µm × 5 µm. The flow upstream of the nozzle comprised large volumes of vapour at all times throughout the injection. The inclusion of ethanol prevented bubble coalescence, altering the internal flow structure and discharge. Radiography measurements confirmed that the nozzle exit area is dominantly occupied by vapour, with a peak liquid volume fraction of 13%. Vapour generation in pMDIs occurs upstream of the sump, and the dominant volume component in the nozzle exit orifice is vapour at all times in the injection. The flow in ethanol-containing pMDIs has a bubbly structure resulting in a comparatively stable discharge, whereas the binary structure of propellant-only flows results in unsteady discharge and the production of unrespirable liquid masses.

The Effect of Active Pharmaceutical Ingredients on Aerosol Electrostatic Charges from Pressurized Metered Dose Inhalers

Publisher: Springer Science and Business Media LLC

Date: 19-03-2015

DOI: 10.1007/S11095-015-1674-6

Abstract: This study investigated the effect of different active pharmaceutical ingredients (API) on aerosol electrostatic charges and aerosol performances for pressurized metered dose inhalers (pMDIs), using both insulating and conducting actuators. Five solution-based pMDIs containing different API ingredients including: beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FS), salbutamol base (SB) and ipratropium bromide (IPBr) were prepared using pressure filling technique. Actuator blocks made from nylon, polytetrafluoroethylene (PTFE) and aluminium were manufactured with 0.3 mm nominal orifice diameter and cone nozzle shape. Aerosol electrostatics for each pMDI formulation and actuator were evaluated using the electrical low-pressure impactor (ELPI) and drug depositions were analysed using high performance liquid chromatography (HPLC). All three actuator materials showed the same net charge trend across the five active drug ingredients, with BDP, BUD and FS showing positive net charges for both nylon and PTFE actuators, respectively. While SB and IPBr had significantly negative net charges across the three different actuators, which correlates to the ionic functional groups present on the drug molecule structures. The API present in a pMDI has a dominant effect on the electrostatic properties of the formulation, overcoming the charge effect arising from the actuator materials. Results have shown that the electrostatic charges for a solution-based pMDI could be related to the interactions of the chemical ingredients and change in the work function for the overall formulation.

Development of an Inhaled Controlled Release Voriconazole Dry Powder Formulation for the Treatment of Respiratory Fungal Infection

Publisher: American Chemical Society (ACS)

Date: 07-05-2015

DOI: 10.1021/MP500808T

Abstract: The present research aimed to develop and characterize a sustained release dry powder inhalable formulation of voriconazole (VRZ) for invasive pulmonary aspergillosis. The developed formulations were studied for their in vitro release profile, aerosol, and physicochemical properties as well as interactions with lung epithelia in terms of toxicity and transport/uptake. VRZ and VRZ loaded poly lactide microparticles (VLM) were prepared by aqueous/organic cosolvent and organic spray drying, respectively. Powders were characterized using laser diffraction, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS), and electron microscopy. Aerosol performance was evaluated using an RS01 dry powder inhaler and in vitro cascade impaction. Uptake across Calu-3 lung epithelia was studied, using aerosol deposition of the powder onto cells cultured in an air interface configuration, and compared to dissolution using a conventional dialysis membrane. Additionally, toxicity of VRZ and VLM and the potential impact of transmembrane proteins on uptake were investigated. The particle size and the aerosol performance of spray-dried VRZ and VLM were suitable for inhalation purposes. VRZ exhibited a median volume diameter of 4.52 ± 0.07 μm while VLM exhibited 2.40 ± 0.05 μm. Spray-dried VRZ was crystalline and VLM amorphous as evaluated by DSC and XRPD, and both powders exhibited low moisture sorption between 0 and 90% RH (<1.2% w/w) by DVS. The fine particle fraction (FPF) (% aerosol <5 μm) for the VRZ was 20.86 ± 1.98% while the VLM showed significantly improved performance (p < 0.01) with an FPF of 43.56 ± 0.13%. Both VRZ and VLM were not cytotoxic over a VRZ concentration range of 1.2 nM to 30 μM, and the VLM particles exhibited a sustained release over 48 h after being deposited on the Calu-3 cell line or via conventional dialysis-based dissolution measurements. Lastly, VRZ exhibited polarized transport across epithelia with basal to apical transport being slower than apical to basal. Influx and efflux transports may also play a role as transport was altered in the presence of a number of inhibitors. This study has established an inhalable and sustained release powder of VRZ for targeting invasive pulmonary aspergillosis.

Inhaled simvastatin nanoparticles for inflammatory lung disease

Publisher: Future Medicine Ltd

Date: 10-2017

DOI: 10.2217/NNM-2017-0188

Abstract: Aim: Current inhaled treatments are not adequate to treat all lung diseases. In this study, a promising nanotechnology has been developed to deliver a potential anti-inflammatory and muco-inhibitory compound, simvastatin, for treatment of inflammatory lung diseases via inhalation. Materials & methods: Simvastatin nanoparticles (SV-NPs) encapsulated with poly(lactic-co-glycolic) acid were fabricated using the solvent and anti-solvent precipitation method. Results: SV-NPs were found to be stable up to 9 months at 4°C in a freeze-dried form prior to reconstitution. The amount of mucus produced was significantly reduced after SV-NPs treatment on inflammation epithelial cell models and were effective in suppressing the proinflammatory marker expression. Conclusion: This study suggests that SV-NPs nebulization could potentially be used for the treatment of chronic pulmonary diseases.

Development of excipients free inhalable co-spray-dried tobramycin and diclofenac formulations for cystic fibrosis using two and three fluid nozzles

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.IJPHARM.2022.121989

Abstract: This study aims to investigate the effect of physicochemical properties and aerosol performance of two (2FN) and three-fluid nozzles (3FN) on the inhalable co-formulation of tobramycin and diclofenac dry powders. Combination formulations of tobramycin and diclofenac at 2:1 and 4:1 w/w ratios were prepared at a laboratory scale using a spray dryer in conjunction with a 2FN or 3FN. Powder size, morphology, solid-state characteristics, and aerodynamic and dissolution properties were characterised. The nozzle types and the formulation composition influenced the yield, particle size, solid-state properties, aerosolization behaviour and dissolution of the co-spray dried formulations. In particular, using the 2FN the co-spray dried formulation of tobramycin and diclofenac at 2:1 w/w showed smaller particle size (D50, 3.01 ± 0.06 μm), high fine particle fractions (FPF) (61.1 ± 3.6% for tobramycin and 65.92 ± 3 for diclofenac) and faster dissolution with approx. 70% diclofenac released within 3 h and approx. 90% tobramycin was released within 45 min. However, the 3FN for the co-spray dried formulation of tobramycin and diclofenac at a 2:1 w/w ratio showed a larger particle size (D50, 3.42 ± 0.02 μm), lower FPF (40.6 ± 3.4% for tobramycin and 36.9 ± 0.84 for diclofenac) and comparative slower dissolution with approx. 60% diclofenac was released within 3 h and 80% tobramycin was released within 45 min. A similar trend was observed when the tobramycin to diclofenac ratio was increased to 4:1 w/w. Overall results suggest that spray drying with 2FN showed a superior and viable approach to producing excipients-free inhalable co-spray dried formulations of tobramycin and diclofenac. However, the formulation produced using the 3FN showed higher enrichment of hydrophobic diclofenac and an ability to control the tobramycin drug release in vitro.

