ORCID Profile
0000-0001-5401-7535
Current Organisation
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 05-03-2021
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.EJPS.2018.03.018
Abstract: A novel hybrid microparticulate system composed of poly(lactic-co-glycolic) acid (PLGA) nanoparticles and submicron medium-chain triglyceride (MCT) droplets was fabricated to overcome the pH-dependent solubility and precipitation challenges associated with a model poorly water-soluble weak base, cinnarizine (CIN). Molecular CIN was confined within both the lipid and polymer phase of PLGA-lipid hybrid (PLH) and PLGA-lipid-mannitol hybrid (PLMH) particles, which offered significant biopharmaceutical advantages in comparison to the unformulated drug, submicron MCT droplets and PLGA nanoparticles. This was highlighted by a substantial reduction in the pH-induced precipitation during in vitro gastrointestinal two-step dissolution studies. A >2.5-fold solubilisation enhancement was observed for the composite particles during simulated intestinal conditions, compared to pure CIN. Furthermore, the drug solubilisation capacity during in vitro intestinal digesting conditions was ~2-2.5 times greater for PLMH particles compared to the precursor emulsion droplets and PLGA nanoparticles. The observations from this study indicate that a synergy exists between the degradation products of PLGA nanoparticles and lipid droplets, whereby the dual-phase release and dissolution mechanism of the hybrid particles aids in prolonging pH-provoked precipitation. Subsequently, the ability for PLGA polymers and oligomers to act as polymeric precipitation inhibitors has been highlighted for the first time.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JCONREL.2014.05.013
Abstract: Cardiovascular diseases (CVDs) remain the major cause of morbidity and mortality globally. Despite the large number of cardiovascular drugs available for pharmacological therapies, factors limiting the efficient oral use are identified, including low water solubility, pre-systemic metabolism, food intake effects and short half-life. Numerous in vivo proof-of-concepts studies are presented to highlight the viability of lipid-based delivery to optimize the oral delivery of cardiovascular drugs. In particular, the key performance enhancement roles of oral lipid-based drug delivery systems (LBDDSs) are identified, which include i) improving the oral bioavailability, ii) sustaining/controlling drug release, iii) improving drug stability, iv) reducing food intake effect, v) targeting to injured sites, and vi) potential for combination therapy. Mechanisms involved in achieving these features, range of applicability, and limits of available systems are detailed. Future research and development efforts to address these issues are discussed, which is of significant value in directing future research work in fostering translation of lipid-based formulations into clinical applications to reduce the prevalence of CVDs.
Publisher: American Chemical Society (ACS)
Date: 13-03-2021
Publisher: Springer Science and Business Media LLC
Date: 18-06-2018
DOI: 10.1007/S11095-013-1107-3
Abstract: The ersity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.BIOMATERIALS.2019.119521
Abstract: Epithelial cells experience constant mechanical forces, including fluid shear stress (FSS) on their apical surface. These forces alter both structure and function. While precise recapitulation of the complex mechanobiology of organs remains challenging, better understanding of the effect of mechanical stimuli is necessary towards the development of biorelevant in vitro models. This is especially relevant to organs-on-chip models which allow for fine control of the culture environment. In this study, the effects of the FSS on Caco-2 cell monolayers were systematically determined using a microfluidic device based on Hele-Shaw geometry. This approach allowed for a physiologically relevant range of FSS (from ∼0 to 0.03 dyn/cm
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JCONREL.2013.07.022
Abstract: SN38 (7-ethyl-10-hydroxy c tothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.IJPHARM.2020.119069
Abstract: Abiraterone acetate, marketed as Zytiga®, is an antiandrogen medication used in the treatment of prostate cancer. Abiraterone acetate is a BCS Class IV compound associated with several oral delivery challenges. Its low solubility and high lipophilicity lead to poor oral bioavailability (<10%) and a dramatic positive food effect (5-10-fold). Hence, a large dose of abiraterone acetate (1000 mg per day) is prescribed to patients who must fast for at least 1 h before and 2 h after administration. The recent expiry of Zytiga®s' patent has led to the emergence of publications describing improved oral formulation strategies for abiraterone acetate. This review aims to discuss the characteristics of abiraterone acetate that lead to its unfavorable oral delivery, examine the oral formulation strategies that have been applied, and to describe potential alternative oral formulation strategies that have been used for other BCS Class IV drugs, to determine the most valuable strategies to develop novel and improved alternatives to the current commercial product. Specific emphasis of this review is placed on enabling oral formulation strategies that can improve solubilization and bioavailability, reduce the clinical dose and remove the pharmaceutical food effect to ultimately provide prostate cancer patients with a more efficient formulation with greater patient compliance.
Publisher: Wiley
Date: 21-03-2014
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.IJPHARM.2019.05.069
Abstract: Staphylococcal biofilms cause many infectious diseases and are highly tolerant to the effects of antimicrobials this is partly due to the biofilm matrix, which acts as a physical barrier retarding the penetration and reducing susceptibility to antimicrobials, thereby decreasing successful treatment outcomes. In this study, both single and mixed micellar systems based on poly vinyl caprolactam (PCL)-polyethylene glycol (PEG) copolymers were optimised for delivery of chlorhexidine (CHX) to S. aureus, MRSA and S. epidermidis biofilms and evaluated for their toxicity using Caenorhabditis elegans. The respective polyethylene glycol (PEG) and poly vinyl caprolactam (PCL) structural components promoted stealth properties and enzymatic responsive release of CHX inside biofilms, leading to significantly enhanced penetration (56%) compared with free CHX and improving the efficacy against Staphylococcus aureus biofilms grown on an artificial dermis (2.4 log reduction of CFU). Mixing Soluplus-based micelles with Solutol further enhanced the CHX penetration (71%) and promoted maximum reduction in biofilm biomass (>60%). Nematodes-based toxicity assay showed micelles with no lethal effects as indicated by their high survival rate (100%) after 72 h exposure. This study thus demonstrated that bio-responsive carriers can be designed to deliver a poorly water-soluble antimicrobial agent and advance the control of biofilm associated infections.
Publisher: Public Library of Science (PLoS)
Date: 30-06-2015
Publisher: MDPI AG
Date: 11-06-2020
DOI: 10.3390/PH13060121
Abstract: Classified as a Biopharmaceutical Classification System (BCS) class IV drug, hotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (Soluplus®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index .2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JCONREL.2015.12.047
Abstract: Psychiatric illnesses are a leading cause of disability and morbidity globally. However, the preferred orally dosed pharmacological treatment options available for depression, anxiety and schizophrenia are often limited by factors such as low drug aqueous solubility, food effects, high hepatic first-pass metabolism effects and short half-lives. Furthermore, the discovery and development of more effective psychotropic agents has stalled in recent times, with the majority of new drugs reaching the market offering similar efficacy, but suffering from the same oral delivery concerns. As such, the application of nanomedicine formulation approaches to currently available drugs is a viable option for optimizing oral drug delivery and maximizing treatment efficacy. This review focuses on the various delivery challenges encountered by psychotropic drugs, and the ability of nanomedicine formulation strategies to overcome these. Specifically, we critically review proof of concept in vitro and in vivo studies of nanoemulsions/microemulsions, solid lipid nanoparticles, dendrimers, polymeric micelles, nanoparticles of biodegradable polymers and nanosuspensions, and provide new insight into the various mechanisms for improved drug performance. The advantages and limitations of current oral nanomedicine approaches for psychotropic drugs are discussed, which will provide guidance for future research directions and assist in fostering the translation of such delivery systems to the clinical setting. Accordingly, emphasis has been placed on correlating the in vitro/in vivo performance of these nanomedicine approaches with their potential clinical outcomes and benefits for patients.
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.IJPHARM.2011.01.043
Abstract: We review the application of time-of-flight secondary-ion mass spectrometry (ToF-SIMS) for the surface chemical identification and distribution analysis (mapping) of pharmaceutically relevant materials. Specifically we explore the characterization of both solid state pharmaceuticals and bio-pharmaceuticals by ToF-SIMS highlighting specific case studies concerning the distribution and stability of pharmaceutical actives within solid matrices, the face-specific properties of pharmaceutical crystals and elucidation of the structure/conformation of adsorbed proteins. Finally, potential future applications of ToF-SIMS in pharmaceutics are detailed.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2022
DOI: 10.1007/S10753-022-01714-0
Abstract: Activation of toll-like receptor 4 (TLR4) has been shown to be a major influence on the inflammatory signalling pathways in intestinal mucositis (IM), as demonstrated by TLR4 knock-out mice. Pharmacological TLR4 inhibition has thus been postulated as a potential new therapeutic approach for the treatment of IM but specific TLR4 inhibitors have yet to be investigated. As such, we aimed to determine whether direct TLR4 antagonism prevents inflammation in pre-clinical experimental models of IM. The non-competitive and competitive TLR4 inhibitors, TAK-242 (10 µM) and IAXO-102 (10 µM), respectively, or vehicle were added to human T84, HT-29, and U937 cell lines and mouse colonic explants 1 h before the addition of lipopolysaccharide (LPS) ( in vitro : 100 µg/mL ex vivo : 10 µg/mL), SN-38 ( in vitro : 1 µM or 1 nM ex vivo : 2 µM), and/or tumour necrosis factor-alpha (TNF-α) (5 µg/mL). Supernatant was collected for human IL-8 and mouse IL-6 enzyme-linked immunosorbent assays (ELISAs), as a measure of inflammatory signalling. Cell viability was measured using XTT assays. Explant tissue was used in histopathological and RT-PCR analysis for genes of interest: TLR4, MD2, CD14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, CXCR2. SN-38 increased cytostasis compared to vehicle ( P 0.0001). However, this was not prevented by either antagonist ( P 0.05) in any of the 3 cell lines. Quantitative histological assessment scores showed no differences between vehicle and treatment groups ( P 0.05). There were no differences in in vitro IL-8 ( P 0.05, in all 3 cells lines) and ex vivo IL-6 ( P 0.05) concentrations between vehicle and treatment groups. Transcript expression of all genes was similar across vehicle and treatment groups ( P 0.05). TLR4 antagonism using specific inhibitors TAK-242 and IAXO-102 was not effective at blocking IM in these pre-clinical models of mucositis. This work indicates that specific epithelial inhibition of TLR4 with these compounds is insufficient to manage mucositis-related inflammation. Rather, TLR4 signalling through immune cells may be a more important target to prevent IM.
Publisher: MDPI AG
Date: 24-04-2020
DOI: 10.3390/NANO10040815
Abstract: An urgent demand exists for the development of novel delivery systems that efficiently transport antibacterial agents across cellular membranes for the eradication of intracellular pathogens. In this study, the clinically relevant poorly water-soluble antibiotic, rif icin, was confined within mesoporous silica nanoparticles (MSN) to investigate their ability to serve as an efficacious nanocarrier system against small colony variants of Staphylococcus aureus (SCV S. aureus) hosted within Caco-2 cells. The surface chemistry and particle size of MSN were varied through modifications during synthesis, where 40 nm particles with high silanol group densities promoted enhanced cellular uptake. Extensive biophysical analysis was performed, using quartz crystal microbalance with dissipation (QCM-D) and total internal reflection fluorescence (TIRF) microscopy, to elucidate the mechanism of MSN adsorption onto semi-native supported lipid bilayers (snSLB) and, thus, uncover potential cellular uptake mechanisms of MSN into Caco-2 cells. Such studies revealed that MSN with reduced silanol group densities were prone to greater particle aggregation on snSLB, which was expected to restrict endocytosis. MSN adsorption and uptake into Caco-2 cells correlated well with antibacterial efficacy against SCV S. aureus, with 40 nm hydrophilic particles triggering a ~2.5-log greater reduction in colony forming units, compared to the pure rif icin. Thus, this study provides evidence for the potential to design silica nanocarrier systems with controlled surface chemistries that can be used to re-sensitise intracellular bacteria to antibiotics by delivering them to the site of infection.
Publisher: Public Library of Science (PLoS)
Date: 21-03-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA16028J
Abstract: Combining 1 H NMR and sSAXS to discriminate the speciation and structure evolution of lipolysis products for submicron lipid droplets and lipid loaded in porous silica particles.
Publisher: American Chemical Society (ACS)
Date: 08-2018
DOI: 10.1021/ACS.MOLPHARMACEUT.8B00555
Abstract: Solid-state lipid-based formulations offer great potential for the improved oral delivery of poorly water-soluble drugs. This study investigates the use of the high-surface-area clay materials, montmorillonite and laponite, as solid carriers for lipid-based formulations. The unique cation-exchange properties of clay platelets were exploited to preload the ionizable hydrophobic compound, blonanserin, prior to encapsulating a drug-loaded lipid solution. Thus, solid-state lipid-based formulations with dual-loading capabilities were developed and studied. These formulations were compared with simple clay-based lipid formulations, where blonanserin was loaded in the lipid phase only. The drug release behavior of all clay-based formulations was assessed during in vitro dissolution studies under simulated gastric conditions and in vitro fasting intestinal lipolysis studies. Montmorillonite- and laponite-based lipid formulations significantly reduced blonanserin solubilization relative to a control lipid solution and silica-lipid hybrid particles, owing to incomplete drug release from the clay cation-exchange sites. This phenomenon was replicated during in vivo pharmacokinetic studies, whereby the bioavailability of simple clay-based lipid formulations was decreased relative to controls. Importantly, the solid-state dual-loaded montmorillonite-based lipid formulation provided an optimal pharmacokinetic performance, achieving the same degree of bioavailability enhancement as the control lipid solution. These findings indicate the potential of solid-state dual-loaded clay-based lipid formulations for increasing drug loading levels and enhancing the oral absorption of poorly soluble weak base compounds.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.EJPS.2018.01.003
Abstract: The use of nitric oxide (NO), a naturally occurring antimicrobial agent, as an alternative strategy to combat bacterial biofilms has recently gained considerable momentum in light of the global threat of emerging antibiotic resistance. While previous NO-based anti-biofilm approaches were aimed at killing bacterial cells within biofilms, NO has also been recently identified as a key mediator of biofilm dispersal, causing the release of cells from the biofilm community. This is of great interest towards the design of more effective anti-biofilm strategies but further studies are warranted to validate this concept. Therefore, in the present study we investigated whether a NO precursor, isosorbide mononitrate (ISMN) or its analogue D-isosorbide can induce bacteria cell dispersal from Staphylococcus aureus (S. aureus) biofilms and explored the potential synergy of ISMN and the antimicrobial compounds mupirocin and ciprofloxacin in biofilm eradication. This study demonstrate that ISMN causes dispersal of S. aureus biofilm bacteria, particularly when exposed to high levels of drug. ISMN at 60mg/mL increased the number of colony forming units (CFU) (~3log
Publisher: Bentham Science Publishers Ltd.
Date: 09-2011
DOI: 10.2174/157016311796799026
Abstract: In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9TB02586C
Abstract: Candida albicans ( C. albicans ) is a common fungal pathogen causing both localised and systemic infections.
Publisher: Bentham Science Publishers Ltd.
Date: 10-03-2015
DOI: 10.2174/1567201811666140716122644
Abstract: The study aims to develop and optimise lipid-based colloidal carriers (LBCC) for enhancing solubilisation and reducing fed/fasted variation for the poorly water-soluble danazol (DAN). Oil-based and self-microemulsifying delivery systems (SMEDDS) were developed, and the effect of solidification was investigated. Liquid SMEDDS (L-SMEDDS, Capmul MCM:Tween 80:Transcutol HP 1:2:1, w/w) and emulsion (Capmul MCM:soya lecithin 100:0.6, w/w) were developed. Solid-state formulations were prepared via (i) physical adsorption of L-SMEDDS (P-SMEDDS) or (ii) spray drying of emulsion (silica-lipid hybrid, SLH) and L-SMEDDS (spray-dried SMEDDS, S-SMEDDS) using Aerosil 380 silica nanoparticles as the solid carrier. In vitro lipid digestion and drug solubilisation under simulated intestinal conditions in both fasted and fed states were investigated. Solubilisation of unformulated DAN under both fasted and fed conditions was low, and a large fed/fasted variation was observed, i.e. 6.6-fold difference. All LBCC formulations provided enhanced drug solubilisation and significantly reduced the fed/fasted variation. For self-emulsifying LBCC, the fasted state drug solubilisation was ranked as L-SMEDDS > PSMEDDS > S-SMEDDS, suggesting that solidification reduced the capability of SMEDDS in presenting DAN to the aqueous phase. However, in the case of oil-based LBCC, improved drug solubility was observed with the solid form SLH under both fasted and fed state in comparison to that of the equivalent liquid form. Overall, the SLH, which provided the highest drug solubilisation in the fasted state (i.e. 10-fold higher than the pure DAN) and the smallest fed/fasted variation, was considered an optimised solid LBCC to enhance the solubilisation of DAN and reduce the fed/fasted variation.
Publisher: Informa UK Limited
Date: 11-04-2018
DOI: 10.1080/03639045.2018.1459676
Abstract: Novel antibiotic Ramizol The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. Ramizol Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol
Publisher: American Chemical Society (ACS)
Date: 13-07-2018
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.IJPHARM.2021.121382
Abstract: Cromoglycate is a mast cell stabiliser typically administered via inhalation or intranasally for the treatment of allergy-based respiratory issues. Oral dosing of cromoglycate remains challenging due to its high solubility but low permeability across epithelial membranes in the gastrointestinal tract: effective formulation strategies are clearly needed. Here, we investigate and preclinically develop chitosan-cromoglycate complexes and associated nano/microparticle formulations with muco-adhesive and permeation enhancing capabilities to overcome the biopharmaceutical challenges for oral dosing.The synthesized complexes were optimized with respect to chitosan grade, particle size, and drug loading and demonstrated up to a 9.3-fold enhancement in permeability across a Caco-2 monolayer for chitosan-cromoglycate particles, compared to the pure drug. This increased intestinal permeability led to improved pharmacokinetic performance of cromoglycate, e.g. up to 1.82-fold increase in relative oral bioavailability when dosed to Sprague-Dawley rats in a fasted state. These findings confirm the potential for chitosan particles to serve as an effective oral delivery vehicle for cromoglycate, with additional formulation optimization presenting the opportunity to reduce dosing frequency for treatment of allergy-based respiratory ailments.
Publisher: Wiley
Date: 17-11-2017
Publisher: Informa UK Limited
Date: 07-07-2023
Publisher: American Chemical Society (ACS)
Date: 28-04-2021
Publisher: MDPI AG
Date: 04-09-0023
Publisher: Elsevier BV
Date: 10-09-2010
DOI: 10.1016/J.JCONREL.2010.01.008
Abstract: We report on a porous silica-lipid hybrid microcapsule (SLH) oral delivery system for indomethacin fabricated from Pickering emulsion templates, where the drug forms an electrostatic complex with cationic lipid present in the oil phase. Dry SLH microcapsules prepared either by spray drying (approximately 1-5 microm) or phase coacervation (20-50 microm) exhibit a specific internal porous matrix structure with pore diameters in the range of 20 to 100 nm. Dissolution studies under sink conditions and in the presence of electrolytes revealed a decreased extent of dissolution this confirms the lipophilic nature the drug-lipid complex and its location in the oil phase. Orally dosed in-vivo studies in rats showed complete drug absorption and statistically higher fasted state bioavailability (F) (p<0.05) in comparison to aqueous suspensions and o/w submicron emulsions of indomethacin. It is postulated that the SLH microcapsules improve oral absorption via complete solubilisation of drug-lipid electrostatic complexes during enzymatic lipolysis in the GI track.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.JCONREL.2008.10.014
Abstract: A silica-lipid hybrid (SLH) microcapsule system for oral delivery of poorly water-soluble drugs is reported for the first time. For the model drug celecoxib (CEL), SLH microcapsules composed of medium-chain triglycerides, lecithin and silica nanoparticles with an internal porous matrix structure, were shown to offer several physicochemical and biopharmaceutical advantages in comparison with unmodified drug, lipid emulsion, dry emulsion and the commercial product, Celebrex. DSC and XRD analyses confirmed non-crystalline CEL in SLH microcapsules and verified medium term physical stability. Dissolution under sink conditions revealed a 2- to 5-fold increase in dissolution efficiencies (%DE) and significantly reduced t(50%) (> or =50-fold) for CEL formulated as SLH microcapsules. Orally dosed in vivo studies in rats demonstrated superior pharmacokinetics for SLH microcapsules. Specifically, the fasted-state bioavailability (F) was statistically higher (p<0.05) than for aqueous suspension, lipid solution, o/w emulsion and a maltodextrin-stabilised dry emulsion, and was greater than for Celebrex. SLHs showed the highest maximum plasma concentration (C(max)) among all tested formulations (p<0.05). Linear correlations were observed between %DE and the pharmacokinetic parameters (F and C(max)). It is postulated that SLH microcapsules improve CEL oral absorption via dissolution enhancement, potentially in conjunction with other unexplored mechanisms, hence offering the possibility of dose reduction for improved therapeutic efficacy and cost-effectiveness of poorly soluble drugs.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C1NR11273B
Abstract: Lipid based colloids (e.g. emulsions and liposomes) are widely used as drug delivery systems, but often suffer from physical instabilities and non-ideal drug encapsulation and delivery performance. We review the application of engineered nanoparticle layers at the interface of lipid colloids to improve their performance as drug delivery systems. In addition we focus on the creation of novel hybrid nanomaterials from nanoparticle-lipid colloid assemblies and their drug delivery applications. Specifically, nanoparticle layers can be engineered to enhance the physical stability of submicron lipid emulsions and liposomes, satbilise encapsulated active ingredients against chemical degradation, control molecular transport and improve the dermal and oral delivery characteristics, i.e. increase absorption, bioavailability and facilitate targeted delivery. It is feasible that hybrid nanomaterials composed of nanoparticles and colloidal lipids are effective encapsulation and delivery systems for both poorly soluble drugs and biological drugs and may form the basis for the next generation of medicines. Additional pre-clinical research including specific animal model studies are required to advance the peptide rotein delivery systems, whereas the silica lipid hybrid systems have now entered human clinical trials for poorly soluble drugs.
Publisher: American Chemical Society (ACS)
Date: 20-01-2010
DOI: 10.1021/MP9002442
Abstract: We investigate the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid emulsions, hence further exploring the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by silica-lipid hybrid (SLH) microcapsules. An in vitro lipolysis model was used to quantify the lipase-mediated digestion kinetics of a series of lipid vehicles formulated with caprylic/capric triglycerides: lipid solution, submicrometer lipid emulsions (in the presence and absence of silica), and SLH microcapsules. The importance of emulsification on lipid digestibility is evidenced by the significantly higher initial digestion rate constants for SLH microcapsules and lipid emulsions (>15-fold) in comparison with that of the lipid solution. Silica particles exerted an inhibitory effect on the digestion of submicrometer lipid emulsions regardless of their initial location, i.e., aqueous or lipid phases. This inhibitory effect, however, was not observed for SLH microcapsules. This highlights the importance of the matrix structure and porosity of the hybrid microcapsule system in enhancing lipid digestibility as compared to submicrometer lipid emulsions stabilized by silica. For each studied formulation, the digestion kinetics is well correlated to the corresponding in vivo plasma concentrations of a model drug, celecoxib, via multiple-point correlations (R(2) > 0.97). This supports the use of the lipid digestion model for predicting the in vivo outcome of an orally dosed lipid formulation. SLH microcapsules offer the potential to enhance the oral absorption of poorly soluble drugs via increased lipid digestibility in conjunction with improved drug dissolution/dispersion.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2200
Publisher: Springer Science and Business Media LLC
Date: 02-2021
Publisher: Springer Science and Business Media LLC
Date: 11-01-2023
DOI: 10.1007/S13346-022-01287-3
Abstract: Intracellular bacteria serve as a problematic source of infection due to their ability to evade biological immune responses and the inability for conventional antibiotics to efficiently penetrate cellular membranes. Subsequently, new treatment approaches are urgently required to effectively eradicate intracellular pathogens residing within immune cells (e.g. macrophages). In this study, the poorly soluble and poorly permeable antibiotic, rif icin, was re-purposed via micro-encapsulation within inulin-lipid hybrid (ILH) particles for the treatment of macrophages infected with small colony variants of Staphylococcus aureus (SCV S. aureus ). Rif icin-encapsulated ILH (Rif-ILH) microparticles were synthesized by spray drying a lipid nano-emulsion, with inulin dissolved throughout the aqueous phase and rif icin pre-loaded within the lipid phase. Rif-ILH were strategically designed and engineered with pH-responsive properties to promote lysosomal drug release upon cellular internalization, while preventing premature rif icin release in plasma-simulating media. The pH-responsiveness of Rif-ILH was controlled by the acid-mediated hydrolysis of the inulin coating, where exposure to acidic media simulating the lysosomal environment of macrophages triggered hydrolysis of the oligofructose chain and the subsequent diffusion of rif icin from Rif-ILH. This pH-provoked release mechanism, as well as the ability for ILH microparticles to be more readily internalized by macrophages, was found to be influential in triggering a 2.9-fold increase in intracellular rif icin concentration within infected macrophages, compared to the pure drug. The subsequent increase in exposure of intracellular pathogens to rif icin leads to a ~ 2-log improvement in antibacterial activity for Rif-ILH, at a rif icin dose of 2.5 µg/mL. Thus, the reduction in viability of intracellular SCV S. aureus , in the absence of cellular toxicity, is indicative of ILH microparticles serving as a unique approach for the safe and efficacious delivery of antibiotics to phagocytic cells for the treatment of intracellular infections. Graphical Abstract
Publisher: Wiley
Date: 22-12-2022
Abstract: Understanding the intestinal transport of particles is critical in several fields ranging from optimizing drug delivery systems to capturing health risks from the increased presence of nano‐ and micro‐sized particles in human environment. While Caco‐2 cell monolayers grown on permeable supports are the traditional in vitro model used to probe intestinal absorption of dissolved molecules, they fail to recapitulate the transcytotic activity of polarized enterocytes. Here, an intestine‐on‐chip model is combined with in silico modeling to demonstrate that the rate of particle transcytosis is ≈350× higher across Caco‐2 cell monolayers exposed to fluid shear stress compared to Caco‐2 cells in standard “static” configuration. This relates to profound phenotypical alterations and highly polarized state of cells grown under mechanical stimulation and it is shown that transcytosis in the microphysiological model is energy‐dependent and involves both clathrin and macropinocytosis mediated endocytic pathways. Finally, it is demonstrated that the increased rate of transcytosis through cells exposed to flow is explained by a higher rate of internal particle transport (i.e., vesicular cellular trafficking and basolateral exocytosis), rather than a change in apical uptake (i.e., binding and endocytosis). Taken together, the findings have important implications for addressing research questions concerning intestinal transport of engineered and environmental particles.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.JCIS.2011.07.063
Abstract: Interactions between porous silicon (pSi) particles and probe molecules were evaluated to determine the effect of pSi and probe molecule chemistry on adsorption. Methylene blue, ethyl violet and orange G dyes were chosen for investigation as they possess distinct functionalities and charges. Several distinct pSi surface species were produced via thermal oxidation at 200-800 °C and their effect on adsorption investigated. The adsorption mechanisms were elucidated from equilibrium adsorption and desorption isotherms. Methylene blue adsorption was attributed to electrostatic attraction where a gradual increase in adsorption with oxidation temperature was observed. Significant methylene blue desorption was observed at pH 3, confirming adsorption occurs via electrostatic attraction. Ethyl violet demonstrated an increase in plateau adsorption capacity and affinity with increased oxidation temperatures and adsorption was initially attributed to electrostatic attraction, however desorption of ethyl violet was not observed, thus indicating potential chemisorption. Orange G exhibited high affinity adsorption for Si(y)SiH(x) terminated surfaces but no orange G desorption was detected, indicating a chemisorption adsorption mechanism. It has been successfully demonstrated that the surface modification of pSi enabled the manipulation of molecular interactions. By interacting probe molecules with similar functionalities to drug molecule with pSi, greater understanding of drug-pSi interactions can be ascertained which are of great importance. pSi surface chemistry can be tailored to enable control over molecular interactions and ultimately dictate loading, encapsulation and release behavior.
Publisher: International Association of Physical Chemists (IAPC)
Date: 17-07-2020
DOI: 10.5599/ADMET.830
Abstract: class="ADMETabstracttext" Lipid-based formulations (LBFs) are well-known to improve the oral bioavailability of poorly water-soluble drugs (PWSDs) by presenting the drug to the gastrointestinal environment in a molecularly dispersed state, thus avoiding the rate-limiting dissolution step. Risperidone and lurasidone are antipsychotics drugs which experience erratic and variable absorption, leading to a low oral bioavailability. The aim of this research was to develop and investigate the performance of risperidone and lurasidone when formulated as an emulsion and silica-lipid hybrid (SLH). Lurasidone and risperidone were dissolved in Capmul® MCM at 100% and 80% their equilibrium solubility, respectively, prior to forming a sub-micron emulsion. SLH microparticles were fabricated by spray-drying a silica stabilised sub-micron emulsion to form a solid powder. The performances of the formulations were evaluated in simulated intestinal media under digesting conditions, where the emulsion and SLH provided a 17-fold and 23-fold increase in LUR solubilisation, respectively. However, the performance of RIS was reduced by 2.2-fold when encapsulated within SLH compared to pure drug. Owing to its pKa, RIS adsorbed to the silica and thus, dissolution was significantly hindered. The results reveal that LBFs may not overcome the challenges of all PWSDs and physiochemical properties must be carefully considered when predicting drug performance.
Publisher: Future Science Ltd
Date: 07-2013
DOI: 10.4155/TDE.13.52
Abstract: Porous silicon (pSi) is a nanostructured carrier system that has received considerable attention over the past 10 years, for use in a wide variety of biomedical applications, including biosensing, biomedical imaging, tissue scaffolds and drug delivery. This interest is due to several key features of pSi, including excellent in vivo biocompatibility, the ease of surface chemistry modification and the control over its 3D porous network structure. With control of these physical parameters pSi has successfully been used for the delivery of a variety of therapeutics, ranging from small-molecule drugs to larger peptide rotein-type therapeutics. In this review, the authors provide a brief overview of pSi fabrication methods, particularly with regard to the need to passivate the highly reactive Si-Hx surface species of native pSi, typically via thermal oxidation, hydrocarbonization or hydrosilylation. This surface modification, in turn, controls both the loading and release of therapeutics. The authors will then report on specific case studies of leading ex les on the use of pSi as a therapeutic-delivery system. Specifically, the first reported in vivo study that demonstrated the use of pSi to improve the delivery of a Biopharmaceutical Classification System Class 2 poorly soluble drug (indomethacin), by using thermally oxidized pSi, is discussed, as well as highlighting a study that determined the biodistribution of 18 F-radiolabeled thermally hydrocarbonized pSi after oral dosing. The authors also report on the development of composite pSi–poly(D,L-lactide-co-glycolide) microparticles for the controlled delivery of protein therapeutics. Finally, the use of pSi in the delivery of bioactives, such as the successful use of thermally carbonized pSi to deliver Melanotan II, an unspecific agonist for the melanocortin receptors that are involved in controlling fluid uptake is discussed. With a growing body of literature reporting the successful use of pSi to deliver a range of therapeutics, we are entering what may be a golden age for this drug-delivery system, which may finally see the long-held promises finally achieved.
Publisher: American Chemical Society (ACS)
Date: 28-07-2015
Abstract: Biodegradable and bioactive hybrid particles composed of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles and medium-chain triglycerides were prepared by spray drying lipid-in-water emulsions stabilized by PLGA nanoparticles, to form PLGA-lipid hybrid (PLH) microparticles approximately 5 μm in mean diameter. The nanoparticle stabilizer was varied and mannitol was also incorporated during the preparation to investigate the effect of stabilizer charge and cryoprotectant content on the particle microstructure. An in vitro lipolysis model was used to demonstrate the particles' bioactivity by manipulating the digestion kinetics of encapsulated lipid by pancreatic lipase in simulated gastrointestinal fluid. Lipid digestion kinetics were enhanced in PLH and PLGA-lipid-mannitol hybrid (PLMH) microparticles for both stabilizers, compared to a coarse emulsion, in biorelevant media. An optimal digestion rate was observed for the negatively charged PLMH system, evidenced by a 2-fold increase in the pseudo-first-order rate constant compared to a coarse emulsion. Improved microparticle redispersion, probed by dual dye confocal fluorescence microscopy, increased the available surface area of lipid for lipase adsorption, enhancing digestion kinetics. Thereby, lipase action was controlled in hybrid microparticles by altering the surface charge and carbohydrate content. Our results demonstrate that bioactive microparticles composed of versatile and biodegradable polymeric particles and oil droplets have great potential for use in smart food and nutrient delivery, as well as safer and more efficacious oral delivery of drugs and drug combinations.
Publisher: The Chemical Society of Japan
Date: 05-10-2012
DOI: 10.1246/CL.2012.1334
Publisher: MDPI AG
Date: 06-05-2020
DOI: 10.3390/PHARMACEUTICS12050426
Abstract: Lipid-based formulations can circumvent the low aqueous solubility of problematic drug compounds and increase their oral absorption. As these formulations are often physically unstable and costly to manufacture, solidification has been suggested as a way to minimize these issues. This study evaluated the physicochemical stability and in vitro performance of lipid-loaded mesoporous magnesium carbonate (MMC) particles with an average pore size of 20 nm. A medium chain lipid was loaded onto the MMC carrier via physical adsorption. A modified in vitro lipolysis setup was then used to study lipid release and digestion with 1H nuclear magnetic resonance spectroscopy. The lipid loading efficiency with different solidification techniques was also evaluated. The MMC, unlike more commonly used porous silicate carriers, dissolved during the lipolysis assay, providing a rapid release of encapsulated lipids into solution. The digestion of the dispersed lipid-loaded MMC therefore resembled that of a coarse dispersion of the lipid. The stability data demonstrated minor degradation of the lipid within the pores of the MMC particles, but storage for three months did not reveal extensive degradation. To conclude, lipids can be adsorbed onto MMC, creating a solid powder from which the lipid is readily released into the solution during in vitro digestion. The chemical stability of the formulation does however merit further attention.
Publisher: American Chemical Society (ACS)
Date: 05-11-2020
Abstract: Porous colloids have been shown to exert unique bioactivities for mediating lipid (fat) metabolism and thereby offer significant potential as anti-obesity therapies. In this study, we compare the capacity for two classes of colloids, that is, smectite clays (Laponite XLG, LAP montmorillonite, MMT) and mesoporous silica (SBA-15 ordered silica MPS), to impede intestinal lipid hydrolysis and provoke lipid and carbohydrate excretion through adsorption within their particle matrices. A two-stage
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.JCONREL.2019.12.037
Abstract: In the advent of the post-antibiotic era, new strategies are urgently required to improve the efficacy of antimicrobials and outsmart multi-drug resistant bacteria. Exploiting a basic survival mechanism of bacteria, lipase production, monoolein liquid crystal nanoparticles (MO-LCNPs) were investigated as a bacterial-triggered drug delivery system for three different antimicrobial compounds and compared with model sn-1/3 regiospecific and non-regiospecific lipases via pH-stat titration, proton nuclear magnetic resonance and in situ synchrotron small-angle X-ray scattering. The release of model hydrophobic (rif icin) and macromolecular (alginate lyase) antimicrobials were triggered from MO-LCNPs at 82-fold and 7-fold higher rates (respectively) due to bacterial lipase digestion of MO-LCNPs, which could not be stimulated with a small hydrophilic antibiotic (ciprofloxacin HCl) or non-digestible, phytantriol-LCNPs. While sn-1/3 regiospecific lipase rapidly digested MO-LCNPs in a two-phase process, the single-phase digestion kinetics of the non-regiospecific lipase steadily digested the cubic Im3m structure and gave rise to lamellar structures that ultimately stimulated the triggered antibiotic release. Accordingly, MO-LCNPs have an application for localised Pseudomonas aeruginosa and Staphylococcus aureus infections that produce non-regiospecific lipases and for concentration-dependent antibiotics that have macromolecular (MW ~ 30 kDa) or hydrophobic (logP ~ 4) chemistries, as a triggered bolus release would be clinically efficacious for improved bacterial eradication.