Minoxidil 1 mg oral versus minoxidil 5% topical solution for the treatment of female-pattern hair loss: A randomized clinical trial

Publisher: Elsevier BV

Date: 2020

DOI: 10.1016/J.JAAD.2019.08.060

The use of organic vapor sorption to determine low levels of amorphous content in processed pharmaceutical powders

Publisher: Informa UK Limited

Date: 2007

DOI: 10.1080/03639040600969991

Abstract: Organic dynamic vapor sorption (organic-DVS) was used to characterize amorphous content in known amorphous-crystalline mixtures of lactose and salbutamol sulfate. N-octane was chosen as an apolar probe and measurements were carried out by exposing mixtures of each s le to partial pressures 0-90% p (0). A linear relationship between amorphous content and n-octane partial pressure was observed for both lactose and salbutamol sulfate with R(2) values of 0.992 and 0.999, respectively. In addition, the influence of sequential mechanical processing in a ball mill on the amorphous content in crystalline lactose was investigated. Cumulative milling times resulted in an exponential increase in amorphous content (using the linear relationship obtained for lactose), with a maximum amorphous content of 14% being induced after 60 min milling. In comparison, analysis of the 60 min mill time s les after exposure to 85% relative humidity suggested 0.00% amorphous content.

Substitute and add-on devices used in inhalation therapy

Publisher: Bentham Science Publishers Ltd.

Date: 18-10-2016

DOI: 10.2174/2210303106666160506151721

Impact of amino acids on the properties of nasal dry powders

Publisher: Elsevier BV

Date: 09-2023

DOI: 10.1016/J.JDDST.2023.104848

Repurposing of statins via inhalation to treat lung inflammatory conditions

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.ADDR.2018.06.005

Abstract: Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy.

The influence of mechanical processing of dry powder inhaler carriers on drug aerosolization performance

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1002/JPS.20933

Role of agglomeration in the dispersion of salmeterol xinafoate from mixtures for inhalation with differing drug to fine lactose ratios

Publisher: Elsevier BV

Date: 08-2008

DOI: 10.1002/JPS.21228

The Development and Achievement of Polymeric Nanoparticles for Cancer Drug Treatment

Publisher: Springer Singapore

Date: 2017

DOI: 10.1007/978-981-10-3647-7_2

Assessing Aerosol Performance of a Dry Powder Carrier Formulation with Increasing Doses Using a Novel Inhaler

Publisher: Springer Science and Business Media LLC

Date: 28-01-2019

DOI: 10.1208/S12249-019-1302-6

Abstract: This study aims to investigate the implications of loaded formulation mass on aerosol performance using a reservoir novel dry powder inhaler containing a custom dosing cup to deliver carrier-based formulation to the lungs. A 3D printed dosing cup with volume size of 133.04 mm

Bronchial epithelial cell extracellular vesicles ameliorate epithelial–mesenchymal transition in COPD pathogenesis by alleviating M2 macrophage polarization

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.NANO.2019.03.010

Abstract: Chronic obstructive pulmonary disease (COPD) is partly characterized as epithelial-mesenchymal transition (EMT)-related airflow limitation. Extracellular vesicles (EVs) play crucial roles in the crosstalk between cells, affecting many diseases including COPD. Up to now, the roles of EVs in COPD are still debated. As we found in this investigation, COPD patients have higher miR-21 level in total serum EVs. EMT occurs in lungs of COPD mice. Furthermore, bronchial epithelial cells (BEAS-2B) could generate EVs with less miR-21 when treated with cigarette smoke extract (CSE), impacting less on the M2-directed macrophage polarization than the control-EVs (PBS-treated) according to EVs miR-21 level. Furthermore, the EMT processes in BEAS-2B cells were enhanced with the M2 macrophages proportion when co-cultured. Collectively, these results demonstrate that CSE-treated BEAS-2B cells could alleviate M2 macrophages polarization by modulated EVs, and eventually relieve the EMT process of BEAS-2B cells themselves under COPD pathogenesis, revealing a novel compensatory role of them in COPD.

Co-deposition of a triple therapy drug formulation for the treatment of chronic obstructive pulmonary disease using solution-based pressurised metered dose inhalers

Publisher: Oxford University Press (OUP)

Date: 27-10-2012

DOI: 10.1111/J.2042-7158.2011.01370.X

Abstract: The formulation of multi-drug pressurised metered dose inhalers (pMDIs) opens up exciting therapeutic opportunities for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We have investigated the formulation of a solution-based triple therapy pMDI containing ipratropium, formoterol, budesonide and ethanol as co-solvent. This system was characterised for in-vitro performance and compared with marketed pMDIs (Atrovent and Symbicort). No significant difference was found in the stage deposition of each drug from the triple therapy formulation, suggesting that the droplets contained a fixed ratio of the three components used. Stage deposition of formoterol and budesonide from the suspension-based marketed Symbicort were significantly different, suggesting that the two drugs were deposited as separate entities. Calculation of the mass median aerodynamic diameter (MMAD) of each formulation suggested Atrovent (ipratropium, MMAD = 0.9 ± 0.0 µm) to have a small particle size, similar to the triple therapy formulation. Atrovent, like the triple therapy formulation was solution based and it contained ethanol as a co-solvent (triple therapy formulation, MMAD = 1.3 ± 0.0 µm). This study demonstrated the feasibility of formulating a solution-based pMDI containing a triple therapy with identical deposition pattern for the treatment of several respiratory diseases where multi-drug cell targeting is required.

The effect of ethanol on the formation and physico-chemical properties of particles generated from budesonide solution-based pressurized metered-dose inhalers

Publisher: Informa UK Limited

Date: 02-10-2013

DOI: 10.3109/03639045.2012.728230

Abstract: The aerosol performance of budesonide solution-based pressurized metered-dose inhalers (HFA 134a), with various amounts of ethanol (5-30%, w/w) as co-solvents, was evaluated using impaction and laser diffraction techniques. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter was increased and the fine particle fraction showed a significant decline. Although data obtained from laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology - the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from 52% to 2.5% approximately, when the ethanol concentration was increased from 5% to 30%, respectively. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.

Solid lipid microparticles as an approach to drug delivery

Publisher: Informa Healthcare

Date: 13-11-2015

DOI: 10.1517/17425247.2015.980812

Abstract: Solid lipid particles were introduced in the early 1990s as an alternative drug carrier system to emulsions, liposomes and polymeric microparticles. Although lipid nanoparticles have been the object of a substantial number of reviews, fewer are available on lipid microparticles (LMs), despite their distinct advantages, including biocompatibility, ease of production and characterisation, extended release properties and high loading. This review presents an overview of the advantages and drawbacks of LMs, that is, lipid-based particles with dimensions in the micrometre range. Specific focus is on the role of the main excipients used for LM formulations, lipids and surfactants and their effects on LM properties. An update on preparation techniques and characterisation methods are also presented, with particular emphasis on more recent technologies. The interaction of LMs with biological systems and with cells in particular is reviewed. The various LM administration routes are examined, with special attention to most recent applications (i.e., pulmonary and nasal delivery). LMs represent attractive and versatile carrier systems however, their pharmaceutical applicability has been rather limited. Investigation on the use of LMs for less-established administration routes, such as pulmonary delivery, may provide further interest within the area of LM-based systems, both in industry and in the clinic.