Publisher: American Chemical Society (ACS)
Date: 04-03-2014
DOI: 10.1021/LA500094B
Abstract: The rate and extent of lipolysis, the breakdown of fat into molecules that can be absorbed into the bloodstream, depend on the interfacial composition and structure of lipid (fat) particles. A novel method for controlling the interfacial properties is to load the lipid into porous colloidal particles. We report on the role of pore nanostructure and surface coverage in controlling the digestion kinetics of medium-chain and long-chain triglycerides loaded into porous silica powders of different particle size, porosity, and hydrophobicity/hydrophilicity. An in vitro lipolysis model was used to measure digestion kinetics of lipid by pancreatic lipase, a digestive enzyme. The rate and extent of lipid digestion were significantly enhanced when a partial monolayer of lipid was loaded in porous hydrophilic silica particles compared to a submicrometer lipid-in-water emulsion or a coarse emulsion. The inhibitory effect of digestion products was clearly evident for digestion from a submicrometer emulsion and coarse emulsion. This effect was minimal, however, in the two silica-lipid systems. Lipase action was inhibited for lipid loaded in the hydrophobic silica and considered due to the orientation of lipase adsorption on the methylated silica surface. Thus, hydrophilic silica promotes enhanced digestion kinetics, whereas hydrophobic silica exerts an inhibitory effect on hydrolysis. Evaluation of digestion kinetics enabled the mechanism for enhanced rate of lipolysis in silica-lipid systems to be derived and detailed. These investigations provide valuable insights for the optimization of smart food microparticles and lipid-based drug delivery systems based on lipid excipients and porous nanoparticles.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JPHOTOBIOL.2022.112474
Abstract: Antimicrobial photodynamic therapy (aPDT) has emerged as an innovative strategy to combat antibiotic resistant microbes yet aPDT efficacies against biofilms are sub-optimal due to inability of photosenstizers to reach microbes embedded in biofilm matrix. To overcome this challenge, liquid crystal lipid nanoparticles (LCNP) were employed in this study as a smart, biocompatible and triggerable delivery system for the new photosensitizer gallium protoporphyrin (GaPP), due to their capabilities in promoting efficient antimicrobial delivery to biofilms. The relationship between GaPP loading of LCNP, reactive oxygen species (ROS) production and the in vitro antibacterial activity against two antibiotic resistant Staphylococcus aureus strains was established. LCNP substantially improved the antibacterial activity of GaPP, completely eradicating S. aureus and MRSA planktonic cultures, using a GaPP concentration of 0.8 μM and light dose 1.9 J/cm
Publisher: Elsevier BV
Date: 2011
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.CIS.2016.10.003
Abstract: This review describes the development of novel lipid-based biomaterials that modulate fat digestion for the enhanced uptake of encapsulated lipophilic bioactive compounds (e.g. drugs and vitamins). Specific focus is directed towards analysing how key material characteristics affect the biological function of digestive lipases and manipulate lipolytic digestion. The mechanism of lipase action is a complex, interfacial process, whereby hydrolysis can be controlled by the ability for lipase to access and adsorb to the lipid-in-water interface. However, significant conjecture exists within the literature regarding parameters that influence the activities of digestive lipases. Important findings from recent investigations that strategically examined the interplay between the interfacial composition of the lipid microenvironment and lipolysis kinetics in simulated biophysical environments are presented. The correlation between lipolysis and the rate of solubilisation and absorption of lipophilic compounds in the gastrointestinal tract (GIT) is detailed. Greater insights into the mechanism of lipase action have provided a new approach for designing colloidal carriers that orally deliver poorly soluble compounds, directly impacting the pharmaceutical and food industries.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.EJPS.2019.05.001
Abstract: Obesity is a rapidly growing epidemic, with over one-third of the global population classified as overweight or obese. Consequently, an urgent need exists to develop innovative approaches and technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions of commercial clay platelets (Veegum® HS and LAPONITE® XLG), were delivered as complimentary, bioactive excipients with the potent lipase inhibitor, orlistat, for the inhibition of fat (lipid) hydrolysis. Simulated intestinal lipolysis studies were performed by observing changes in free fatty acid concentration and revealed that a combinatorial effect existed when NSC particles were co-administered with orlistat, as evidenced by a 1.2- to 1.6-fold greater inhibitory response over 60 min, compared to dosing orlistat alone. Subsequently, it was determined that a multifaceted approach to lipolysis inhibition was presented, whereby NSC particles adsorbed high degrees of lipid (up to 80% of all lipid species present in lipolysis media) and thus physically shielded the lipid-in-water interface from lipase access, while orlistat covalently attached and blocked the lipase enzyme active site. Thus, the ability for NSC particles to enhance the biopharmaceutical performance and potency of orlistat is hypothesised to translate into promising in vivo pharmacodynamics, where this novel approach is predicted to lead to considerably greater weight reductions for obese patients, compared to dosing orlistat alone.
Publisher: American Chemical Society (ACS)
Date: 21-11-2016
Abstract: Biocompatible lipid hybrid particles composed of montmorillonite and medium chain triglycerides were engineered for the first time by spray drying oil-in-water emulsions stabilized by montmorillonite platelets to form montmorillonite-lipid hybrid (MLH) microparticles containing up to 75% w/w lipid. In vitro lipolysis studies under simulated intestinal conditions indicated that the specific porous nanoarchitecture and surface chemistry of MLH particles significantly increased the rate (>10-fold) and extent of lipase-mediated digestion compared to that of coarse and homogenized submicrometer triglyceride emulsions. Proton nuclear magnetic resonance studies verified the rapid and enhanced production of fatty acids for MLH particles these are electrostatically repelled by the negatively charged montmorillonite platelet faces and avoid the "interfacial poisoning" caused by incomplete digestion that retards lipid droplet digestion. MLH particles are a novel biomaterial and encapsulation system that optimize lipase enzyme efficiency and have excellent potential as a smart delivery system for lipophilic biomolecules owing to their exceptional physicochemical and biologically active properties. These particles can be readily fabricated with varying lipid loads and thus may be tailored to optimize the solubilization of specific bioactive molecules requiring reformulation.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2022
DOI: 10.1007/S11095-022-03229-7
Abstract: Cationic polymers have many advantages as vectors for mediated cellular entry and delivery of siRNA. However, toxicity related to their cationic charge has compromised clinical use. It is hypothesized that the siRNA-vector complex composition and properties can be controlled to optimize therapeutic performance. Here we investigate siRNA complexes with branched polyethylenimine (bPEI) versus generation 4 polyamidoamine dendrimers (PAMAM) on interactions with immobilized lipid membranes, and cellular uptake and toxicity. A model siRNA was complexed with either PAMAM or bPEI, and their size and zeta-potential characterized. Interaction of the complexes and parent polymers with lipid bilayers was investigated using atomic force microscopy and correlated with the uptake and toxicity in HeLa cells. PAMAM and its siRNA complexes formed circular shaped micron-sized holes in lipid bilayers, while bPEI formed nanoscale holes. Flow cytometry and fluorescence microscopy demonstrated PAMAM-siRNA complexes to have a higher cellular uptake than bPEI-siRNA complexes. bPEI-siRNA complexes did not impact on viability, however PAMAM-siRNA complexes demonstrated increasing cell toxicity as N/P ratio increased. PAMAM-siRNA complexes accumulated around the cell nucleus, while PEI-siRNA complexes were located closer to the cell wall. Complexation of PAMAM dendrimer or bPEI with siRNA modified physicochemical properties of the parent polymer, however it did not impact on the mechanism of interaction with model lipid bilayers or how the polymer/siRNA complex interacted and was internalized by HeLa cells. Interaction of siRNA polymer complexes with cells is related to the action of the parent polymer.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.ADDR.2018.11.006
Abstract: Self-emulsifying drug delivery systems (SEDDS) offer potential for overcoming the inherent slow dissolution and poor oral absorption of hydrophobic drugs by retaining them in a solubilised state during gastrointestinal transit. However, the promising biopharmaceutical benefits of liquid lipid formulations has not translated into widespread commercial success, due to their susceptibility to long term storage and in vivo precipitation issues. One strategy that has emerged to overcome such limitations, is to combine the solubilisation and dissolution enhancing properties of lipids with the stabilising effects of solid carrier materials. The development of intelligent hybrid drug formulations has presented new opportunities to harness the potential of emulsified lipids in optimising oral bioavailability for lipophilic therapeutics. Specific emphasis of this review is placed on the impact of solidification approaches and excipients on the biopharmaceutical performance of self-emulsifying lipids, with findings highlighting the key design considerations that should be implemented when developing hybrid lipid-based formulations.
Publisher: Informa UK Limited
Date: 03-2009
DOI: 10.1080/08982100802673940
Abstract: The encapsulation and release kinetics of guanosine from liposomes and polyethylene glycol (PEG)-modified liposomes are reported. Specifically, the influence of PEG chain length, PEGylation level, lipid type, drug-loading level, temperature, and solution conditions (i.e., salt and pH effects) on the rate and mechanism for release have been determined. Increasing PEGylation significantly reduced the guanosine release kinetics this is more significant for greater molecular weight PEG and is correlated with the PEG layer thickness. Further, the mechanism for guanosine release changed from diffusion to interfacial control as the PEG level increased. The interfacial structure introduced by PEG also increased the activation energy required for guanosine transport across the lipid bilayer from 14 to 22 kJ mol(-1). Findings from this study provide further insight into optimizing the formulation of Stealth liposomes.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.CIS.2012.03.006
Abstract: Porous silicon (pSi) has a number of unique properties that appoint it as a potential drug delivery vehicle high loading capacity, controllable surface chemistry and structure, and controlled release properties. The native Si(y)SiH(x) terminated pSi surface is highly reactive and prone to spontaneous oxidation. Surface modification is used to stabilize the pSi surface but also to produce surfaces with desired drug delivery behavior, typically via oxidation, hydrosilylation or thermal carbonization. A number of advanced characterization techniques have been used to analyze pSi surface chemistry, including X-ray photoelectron spectroscopy and time of flight secondary ion mass spectrometry. Surface modification not only stabilizes the pSi surface but determines its charge, wettability and dissolution properties. Manipulation of these parameters can impact drug encapsulation by altering drug-pSi interactions. pSi has shown to be a successful vehicle for the delivery of poorly soluble drugs and protein therapeutics. Surface modification influences drug pore penetration, crystallinity, loading level and dissolution rate. Surface modification of pSi shows great potential for drug delivery applications by controlling pSi-drug interactions. Controlling these interactions allows specific drug release behaviors to be engineered to aid in the delivery of previously challenging therapeutics. Within this review, different pSi modification techniques will be outlined followed by a summary of how pSi surface modification has been used to improve drug encapsulation and delivery.
Publisher: American Chemical Society
Date: 2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1JM10317B
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.IJPHARM.2011.02.038
Abstract: This study reports on the physicochemical characterisation and in vitro investigations of macro-porous silica-lipid hybrid (SLH) microcapsules when formulated using various lipids: long-chain triglycerides (LCT), medium-chain triglycerides (MCT), medium-chain mono-, diglycerides (MCMDG) and emulsifiers: anionic lecithin and cationic oleylamine. For the lipophilic compound coumarin 102 (logP=4.09), a complete and immediate in vitro release was attained for the SLH microcapsules under simulated intestinal sink conditions. The in vitro digestion study of various types of SLH microcapsules demonstrates: (i) reduced variability and enhanced lipid digestibility for the MCMDG-based microcapsules (i.e. 90-100% lipolysis) in comparison with an equivalent lipid solution and emulsion (50-90% lipolysis) and (ii) more controllable digestion kinetics for the LCT-based microcapsules which produce a lipolysis rate higher than that of a lipid solution but lower than that of a lipid emulsion. The drug phase partition results show approximately 5- to 17-fold increase in the drug solubilisation degree resulting from the digestion of MCT and MCMDG-based microcapsules (116 μg/mL), and LCT-based microcapsules (416 μg/mL) in comparison with the blank micellar medium (24 μg/mL). In conclusion, the SLH microcapsules could be tailored to manipulate the digestion patterns of both medium- and long-chain lipids in order to maximise the drug solubilisation capacity.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.EJPB.2016.01.010
Abstract: Ziprasidone is a poorly water-soluble antipsychotic drug that demonstrates low fasted state oral bioavailability and a clinically significant two-fold increase in absorption when dosed postprandially. Owing to significant compliance challenges faced by schizophrenic patients, a novel oral formulation of ziprasidone that demonstrates improved fasted state absorption and a reduced food effect is of major interest, and is therefore the aim of this research. Three lipid-based drug delivery systems (LBDDS) were developed and investigated: (a) a self-nanoemulsifying drug delivery system (SNEDDS), (b) a solid SNEDDS formulation, and (c) silica-lipid hybrid (SLH) microparticles. SNEDDS was developed using Capmul MCM® and Tween 80®, and solid SNEDDS was fabricated by spray-drying SNEDDS with Aerosil 380® silica nanoparticles as the solid carrier. SLH microparticles were prepared in a similar manner to solid SNEDDS using a precursor lipid emulsion composed of Capmul MCM® and soybean lecithin. The performance of the developed formulations was evaluated under simulated digesting conditions using an in vitro lipolysis model, and pure (unformulated) ziprasidone was used as a control. While pure ziprasidone exhibited the lowest rate and extent of drug solubilization under fasting conditions and a significant 2.4-fold increase in drug solubilization under fed conditions, all three LBDDS significantly enhanced the extent of drug solubilization under fasting conditions between 18- and 43-folds in comparison to pure drug. No significant difference in drug solubilization for the fed and fasted states was observed for the three LBDDS systems. To highlight the potential of LBDDS, mechanism(s) of action and various performance characteristics are discussed. Importantly, LBDDS are identified as an appropriate formulation strategy to explore further for the improved oral delivery of ziprasidone.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4TB01953A
Abstract: The anti-biofilm effect of drug delivery systems composed of the antiseptic quaternary ammonium compound cetylpyridinium chloride (CPC) and cholesterol was evaluated in Staphylococcus aureus biofilm.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2013
Publisher: Springer Science and Business Media LLC
Date: 18-05-2016
DOI: 10.1038/JA.2016.45
Publisher: Springer Science and Business Media LLC
Date: 10-11-2015
DOI: 10.1038/NCOMMS9791
Abstract: The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.
Publisher: Informa Healthcare
Date: 23-02-2016
DOI: 10.1517/17425247.2016.1151872
Abstract: A number of biobarriers limit efficient oral drug absorption both polymer-based and lipid-based nanocarriers have demonstrated properties and delivery mechanisms to overcome these biobarriers in preclinical settings. Moreover, in order to address the multifaceted oral drug delivery challenges, polymer-lipid hybrid systems are now being designed to merge the beneficial features of both polymeric and lipid-based nanocarriers. Recent advances in the development of polymer-lipid hybrids with a specific focus on their viability in oral delivery are reviewed. Three classes of polymer-lipid hybrids have been identified, i.e. lipid-core polymer-shell systems, polymer-core lipid-shell systems, and matrix-type polymer-lipid hybrids. We focus on their application to overcome the various biological barriers to oral drug absorption, as exemplified by selected preclinical studies. Numerous studies have demonstrated the superiority of polymer-lipid hybrid systems to their non-hybrid counterparts in providing improved drug encapsulation, modulated drug release, and improved cellular uptake. These features have encouraged their applications in the delivery of chemotherapeutics, proteins, peptides, and vaccines. With further research expected to optimize the manufacturing and scaling up processes and in-depth pre-clinical pharmacological and toxicological assessments, these multifaceted drug delivery systems will have significant clinical impact on the oral delivery of pharmaceuticals and biopharmaceuticals.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.JCIS.2018.08.015
Abstract: Solid-state lipid formulations, whereby liquid lipids are encapsulated in inorganic particle matrices, have attracted significant interest for drug/nutrient delivery in recent years. We hypothesized that the surface chemistry of the inorganic material used to encapsulate lipids impacts the lipase-mediated digestion and partitioning of lipolytic species between the solubilized aqueous and insoluble pellet phases. Medium chain triglycerides were spray dried with silica nanoparticles, montmorillonite or laponite platelets to form inorganic-lipid hybrid particles. In vitro lipolysis studies were conducted under gastric (pH 1.6) and intestinal (pH 7.5) conditions, and the speciation and partitioning of lipolytic products between the aqueous and pellet phases was characterized using solution-state proton nuclear magnetic resonance and fourier transform infrared spectroscopy. Under gastric conditions, greater than 80% of all lipid species remained adsorbed within each lipolysis pellet after 60 min. Approximately 40%, 50-60% and 80-90% of all lipid species were adsorbed from solution by silica-, montmorillonite- and laponite-based particle matrices during intestinal lipolysis. Monoglycerides were preferentially adsorbed by silica, whereas triglycerides and fatty acids were adsorbed by montmorillonite and laponite. Adsorption of lipolytic products from solution is expected to impact significantly on drug/nutrient solubilization and absorption in vivo. To the best of our knowledge, this is the first report characterizing the speciation and phase behavior of lipolytic products released from solid-state lipid formulations during in vitro lipolysis studies.