The development of a 3D-printed in vitro integrated oro-pharyngeal air–liquid interface cellular throat model for drug transport

Publisher: Springer Science and Business Media LLC

Date: 14-02-2023

DOI: 10.1007/S13346-023-01302-1

Prospective nanoparticle treatments for lymphangioleiomyomatosis

Publisher: Informa UK Limited

Date: 02-01-2022

DOI: 10.1080/17425247.2022.2029401

Abstract: Lymphangioleiomyomatosis (LAM) is a rare lung disease that is characterized by smooth muscle-like cell growth in the lungs. The current available oral treatment rapamycin slows down the disease progression but does not result in a cure. Rapamycin is also limited by its low bioavailability and dose-related adverse side effects. New treatments are, therefore, underway to investigate alternative targets and combination therapies for LAM. In recent years, much focus has been on the development of therapies based on inhaled nanotechnology using carriers to deliver drugs, as it is shown to improve drug solubility, local targeted treatment, and bioavailability. This review, therefore, focuses on future prospective treatments for LAM using nanoparticles and lipid-based nanocarriers, including liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. It also investigates how nanoparticles' physicochemical factors such as size and charge can affect the treatment of both pulmonary and extrapulmonary LAM. Advanced clinical research is still needed to demonstrate the full potential and drive future commercialization of LAM treatments delivered via inhaled lipid nanobased formulations. If successful, the resultant effects will be seen in the improvement in the life expectancy and life quality of LAM patients.

Particle aerosolisation and break-up in dry powder inhalers: Evaluation and modelling of the influence of grid structures for agglomerated systems

Publisher: Elsevier BV

Date: 11-2011

DOI: 10.1002/JPS.22663

Effect of moisture on the compressibility and compactibility of sodium starch glycolate

Publisher: No publisher found

Date: 2007

DOI: 10.1080/10837450601168797

Abstract: The relationship between the apparent moisture content and compactibility of sodium starch glycolate was compared to similarly obtained data for pregelatinized starch. S les of sodium starch glycolate (SSG) and pregelatinised starch (PGS) were stored at 44% or 75% relative humidity (RH), producing s les exhibiting moisture contents of up to 14% w/w, as determined by loss on drying (LOD). Increasing the moisture content of SSG and PGS resulted in an increase in compressibility and compactibility for both materials. However, the effect was more dramatic for SSG with unlubricated compactibilities of 2.0 MPa and 0.9 MPa at approximately 11.5% LOD for SSG and PGS, respectively, which was further exemplified in the compactibility of lubricated materials and in blends with microcrystalline cellulose. These results suggested that moisture content had a greater effect on the compactibility of SSG compared with PGS and that the interactions of water with the components of the SSG starch granules may be different from those within the PGS starch granules at comparable LOD values.

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Publisher: MDPI AG

Date: 22-02-2022

DOI: 10.3390/IJMS23052408

Abstract: Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.

Brain targeting of resveratrol by nasal administration of chitosan-coated lipid microparticles

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.EJPB.2018.02.010

Abstract: Lipid microparticles (LMs) uncoated or coated with chitosan and containing the neuroprotective polyphenol resveratrol were developed for its targeting to the brain via nasal administration. The lipid microparticles loaded with resveratrol (LMs-Res) were produced by melt emulsification, using stearic acid as lipid material and phosphatidylcholine as the surfactant. The chitosan coated particles LMs-Res-Ch (1.75% w/v chitosan solution) and LMs-Res-Ch-plus (8.75% w/v chitosan solution) were prepared by adding a chitosan solution to the formed particles. The mean diameter of the particles were 68.5 ± 3.1 μm, 76.3 ± 5.2 μm and 84.5 ± 8.1 μm for LMs-Res, LMs-Res-Ch and LMs-Res-Ch-plus respectively, suitable for nasal delivery. Chitosan coating changed the particle surface charge from a negative zeta potential value (-12.7 ± 2.1 mV) for the uncoated particles to a higher positive values respectively, 24.0 ± 4.7 and 44.6 ± 3.1 mV for the chitosan coated LM-Res-Ch and LM-Res-Ch-plus. Permeation studies across human NCM460 cell monolayers demonstrated that their transepithelial electrical resistance (TEER) values were not modified in the presence of free resveratrol, unloaded LMs, loaded LMs-Res or LMs-Res-Ch. On the other hand, the TEER values decreased from 150 ± 7 to 41 ± 3 Ω cm

A novel high-speed imaging technique to predict the macroscopic spray characteristics of solution based pressurised metered dose inhalers

Publisher: Springer Science and Business Media LLC

Date: 17-06-2014

DOI: 10.1007/S11095-014-1391-6

Abstract: Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient's inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing. Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imaging is used to extract time-resolved velocity, penetration and spreading angle measurements of the pMDI spray plume. The experimental data are used to validate the analytical model. The pMDI spray develops in a manner characteristic of a fully-developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol-containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiologically relevant co-flow rates. Using the proposed model, the mean leading edge penetration, velocity and spreading rate of a pMDI spray may be estimated a priori for any co-flow conditions. The effects of different formulations are captured in two scaling constants. This allows formulators to predict the effects of variation between pMDIs without the need for repeated testing. Ultimately, this approach will allow pharmaceutical scientists to rapidly test a number of variables during pMDI development.

The role of direct support professionals in asthma management

Publisher: Informa UK Limited

Date: 12-05-2015

DOI: 10.3109/13668250.2015.1041100

Allergic environment enhances airway epithelial pro-inflammatory responses to rhinovirus infection

Publisher: Portland Press Ltd.

Date: 04-0003

DOI: 10.1042/CS20160939

Abstract: Airway epithelial cells (AEC) exhibit a pro-inflammatory phenotype in patients with allergic asthma. We examined the effect of an allergic cytokine environment on the response of AEC to rhinovirus (RV), the most common trigger of acute exacerbations of asthma. Calu-3 cells, a well-differentiated human AEC line, were cultured with or without the T-helper type 2 cytokines interleukin (IL)-4 and IL-13, then stimulated with a toll-like receptor (TLR) 3 agonist (poly I:C, dsRNA) or a TLR7 agonist (imiquimod), or infected with RV 16. Expression of pro-inflammatory and antiviral mediators, and of viral pattern-recognition molecules, was assessed using nCounter assays, quantitative real-time PCR (qRT-PCR) and protein immunoassays. Both dsRNA and imiquimod stimulated expression of mRNA for IL6 and IL8 whereas expression of several chemokines and antiviral response genes was induced only by dsRNA. Conversely, expression of other cytokines and growth factors was induced only by imiquimod. RV infection not only stimulated expression of the inflammation-related genes induced by dsRNA, but also of complement factor B and the novel pro-inflammatory cytokine IL-32. In the T helper type 2 (Th2) cytokine environment, several mediators exhibited significantly enhanced expression, whereas expression of interferons was either unchanged or enhanced. The allergic environment also increased expression of pattern-recognition receptors and of intercellular adhesion molecule 1, the cell surface receptor for RV. We conclude that Th2 cytokines promote increased production of pro-inflammatory mediators by AEC following infection with RV. Increased viral entry or enhanced signalling via pattern-recognition receptors could also contribute to the exaggerated inflammatory response to RV observed in allergic asthmatics.

Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis

Publisher: Informa UK Limited

Date: 09-05-2014

DOI: 10.3109/03639045.2014.909841

Abstract: A series of co-engineered macrolide-mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital(™) inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ: mannitol had 57.6% ± 7.6% delivery efficiency with a fine particle fraction (≤6.8 µm) of the emitted aerosol cloud being 80.4% ± 1.1%, with minimal throat deposition (5.3 ± 0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide-mannitol therapy may provide a means of treating bronchiectasis.