Publisher: American Chemical Society (ACS)
Date: 30-05-2017
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.XPHS.2017.08.006
Abstract: Extracellular polymeric substances in bacterial biofilms reduce the penetration of antimicrobials and give rise to extreme recalcitrance and treatment challenges for many persistent biofilms and associated infections. Nitric oxide (NO) is a promising alternative to conventional antimicrobials but is challenging to deliver at precise concentrations for significant periods in a convenient and nontoxic manner. Here we report a unique NO delivery platform by incorporating the NO precursor isosorbide mononitrate (ISMN) into chitosan gels to facilitate sustained ISMN release and effective delivery. The chitosan gels were characterized with respect to the drug release kinetics, rheological properties, as well as antimicrobial efficacy against biofilms of Staphylococcus aureus in the absence and presence of the antibiotic ciprofloxacin. Chitosan gels loaded with ISMN alone (CS-ISMN) showed comparable antimicrobial effects compared to blank chitosan gel (approximately 2 log
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1002/JPS.21882
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Publisher: American Chemical Society (ACS)
Date: 28-04-2021
Publisher: Wiley
Date: 13-04-2012
Publisher: MDPI AG
Date: 14-01-2023
DOI: 10.3390/PHARMACEUTICS15010284
Abstract: Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90–300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.JCONREL.2021.12.003
Abstract: Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs ( 5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Chemical Society (ACS)
Date: 23-06-2017
Abstract: Biofilms are aggregates of bacteria residing in a self-assembled matrix, which protects these sessile cells against external stress, including antibiotic therapies. In light of emerging multidrug-resistant bacteria, alternative strategies to antibiotics are emerging. The present study evaluated the activity of colloidal silver nanoparticles (AgNPs) of different shapes against biofilms formed by Staphylococcus aureus (SA), methicillin-resistant SA (MRSA), and Pseudomonas aeruginosa (PA). Colloidal quasi-spherical, cubic, and star-shaped AgNPs were synthesized, and their cytotoxicity on macrophages (THP-1) and bronchial epithelial cells (Nuli-1) was analyzed by the lactate dehydrogenase assay. The antibiofilm activity was assessed in vitro by the resazurin assay and in an in vivo infection model in Caenorhabditis elegans. Cubic and star-shaped AgNPs induced cytotoxicity, while quasi-spherical AgNPs were not toxic. Quasi-spherical AgNPs showed substantial antibiofilm activity in vitro with 96% (±2%), 97% (±1%), and 98% (±1%) biofilm killing of SA, MRSA, and PA, respectively, while significantly reducing mortality of infected nematodes. The in vivo antibiofilm activity was linked to the accumulation of AgNPs in the intestinal tract of C. elegans as observed by 3D X-ray tomography. Quasi-spherical AgNPs were physically stable in suspension for over 6 months with no observed loss in antibiofilm activity. While toxicity and stability limited the utilization of cubic and star-shaped AgNPs, quasi-spherical AgNPs could be rapidly synthesized, were stable and nontoxic, and showed substantial in vitro and in vivo activity against clinically relevant biofilms. Quasi-spherical AgNPs hold potential as pharmacotherapy, for ex le, as topical treatment for biofilm-related infections.
Publisher: MDPI AG
Date: 23-03-2023
DOI: 10.3390/PHARMACEUTICS15041037
Abstract: Intracellular bacteria are inaccessible and highly tolerant to antibiotics, hence are a major contributor to the global challenge of antibiotic resistance and recalcitrant clinical infections. This, in tandem with stagnant antibacterial discovery, highlights an unmet need for new delivery technologies to treat intracellular infections more effectively. Here, we compare the uptake, delivery, and efficacy of rif icin (Rif)-loaded mesoporous silica nanoparticles (MSN) and organo-modified (ethylene-bridged) MSN (MON) as an antibiotic treatment against small colony variants (SCV) Staphylococcus aureus (SA) in murine macrophages (RAW 264.7). Macrophage uptake of MON was five-fold that of equivalent sized MSN and without significant cytotoxicity on human embryonic kidney cells (HEK 293T) or RAW 264.7 cells. MON also facilitated increased Rif loading with sustained release, and seven-fold increased Rif delivery to infected macrophages. The combined effects of increased uptake and intracellular delivery of Rif by MON reduced the colony forming units of intracellular SCV-SA 28 times and 65 times compared to MSN-Rif and non-encapsulated Rif, respectively (at a dose of 5 µg/mL). Conclusively, the organic framework of MON offers significant advantages and opportunities over MSN for the treatment of intracellular infections.
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/NNM.14.37
Abstract: Aim: To investigate the role of self-emulsifying lipids and porous silica particles in enhancing supersaturated drug loading and biopharmaceutical performance of nanostructured silica–lipid hybrid (SLH) systems. Materials & methods: Two lovastatin (LOV)-SLHs were engineered from self-emulsifying lipid (Gelucire ® 44/14 Gattefossé, Lyon, France) and Aerosil ® 380 (SLH-A Evonik Industries, Essen, Germany) or Syloid ® 244FP silica (SLH-S Grace Davison Discovery Sciences, Rowville, Australia). Results & discussion: The LOV-SLHs encapsulated LOV at 10% w/w, which is ≥3-fold higher than typical lipid formulations in the absence of porous silica. The LOV-SLHs retained self-emulsifying lipid-associated solubilization benefits and improved drug solubilization by twofold in simulated intestinal condition. SLH-S, with larger surface area (299 m 2 /g), was superior to SLH-A (184 m 2 /g) in optimizing oral bioavailability, suggesting a critical role of the silica geometry. Bioavailability of SLH-S was 2.8- and 1.3-fold higher than pure drug and drug suspension in Gelucire 44/14, respectively. Conclusion: In conclusion, SLHs profit from advantages associated with both self-emulsifying lipids and porous silica, and provide potentially improved therapy against coronary artery disease.
Publisher: MDPI AG
Date: 06-10-2022
DOI: 10.3390/PHARMACEUTICS14102124
Abstract: The looming antimicrobial resistance pandemic has encouraged the investigation of antimicrobial photodynamic therapy (aPDT) as a promising technology to combat recalcitrant bacterial infections caused by antibiotic resistant strains. Here, we report on the optimization and effective application of gallium protoporphyrin liquid crystalline lipid nanoparticles (GaPP-LCNP) as a photosensitizer for aPDT against the Gram-negative bacteria P. aeruginosa in both planktonic and biofilm modes of growth. LCNP significantly enhanced the performance of GaPP as photosensitizer by two-fold, which was correlated with higher antibacterial activity, reducing the viability of planktonic P. aeruginosa by 7 log10 using 0.8 µM GaPP-LCNP and a light dose of 17 J.cm−2. Importantly, GaPP-LCNP also reduced the viability of biofilms by 6 log10 at relatively low light dose of 34.2 J.cm−2 using only 3 µM GaPP-LCNP. The high antibiofilm activity of GaPP-LCNP at low GaPP-LCNP dose indicated the high efficiency and safety profile of GaPP-LCNP as a promising platform for photodynamic inactivation of recalcitrant infections.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2016
DOI: 10.1208/S12248-015-9864-Z
Abstract: Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.
Publisher: Bentham Science Publishers Ltd.
Date: 18-10-2016
Publisher: Future Science Ltd
Date: 02-2015
DOI: 10.4155/TDE.14.112
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.EJPB.2018.05.028
Abstract: The synergistic effect of nanosizing and lipid-based drug delivery systems (LBDDS) was explored to enhance formulation drug loading levels and improve drug solubilisation in the gastrointestinal environment. A novel formulation combining drug nanocrystals and silica-lipid hybrid (SLH) microparticles as a solid-state LBDDS was developed for the challenging poorly water-soluble drug, ziprasidone. A ziprasidone nanosuspension was fabricated via high-pressure homogenisation, achieving a mean particle size of 280 nm. In vitro dissolution studies revealed the nanosuspension to exhibit a significant 2.4-fold increase in the extent of drug dissolution, relative to pure drug. Novel ziprasidone nanocrystal-loaded SLH microparticles (ncSLH) were formulated by freeze-drying a precursor drug-loaded emulsion with drug nanocrystals and silica nanoparticles. Drug loading levels were increased at least 17-fold relative to conventional SLH microparticles, resulting in an increase in crystalline drug content and a change in surface atomic composition. The in vitro performance was evaluated by quantifying solubilisation levels during simulated intestinal lipolysis studies. Novel ncSLH significantly improved the in vitro fasted state solubilisation of ziprasidone (up to 4.7-fold), thus indicating the potential for such a formulation to overcome some of the various challenges faced by poorly water-soluble, brick-dust drug molecules.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Wiley
Date: 28-04-2020
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.EJPB.2015.09.018
Abstract: The gastric mucosa provides the entry point for the majority of pathogens, as well as being the induction site for protective immunity however, there remain few ex les of oral vaccines due to the challenges presented by the gastrointestinal route. In this study, we develop a lipid-based multi-compartmental system for oral vaccine delivery. Specifically, we have optimised the formulation of a water-in-oil-in-water double emulsion prepared from a triglyceride - soya bean oil, using surfactants Span 80/Tween 80 and Pluronic F127 to stabilise the internal and external water phases, respectively. Into the internal water phase, we also incorporated a PEGylated liposome, prepared using hydrogenated phosphatidyl choline as a carrier for our model protein, FITC-labelled ovalbumin. We demonstrated the successful incorporation of intact liposomes into the internal water phase of the double emulsion using imaging techniques including cryo-SEM and confocal microscopy. Finally, we use in vitro release studies of FITC-ovalbumin, to provide further confirmation of the multi-compartmental structure of the double emulsion system and demonstrate significant extended release of the entrapped model antigen compared with PEG-liposomes these characteristics are attractive for oral vaccine delivery.
Publisher: Wiley
Date: 06-2017
Abstract: There is a pressing need to develop more effective therapeutics to fight cancer. An idyllic chemotherapeutic is expected to overcome drug resistance of tumors and minimize harmful side effects to healthy tissues. Antibody-functionalized porous silicon nanoparticles loaded with a combination of chemotherapy drug and gold nanoclusters (AuNCs) are developed. These nanocarriers are observed to selectively deliver both payloads, the chemotherapy drug and AuNCs, to human B cells. The accumulation of AuNCs to target cells and subsequent exposure to an external electromagnetic field in the microwave region render them more susceptible to the codelivered drug. This approach represents a targeted two-stage delivery nanocarrier that benefits from a dual therapeutic action that results in enhanced cytotoxicity.
Publisher: Springer New York
Date: 2016
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.ADDR.2021.113948
Abstract: Bacteria have developed a wealth of strategies to avoid and resist the action of antibiotics, one of which involves pathogens invading and forming reservoirs within host cells. Due to the poor cell membrane permeability, stability and retention of conventional antibiotics, this renders current treatments largely ineffective, since achieving a therapeutically relevant antibiotic concentration at the site of intracellular infection is not possible. To overcome such challenges, current antibiotics are 'repurposed' via reformulation using micro- or nano-carrier systems that effectively encapsulate and deliver therapeutics across cellular membranes of infected cells. Bioinspired materials that imitate the uptake of biological particulates and release antibiotics in response to natural stimuli are recently explored to improve the targeting and specificity of this 'nanoantibiotic' approach. In this review, the mechanisms of internalization and survival of intracellular bacteria are elucidated, effectively accentuating the current treatment challenges for intracellular infections and the implications for repurposing conventional antibiotics. Key case studies of nanoantibiotics that have drawn inspiration from natural biological particles and cellular uptake pathways to effectively eradicate intracellular pathogens are detailed, clearly highlighting the rational for harnessing bioinspired drug delivery strategies.
Publisher: Bentham Science Publishers Ltd.
Date: 18-10-2016
Publisher: MDPI AG
Date: 21-07-2020
DOI: 10.3390/PHARMACEUTICS12070687
Abstract: The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3–22.7% w/w, (ii) lipid type: medium-chain triglyceride (Captex 300) and mono and diester of caprylic acid (Capmul PG8), and (iii) silica nanostructure: spray dried fumed silica (FS) and mesoporous silica (MPS), on the in vitro dissolution, solubilization, and solid-state stability of the model drug fenofibrate (FEN). Greater FEN crystallinity was detected at higher drug loads and within the MPS formulations. Furthermore, an increased rate and extent of dissolution was achieved by FS formulations when compared to crystalline FEN (5–10-fold), a commercial product APO-fenofibrate (2.4–4-fold) and corresponding MPS formulations (2–4-fold). Precipitation of FEN during in vitro lipolysis restricted data interpretation, however a synergistic effect between MPS and Captex 300 in enhancing FEN aqueous solubilization was attained. It was concluded that a balance between in vitro performance and drug loading is key, and the optimum drug load was determined to be between 7–16% w/w, which corresponds to (200–400% equilibrium solubility in lipid Seq). This study provides valuable insight into the impact of key characteristics of SLHs, in constructing optimized solid-state lipid-based formulations for the oral delivery of PWSDs.
Publisher: Elsevier BV
Date: 05-2020
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.
Publisher: Elsevier BV
Date: 2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9BM00058E
Abstract: An intestine-on-a-chip model was used for the first time to study the intestinal uptake of nanoparticulate oral drug carriers and their ability to overcome the mucus barrier.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JCONREL.2022.04.035
Abstract: Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach to aid the fight against looming antibiotic resistance. aPDT harnesses the energy of light through photosenstizers to generate highly reactive oxygen species that can inactivate bacteria and fungi with no resistance. To date aPDT has shown great efficacy against microbes causing localized infections in the skin and the oral cavity. However, its wide application in clinical settings has been limited due to both physicochemical and biological challenges. Over the past decade nanomaterials have contributed to promoting photosensitizer performance and aPDT efficiency, yet further developments are required to establish accredited treatment options. In this review we discuss the challenges facing the clinical application of aPDT and the opportunities that nanotechnology may offer to promote the safety and efficiency of aPDT.
Publisher: Frontiers Media SA
Date: 11-05-2018
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.IJPHARM.2011.12.027
Abstract: Submicron oil-in-water (o/w) emulsions stabilised with conventional surfactants and silica nanoparticles were prepared and freeze-dried to obtain free-flowing powders with good redispersibility and a three-dimensional porous matrix structure. Solid-state emulsions were characterised for visual appearance, particle size distribution, zeta potential and reconstitution properties after freeze-drying with various sugars and at a range of sugar to oil ratios. Comparative degradation kinetics of all-trans-retinol from freeze-dried and liquid emulsions was investigated as a function of storage temperatures. Optimum stability was observed for silica-coated oleylamine emulsions at 4 °C in their wet state. The half-life of all-trans-retinol was 25.66 and 22.08 weeks for silica incorporation from the oil and water phases respectively. This was ∼4 times higher compared to the equivalent solid-state emulsions with drug half-life of 6.18 and 6.06 weeks at 4 °C. Exceptionally, at a storage temperature of 40 °C, the chemical stability of the drug was 3 times higher in the solid-state compared to the wet emulsions which confirmed that freeze-drying is a promising approach to improve the chemical stability of water-labile compounds provided that the storage conditions are optimised.
Publisher: Bentham Science Publishers Ltd.
Date: 29-03-2014
DOI: 10.2174/1568026614666140329232252
Abstract: Statins are effective lipid lowering agents traditionally used for the primary and secondary prevention of cardiovascular disease. Statins also exert a range of pleiotropic effects that make them attractive candidates for use in a wide range of disorders, in particular inflammatory and immune mediated conditions. However, the exploitation of such pleiotropic effects has been greatly hindered by poor bioavailability and adverse effects on muscles and the liver at higher doses. Nanotechnology is often suggested as the solution to this problem, as it enables an increased bioavailability of statins. Moreover, colloidal carriers can offer targeted drug delivery approaches that enable localised biological effects of statins, further reducing their potential for unwanted toxicity and adverse effects. This article reviews the available evidences for the increased potential of statin therapy when administered in nano-formulations such as nanocrystals, nanoparticles, liposomes, micelles and various nano-enabled devices.