Fluticasone uptake across Calu-3 cells is mediated by salmeterol when deposited as a combination powder inhale

Publisher: Wiley

Date: 28-10-2013

DOI: 10.1111/RESP.12146

Abstract: We assessed whether co-deposition of a long-acting β2 -agonist and a corticosteroid affects their respective transport rates across epithelial cells. Drug particles were deposited on the air-interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations (Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 ± 0.20%) compared with the single fluticasone formulation (2.36 ± 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects.

Could simvastatin be considered as a potential therapy for chronic lung diseases? A debate on the pros and cons

Publisher: Informa UK Limited

Date: 06-06-2016

DOI: 10.1080/17425247.2016.1193150

Abstract: Simvastatin (SV) is a drug from the statin class, currently used orally as an anti-cholesterolemic drug. It inhibits the 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase to reduce cholesterol synthesis. Recently, it has been found that SV also has several other protective pharmacological actions unrelated to its anti-cholesterol effects that might be beneficial in the treatment of chronic airway diseases. This review summarizes the evidence relating to SV as a potential anti-inflammatory, anti-oxidant and muco-inhibitory agent, administered both orally and via pulmonary inhalation, and discusses its pro and cons. Evidence could potentially be used to support the delivery of SV as inhaled formulation for the treatment of chronic respiratory diseases. The use of SV as anti-inflammatory, anti-oxidant and muco-inhibitory agent for drug delivery to the lung is promising. Inhaled SV formulations could allow the delivery profile to be customized and optimized to take advantage of the rapid onset of action, low systemic side effect and improved physico-chemical stability. This treatment could potentially to be used clinically for the localized treatment of lung diseases where inflammation and oxidative stress production is present.

The Influence of Actuator Materials and Nozzle Designs on Electrostatic Charge of Pressurised Metered Dose Inhaler (pMDI) Formulations

Publisher: Springer Science and Business Media LLC

Date: 03-12-2013

DOI: 10.1007/S11095-013-1253-7

Abstract: To investigate the influence of different actuator materials and nozzle designs on the electrostatic charge properties of a series of solution metered dose inhaler (pMDI) aerosols. Actuators were manufactured with flat and cone nozzle designs using five different materials from the triboelectric series (Nylon, Polyethylene terephthalate, Polyethylene-High density, Polypropylene copolymer and Polytetrafluoroethylene). The electrostatic charge profiles of pMDI containing beclomethasone dipropionate (BDP) as model drug in HFA-134a propellant, with different concentrations of ethanol were studied. Electrostatic measurements were taken using a modified electrical low-pressure impactor (ELPI) and the deposited drug mass assayed chemically using HPLC. The charge profiles of HFA 134a alone have shown strong electronegativity with all actuator materials and nozzle designs, at an average of -1531.34 pC ± 377.34. The presence of co-solvent ethanol significantly reduced the negative charge magnitude. BDP reduced the suppressing effect of ethanol on the negative charging of the propellant. For all tested formulations, the flat nozzle design showed no significant differences in net charge between different actuator materials, whereas the charge profiles of cone designs followed the triboelectric series. The electrostatic charging profiles from a solution pMDI containing BDP and ethanol can be significantly influenced by the actuator material, nozzle design and formulation components. Ethanol concentration appears to have the most significant impact. Furthermore, BDP interactions with ethanol and HFA have an influence on the electrostatic charge of aerosols. By choosing different combinations of actuator materials and orifice design, the fine particle fractions of formulations can be altered.

Scanning white-light interferometry as a novel technique to quantify the surface roughness of micron-sized particles for inhalation

Publisher: American Chemical Society (ACS)

Date: 28-08-2008

DOI: 10.1021/LA8016062

Abstract: A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and alpha-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four s les of BSA) or decantation (two s les of lactose). Particle size distributions were characterized by laser diffraction, and particles were imaged by scanning electron microscopy (SEM). Surface roughness of the BSA and lactose particles was quantified by white-light optical profilometry using vertical scanning interferometry (VSI) at full resolution using a 50x objective lens with 2.0x and 0.5x fields of view for BSA and lactose, respectively. Data were analyzed using Vision software (version 32, WYKO), and surface roughness values are expressed as root-mean-square roughness ( Rrms). Furthermore, data were compared to topographical measurements made using conventional atomic force microscopy. Analysis of the optical profilometry data showed significant variation in BSA roughness ranging from 18.58 +/- 3.80 nm to 110.90 +/- 13.16 nm for the smoothest and roughest BSA particles, respectively, and from 81.20 +/- 15.90 nm to 229.20 +/- 68.20 nm for decanted and normal lactose, respectively. The Rrms values were in good agreement with the AFM-derived values. The particle morphology was similar to SEM and AFM images. In conclusion, scanning white-light interferometry provides a useful complementary tool for rapid evaluation of surface morphology and roughness in particles used for dry powder inhalation formulation.

Microfluidics assembly of inhalable liposomal ciprofloxacin characterised by an innovative in vitro pulmonary model

Publisher: Elsevier BV

Date: 03-2023

DOI: 10.1016/J.IJPHARM.2023.122667

Novel topical booster enhances follicular sulfotransferase activity in patients with androgenetic alopecia: a new strategy to improve minoxidil response

Publisher: Wiley

Date: 10-06-2020

DOI: 10.1111/JDV.16645

Agglomerate strength and dispersion of salmeterol xinafoate from powder mixtures for inhalation

Publisher: Springer Science and Business Media LLC

Date: 14-09-2006

DOI: 10.1007/S11095-006-9082-6

Abstract: The study investigated the role of agglomeration and the effect of fine lactose size on the dispersion of salmeterol xinafoate (SX) from SX-lactose mixtures for inhalation. Particle size distributions were characterised by Malvern Mastersizer S, Aerosizer and Spraytec, and imaging conducted by scanning electron microscopy (SEM). Inter-particulate adhesion was quantified by atomic force microscopy. Deposition of SX was measured using a twin stage impinger. SX was analysed using validated high-performance liquid chromatography method (r(2)=1.0, CV=0.4-1.0%). Addition of fine lactose with a volume median diameter (VMD) of 7.9 microm to a SX-lactose carrier and carrier-free mixture resulted in significantly better dispersion (16.8% for 20% added fine lactose) than fractions with VMD of 3.0, 17.7 and 33.3 microm (less than 9.1% for 20% fine lactose). Using the carrier-free mixtures, particle sizing of the aerosol cloud using the Spraytec, coupled with the application of the Aerosizer using differing dispersion energies and SEMs of the s les, indicated that an open packed, agglomerate structure improved SX dispersion. The highest extent of SX dispersion occurred when SX and fine lactose were detached from the surface, usually in the form of loose agglomerates. The outcomes of this research demonstrated how agglomerate structure influenced dispersion and the key role of fine lactose particle size in SX dispersion from mixtures for inhalation.