Publisher: American Chemical Society (ACS)
Date: 16-12-2016
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00785
Abstract: SN38 (7-ethyl-10-hydroxy c tothecin) is a potent anticancer agent belonging to the c tothecin family however, its oral delivery is extensively restricted by poor solubility in pharmaceutically acceptable excipients and low transmucosal permeability. Lipid-based carriers are well-known for their ability to improve oral absorption and bioavailability of lipid soluble and highly permeable compounds. Thus, this study has focused on improving solubility in lipid excipients, controlling stability, and enhancing transmucosal permeability of SN38 by specific chemical modification. To achieve these aims, a series of lipophilic prodrugs were designed and synthesized by esterification at the C10 and/or C20 positon(s) of SN38 with dietary fatty acids of erse hydrocarbon chain lengths. The solubility of these novel prodrugs in long-chain triglycerides was increased up to 444-fold, and cytotoxicity was significantly reduced in comparison to SN38. The prodrugs were stable in simulated gastric fluids but exhibited different rates of hydrolysis (t1/2 2 h) in simulated intestinal fluids (in the presence of enzymes) depending on the alkyl chain length and the position modified. A predictable reconversion of prodrugs to SN38 in plasma was also confirmed. On the basis of these studies, SN38-undecanoate (C20) was identified as the optimal prodrug. Finally, in vitro permeability and uptake studies in rat intestinal mucosal membrane using an Ussing chamber showed significant improvement in transepithelial drug transport and cellular uptake. Together, these results indicate that well designed lipophilic prodrugs have potential for the efficacious and safe oral delivery of SN38.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.NANO.2022.102536
Abstract: Bacterial biofilm infections tolerate high concentrations of antibiotics and are insidiously challenging to treat. Liquid crystal nanoparticles (LCNPs) advance the efficacy of tobramycin in biofilm-related infections by increasing the penetration of antibiotics across the biofilm matrix. Herewith, we develop the LCNPs as a platform technology, demonstrating that the LCNPs can increase the efficacy of two antibiotic classes (i.e. aminoglycosides and colistin) in P. aeruginosa biofilm infections. In C. elegans, the LCNPs potentiated the antimicrobial effect and significantly improved the survival of the nematodes. In mice with a full-thickness excisional wound, LCNPs were non-toxic and did not impair wound repair. Compared to the unformulated antibiotic treatment, tobramycin-LCNPs reduced the chronic bacterial load by 100-fold in the wound. This was also emulated in an ex vivo P. aeruginosa porcine wound infection model. The LCNPs represent a versatile platform technology that improves the efficacy of cationic antibiotics against biofilm infections utilizing multiple administration routes.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.COLSURFB.2016.02.059
Abstract: Bio-active materials consisting of lipase encapsulated within porous silica particles were engineered to control the adsorption kinetics and molecular orientation of lipase, which play critical roles in the digestion kinetics of triglycerides. The adsorption kinetics of Candida antartica lipase A (CalA) was monitored using quartz crystal microbalance with dissipation (QCM-D) and controlled by altering the hydrophobicity of a silica binding support. The extent of adsorption was 2-fold greater when CalA was adsorbed onto hydrophobic silica compared to hydrophilic silica. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) fragmentation patterns, in conjunction with multivariate statistics, demonstrated enhanced exposure of the lipase's catalytic domain, specifically the histidine group responsible for activity, when CalA was adsorbed on hydrophilic silica. Consequently, lipid digestion kinetics were enhanced when CalA was loaded in hydrophilic porous silica particles, i.e., a 2-fold increase in the pseudo-first-order rate constant for digestion when compared to free lipase. In contrast, digestion kinetics were inhibited when CalA was hosted in hydrophobic porous silica, i.e., a 5-fold decrease in pseudo-first-order rate constant for digestion when compared to free lipase. These findings provide valuable insights into the mechanism of lipase action which can be exploited to develop smarter food and drug delivery systems consisting of porous lipid-based materials.
Publisher: Springer Science and Business Media LLC
Date: 15-12-2023
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-12-2019
Abstract: Supersaturated silica-lipid hybrid (super-SLH) drug carriers are a recent strategy to improve the drug loading of oral solid lipid based formulations, however they are yet to be studied in vivo. This study investigated the in vivo pharmacokinetics (PK) of super-SLH containing ibuprofen (IBU), as a model Biopharmaceutics Classification Scheme (BCS) class II drug, analyzing the influence of supersaturated drug loading on oral bioavailability and assessing in vitro-in vivo correlation (IVIVC). In addition, super-SLH was directly compared with spray-dried SLH and Nurofen to explore its potential advantages over the well-established and commercial formulations. Fasted male Sprague-Dawley rats were administered formulation suspensions (10 mg/kg IBU) via oral gavage, and blood s les were acquired and plasma was analyzed for IBU concentrations over 24 hours. In vivo, super-SLH with drug loads of 9.5 (99.5% saturated) and 19.3% w/w (227% saturated) achieved bioavailabilities equal to spray-dried SLH and 2.2-fold greater than Nurofen. This effect diminished for super-SLH with a drug load of 29.1% w/w (389% saturated), which exhibited a bioavailability of less than Nurofen due to its greater extent of supersaturation and larger content of crystalline IBU. The super-SLH containing 19.3% w/w IBU provided the greatest PK performance, achieving the same degree of bioavailability enhancement as spray-dried SLH and requiring 63% less formulation. A significant positive IVIVC was observed between the performances of the formulations. These findings indicate the potential of super-SLH as an improved oral solid lipid based formulation strategy for enhancing oral bioavailability of other BCS class II drugs.
Publisher: American Chemical Society (ACS)
Date: 03-06-2020
Abstract: Strategies to improve the uptake of particulate delivery systems to macrophages are required for the advancement of therapeutic solutions to a range of disease states, including human immunodeficiency virus (HIV), tuberculosis, and cystic fibrosis. In this study, poly(lactic-
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.IJPHARM.2017.04.063
Abstract: Lipid-based formulations (LBFs) are a popular strategy for enhancing the gastrointestinal solubilization and absorption of poorly water-soluble drugs. In light of this, montmorillonite-lipid hybrid (MLH) particles, composed of medium-chain triglycerides, lecithin and montmorillonite clay platelets, have been developed as a novel solid-state LBF. Owing to the unique charge properties of montmorillonite, whereby the clay platelet surfaces carry a permanent negative charge and the platelet edges carry a pH-dependent charge, three model poorly water-soluble drugs with different charge properties blonanserin (weak base, pKa 7.7), ibuprofen (weak acid, pKa 4.5) and fenofibrate (neutral), were formulated as MLH particles and their performance during biorelevant in vitro lipolysis at pH 7.5 was investigated. For blonanserin, drug solubilization during in vitro lipolysis was significantly reduced 3.4-fold and 3.2-fold for MLH particles in comparison to a control lipid solution and silica-lipid hybrid (SLH) particles, respectively. It was hypothesized that strong electrostatic interactions between the anionic montmorillonite platelet surfaces and cationic blonanserin molecules were responsible for the inferior performance of MLH particles. In contrast, no significant influence on drug solubilization was observed for ibuprofen- and fenofibrate-loaded MLH particles. The results of the current study indicate that whilst MLH particles are a promising novel formulation strategy for poorly water-soluble drugs, drug ionization tendency and the potential for drug-clay interactions must be taken into consideration to ensure an appropriate performance.
Publisher: Wiley
Date: 25-02-2016
DOI: 10.1002/ALR.21735
Abstract: Biofilms are clusters of bacteria embedded in a protective matrix that frequently cause failure of medical treatments and increase the risk of recurrent infections. In particular, Staphylococcus aureus biofilms are associated with a series of chronic and nosocomial infections that are increasingly resistant to antibiotics. This study proposes a novel intervention strategy targeting the essential iron metabolism for bacterial growth, survival and pathogenesis using the compounds deferiprone (Def) and gallium-protoporphyrin (GaPP). S. aureus biofilms were challenged with Def/GaPP as single and dual treatments. In vitro anti-biofilm efficacy was assessed by the AlamarBlue viability assay and confocal microscopy. In vitro cytotoxicity of the treatments was examined by the lactate dehydrogenase assay on mouse fibroblast (L929) and human bronchial epithelial cells (Nuli-1). Def (20 mM) and GaPP (200 μg/mL) monotherapy for 2 hours showed 35% and 74% biofilm removal, respectively, whereas simultaneous Def/GaPP administration showed 55% biofilm removal. In contrast, the consecutive treatment (2 hours Def followed by 2 hours GaPP) achieved 95% biofilm removal. Cytotoxicity studies indicated no cell hazard in all treatments. This study demonstrated the in vitro efficacy of a novel treatment combination against S. aureus biofilms targeting the bacterial iron metabolism. The consecutive Def/GaPP treatment showed significantly enhanced biofilm efficacy than the in idual compounds, while being not toxic to 2 cell lines. This novel treatment combination is a promising approach to combat S. aureus-associated biofilm infections having high potential for future clinical application.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.JCIS.2011.02.056
Abstract: The interfacial and bulk properties of submicron oil-in-water emulsions simultaneously stabilised with a conventional surfactant (either lecithin or oleylamine) and hydrophilic silica nanoparticles (Aerosil®380) were investigated and compared with emulsions stabilised by either stabiliser. Emulsions solely stabilised with lecithin or oleylamine showed poor physical stability, i.e., sedimentation and the release of pure oil was observed within 3 months storage. The formation and long-term stability of silica nanoparticle-coated emulsions was investigated as a function of the surfactant type, charge, and concentration the oil phase polarity (Miglyol®812 versus liquid paraffin) and loading phase of nanoparticles, either oil or water. Highly stable emulsions with long-term resistance to coalescence and creaming were formulated even at low lecithin concentrations in the presence of optimum levels of silica nanoparticles. The attachment energy of silica nanoparticles at the non-polar oil-water interface in the presence of lecithin was significantly higher compared to oleylamine in line with good long-term stability of the former compared to the sedimentation and release of oil in the latter. The attachment energy of silica nanoparticles at the polar oil-water interface especially in the presence of oleylamine was up to five-times higher compared to the non-polar liquid paraffin. The interfacial layer structure of nanoparticles (close-packed layer of particle aggregates or scattered particle flocs) directly related to the free energy of nanoparticle adsorption at both MCT oil and liquid paraffin-water interfaces.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.JCIS.2012.02.058
Abstract: The structure and stability of emulsions formed in the presence of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) were characterised. From oil-water contact angles on PLGA films, it was deduced that particle surface hydrophobicity is linked to the oil phase polarity. Incorporation of polyvinyl alcohol molecules into the nanoparticle surfaces reduces the particle hydrophobicity sufficiently for oil-in-water emulsions to be preferentially stabilised. PLGA nanoparticles enhance the stability of emulsions formed from a wide range of oils of different polarities. The nanoparticle concentration was found to be a key parameter controlling the average size and coalescence stability of the emulsion drops. Visualisation of the interfacial structure by electron microscopy indicated that PLGA nanoparticles were located at the drop surfaces, evidence of the capacity of these particles to stabilise Pickering-type emulsions. These results provide insights into the mechanism of PLGA nanoparticle stabilisation of emulsions.
Publisher: Elsevier
Date: 2014
Publisher: American Chemical Society (ACS)
Date: 09-05-2014
DOI: 10.1021/LA5003447
Abstract: High-symmetry lipid nanoparticles with internal bicontinuous cubic phase structure (cubosomes) are prepared from a simple emulsion containing a mixture of a nondigestible lipid (phytantriol) and a digestible short-chained triglyceride using enzymatic lipolysis of the incorporated short-chained triglyceride. The lipolytic products partition away from the nondigestible lipid, resulting in crystallization of the cubic-phase internal structure. Time-resolved small-angle X-ray scattering revealed the kinetics of the disorder-to-order transition, with cryo-transmission electron microscopy showing an absence of liposomes. The new approach offers a new "sideways" method for the generation of lipid-based nanostructured materials that avoids the problems of top-down and bottom-up approaches.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2021
DOI: 10.1007/S13346-020-00853-X
Abstract: Simvastatin (SIM) is a commonly used cholesterol-lowering drug that can reduce the risk of major cardiovascular events. However, due to its poor intrinsic water solubility, the drug is poorly absorbed from the gastrointestinal tract and exhibits a low oral bioavailability of approximately 5%. The aim of this study was to fabricate and optimize SIM encapsulated silica-lipid hybrids (SLH) as a solid-state lipid-based formulation to enhance absorption and bioavailability during a human in vivo pharmacokinetic study. SLH formulations were formulated by spray drying a submicron emulsion with either Aerosil® 300 fumed silica nanoparticles (SLH-A) or Syloid® 244 amorphous micronized silica (SLH-B). A cross-over, double-blinded study design was implemented to evaluate the performance of SLH formulations compared with a commercially available formulation in 12 healthy male participants after oral administration under fasting conditions. SLH formulations enhanced the bioavailability of SIM up to 1.6-fold and more importantly the active simvastatin acid (SIMA), 3.5-fold when compared with an equivalent dose of commercial formulation. The results demonstrate that the porous nanostructure of SLH impact systemic SIM and SIMA concentrations and may serve as a novel approach to enhance the bioavailability of specifically the parent or metabolite. No significant difference was observed in exposure when SLH formulations were administered at 10 mg in comparison with 20 mg of the commercial formulation, suggesting the potential for dose reduction. The study indicated that SLH formulations were safe and well-tolerated when administered to healthy males, confirming the commercial potential of SLH to enhance the bioavailability of poorly water-soluble drugs. Graphical abstract.
Publisher: SPIE-Intl Soc Optical Eng
Date: 07-12-2016
Publisher: Springer Science and Business Media LLC
Date: 12-08-2022
DOI: 10.1007/S00280-022-04463-X
Abstract: Gastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11. 24 C57BL/6 mice received a vehicle, daily i.p. IAXO-102 (3 mg/kg), i.p. CPT-11 (270 mg/kg) or a combination of CPT-11 and IAXO-102. GIM was assessed using validated toxicity markers. At 72 h, colon and tumour tissue were collected and examined for histopathological changes and RT-PCR for genes of interest TLR4, MD-2, CD-14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, and CXCR2. IAXO-102 prevented diarrhoea in mice treated with CPT-11. Tumour volume in IAXO-102-treated mice was lower compared to vehicle at 48 h ( P 0.05). There were no differences observed in colon and tumour weights between the treatment groups. Mice who received the combination treatment had improved tissue injury score ( P 0.05) in the colon but did not show any improvements in cell proliferation or apoptotic rate. Expression of all genes was similar across all treatment groups in the tumour ( P 0.05). In the colon, there was a difference in transcript expression in vehicle vs. IAXO-102 ( P 0.05) and CPT-11 vs. combination ( P 0.01) in MD-2 and IL-6R, respectively. IAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.
Publisher: Elsevier BV
Date: 2020
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.EJPB.2017.12.012
Abstract: The method of supersaturation for achieving high drug loads in lipid-based formulations is under exploited and relatively unexplored, especially in the case of solid-state lipid-based formulations. Silica-lipid hybrids are solid-state lipid-based formulations designed for improving the oral delivery of poorly water-soluble drugs. However, their application to compounds of low potency and requiring large doses is limited by their low drug loading capacity. Here, an innovative technique to fabricate supersaturated silica-lipid hybrid formulations (super-SLH) has been established and the relationship between drug load and performance investigated. Using the model poorly water-soluble drug, ibuprofen, super-SLH was fabricated possessing drug loads ranging from 8 to 44% w/w, i.e. greater than the previously developed standard ibuprofen silica-lipid hybrids (5.6% w/w). Drug crystallinity of the encapsulated ibuprofen ranged from non-crystalline to part-crystalline with an increase in drug load. Super-SLH achieved improved rates and extents of dissolution when compared to pure ibuprofen, regardless of the drug load. The percentage increase in dissolution extent at 60 min varied from 200 to 600%. The results of the current study indicate that supersaturation greatly improves drug loading and that 16-25% w/w is the optimum loading level which retains optimal dissolution behaviour for the oral delivery of ibuprofen, which has the potential to be translated to other poorly water-soluble drugs.
Publisher: American Chemical Society (ACS)
Date: 18-07-2023
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1002/JPS.23406
Publisher: American Chemical Society (ACS)
Date: 09-05-2011
DOI: 10.1021/AM2003069
Abstract: The adsorption of nanostructured lyotropic liquid-crystal particles, cubosomes and hexosomes, at surfaces was investigated for potential use in surface-specific agrochemical delivery. Adsorption of phytantriol (PHYT) and glyceryl monooleate (GMO)-based cubosomes and hexosomes, stabilized using Pluronic F127, at tristearin-coated (model leaf surface) and uncoated zinc selenide surfaces was studied using attenuated total reflectance Fourier transform IR (ATR-FTIR) spectroscopy, by quantifying the IR absorbance due to the lipid components of the particles over time. The delivery of an encapsulated hydrophobic model herbicide [dichlorodiphenyldichloroethylene (DDE)] was also examined on the model and real leaf surfaces. The adsorption behavior of the particles by ATR-FTIR was dependent on the internal nanostructure and lipid composition, with PHYT cubosomes adsorbing more avidly at tristearin surfaces than GMO-based cubosomes or hexosomes. There was a direct correlation between DDE associated with the surfaces and the particle adsorption observed in the ATR-FTIR study, strongly implicating particle adsorption with the delivery efficiency. Differences between the mode of interaction of the Pluronic stabilizer with the different lipids and particle nanostructures were proposed to lead to differences in the particle adsorption behavior.
Publisher: Informatics Publishing Limited
Date: 03-11-2017
Abstract: Large aggregate (LA) fraction of the pulmonary surfactant (PS) isolated from five different animals of the vertebrate group, lungfish, chicken, crocodile, stumpie lizard and guinea pig were isolated and characterized. Active pulmonary surfactant components were obtained by chloroform-methanol extraction of the saline suspended LA fraction. Total phospholipid (PL) and protein content were estimated biochemically by standard enzymatic methods. A systematic progression in the PL and protein content was noticed with the developmental sequence of the animals, except the crocodile, which could be due to the difficulty in the PS isolation procedure. em In vitro /em functionality of the solvent spread film was carried out in a Langmuir surface balance by way of surface pressure (π)-area (A) measurements. PS from all the species exhibited reversible compression and expansion cycles. A clear correlation between the maximum attainable surface pressure (π sub max /sub ), also known as the collapse pressure (π sub c /sub ) and the developmental sequence, with some exceptions, could have been established. Langmuir-Blodgett deposits, transferred onto freshly cleaved mica, were imaged by atomic force microscopy for the five different species. DPPC enriched domains showed different dimensions for the five different species. The comprehensive set of studies shed light on the composition, film functionality and structure of the pulmonary surfactants of the vertebrates where a correlation with the evolution sequence is observed.
Publisher: SAGE Publications
Date: 24-03-2019
Abstract: M cells are an epithelial cell population found in the follicle-associated epithelium overlying gut-associated lymphoid tissues. They are specialized in the transcytosis of luminal antigens. Their transcytotic capacity and location in an immunocompetent environment has prompted the study of these cells as possible targets for oral drug delivery systems. Currently, the models most commonly used to study M cells are restricted to in vivo experiments conducted in mice, and in vitro studies conducted in models comprised either of primary epithelial cells or established cell lines of murine or human origin. In vitro models of the follicle-associated epithelium can be constructed in several ways. Small intestinal Lgr5+ stem cells can be cultured into a 3D organoid structure where M cells are induced with RANKL administration. Additionally, in vitro models containing an “M cell-like” population can be obtained through co-culturing intestinal epithelial cells with cells of lymphocytic origin to induce the M cell phenotype. The evaluation of the efficiency of the variations of these models and their relevance to the in vivo human system is h ered by the lack of a universal M cell marker. This issue has also hindered the advancement of M cell-specific targeting approaches aimed at improving the bioavailability of orally administered compounds. This critical review discusses the different approaches utilized in the literature to identify M cells, their efficiency, reliability and relevance, in the context of commonly used models of the follicle-associated epithelium. The outcome of this review is a clearly defined and universally recognized criteria for the assessment of the relevance of models of the follicle-associated models currently used. The study of M cells, a specialized epithelial cell type found in the follicle-associated epithelium, is h ered by the lack of a universal M cell marker. As such, many studies lack reliable and universally recognized methods to identify M cells in their proposed models. As a result of this it is difficult to ascertain whether the effects observed are due to the presence of M cells or an unaccounted variable. The outcome of this review is the thorough evaluation of the many M cell markers that have been used in the literature thus far and a proposed criterion for the identification of M cells for future publications. This will hopefully lead to an improvement in the quality of future publications in this field.
Publisher: MDPI AG
Date: 28-11-2019
DOI: 10.3390/PHARMACEUTICS11120634
Abstract: Porous silicon (pSi) continues to receive considerable interest for use in applications ranging from sensors, biological scaffolds, therapeutic delivery systems to theranostics. Critical to all of these applications is pSi degradation and stabilization in biological media. Here we report on progress towards the development of a mechanistic understanding for the dissolution behavior of native (unoxidized) and thermally oxidized (200–600 °C) pSi microparticles. Fourier transform infrared (FTIR) spectroscopy was used to characterize the pSi surface chemistry after thermal oxidation. PSi dissolution was assessed using a USP method II apparatus by monitoring the production of orthosilicic acid, and the influence of gastro-intestinal (GI) fluids were examined. Fitting pSi dissolution kinetics with a sum of the exponential model demonstrated that the dissolution process strongly correlates with the three surface hydride species and their relative reactivity, and was supported by the observed FTIR spectral changes of pSi during dissolution. Finally, the presence of GI proteins was shown to h er pSi dissolution by adsorption to the pSi surface acting as a barrier preventing water attack. These findings are significant in the optimal design of pSi particles for oral delivery and other controlled drug delivery applications.
Publisher: MDPI AG
Date: 11-04-2019
DOI: 10.3390/ANTIBIOTICS8020039
Abstract: Infectious diseases remain a major burden in today’s world, causing high mortality rates and significant economic losses, with million deaths per year predicted by 2030. Invasion of host cells by intracellular bacteria poses treatment challenges due to the poor permeation of antimicrobials into the infected cells. To overcome these limitations, mesoporous silica nanoparticles (MSNP) loaded with the antibiotic rif icin were investigated as a nanocarrier system for the treatment of intracellular bacterial infection with specific interest in the influence of particle size on treatment efficiency. An intracellular infection model was established using small colony variants (SCV) of S. aureus in macrophages to systemically evaluate the efficacy of rif icin-loaded MSNP against the pathogen as compared to a rif icin solution. As hypothesized, the superior uptake of MSNP by macrophages resulted in an enhanced treatment efficacy of the encapsulated rif icin as compared to free antibiotic. This study provides a potential platform to improve the performance of currently available antibiotics against intracellular infections.
Publisher: American Chemical Society (ACS)
Date: 16-11-2023
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.IJPHARM.2009.04.036
Abstract: The influence of silica nanoparticle coating on the chemical stability and phase distribution of all-trans-retinol in submicron oil-in-water emulsions is reported. The chemical stability was studied as a function of UVA+UVB irradiation, and storage temperature (4 degrees C, ambient temperature, and 40 degrees C) for emulsions stabilised with lecithin and oleylamine as the initial emulsifier with and without silica nanoparticle layers. The chemical stability of all-trans-retinol was highly dependent on the emulsifier type and charge, with negligible influence of the initial loading phase of silica nanoparticles. A significant stability improvement (approximately 2-fold increase in the half-life of the drug) was observed by nanoparticle incorporation into oleylamine-stabilised droplets (i.e. electrostatically coated), with no considerable effect for partially coated lecithin-stabilised droplets. The chemical stability of all-trans-retinol incorporated into nanoparticle-coated emulsions was well-correlated to the phase distribution of the active agent, and the interfacial structure of emulsions as determined by freeze fracture-SEM. Specifically engineered nanoparticle layers can be used to enhance the chemical stability of active ingredients in emulsion carriers.
Publisher: SPIE
Date: 22-12-2015
DOI: 10.1117/12.2202461
Publisher: Japan Oil Chemists' Society
Date: 2018
DOI: 10.5650/JOS.ESS14081
Abstract: Studies on the interaction of different generation poly (amido amine) (PAMAM) dendrimers (2G, 4G and 6G) and liposomes of different compositions were carried out by a combined turbidity, dynamic light scattering and atomic force microscopic measurements. Liposomes comprising soy lecithin (SLC, negative surface charge), 1, 2-palmitoyl-sn-glycero-3-phosphatidylcholine (DPPC, mildly positive surface charge), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol (DPPG, negatively charged) and a biologically simulated mixture of DPPC + DPPG (7:3, M/M, negatively charged) were used as model bilayers. 30 wt% cholesterol was used in each combination as it is known to control the fluidity of membrane bilayers. Silica was used as a negatively charged hard sphere model with an aim to compare the results. Both the turbidity and hydrodynamic diameter values of all the liposomes, except DPPC, passed through maxima upon the progressive addition of PAMAM the effect was insignificant in case of DPPC. Formation of dendriosome, a complex formed between dendrimer and liposome, resulted in the charge reversal of the negatively charged liposomes. Interaction between PAMAM and liposome was found to be governed by electrostatic as well as hydrogen bonding. Generation dependent PAMAM activity followed the order: 6G >4G>2G in terms of overall dendrimer concentration. However, interestingly, the order was reverse when PAMAM activity was considered in terms of total end group concentrations. AFM studies reveal the rupture of bilayer structure upon addition of dendrimer.
Publisher: Hindawi Limited
Date: 2017
DOI: 10.1155/2013/170201
Abstract: The aim of the present research is to formulate and evaluate polymeric nanosuspensions containing three model water insoluble drugs, nifedipine (NIF), carbamazepine (CBZ), and ibuprofen (IBU) with various physicochemical properties. The nanosuspensions were prepared from hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) by a cosolvent technique with polyethylene glycol (PEG-300) and water as the cosolvents. Physicochemical and morphological characteristics of the nanosuspensions (particle size, polydispersity index, and crystallinity) have been correlated with the drug release behaviour. The effects of polymer, drug ratio on the physical, morphological, and dissolution characteristics of the drugs are reported. Drug release is significantly enhanced from the nanosuspensions for ex le, the maximum NIF, IBU, and CBZ concentrations after 8-hour dissolution are increased approximately 37, 2, and 1.2 times, respectively, in comparison with the pure powdered drugs. Based on this solubilization enhancement performance, the nanosuspensions have potential for increasing the orally dosed bioavailability of NIF, IBU, and CBZ.
Publisher: MDPI AG
Date: 18-01-2022
DOI: 10.3390/PHARMACEUTICS14020221
Abstract: Liposomes are widely used as carriers for anticancer drugs due to their ability to prolong the retention of encapsulated drugs in blood plasma while directing their distribution increasingly into tumor tissue. We report on the development of stealth liposomal formulations for the common chemotherapy drug 5-fluorouracil, where pharmacokinetic studies were undertaken using a microdialysis probe to specifically quantify drug accumulation in tumor, which was contrasted to drug exposure to healthy tissue. Greater accumulation of the drug into the tumor than into healthy subcutaneous tissue was observed for neutral and cationic liposomal 5-fluorouracil polymer complexes in comparison to the conventional delivery by an injected solution. Increased drug accumulation in tumor also correlated to reduced tumor growth. This research has generated new mechanistic insight into liposomal-specific delivery to tumors with potential to improve the efficacy and reduce the toxicity of chemotherapy.
Publisher: American Chemical Society (ACS)
Date: 31-08-2012
DOI: 10.1021/LA302435G
Abstract: Nonlamellar liquid crystalline dispersions such as cubosomes and hexosomes have great potential as novel surface-targeted active delivery systems. In this study, the influence of internal nanostructure, chemical composition, and the presence of Pluronic F127 as a stabilizer, on the surface and interfacial properties of different liquid crystalline particles and surfaces, was investigated. The interfacial properties of the bulk liquid crystalline systems with coexisting excess water were dependent on the internal liquid crystalline nanostructure. In particular, the surfaces of the inverse cubic systems were more hydrophilic than that of the inverse hexagonal phase. The interaction between F127 and the bulk liquid crystalline systems depended on the internal liquid crystalline structure and chemical composition. For ex le, F127 adsorbed to the surface of the bulk phytantriol cubic phase, while for monoolein cubic phase, F127 was integrated into the liquid crystalline structure. Last, the interfacial adsorption behavior of the dispersed liquid crystalline particles also depended on both the internal nanostructure and the chemical composition, despite the dispersions all being stabilized using F127. The findings highlight the need to understand the specific surface characteristics and the nature of the interaction with colloidal stabilizer for understanding and optimizing the behavior of nonlamellar liquid crystalline systems in surface delivery applications.
Publisher: MDPI AG
Date: 30-11-2022
DOI: 10.3390/PHARMACEUTICS14122659
Abstract: High-throughput permeation models are essential in drug development for timely screening of new drug and formulation candidates. Nevertheless, many current permeability assays fail to account for the presence of the gastrointestinal mucus layer. In this study, an optimised high-throughput mucus permeation model was developed employing a highly biorelevant mucus mimic. While mucus permeation is primarily conducted in a simple mucin solution, the complex chemistry, nanostructure and rheology of mucus is more accurately modelled by a synthetic biosimilar mucus (BSM) employing additional protein, lipid and rheology-modifying polymer components. Utilising BSM, equivalent permeation of various molecular weight fluorescein isothiocyanate-dextrans were observed, compared with native porcine jejunal mucus, confirming replication of the natural mucus permeation barrier. Furthermore, utilising synthetic BSM facilitated the analysis of free protein permeation which could not be quantified in native mucus due to concurrent proteolytic degradation. Additionally, BSM could differentiate between the permeation of poly (lactic-co-glycolic) acid nanoparticles (PLGA-NP) with varying surface chemistries (cationic, anionic and PEGylated), PEG coating density and size, which could not be achieved by a 5% mucin solution. This work confirms the importance of utilising highly biorelevant mucus mimics in permeation studies, and further development will provide an optimal method for high-throughput mucus permeation analysis.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.CBPC.2018.12.007
Abstract: In an effort to overcome the palatability issues currently constraining the effective delivery of praziquantel (PZQ) via feed to treat monogenean parasites in yellowtail kingfish, this study compared the bioavailability and palatability of PZQ in hydrogenated castor oil (HCO) solid lipid nanoparticles (SLN) against pure PZQ in this species. Improving bioavailability would facilitate lower dietary inclusion levels to achieve the same therapeutic dose and therefore reduce the bitterness of feeds containing PZQ. Bioavailability was determined by co-administering feed with either pure PZQ, HCO-SLN or HCO-SLN coated with chitosan via intubation and quantifying the pharmacokinetics response. In contrast to studies with mammals, the results demonstrated that PZQ in HCO-SLN had equal bioavailability to pure PZQ in yellowtail kingfish, including when HCO-SLN were coated with chitosan. We hypothesise that the lack of improvement in bioavailability may be due to the lack of M cells and Peyer's patches in fish and the subsequent inability of fish to take nanoparticles directly into the lymphatic system. Furthermore, palatability of the feeds medicated with PZQ was not improved when the PZQ was incorporated into HCO-SLN, possibly due to the low loading rate of PZQ within the HCO-SLN and the subsequent thick coating of nanoparticles that was required on the surface of the feed pellets. Combined, these data demonstrate that the SLN used in the current study are not capable of delivering the benefits required to enable effective in-feed treatment of PZQ against monogenean parasites in yellowtail kingfish.
Publisher: American Chemical Society (ACS)
Date: 07-03-2022
DOI: 10.1021/ACSINFECDIS.1C00606
Abstract: Chronic
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.IJPHARM.2014.10.039
Abstract: This study aims at evaluating the combination of self-nanoemulsifying drug delivery systems (SNEDDS) and enteric-coated capsules as a potential delivery strategy for oral delivery of insulin. The SNEDDS preconcentrates, loaded with insulin-phospholipid complex at different levels (0, 2.5 and 10% w/w), were readily dispersed in water to form nanoemulsions of 35 nm and vesicles of 300 nm. The association efficiency of non-complexed insulin in the dispersed SNEDDS was 18.6%, and was increased to 73.1% for insulin-phospholipid complex (at 10% loading level). The morphology of the dispersed SNEDDS changed from nanoemulsion droplets to vesicular structures with increasing complex loading levels. A pH-dependent insulin release profile was observed for SNEDDS filled into capsules coated with the enteric polymer, Eudragit(®) L100. Using a Caco-2 cell model, it was observed that the transport of insulin was enhanced by factors of 7.7- and 9.3- for SNEDDS loaded with 2.5 and 10% complex, respectively. In healthy fasted rats, administration of SNEDDS (10% complex) filled in enteric-coated capsules produced a 2.7-fold and 3.4-fold enhancement in the relative bioavailability and glucose reduction, respectively. This study shows the effectiveness of combining SNEDDS (loaded with insulin-phospholipid complex) with enteric-coated capsules for enhancing the oral absorption and efficacy of insulin.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA08934H
Abstract: Surface immobilised lipases are important bioactive materials that have a wide range of applications in the biotechnology, chemical and pharmaceutical industries.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1002/JPS.23914
Publisher: Springer Science and Business Media LLC
Date: 04-09-2013
DOI: 10.1007/S13346-013-0172-9
Abstract: Clinical trials addressing the viability of lipid and nanoparticle-based solid dosage forms for the oral delivery of poorly water-soluble drugs are limited to date. This Phase I study aimed to assess the comparative tolerability and oral pharmacokinetics of a novel silica nanoparticle-lipid hybrid formulation encapsulating ibuprofen (i.e., Lipoceramic-IBU) with reference to a commercial tablet (i.e., Nurofen®). The test (Lipoceramic-IBU) and reference (Nurofen®) ibuprofen formulations were characterised for physicochemical properties and in vitro solubilisation performance prior to the clinical study. A randomised, double-blinded, one-period single oral dose (20 mg ibuprofen) study was performed in 16 healthy male subjects under fasting conditions. Encapsulation of ibuprofen in a molecularly dispersed form in the Lipoceramic nanostructured silica-lipid matrices was shown to produce superior drug solubilisation in comparison to Nurofen® and the pure drug during a two-step dissolution (or solubilisation) study in aqueous buffers of pH 1.2 followed by pH 6.5. Pharmacokinetic profiles revealed an approximately 1.95-fold increased bioavailability (p=0.02) and a 1.5-fold higher maximum plasma concentration (p=0.14) for Lipoceramic-IBU with reference to Nurofen®. Review of the safety assessments, including physical examinations, clinical laboratory tests and reports of adverse events, confirmed negligible acute side effects related to the administration of blank and ibuprofen-loaded Lipoceramic formulations. This first in man study of a dry lipid and nanoparticle-based formulation successfully demonstrated the safe use and effectiveness of the nanostructured Lipoceramic microparticles in mimicking the food effects for optimising the oral absorption of poorly water-soluble compounds.
Publisher: Bentham Science Publishers Ltd.
Date: 08-2009
DOI: 10.2174/156720109789000456
Abstract: The dermal delivery characteristics of hydrophilic silica nanoparticle coated medium chain triglyceride oil-in-water emulsions are reported and correlated with the physicochemical and interfacial properties of the emulsion based drug carriers. The synergistic drug/stabiliser/nanoparticle interactions are demonstrated to be a function of the charge and concentration of the initial emulsion stabiliser charge and initial loading phase of nanoparticles and physicochemical properties of the drug molecule. The improved physical stability of the emulsions and the chemical stability of two model lipophilic agents (all-trans-retinol and acridine orange 10-nonyl bromide) confirm that engineered nanoparticle layers can enhance the shelf-life of liable lipophilic agents. Nanoparticle coatings are shown to control the in-vitro release of active agents from emulsions and significantly promote skin retention. The lipophilic agents distributed into the deeper viable skin layers without permeation through full-thickness skin and hence systemic exposure. Nanoparticle-coated submicron oil-in-water emulsions can serve as novel dermal carriers with controlled release kinetics and targeted drug delivery.
Publisher: American Chemical Society (ACS)
Date: 25-08-2014
DOI: 10.1021/AM5038577
Abstract: Solid nanoparticle-lipid hybrids have been engineered by using spray drying to assemble monodisperse hydrophilic silica nanoparticles and submicron lipid (triglyceride) emulsions together into composite microparticles, which have specific activity toward enzymes. The influence of silica particle size (100-1000 nm) and emulsifier type (anionic and cationic) on the three-dimensional structure of the composite particles was investigated. The nanostructure of the hybrid particles, which is controlled by the size of the voids between the closely packed silica particles, plays a critical role in lipase action and hence lipid digestion kinetics. Confining lipid droplets within the nanostructured silica aggregates led to 2- to 15-fold enhanced rate of lipolysis in comparison with dispersed coarse oil droplets. The composite particles were tailored to enhance, retain or sustain the lipolysis kinetics of submicron lipid emulsions. The presence of repulsive nanoparticle-droplet interactions favored aqueous redispersion and fast lipolysis of the hybrid composite materials, while attractive interactions hindered redispersion and delayed lipolysis of the confined lipid droplets. Such hybrid nanomaterials can be exploited to control the gastrointestinal enzymatic action and promisingly form the basis for the next generation of foods and medicines.