Lactose composite carriers for respiratory delivery

Publisher: Springer Science and Business Media LLC

Date: 18-11-2009

DOI: 10.1007/S11095-008-9779-9

Abstract: Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug-carrier adhesion, variability in drug-carrier forces and influence on drug aerosol performance from carrier-drug blends. Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 microm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63-90 microm carriers. The carriers were evaluated in terms of size (laser diffraction) morphology (electron microscopy and atomic force microscopy), crystallinity and drug adhesion (colloid probe microscopy). In addition, blends containing drug and carrier were prepared and evaluated in terms of drug aerosol performance. The surface morphology and physico-chemical properties of the composite carriers were significantly different. Depending on the initial primary lactose size, the composite particles could be prepared with different surface roughness. Variation in composite roughness could be related to the change in drug adhesion (via modification in contact geometry) and thus drug aerosol performance from drug-lactose blends. Composite based carriers are a potential route to control drug-carrier adhesion forces and variability thus allowing more precise control of formulation performance.

Knowledge that people with intellectual disabilities have of their inhaled asthma medications

Publisher: Springer Science and Business Media LLC

Date: 11-11-2016

DOI: 10.1007/S11096-015-0217-X

Abstract: Fifteen percent of Australians with intellectual disability (ID) are reported to have asthma. People with ID are at risk of poor health knowledge due to deficits in intellectual and adaptive functioning, but their medication knowledge has largely been ignored in research to date. To explore the level of understanding of asthma medication use of people with ID who self-administer their inhaled medications, in order to inform future educational support. Setting The research was conducted in NSW, Australia, at the participants' homes, the point of health care access, or the offices of relevant support organisations. In this qualitative study face-to-face interviews were conducted with people with ID using a semi-structured interview guide. The interviews were recorded, transcribed and thematically analysed. Main outcome Identification of barriers to asthma medication self-management by people with ID. Seventeen people with ID who self-administer their asthma medications were interviewed. Factors influencing their asthma medication knowledge and use included understanding of their illness and the need for medication aspects of self-management and autonomy versus dependence. This s le of people with ID had a good understanding of the importance of using their inhaled asthma medications, as well as asthma triggers, and the difference between use of preventer and reliever medications. Both enablers and barriers to asthma medication self-management were identified in the domains of managing attacks, adherence, knowledge of side effects and sources of information on correct use of inhalers. The level of autonomy for medication use varied, with motivation to self-manage asthma influenced by the level of support that was practically available to in idual participants. This research investigated aspects of asthma medication self-management of people with ID. Based on the barriers identified, pharmacists should promote use of spacers and written asthma action plans as well as counsel people with ID about how to recognise and minimise side effects of asthma medications. Specific strategies for pharmacists when educating people with ID and their caregivers include active listening to determine understanding of concepts, exercising care with language, and working with the person's known routines to maximise adherence with preventer medications.

Modelling of molecular phase transitions in pharmaceutical inhalation compounds: An in silico approach

Publisher: Elsevier BV

Date: 05-2011

DOI: 10.1016/J.EJPB.2010.12.019

Abstract: Molecular dynamic simulations have been successfully utilised with molecular modelling to estimate the glass transition temperature (T(g)) of polymers. In this paper, we use a similar approach to predict the T(g) of a small pharmaceutical molecule, beclomethasone dipropionate (BDP). Amorphous beclomethasone dipropionate was prepared by spray-drying. The amorphous nature of the spray-dried material was confirmed with scanning electron microscopy, differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). Molecular models for amorphous BDP were constructed using the amorphous cell module in Discovery studio™. These models were used in a series of molecular dynamic simulations to predict the glass transition temperature. The T(g) of BDP was determined by isothermal-isobaric molecular dynamic simulations, and different thermodynamic parameters were obtained in the temperature range of -150 to 400°C. The discontinuity at a specific temperature in the plot of temperature versus amorphous cell volume (V) and density (ρ) was considered to be the simulated T(g.) The predicted T(g) from four different simulation runs was 63.8°C ± 2.7°C. The thermal properties of amorphous BDP were experimentally determined by DSC and the experimental T(g) was found to be ∼ 65°C, in good agreement with computational simulations.

In-vitro and particle image velocimetry studies of dry powder inhalers

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.IJPHARM.2020.119966

Application of Micro-Engineered Kidney, Liver, and Respiratory System Models to Accelerate Preclinical Drug Testing and Development

Publisher: MDPI AG

Date: 02-04-2022

DOI: 10.3390/BIOENGINEERING9040150

Abstract: Developing novel drug formulations and progressing them to the clinical environment relies on preclinical in vitro studies and animal tests to evaluate efficacy and toxicity. However, these current techniques have failed to accurately predict the clinical success of new therapies with a high degree of certainty. The main reason for this failure is that conventional in vitro tissue models lack numerous physiological characteristics of human organs, such as biomechanical forces and biofluid flow. Moreover, animal models often fail to recapitulate the physiology, anatomy, and mechanisms of disease development in human. These shortfalls often lead to failure in drug development, with substantial time and money spent. To tackle this issue, organ-on-chip technology offers realistic in vitro human organ models that mimic the physiology of tissues, including biomechanical forces, stress, strain, cellular heterogeneity, and the interaction between multiple tissues and their simultaneous responses to a therapy. For the latter, complex networks of multiple-organ models are constructed together, known as multiple-organs-on-chip. Numerous studies have demonstrated successful application of organ-on-chips for drug testing, with results comparable to clinical outcomes. This review will summarize and critically evaluate these studies, with a focus on kidney, liver, and respiratory system-on-chip models, and will discuss their progress in their application as a preclinical drug-testing platform to determine in vitro drug toxicology, metabolism, and transport. Further, the advances in the design of these models for improving preclinical drug testing as well as the opportunities for future work will be discussed.

Pharmaceutical applications of the Calu-3 lung epithelia cell line.

Publisher: Informa UK Limited

Date: 04-06-2013

DOI: 10.1517/17425247.2013.805743

Abstract: The Calu-3 lung cell line has been shown to be a promising in vitro model of airway epithelia due to its similarity to in vivo physiology. Hence, over the past decade, it has found increasing applications in the pharmaceutical industry. This review focuses on the pharmaceutical applications of the Calu-3 cell line in areas such as mechanisms of drug transport, studying aerosol deposition, controlled release studies and identification of possible drug-drug interactions. The main findings of various studies, as well as the predictive potential of this model, are presented and discussed in this review. There is still a lack of mechanistic knowledge regarding transport of inhaled therapeutics across the lungs. Cell culture models such as Calu-3 provide a simple and reproducible system to study the underlying mechanisms by which inhaled therapeutics interact with the lungs. However, more complex systems that integrate particle deposition onto different cell culture systems may be useful in addressing some fundamental questions to generate a better understanding of determinants that influences pulmonary drug dissolution, absorption, metabolism and efficacy. Ultimately the use of the Calu-3 cell line provides a basic research tool that enables the development of safer and more effective inhaled therapeutics.

Determination of reference ultrasound parameters for model and hydrofluoroalkane propellants using high-resolution ultrasonic spectroscopy

Publisher: Springer Science and Business Media LLC

Date: 06-05-2008

DOI: 10.1208/S12249-008-9087-Z

Combining experimental and computational techniques to understand and improve dry powder inhalers

Publisher: Informa UK Limited

Date: 02-01-2022

DOI: 10.1080/17425247.2022.2026922

Abstract: Dry Powder Inhalers (DPIs) continue to be developed to deliver an expanding range of drugs to treat an ever-increasing range of medical conditions with each drug and device combination needing a specifically designed inhaler. Fast regulatory approval is essential to be first to market, ensuring commercial profitability. Experimental techniques and computational methods are improving rapidly, but each needs a skilled user to maximize results obtained from these techniques. Multidisciplinary teams are therefore key to making optimal use of these methods and such qualified teams can provide enormous benefits to pharmaceutical companies to improve device efficacy and thus time to market. There is already a move to integrate the benefits of Industry 4.0 into inhaler design and usage, a trend that will accelerate.