Publisher: Informa UK Limited
Date: 18-04-2019
DOI: 10.1080/17425247.2019.1605353
Abstract: A promising approach that has recently emerged to overcome the complex biobarriers and interrelated challenges associated with oral drug absorption is to combine the benefits of polymeric and lipid-based nanocarriers within one hybrid system. This multifaceted formulation strategy has given rise to a plethora of polymer-lipid hybrid (PLH) systems with varying nanostructures and biological activities, all of which have demonstrated the ability to improve the biopharmaceutical performance of a wide range of challenging therapeutics. The multitude of polymers that can be combined with lipids to exert a synergistic effect for oral drug delivery have been identified, reviewed and critically evaluated. Specific focus is attributed to preclinical studies performed within the past 5 years that have elucidated the role and mechanism of the polymer phase in altering the oral absorption of encapsulated therapeutics. The potential of PLH systems has been clearly identified however, improved understanding of the structure-activity relationship between PLH systems and oral absorption is fundamental for translating this promising delivery approach into a clinically relevant formulation. Advancing research within this field to identify optimal polymer, lipid combinations and engineering conditions for specific therapeutics are therefore encouraged.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.XPHS.2018.09.016
Abstract: Solution proton nuclear magnetic resonance analysis was used in conjunction with in vitro lipolysis to elucidate the time-dependent speciation and release of lipolytic products during the digestion of lipid-loaded inorganic particles, allowing correlations to be made between the phase partitioning of lipolytic products and an encapsulated poorly soluble drug. Silicon dioxide, montmorillonite, and laponite were used to encapsulate medium chain triglycerides into solid-state lipid-based formulations (LBFs), and coumarin 102 was selected as a model poorly soluble compound. The specific inorganic carrier material used to encapsulate medium chain triglycerides significantly impacted the release and partitioning of the solubilizing lipolytic products, that is, diglycerides, monoglycerides, and fatty acids. A strong linear correlation was obtained between drug solubilization and fatty acid release to the aqueous phase (R
Publisher: Springer Science and Business Media LLC
Date: 28-08-2012
DOI: 10.1007/S11095-018-2552-9
Abstract: To explore the feasibility of spray dried smectite clay particles fabricated from montmorillonite or laponite materials for adsorbing dietary lipids and reducing rodent weight gain in vivo. Spray dried montmorillonite (SD-MMT) and spray dried laponite (SD-LAP) particles were prepared via spray drying. Particle morphology, surface area and redispersion/aggregation properties in aqueous media were characterized. The ability of SD-MMT and SD-LAP particles to inhibit lipid digestion kinetics and adsorb lipid species from solution was assessed during in vitro lipolysis using proton nuclear magnetic resonance analysis. SD-MMT and SD-LAP particles were dosed to rodents fed a high-fat diet and their effect on body weight gain was evaluated. Both SD-MMT and SD-LAP particles adsorbed significant quantities of medium chain triglycerides and lipolytic products from solution during in vitro lipolysis. At a concentration of 50% w/w relative to lipid content, SD-MMT and SD-LAP particles adsorbed 42% and 94% of all lipid species, respectively. SD-MMT and SD-LAP particles also reduced the extent of rodent weight gain relative to the negative control treatment group and performed similarly to orlistat via an alternate mechanism of action. Spray dried smectite clay particles (SD-MMT and SD-LAP) with significant adsorptive capacities for dietary lipids and digestion products were successfully fabricated. These particles may be developed as novel anti-obesity treatments with fewer adverse effects than currently marketed treatment options.
Publisher: American Chemical Society (ACS)
Date: 03-03-2022
DOI: 10.1021/ACS.MOLPHARMACEUT.1C00781
Abstract: SBA-15 mesoporous silica (MPS) has been widely used in oral drug delivery however, it has not been utilized for solidifying lipid-based formulations, and the impact of their characteristic intrawall microporosity remains largely unexplored. Here, we derive the impact of the MPS microporosity on the
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.TRSL.2015.06.009
Abstract: The burden of drug resistance emerges in the wake of chronic and repeated antibiotic use. This underpins the importance of discovering alternatives to current antibiotic regimens. In chronic rhinosinusitis (CRS), topical therapy such as nasal douches and steroid sprays is the mainstay of treatment. However, bacterial sinusitis such as those with Staphylococcus aureus biofilm infection point to more recalcitrant CRS subtypes, focusing research efforts into topical antimicrobial therapies. In the sinuses, both local mucosal and systemic effects must be considered in designing any new topical medication. Nitric oxide (NO), an endogenous antimicrobial agent, is found at extremely low levels in CRS sinuses and high levels in healthy sinuses. As a novel treatment modality, we have designed a liposomal formulation of an NO donor (LFNO) using isosorbide mononitrate, as a topical sinus wash in a sheep model of S. aureus biofilm rhinosinusitis. Heart rate (HR), blood pressure, mean arterial pressure (MAP), and histologic and ciliary analyses were assessed in the safety component. Efficacy was assessed by quantifying biofilm biomass post-treatment. LFNO-treated sheep had lesser inflammation (P = 0.02), and comparable ciliary preservation (P = 0.86) than the control group. A transient increase in HR and decrease in MAP were observed in the LFNO group (P < 0.05), but this was not accompanied by observable side effects. LFNO sheep had significantly lower biofilm biomass vs controls (P = 0.044). Our findings demonstrate the localized and systemic safety of LFNO in an animal model despite using high NO concentrations, thus warranting further investigation for its possible therapeutic role in CRS.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2020
DOI: 10.1007/S00394-019-02118-X
Abstract: Application of intelligent formulation design has the ability to address the poor bioavailability and improve the fasted state bioavailability of fish oils. In this study we assessed the ability of a self-emulsifying drug delivery system (SEDDS), AquaCelle Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) EE were formulated with AquaCelle The AquaCelle Formulating Omega-3 EE with a SEDSS concentrate (AquaCelle
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.JCONREL.2022.02.006
Abstract: Micro- and nano-scale particulate formulations are widely investigated towards improving the oral bioavailability of both biologics and drugs with low solubility and/or low intestinal permeability. Particulate formulations harnessing physiological intestinal transport pathways have recently yielded remarkably high oral bioavailabilities, illustrating the need for better understanding the specific pathways underpinning particle small intestinal absorption and the relative role of intestinal cells. Mechanistic knowledge has been h ered by the well acknowledged limitations of current in vitro, in vivo and ex vivo models relevant to the human intestinal physiology and the lack of standardization in studies reporting absorption data. Here we review the relevant literature and critically discusses absorption pathways with a focus on the role of specific intestinal epithelial and immune cells. We conclude that while Microfold (M) cells are a valid target for oral vaccines, enterocytes play a greater role in the systemic bioavailability of orally administrated particulate formulations, particularly within the sub-micron size range. We also comment on less-reported mechanisms such as paracellular permeability of particles, persorption due to cell damage and uptake by migratory immune cells.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.ADDR.2021.113916
Abstract: Biofilm-dispersing enzymes degrade the extracellular polymeric matrix surrounding bacterial biofilms, disperse the microbial community and increase their susceptibility to antibiotics and immune cells. Challenges for the clinical translation of biofilm-dispersing enzymes involve their susceptibility to denaturation, degradation, and clearance upon administration in vivo. Drug delivery systems aim to overcome these limitations through encapsulation, stabilization and protection from the exterior environment, thereby maintaining the enzymatic activity. Smart drug delivery systems offer target specificity, releasing payloads at the site of infection while minimizing unnecessary systemic exposure. This review highlights critical advances of biofilm-dispersing enzymes as a novel therapeutic approach for biofilm-associated infections. We explore how smart, bio-responsive delivery systems overcome the limiting factors of biofilm-dispersing enzymes and summarize the key systems designed. This review will guide future developments, focusing on utilizing selective and specific therapies in a targeted fashion to meet the unmet therapeutic needs of biofilm infections.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.JCONREL.2013.01.012
Abstract: This study is the first to demonstrate in canines the ability of silica-lipid hybrid (SLH) microparticles to enhance the bioavailability and efficacy of a poorly water-soluble drug after oral administration. Spray-dried SLH microparticles comprising Capmul MCM (mono-diglycerides of C8/C12 fatty acids) and silica nanoparticles (Aerosil® 380) were shown to significantly enhance the fasted state oral bioavailability of celecoxib (CEL) (6.5 fold, relative to an aqueous suspension and more than 2-fold higher relative to the fed state) after oral administration to beagle dogs. Comparable bioavailability was observed between the SLH microparticle formulation and a conventional Capmul lipid solution, however, plasma concentrations were observed to be higher (Cmax, 1.1±0.06 vs. 0.8±0.03μg/mL) (p≤0.05) with the SLH microparticle system. The enhanced bioavailability of CEL observed with the SLH microparticles was reflected in a subsequent efficacy study conducted in an adjuvant-induced arthritis model in the rat. Reduced clinical and histological severity was observed at a dose of 3mg/kg/day, with the progression of arthritic symptoms and tissue damage reduced to a similar degree to that of a higher dose administered at 5mg/kg/day and prepared in an aqueous suspension., The enhanced bioavailability and improved efficacy observed with the SLH microparticles were attributed to the maintenance of CEL in a solubilised form during digestion of the lipid vehicle. We hypothesise that the presence of silica in the formulation may have contributed to the prevention of drug precipitation in the intestinal lumen by providing an alternative binding site for CEL to adsorb to prior to re-solubilisation and absorption. The study highlights the potential utility of novel SLH microparticle formulations as stable dry powders that possess the properties of a lipid-based formulation for the enhanced delivery and efficacy of poorly water-soluble drugs.
Publisher: Frontiers Media SA
Date: 22-06-2017
Publisher: Springer Science and Business Media LLC
Date: 11-05-2011
DOI: 10.1007/S11095-011-0458-X
Abstract: To investigate the dose linearity of celecoxib (CEL) pharmacokinetics from various non-lipid and lipid-based formulations to probe the mechanisms of CEL absorption from a nano-structured silica-lipid hybrid (SLH) microparticle dosage form. Single-dose pharmacokinetic parameters of CEL were determined in fasted rats at dose levels of 5, 20 and 50 mg/kg in aqueous suspensions of pure CEL, Celebrex® and CEL-SLH microparticles formulated using medium-chain lipids (Miglyol 812 or Capmul MCM) and Aerosil® silica nanoparticles. An in vitro lipolysis model was used to characterise the dynamic solubilisation state of CEL under digesting conditions. CEL-SLH formulations and Celebrex® consistently produced a 2-fold higher maximum plasma concentration (C(max)) and bioavailability (AUC(0→∞)) than pure CEL in a dose-linear manner within the dose range of 5-50 mg/kg CEL (R² > 0.8). Lipolysis drug phase partition data indicate a 2.5-7.5-fold higher CEL solubilising capacity resulting from the digestion of SLH microparticles as compared to the simulated fasted state endogenous micelles. Strong correlations were obtained between maximum CEL solubilisation levels during lipolysis and in vivo pharmacokinetic parameters (R² > 0.9). Collectively, the results highlight the potential of the SLH microparticles in enhancing the bioavailability of CEL in a dose-linear manner as facilitated by supersaturated solubilisation of CEL in the intestinal milieu.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2016
Publisher: Elsevier
Date: 2020
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.EJPS.2016.10.026
Abstract: Oral absorption of weakly basic drugs (e.g. cinnarizine (CIN)) is limited by their pH dependent precipitation in intestinal conditions. To overcome this challenge, a novel drug delivery system composed of solid lipid and porous silica, namely silica encapsulated solid lipid (SESL) particles, was developed via hot homogenization of melted lipid dispersion, followed by ultra-sonication of the silica stabilized homogenized melted lipid dispersion. Scanning electron microscope (SEM) images of the SESL formulation revealed non-spherical and aggregated hybrid particles, with rough exterior and structured nanoparticles visible on the surface. A 1.5, 2.2 and 7-fold improvement in the dissolution of CIN was observed for the SESL particles, under simulated intestinal non-digesting conditions, in comparison to the drug loaded in solid lipid (CIN-SL) matrix, drug loaded in porous silica (CIN-PS) and pure drug powder. Under simulated intestinal digestive condition, significant improvement in the drug solubilization was reported for the SESL formulation in compared to the in idual drug loaded systems i.e. CIN-PS and CIN-SL. Thereby, silica encapsulated solid lipid system provides a promising oral delivery approach for poorly water soluble weakly basic drugs.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 08-2018
Publisher: Zhejiang University Press
Date: 07-2015
Publisher: MDPI AG
Date: 04-07-2023
DOI: 10.3390/PHARMACEUTICS15071886
Abstract: Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low solubility or permeability and limited controlled release from nanocarriers), which reduces their effectiveness in new medicines. Anticancer drugs have several major limitations, which include non-specificity, wide biological distribution, a short half-life, and systemic toxicity. Here, we investigate the potential of liposome-micelle-hybrid (LMH) carriers (i.e., drug-loaded micelles encapsulated within drug-loaded liposomes) to enhance the co-formulation and delivery of PTX and 5-FU, facilitating new delivery opportunities with enhanced chemotherapeutic performance. We focus on the combination of liposomes and micelles for co-delivery of PTX and 5_FU to investigate increased drug loading, improved solubility, and transport ermeability to enhance chemotherapeutic potential. Furthermore, combination chemotherapy (i.e., containing two or more drugs in a single formulation) may offer improved pharmacological performance. Compared with in idual liposome and micelle formulations, the optimized PTX-5FU-LMH carriers demonstrated increased drug loading and solubility, temperature-sensitive release, enhanced permeability in a Caco-2 cell monolayer model, and cancer cell eradication. LMH has significant potential for cancer drug delivery and as a next-generation chemotherapeutic.
Publisher: American Chemical Society (ACS)
Date: 11-09-2015
DOI: 10.1021/ACS.LANGMUIR.5B02476
Abstract: Quartz crystal microbalance with dissipation (QCM-D) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used to provide insights into the relationship between lipid adsorption kinetics and molecular behavior in porous silica particles of varying hydrophobicities on lipase activity. Lipase (an interfacial enzyme that cleaves ester bonds to break down lipids to fatty acids and monoglycerides) activity was controlled by loading triglycerides at different surface coverages in hydrophilic and hydrophobic porous silica particles. The rate of lipid adsorption increased 2-fold for the hydrophobic surface compared to the hydrophilic surface. However, for submonolayer lipid coverage, the hydrophilic surface enhanced lipase activity 4-fold, whereas the hydrophobic surface inhibited lipase activity 16-fold, compared to lipid droplets in water. A difference in lipid orientation for low surface coverage, evidenced by ToF-SIMS, indicated that lipid adsorbs to hydrophilic silica in a conformation promoting hydrolysis. Multilayer coverage on hydrophobic and hydrophilic surfaces was indistinguishable with ToF-SIMS analysis. Increased lipid adsorption for both substrates facilitated digestion kinetics comparable to a conventional emulsion. Improved understanding of the interfacial adsorption and orientation of lipid and its digestibility in porous silica has implications in improving the uptake of pharmaceuticals and nutrients from lipid-based delivery systems.
Publisher: SAGE Publications
Date: 2020
Abstract: Staphylococcus aureus and Pseudomonas aeruginosa are primary pathogens in chronic rhinosinusitis (CRS), and the presence of S. aureus and P. aeruginosa biofilms has been associated with negative outcomes after surgery. This study investigated the inhibition effect of cetylpyridinium chloride (CPC)-quatsomes at low concentrations on both S. aureus and P. aeruginosa biofilms in vitro, as well as their toxicities towards cultured human airway epithelial (NuLi-1) cells. S. aureus ATCC 25923 and P. aeruginosa ATCC 15692 were used to establish biofilms. CPC-quatsome and CPC micelle solutions at concentrations of 0.01%, 0.025%, and 0.05% were prepared. AlamarBlue was used to test the viability of both planktonic S. aureus and P. aeruginosa and their biofilms after treatment for 5 min and 2 h, respectively. Confocal laser scanning microscopy (CLSM) was used to investigate the interactions between CPC-quatsomes and S. aureus and P. aeruginosa biofilms. A lactate dehydrogenase (LDH) assay was used to determine the toxicity of CPC-quatsomes on NuLi-1 cells. CPC-quatsome and CPC micelle solutions had significant inhibition effects at all tested concentrations on planktonic S. aureus and P. aeruginosa and their biofilms after 5-min exposure ( P 0.05). In the CLSM study, different interactions between CPC-quatsomes and S. aureus or P. aeruginosa biofilms were observed. After 2-h treatment, the size of S. aureus biofilms decreased, while the number of dead bacteria increased in P. aeruginosa biofilms. Neither CPC-quatsomes nor CPC micelle solutions showed significant toxicity on NuLi-1 cell at all tested CPC concentrations ( P 0.05). CPC-quatsomes at low concentrations inhibited S. aureus and P. aeruginosa in both planktonic form and biofilms. No adverse effects on NuLi-1 cells were observed, indicating their promising potential in the treatment of CRS. Staphylococcus aureus and Pseudomonas aeruginosa biofilms are significant contributors to chronic rhinosinusitis (CRS), and are associated with poor prognosis. The killing effect of CPC-quatsomes on S. aureus biofilm at or above the CPC concentration of 0.5% (5 mg/mL) has been reported previously. This is the first study that showed the significant inhibition effect of CPC-quatsomes at low concentrations on both S. aureus and P. aeruginosa biofilms in vitro, and no adverse effects towards cultured human airway epithelial (NuLi-1) cells. In our study, CPC-quatsomes at concentrations of 0.01%, 0.025%, and 0.05% had significant inhibition effects on both planktonic and biofilms of S. aureus and P. aeruginosa. The result of this study indicates the promising potential of CPC-quatsome in the treatment of CRS.
Publisher: American Chemical Society (ACS)
Date: 30-07-2101
DOI: 10.1021/MP900063T
Abstract: We report on the fabrication and characterization of dry hybrid lipid-silica nanoparticle based microcapsules with an internal porous matrix structure for encapsulation of poorly soluble drugs, and their delivery properties (in vitro release and lipolysis and in vivo pharmacokinetics demonstrated for indomethacin as a model drug). Microcapsules were prepared by spray drying of Pickering o/w emulsions containing either negatively or positively charged lipophilic surfactant in the oil phase and hydrophilic silica nanoparticles in the aqueous phase. Effective microcapsule formation is critically dependent on the interfacial structure of the nanoparticle containing emulsions, which are in turn controlled by the surfactant charge and the nanoparticle to lipid ratio. Microcapsules (containing 50-85% oil) can be prepared with 10 times fewer silica nanoparticles when a droplet-nanoparticle charge neutralizing mechanism is operative. Cross-sectional SEM imaging has confirmed the internal porous matrix structure and identified pore sizes in the range 20-100 nm, which is in agreement with BET average pore diameters determined from gas adsorption experiments. Differential scanning calorimetry and X-ray diffraction analysis have confirmed that the model drug indomethacin remains in a noncrystalline form during storage under accelerated conditions (40 degrees C, 75% RH). Dissolution studies revealed a 2-5-fold increase in dissolution efficiency and significantly reduced the time taken to achieve 50% of drug dissolution values (> or =2- or 10-fold) for indomethacin formulated as microcapsules in comparison to o/w submicron emulsions and pure drug, respectively. Orally dosed in vivo studies in rats have confirmed superior pharmacokinetics for the microcapsules. Specifically, the fasted state absolute bioavailability (F) was statistically higher (93.07 +/- 5.09%) (p < 0.05) than for aqueous suspension (53.54 +/- 2.91%) and o/w submicron emulsion (64.57 +/- 2.11%). The microcapsules also showed the highest maximum plasma concentration (C(max)) among the investigated formulations (p < 0.05). In vitro lipolysis showed statistically higher (p < 0.05) fasted digestion (75.8% after 5 min) and drug solubilization (98% after 5 min) in digestive products for microcapsules than o/w emulsions. The hybrid lipid-silica microcapsules improve oral absorption by enhancing lipolysis and drug dissolution.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 22-04-2009
DOI: 10.1007/S11095-009-9888-0
Abstract: The aim of this research is to investigate the dermal delivery of all-trans-retinol from nanoparticle-coated submicron oil-in-water emulsions as a function of the initial emulsifier type, the loading phase of nanoparticles, and the interfacial structure of nanoparticle layers. The interfacial structure of emulsions was characterized using freeze-fracture-SEM. In-vitro release and skin penetration of all-trans-retinol were studied using Franz diffusion cells with cellulose acetate membrane, and excised porcine skin. The distribution profile was obtained by horizontal sectioning of the skin using microtome-cryostat and HPLC assay. The steady-state flux of all-trans-retinol from silica-coated lecithin emulsions was decreased (up to 90%) and was highly dependent on the initial loading phase of nanoparticles incorporation from the aqueous phase provided more pronounced sustained release. For oleylamine emulsions, sustained release effect was not affected by initial location of nanoparticles. The skin retention significantly (p < or = 0.05) increased and was higher for positive oleylamine-stabilised droplets. All-trans-retinol was mainly localized in the epidermis with deeper distribution to viable skin layers in the presence of nanoparticles, yet negligible permeation (approximately 1% of topically applied dose) through full-thickness skin. Sustained release and targeted dermal delivery of all-trans-retinol from oil-in-water emulsions by inclusion of silica nanoparticles is demonstrated.
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Chemical Society (ACS)
Date: 04-02-2020
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.EJPB.2016.05.021
Abstract: SN38 (7-ethyl-10-hydroxyc tothecin) is a highly potent anti-cancer compound. However, it is poorly soluble in pharmaceutically acceptable excipients, thus the direct formulation and delivery are restricted. The current study focused on lipid-based formulation design to enable oral delivery of SN38 at high doses and at therapeutic levels. The pH dependent ionisation property of SN38 was utilised to form a molecular complex with the cationic surfactant, oleylamine and this increased (>200-fold) solubility/loading in Labrasol (the optimally determined lipid carrier). A SN38 loaded silica-lipid hybrid (SN38-SLH) particle delivery system was prepared by lyophilisation of mesoporous silica nanoparticle stabilised lipid emulsions. The subsequent free-flowing, SLH solid dosage form contained high loading levels of molecularly dispersed SN38 (5%w/w) and significantly enhanced in vitro dissolution in simulated gastrointestinal media. Furthermore, SN38 was chemically stable for at least 12months at 25°C. Orally dosed pharmacokinetics in a rat model demonstrated a 176% increase in SN38 blood plasma exposure in comparison with a raw drug suspension and a significant increase in the period where therapeutic levels are established. SN38-SLH shows potential for enabling injection-to-oral transformation in cancer chemotherapy.
Publisher: Informa UK Limited
Date: 20-11-2019
DOI: 10.1080/03639045.2018.1542709
Abstract: Porous silica-based drug delivery systems have shown considerable promise for improving the oral delivery of poorly water-soluble drugs. More specifically, micro- and meso-porous silica carriers have high surface areas with associated ability to physically adsorb high-drug loads in a molecular or amorphous form this allows molecular state drug release in aqueous gastrointestinal environments, potential for supersaturation, and hence facilitates enhanced absorption and increased bioavailability. This review focuses primarily on the ability of porous silica materials to modulate in vitro drug release and enhance in vivo biopharmaceutical performance. The key considerations identified and addressed are the physicochemical properties of the porous silica materials (e.g. the particle and pore size, shape, and surface chemistry), drug specific properties (e.g. pKa, solubility, and nature of interactions with the silica carrier), potential for both immediate and controlled release, drug release mechanisms, potential for surface functionalization and inclusion of precipitation inhibitors, and importance of utilizing relevant and effective in vitro dissolution methods with discriminating dissolution media that provides guidance for in vivo outcomes (i.e. IVIVC).
Publisher: American Chemical Society (ACS)
Date: 04-10-2017
DOI: 10.1021/ACS.MOLPHARMACEUT.7B00676
Abstract: Three state-of-the-art drug delivery vehicles engineered by nanostructuring lipid colloids within solid particle matrices were fabricated for the oral delivery of the poorly water-soluble, weak base, cinnarizine (CIN). The lipid and solid phase of each formulation was varied to systematically analyze the impact of key material characteristics, such as nanostructure and surface chemistry, on the in vitro and in vivo fate of CIN. The three systems formulated were: silica-stabilized lipid cubosomes (SSLC), silica-solid lipid hybrid (SSLH), and polymer-lipid hybrid (PLH) particles. Significant biopharmaceutical advantages were presented for CIN when solubilized in the polymer (poly(lactic-co-glycolic) acid PLGA) and lipid phase of PLH particles compared to the lipid phases of SSLC and SSLH particles. In vitro dissolution in simulated intestinal conditions highlighted reduced precipitation of CIN when administered within PLH particles, given by a 4-5-fold improvement in the extent of CIN dissolution compared to the other delivery vehicles. Furthermore, CIN solubilization was enhanced 1.5-fold and 6-fold under simulated fasted state lipid digestion conditions when formulated with PLH particles compared to SSLH and SSLC particles, respectively. In vivo pharmacokinetics correlated well with in vitro solubilization data, whereby oral CIN bioavailability in rats, when encapsulated in the corresponding formulations, increased from SSLC < SSLH < PLH. The pharmacokinetic data obtained throughout this study indicated a synergistic effect between PLGA nanoparticles and lipid droplets in preventing CIN precipitation and thus, enhancing oral absorption. This synergy can be harnessed to efficiently deliver challenging poorly water-soluble, weak bases through oral administration.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Elsevier BV
Date: 06-2020
Publisher: Informa UK Limited
Date: 18-06-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6TB03290G
Abstract: Bacteria in biofilms are more difficult to eradicate than planktonic bacteria and result in treatment challenges for many chronic infectious diseases.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.XPHS.2016.06.022
Abstract: Bacterial biofilms are associated with a number of recurring infectious diseases and are a major cause for antibiotic resistance. Despite the broad use of polymeric microparticles and nanoparticles in biomedical research, it is not clear which particle size is more effective against biofilms. The purpose of this study was to evaluate the efficacy of sustained release poly-lactic-co-glycolic acid (PLGA) micro- and nanoparticles containing ciprofloxacin against biofilms of Staphylococcus aureus and Pseudomonas aeruginosa. The PLGA particles were prepared by the double emulsion solvent evaporation method. The resulting microparticles (12 μm) and nanoparticles (300 nm) contained drug loads of 7.3% and 4.5% (wt/wt) ciprofloxacin, respectively. Drug release was complete within 1 week following comparable release profiles for both particle sizes. Micro- and nanoparticles demonstrated a similar in vitro antibiofilm performance against mature P aeruginosa and S aureus with marked differences between the 2 strains. The sustained release of ciprofloxacin from micro- and nanoparticles over 6 days was equally effective as the continuous treatment with ciprofloxacin solution over the same period resulting in the eradication of culturable S aureus suggesting that reformulation of ciprofloxacin as sustained release PLGA micro- and nanoparticles might be valuable formulation approaches for the treatment of biofilms.
Publisher: Elsevier BV
Date: 11-2023
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.IJPHARM.2022.121695
Abstract: The concomitant administration of oral drugs with food can result in significant changes in bioavailability, leading to variable pharmacokinetics and considerable clinical implications, such as over- or under-dosing. Consequently, there is increasing demand for bio-enabling formulation strategies to reduce variability in exposure between the fasted and fed state and/or mitigate the pharmaceutical food effect. The current review critically evaluates technologies that have been implemented to overcome the positive food effects of pharmaceutical drugs, including, lipid-based formulations, nanosized drug preparations, cyclodextrins, amorphisation and solid dispersions, prodrugs and salts. Additionally, improved insight into preclinical models for predicting the food effect is provided. Despite the wealth of research, this review demonstrates that application of optimal formulation strategies to mitigate the positive food effects and the evaluation in preclinical models is not a universal approach, and improved standardisation of models to predict the food effects would be desirable. Ultimately, the successful reformulation of specific drugs to eliminate the food effect provides a panoply of advantages for patients with regard to clinical efficacy and compliance.
Publisher: MDPI AG
Date: 24-12-2020
DOI: 10.3390/PHARMACEUTICS13010017
Abstract: Self-expanding metal stents (SEMSs) are currently the gold standard for the localised management of malignant gastrointestinal (GI) stenosis and/or obstructions. Despite encouraging clinical success, in-stent restenosis caused by tumour growth is a significant challenge. Incorporating chemotherapeutic drugs into GI stents is an emerging strategy to provide localised and sustained release of drugs to intestinal malignant tissues to prevent tumour growth. Therefore, the aim of this work was to develop and evaluate a local GI stent-based delivery system that provides a controlled release of 5-fluorouracil (5FU) over a course of several weeks to months, for the treatment of colorectal cancer and cancer-related stenosis/obstructions. The 5FU-loaded GI stents were fabricated via sequential dip-coating of commercial GI stents with a drug-loaded polyurethane (PU) basecoat and a drug-free poly(ethylene-co-vinyl acetate) (PEVA) topcoat. For comparison, two types of commercial stents were investigated, including bare and silicone (Si) membrane-covered stents. The physicochemical properties of the 5FU-loaded stents were evaluated using photoacoustic Fourier-transform infrared (PA-FTIR) spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and thermal analysis. In vitro release studies in biological medium revealed that the 5FU-loaded stents provided a sustained release of drug over the period studied (18 d), and cell viability, cell cycle distribution and apoptosis assays showed that the released 5FU had comparable anticancer activity against human colon cancer cells (HCT-116) to pure 5FU. This study demonstrates that dip-coating is a facile and reliable approach for fabricating drug-eluting stents (DESs) that are promising candidates for the treatment of GI obstructions and/or restenosis.
Publisher: American Chemical Society (ACS)
Date: 12-11-2015
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00622
Abstract: A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.
Publisher: Bentham Science Publishers Ltd.
Date: 10-03-2015
DOI: 10.2174/1567201811666140822115619
Abstract: The high internal surface area and drug solubilizing capacity of liquid crystal lipids makes them promising oral drug delivery systems. Pluronic F127 is typically used to disperse highly viscous cubic liquid crystal lipids into cubosomes however, such copolymers alter the internal structure and provide little control over enzymatic digestion. This study aimed to use hydrophilic silica nanoparticles to stabilize glyceryl monooleate (GMO) cubosomes prepared by ultrasonication. We investigate the influence of silica nanoparticles size and concentration on the physical (colloidal) and chemical (enzymatic digestion) stability, as well as in vitro solubilization of cinnarizine as a poorly soluble model drug. Silica stabilized nanostructured liquid crystal dispersions (120 nm to150 nm in diameter and zeta potentials of-30 mV to -60 mV) were successfully prepared with excellent long-term stability (<10% size change after 30 days). Silica stabilized GMO cubosomes demonstrated reduced enzymatic digestion compared to pluronic F127 stabilized cubosomes. This reduced digestion was attributed to a combination of adsorbed silica nanoparticles acting as a physical barrier and excess dispersed silica adsorbing/scavenging the lipase enzyme. Under simulated intestinal digestion conditions, silica stabilized GMO cubosomes showed a greater solubilization capacity for cinnarizine, which precipitated in non-crystalline form, in comparison to pure drug suspensions or pluronic F127 stabilized GMO cubosomes. Silica nanoparticle stabilized GMO liquid crystal dispersions are a promising oral delivery vehicle.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2021
Publisher: Wiley
Date: 12-05-2021
Abstract: Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti‐pseudomonal antibiotic however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle‐(LCNP)‐formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically‐relevant co‐culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air–liquid interface, nebulized TOB‐LCNPs completely eradicated 1 × 10 9 CFU mL −1 of P. aeruginosa after two doses, a 100‐fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and lifying the anti‐biofilm activity of the anti‐pseudomonal antibiotic.
Publisher: Walter de Gruyter GmbH
Date: 15-10-2013
Abstract: We investigate the physicochemical characteristics of celecoxib (CEL) entrapped within particles of an oxidized porous silicon matrix (pSiox) determine the oral dose response of CEL compared to pure drug and innovator formulation develop in vivo-in vitro correlation (IVIVC). CEL was loaded into a pSiox matrix by solvent partitioning, with the physical state of the CEL characterized by FTIR, DSC, TGA and XRD, and correlated with in vitro dissolution behavior. Single dose pharmacokinetic parameters of orally dosed CEL were determined in fasted rats for aqueous suspensions of pure CEL, Celebrexr and CEL-pSiox microparticles. Physicochemical testing of CEL-pSiox formulation confirmed the entrapment of CEL within porous nanostructure in an amorphous or non-crystalline form. CEL-pSiox demonstrated superior pharmacokinetics compared with CEL particles or Celebrexr, i.e. increased absolute bioavailability (96.2% vs. 65.2% vs. 88.1%), increased C max (0.91 ± 0.09 μg/mL vs. 0.50 ± 0.16 μg/mL vs. 0.73 ± 0.23 μg/mL) and reduced T max (1.0 ± 0.0 h vs. 2.8 ± 0.8 h vs. 3.4 ± 1.0 h). Single point correlation was established between in vitro dissolution efficiency (% DE) and in vivo absolute bioavailability or C max . Porous silicon microparticles can be formulated as an effective orally dosed solid dispersion preparation for celecoxib
Publisher: MDPI AG
Date: 17-01-2023
DOI: 10.3390/PHARMACEUTICS15020305
Abstract: Cutaneous chronic wounds impose a silent pandemic that affects the lives of millions worldwide. The delayed healing process is usually complicated by opportunistic bacteria that infect wounds. Staphylococcus aureus is one of the most prevalent bacteria in infected cutaneous wounds, with the ability to form antibiotic-resistant biofilms. Recently, we have demonstrated the potential of gallium protoporphyrin lipid liquid crystalline nanoparticles (GaPP-LCNP) as a photosensitizer against S. aureus biofilms in vitro. Herein, we investigate the potential of GaPP-LCNP using a pre-clinical model of infected cutaneous wounds. GaPP-LCNP showed superior antibacterial activity compared to unformulated GaPP, reducing biofilm bacterial viability by 5.5 log10 compared to 2.5 log10 in an ex vivo model, and reducing bacterial viability by 1 log10 in vivo, while unformulated GaPP failed to reduce bacterial burden. Furthermore, GaPP-LCNP significantly promoted wound healing through reduction in the bacterial burden and improved early collagen deposition. These findings pave the way for future pre-clinical investigation and treatment optimizations to translate GaPP-LCNP towards clinical application.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2020
Publisher: MDPI AG
Date: 29-08-2022
DOI: 10.3390/PHARMACEUTICS14091813
Abstract: The potential for porous silica to serve as an effective anti-obesity agent has received growing attention in recent years. However, neither the exact pharmacological mechanism nor the fundamental physicochemical properties of porous silica that drive its weight-lowering effect are well understood. Subsequently, in this study, an advanced in vitro digestion model capable of monitoring lipid and carbohydrate digestion was employed to elucidate the effect of porous silica supplementation on digestive enzyme activities. A suite of porous silica s les with contrasting physicochemical properties was investigated, where it was established that the inhibitory action of porous silica on digestive enzyme functionality was strongly dependent on porous nanostructure, particle size and morphology, and surface chemistry. Insights derived from this study validate the capacity of porous silica to impede the digestive processes mediated by pancreatic lipase and α-amylase within the gastrointestinal tract, while the subtle interplay between porous nanostructure and enzyme inhibition indicates that the anti-obesity effect can be optimized through strategic particle design.
Publisher: Elsevier BV
Date: 02-2021
No related grants have been discovered for Clive Prestidge.