The influence of flow rate on the aerosol deposition profile and electrostatic charge of single and combination metered dose inhalers

Publisher: Springer Science and Business Media LLC

Date: 06-10-2009

DOI: 10.1007/S11095-009-9979-Y

Abstract: The capability of the electrostatic next generation impactor (eNGI) has been investigated as a tool capable of measuring the electrostatic charge of single (Flixotide containing fluticasone propionate (FP)) and combination (Seretide FP and salmeterol xinafoate (SX)) pressurised metered dose inhalers (pMDIs) at different flow rates. Aerosol mass distributions were investigated at 30, 60 and 90 l.min(-1) and simultaneous charge measurements recorded. Analysis of the mass distribution data indicated a flow dependent relationship, where the aerosol performance (aerodynamic diameter <5 mum) of FP significantly increased between 30 l.min(-1) and 60 l.min(-1) for both formulations. No significant increase in SX was observed for Seretide with increased flow rate. Analysis of the charge distribution indicated both formulations to primarily charge negatively with a concurrent increase in charge with increased flow rate. Interestingly, the charge-tomass ratio remained relatively constant between 30 l.min(-1) and 60 l.min(-1) and increased at 90 l.min(-1), indicating that charging was majorly influenced at the highest flow rate. This study has shown how the eNGI could be used as a simple Pharmacopeia based methodology for the evaluation of mass and charge profiles of single and combination pMDIs at a series of flow rates.

The solid-state and morphological characteristics of particles generated from solution-based metered dose inhalers: Influence of ethanol concentration and intrinsic drug properties

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1016/J.COLSURFA.2013.11.034

Primary Air–Liquid Interface Culture of Nasal Epithelium for Nasal Drug Delivery

Publisher: American Chemical Society (ACS)

Date: 09-06-2016

DOI: 10.1021/ACS.MOLPHARMACEUT.5B00852

Abstract: Nasal drug administration is a promising alternative to oral and parenteral administration for both local and systemic delivery of drugs. The benefits include its noninvasive nature, rapid absorption, and circumvention of first pass metabolism. Hence, the use of an in vitro model using human primary nasal epithelial cells could be key to understanding important functions and parameters of the respiratory epithelium. This model will enable investigators to address important and original research questions using a biologically relevant in vitro platform that mimics the in vivo nasal epithelial physiology. The purpose of this study was to establish, systematically characterize, and validate the use of a primary human nasal epithelium model cultured at the air-liquid interface for the study of inflammatory responses and drug transport and to simultaneously quantify drug effects on ciliary activity.

Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.EJPB.2013.02.020

Abstract: Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (∼1000ng or ∼2000ng of the formulation) or equivalent particle number (1000ng of BDP in the glycerol-containing versus 2000ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2h was faster when delivered in glycerol-free particles, 465.01ng±95.12ng of the total drug (20.99±4.29% BDP plus active metabolite) transported across the cell layer, compared to 116.17ng±3.07ng (6.07±0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.

Pulmonary delivery of curcumin and quercetin nanoparticles for lung cancer

Publisher: Elsevier BV

Date: 04-2023

DOI: 10.1016/J.JDDST.2023.104375

Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability.

Publisher: Informa Healthcare

Date: 26-11-2016

DOI: 10.1517/17425247.2016.1114603

Abstract: To develop and characterize a highly respirable dry powder inhalable formulation of voriconazole (VRZ). Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterized in terms of particle size, morphology, thermal, moisture responses and aerosolization performance. Optimized powder was deposited onto an air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimized formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimized formulation were evaluated. Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimized formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimizing systemic exposure and related toxicity. This study supports the potential of inhaled dry powder VRZ for the treatment of fungal infections.

Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics

Publisher: Elsevier BV

Date: 06-2008

DOI: 10.1016/J.EJPB.2007.12.019

Abstract: A series of co-spray dried microparticles containing di-sodium cromoglycate (DSCG) and polyvinyl alcohol (PVA - 0%, 30%, 50%, 70% and 90% w/w, respectively), were prepared as potential controlled release (CR) viscous/gelling vehicles for drug delivery to the respiratory tract. The microparticles were characterised in terms of particle size, crystal structure, density, surface morphology, moisture sorption, surface energy and in vitro aerosolisation efficiency. The co-spray dried particles were amorphous in nature and had spherical geometry. High-resolution atomic force microscopy analysis of the surfaces of the DSCG/PVA suggested no significant differences in roughness between microparticles containing 30-90% w/w PVA (ANOVA, p<0.05), while no specific trend in either size or density was observed with respect to PVA concentration. In comparison, a linear decrease in the relative moisture sorption (R2=0.997) and concurrent increase in total surface free energy (R2=0.870) were observed as PVA concentration was increased. Furthermore a linear increase in the aerosolisation efficiency, measured by inertial impaction, was observed as PVA concentration was increased (R2=0.993). In addition, the increase in aerosolisation efficiency showed good correlation with equilibrium moisture content (R2=0.974) and surface energy measurement (R2=0.905). These relationships can be attributed to the complex interplay of particle forces at the contiguous interfaces in this particulate system.

Co-milled API-lactose systems for inhalation therapy: impact of magnesium stearate on physico-chemical stability and aerosolization performance

Publisher: Informa UK Limited

Date: 09-02-2017

DOI: 10.1080/03639045.2017.1287719

Abstract: Particle micronization for inhalation can impart surface disorder (amorphism) of crystalline structures. This can lead to stability issues upon storage at elevated humidity from recrystallization of the amorphous state, which can subsequently affect the aerosol performance of the dry powder formulation. The aim of this study was to investigate the impact of an additive, magnesium stearate (MGST), on the stability and aerosol performance of co-milled active pharmaceutical ingredient (API) with lactose. Blends of API-lactose with/without MGST were prepared and co-milled by the jet-mill apparatus. S les were stored at 50% relative humidity (RH) and 75% RH for 1, 5, and 15 d. Analysis of changes in particle size, agglomerate structure/strength, moisture sorption, and aerosol performance were analyzed by laser diffraction, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), and in-vitro aerodynamic size assessment by impaction. Co-milled formulation with MGST (5% w/w) led to a reduction in agglomerate size and strength after storage at elevated humidity compared with co-milled formulation without MGST, as observed from SEM and laser diffraction. Hysteresis in the sorption/desorption isotherm was observed in the co-milled s le without MGST, which was likely due to the recrystallization of the amorphous regions of micronized lactose. Deterioration in aerosol performance after storage at elevated humidity was greater for the co-milled s les without MGST, compared with co-milled with MGST. MGST has been shown to have a significant impact on co-milled dry powder stability after storage at elevated humidity in terms of physico-chemical properties and aerosol performance.

The utility of 3D-printed airway stents to improve treatment strategies for central airway obstructions

Publisher: Informa UK Limited

Date: 25-09-2019

DOI: 10.1080/03639045.2018.1522325

Abstract: Airway stents are commonly used in the management of patients suffering from central airway obstruction (CAO). CAO may occur directly from airway strictures, obstructing airway cancers, airway fistulas or tracheobronchomalacia, resulting from the weakening and dynamic collapse of the airway wall. Current airway stents are constructed from biocompatible medical-grade silicone or from a nickel-titanium (nitinol) alloy with fixed geometry. The stents are inserted via the mouth during a bronchoscopic procedure. Existing stents have many shortcomings including the development of obstructing granulation tissue in the weeks and months following placement, mucous build up within the stent, and cough. Furthermore, airway stents are expensive and, if improperly sized for a given airway, may be easily dislodged (stent migration). Currently, in Australia, it is estimated that approximately 12,000 patients will develop CAO annually, many of whom will require airway stenting intervention. Of all stenting procedures, the rate of failure is currently reported to be at 22%. With a growing incidence of lung cancer prevalence globally, the need for updating airway stent technology is now greater than ever and personalizing stents using 3D-printing technology may offer the best chance of addressing many of the current limitations in stent design. This review article will assess what represents the gold standard in stent manufacture with regards to treatment of tracheobronchial CAO, the challenges of current airway stents, and outlines the necessity and challenges of incorporating 3D-printing technology into personalizing airway stents today.

An adaptable microreactor to investigate the influence of interfaces on Pseudomonas aeruginosa biofilm growth

Publisher: Springer Science and Business Media LLC

Date: 11-01-2022

DOI: 10.1007/S00253-021-11746-5

Abstract: Biofilms are ubiquitous and notoriously difficult to eradicate and control, complicating human infections and industrial and agricultural biofouling. However, most of the study had used the biofilm model that attached to solid surface and developed in liquid submerged environments which generally have neglected the impact of interfaces. In our study, a reusable dual-chamber microreactor with interchangeable porous membranes was developed to establish multiple growth interfaces for biofilm culture and test. Protocol for culturing Pseudomonas aeruginosa (PAO1) on the air–liquid interface (ALI) and liquid–liquid interface (LLI) under static environmental conditions for 48 h was optimized using this novel device. This study shows that LLI model biofilms are more susceptible to physical disruption compared to ALI model biofilm. SEM images revealed a unique “dome-shaped” microcolonies morphological feature, which is more distinct on ALI biofilms than LLI. Furthermore, the study showed that ALI and LLI biofilms produced a similar amount of extracellular polymeric substances (EPS). As differences in biofilm structure and properties may lead to different outcomes when using the same eradication approaches, the antimicrobial effect of an antibiotic, ciprofloxacin (CIP), was chosen to test the susceptibility of a 48-h-old P. aeruginosa biofilms grown on ALI and LLI. Our results show that the minimum biofilm eradication concentration (MBEC) of 6-h CIP exposure for ALI and LLI biofilms is significantly different, which are 400 μg/mL and 200 μg/mL, respectively. These results highlight the importance of growth interface when developing more targeted biofilm management strategies, and our novel device provides a promising tool that enables manipulation of realistic biofilm growth. • A novel dual-chamber microreactor device that enables the establishment of different interfaces for biofilm culture has been developed. • ALI model biofilms and LLI model biofilms show differences in resistance to physical disruption and antibiotic susceptibility.

Artesunate-clindamycin multi-kinetics and site-specific oral delivery system for antimalaric combination products

Publisher: Elsevier BV

Date: 08-2010

DOI: 10.1016/J.JCONREL.2010.05.001

Abstract: The aim of this work was to study a multi-kinetics and site-specific oral antimalaria drug delivery system (MKS_DDS), containing artesunate and clindamycin, based on the Dome Matrix module assembly technology. The MKS_DDS assembled system comprises of four modules, i.e., two controlled release (CR) modules for delivery of 160 mg of clindamycin phosphate, one immediate release module containing 50 mg of artesunate and one immediate release module containing 80 mg of clindamycin phosphate. These modules have been assembled in stacked and void configurations. The void configuration is able to float and showed gastro-retentive behavior. The MKS_DDS was investigated for its mechanical characteristics, system behavior during release, drug release rate and mechanism. A bioavailability study (dogs) showed that the clindamycin plasma curve of the MKS_DDS system exhibited a quasi constant release rate, up to 8 h. The MKS_DDS system containing clindamycin and artesunate allows the use of one tablet containing one immediate release dose of artesunate and of clindamycin and a portion of clindamycin released over a prolonged time, by exploiting the gastro-retentive properties of a floating system.

Drug delivery for tuberculosis: Is inhaled therapy the key to success?

Publisher: Future Science Ltd

Date: 10-2017

DOI: 10.4155/TDE-2017-0050

Combined inhaled salbutamol and mannitol therapy for mucus hyper-secretion in pulmonary diseases

Publisher: Springer Science and Business Media LLC

Date: 16-01-2014

DOI: 10.1208/S12248-014-9560-4

A review of co-milling techniques for the production of high dose dry powder inhaler formulation

Publisher: Informa UK Limited

Date: 19-04-2017

DOI: 10.1080/03639045.2017.1313858

Abstract: Drug delivery by inhalation offers several advantages compared to other dosage forms, including rapid clinical onset, high bioavailability, and minimal systemic side effects. Drug delivery to the lung can be achieved as liquid suspensions or solutions in nebulizers and pressurized metered-dose inhalers (pMDI), or as dry powders in dry powder inhalers (DPIs). Compared to other delivery systems, DPIs are, in many cases, considered the most convenient as they are breath actuated and do not require the use of propellants. Currently, the delivery of low drug doses for the treatment of lung conditions such as asthma and chronic obstructive pulmonary disease are well established, with numerous commercial products available on the market. The delivery of low doses can be achieved from either standard carrier- or aggregate-based formulations, which are unsuitable in the delivery of high doses due to particle segregation associated with carrier active site saturation and the cohesiveness of micronized aggregates which have poor flow and de-agglomeration properties. High-dose delivery is required for the treatment of lung infection (i.e. antibiotics) and in the emerging application of drug delivery for the management of systemic conditions (i.e. diabetes). Therefore, there is a demand for new methods for production of high-dose dry powder formulations. This paper presents a review of co-mill processing, for the production of high-efficiency inhalation therapies, including the jet mill, mechanofusion, or ball mill methodologies. We investigate the different techniques, additives, and drugs studied, and impact on performance in DPI systems.

Human Stimulus Factor Is a Promising Peptide for Delivery of Therapeutics.

Publisher: Elsevier BV

Date: 04-2019

DOI: 10.1016/J.XPHS.2018.11.017

Abstract: Fluticasone propionate uptake in the presence of a proprietary cell-penetrating peptide (human stimulus factor, [HSF]) based on the N-terminal domain of lactoferrin was studied, alone and in combination with salmeterol, using an air interface Calu-3 epithelial model. The HSF enhanced uptake and transport of fluticasone propionate across the epithelial barrier when alone and in presence of salmeterol. This was attributed to transcellular-mediated uptake. This HSF is a promising peptide for delivery of therapeutics where enhanced epithelial penetrating is required.

Cell-based therapies for the treatment of idiopathic pulmonary fibrosis (IPF) disease

Publisher: Informa UK Limited

Date: 15-12-2016

DOI: 10.1517/14712598.2016.1124085

Abstract: During the last few decades, cell-based therapies have shown great potential to treat patients with lung diseases. It has been proposed that the administration of cells into an injured lung could be considered as a therapeutic method to repair and replace lost lung tissue. Using this method, transplanted cells with the ability to proliferate and differentiate into alveolar cells, have been suggested as a therapeutic strategy for IPF treatment. In this review, the latest investigations using various types of cells for IPF therapy have been presented. The cells studied for cell-based therapies in IPF are lung alveolar epithelial cells, lung resident stem cells and exogenous adult stem cells such as MSCs. After many years of investigation, the use of cell-based therapies to treat IPF is still at the experimental phase. Problems include bioethical issues, safety of cell transplantation, routes of delivery and the dose and timing of administration. Further investigations are necessary to establish the best strategy for using cell-based therapies effectively for the treatment of IPF.

Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-vol

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.EJPB.2013.02.014

Abstract: A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4μm±0.1 and 2.5μm±0.2), fine particle dose (⩽5μm 66μg±6 and 68μg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.

Validation of a cell integrated next-generation impactor to assess in vitro drug transport of physiologically relevant aerosolised particles

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.IJPHARM.2022.122024

Abstract: The development of novel inhaled formulations in the pre-clinical stage has been impeded by a lack of meaningful information related to drug dissolution and transport at the lung epithelia due to the absence of physiologically relevant in vitro respiratory models. The objective of the present study was to develop an in vitro experimental model, which combined the next generation impactor (NGI) and two respiratory epithelial cell lines, for examining the aerodynamic performance of dry powder inhalers and the fate of aerosolised drugs following lung deposition. The NGI impaction plates of stage 3 (i.e., a cut-off diameter of 2.82-4.46 µm) and stage 7 (i.e., a cut-off diameter of 0.34-0.55 µm) were modified to accommodate 3 cell cultures inserts. Specifically, Calu-3 cells and H441 cells, which are representative of the bronchial and alveolar epithelia in the lung, respectively, were cultivated at the air-liquid interface on Snapwells

In vitro investigation of drug particulates interactions and aerosol performance of pressurised metered dose inhalers

Publisher: Springer Science and Business Media LLC

Date: 14-11-2007

DOI: 10.1007/S11095-006-9130-2

Abstract: To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations. Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI). The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation. It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.

Londrina State University (UEL)

Location: Brazil

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Macquarie University

Location: Australia

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São Paulo State University - UNESP

Location: Brazil

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University Of Sydney

Location: Australia

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Universita' Degli Studi Di Milano

Location: Italy

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University Of Bath

Location: United Kingdom of Great Britain and Northern Ireland

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Vectura Group Plc

Location: United Kingdom of Great Britain and Northern Ireland

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Monitoring Spa

Location: Italy

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Smartdrops - Shaping The Future Of Particle Technology

Start Date: 2015

End Date: 2017

Funder: Australian Research Council

Advanced Nanotechnologies For Targeting Biofilms

Start Date: 2016

End Date: 2019

Funder: Australian Research Council

The Fluid-Particle Mechanics Of A Synthetic Jet-based Dry Powder Inhaler.

Start Date: 2020

End Date: 2023

Funder: Australian Research Council

‘Breathing In A Cure’: Using The Lung As A Delivery Portal For Repurposed Drugs

Start Date: 2020

End Date: 2024

Funder: National Health and Medical Research Council

Smart Hybrid System For The Formulation And Design Of Dry Powder Inhalers

Start Date: 2018

End Date: 2020

Funder: Australian Research Council

National Live Cell Scanning Platform For Nanoparticle Tracking

Start Date: 2015

End Date: 2015

Funder: Australian Research Council

A Drug Delivery Platform For DNA Vaccines To The Lung

Start Date: 2014

End Date: 2017

Funder: Australian Research Council

Targeting Cystic Fibrosis Using A Novel Inhalation Therapy

Start Date: 2017

End Date: 2018

Funder: National Health and Medical Research Council

Engineering Of Co-crystal Drug Molecules For Pharmaceutical Aerosols

Start Date: 2008

End Date: 2010

Funder: Australian Research Council

Engineering A Delivery Device And Development Of A Novel Formulation For Chronic Obstructive Pulmonary Disease And Cystic Fibrosis

Start Date: 2007

End Date: 2010

Funder: Australian Research Council

State-of-the-art High Resolution Thermal Analysis Suite For The Life And Material Sciences

Start Date: 2007

End Date: 2007

Funder: Australian Research Council

Ultra-low Dose Dry Powder Inhaler Technology For The Treatment Of Respiratory Diseases

Start Date: 2012

End Date: 2015

Funder: Australian Research Council

Mannitol Powders For Assessment Of Asthma In Children

Start Date: 2007

End Date: 2008

Funder: Australian Research Council

A Multi-Resolution X-ray Microtomography Facility (NanoCT & MicroCT) For Non-Destructive 3D Characterisation

Start Date: 2009

End Date: 2009

Funder: Australian Research Council

Advanced Focused Ion Beam (FIB) / Scanning Electron Microscopes (SEM) For Nanometre Scale Characterisation And Fabrication

Start Date: 2010

End Date: 2010

Funder: Australian Research Council

Project LP130101123

Start Date: 2013

End Date: 2016

Funder: Australian Research Council

Integrated Vibrational Spectroscopic Mapping For Archeological, Biological, Geological, Materials, And Medical Research

Start Date: 2008

End Date: 2008

Funder: Australian Research Council

Cause And Effect: New Mechanisms Of Particles Formation In Thunderstorms

Start Date: 2019

End Date: 2021

Funder: Australian Research Council

A 5-D Correlative Imaging Platform: Combining The Strengths Of Light And Electron Microscopy

Start Date: 2010

End Date: 2010

Funder: Australian Research Council

Discovery Projects - Grant ID: DP190100376

Start Date: 02-2019

End Date: 12-2023

Amount: $550,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0775441

Start Date: 07-2007

End Date: 07-2009

Amount: $145,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP140100181

Start Date: 05-2015

End Date: 05-2018

Amount: $482,738.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP160100427

Start Date: 2017

End Date: 12-2019

Amount: $420,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP100100451

Start Date: 04-2011

End Date: 06-2015

Amount: $335,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100010

Start Date: 12-2010

End Date: 12-2010

Amount: $720,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP120100251

Start Date: 03-2012

End Date: 12-2015

Amount: $325,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP120103510

Start Date: 06-2012

End Date: 10-2015

Amount: $355,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP130101123

Start Date: 04-2014

End Date: 04-2017

Amount: $370,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0881708

Start Date: 06-2008

End Date: 12-2011

Amount: $300,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP100200156

Start Date: 05-2011

End Date: 05-2016

Amount: $290,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP170100551

Start Date: 06-2018

End Date: 05-2021

Amount: $555,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP120200744

Start Date: 06-2013

End Date: 12-2015

Amount: $340,000.00

Funder: Australian Research Council

ARC Future Fellowships - Grant ID: FT120100630

Start Date: 10-2012

End Date: 10-2016

Amount: $678,728.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0776892

Start Date: 04-2008

End Date: 11-2011

Amount: $333,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP190100917

Start Date: 04-2022

End Date: 03-2025

Amount: $752,366.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775720

Start Date: 06-2007

End Date: 06-2008

Amount: $100,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100030

Start Date: 06-2011

End Date: 09-2011

Amount: $1,200,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0883036

Start Date: 01-2008

End Date: 10-2008

Amount: $400,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP150100865

Start Date: 01-2015

End Date: 08-2018

Amount: $521,800.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989859

Start Date: 06-2009

End Date: 12-2010

Amount: $1,000,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100177

Start Date: 2015

End Date: 12-2015

Amount: $440,000.00

Funder: Australian Research Council