ORCID Profile
0000-0002-7521-6020
Current Organisations
IT University of Copenhagen
,
Københavns Universitet
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Publisher: MDPI AG
Date: 18-05-2023
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.JPBA.2012.06.024
Abstract: The aim of this study was to examine the potential forensic utilisation of blowfly larvae (Diptera: Calliphoridae) as an alternative toxicological specimen for the detection of the psychotropic model drug methylphenidate (MPH). MPH was extracted from biological matrices (rat brain, serum and Calliphorid larvae) by liquid-liquid extraction with recovery of >80%, and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS assay was validated for entomotoxicological use and initially applied to male Sprague-Dawley rats (n=6) that were dosed with MPH (20mg/kg) ante-mortem. MPH could be detected in Calliphorid larvae (n=15) reared on the rat brains at 3.2±1.6 ng/g. Secondly, MPH-spiked porcine brain tissue (450 mg/kg) was used to investigate drug concentration in larvae over a period of 72 h. After larvae had feed for 60 h, MPH was detected at 19.8±1.4 μg/g in the feeding larvae and at 3.5±0.1 μg/g in the MPH-spiked porcine brain tissue. It could be advantageous to use Calliphorid larvae as an alternative toxicological specimen to detect alkaline labile drugs, such as MPH.
Publisher: American Chemical Society (ACS)
Date: 06-01-2021
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.IJPHARM.2019.118724
Abstract: The use of amino acids as excipients is a promising approach to improve the physical stability and powder dispersibility of spray-dried powders for inhalation. The aim of this study was to investigate the stabilizing effect of different amino acids on spray-dried amorphous powders for inhalation using simvastatin (SV) as a model compound. Two hydrophobic amino acids (leucine, LEU and tryptophan, TRP), and one hydrophilic amino acid (lysine, LYS) were spray dried from 1% (w/v) solutions with SV at a molar ratio of 1:1 into dry powders for inhalation. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to characterize the morphology, solid form and potential intermolecular interactions of the spray-dried powders. X-ray photoelectron spectroscopy (XPS) was used to analyse the chemical composition of the surface of the particles. The physical stability of the dry powders was examined upon storage in controlled conditions. A Next generation impactor (NGI) was applied to assess the in vitro aerosol performance of the powders. XRPD and DSC results confirmed that the spray-dried SV-LEU was composed of crystalline LEU and amorphous SV, the spray-dried SV-LYS was co-amorphous, and the spray-dried SV-TRP was an amorphous system with two phases. XPS analyses revealed that the surface of the spray-dried SV-LEU particles were LEU rich, indicating surface-enrichment of LEU in these particles. In contrast, an almost even distribution of TRP and SV at the surface of spray-dried SV-TRP was observed. FTIR results indicated no intermolecular interaction between SV and the amino acids used in the present study. The three spray-dried s les were physically stable after eight months storage in a desiccator (12% RH, ca. 22 °C). Nevertheless, spray-dried SV-LEU exhibited the best storage stability as compared to the other two spray-dried s les when the s les were stored at 60% RH, 25 °C. Both, the spray-dried SV-LEU and SV-TRP exhibited higher fine particle fractions than the spray-dried SV-LYS. Both the spray-dried SV-LEU and SV-TRP exhibited better aerosol performance and storage stability compared to the spray-dried SV-LYS. Compared to TRP, LEU exhibited better protection of spray-dried amorphous SV from re-crystallization, which could be attributed to the formation of a LEU crystalline shell covering SV upon the spray drying process.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5RA25898G
Abstract: In response to freeze–thaw, liposome-encapsulated antibiotic (A) is converted into nanocrystalline form (B) resulting in an attenuated drug release profile.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCIS.2019.07.081
Abstract: Drug nanocrystals precipitated inside liposomes are of increasing interest in liposomal drug delivery. For liposomal nanocrystal formulations, the size and shape of the drug nanocrystals can influence the apparent drug release properties, providing opportunities for developing tailored liposomal drug release systems. Small angle X-ray scattering (SAXS) and quantitative transmission electron microscopy (TEM) can be used to analyse the size distributions of the nanoparticles. In this study, by changing the fluidity of the membrane through the use of different membrane phospholipids with varying cholesterol content, the impact of lipid phase, fluidity and permeability on the size distribution of ciprofloxacin nanocrystals were investigated using standard TEM and SAXS as orthogonal techniques. The results show that the phospholipid phase behaviour has a direct effect on the nanocrystal size distribution, where shorter and thinner nanocrystals were formed in liposomes made from hydrogenated soy phosphatidylcholine (HSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) phospholipids with higher phase transition temperatures than 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with lower transition temperatures. This is mainly due to the phase behaviour of the liposome during nanocrystal formation. The addition of cholesterol that reduces fluidity and permeability of the DOPC liposomes was also shown to restrict the growth of the ciprofloxacin nanocrystals. Moreover, increasing the drug loading of the liposomes made from HSPC and DPPC produced longer and wider nanocrystals. The findings open new opportunities to tailor nanocrystal size distributions, as well as the aspect ratio of the enclosing liposomes with potential to alter drug release and in vivo behaviour.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA90006B
Abstract: Correction for ‘Formation of drug nanocrystals under nanoconfinement afforded by liposomes’ by D. Cipolla et al. , RSC Adv. , 2016, 6 , 6223–6233.
Publisher: Elsevier BV
Date: 07-2000
DOI: 10.1016/S0731-7085(00)00256-9
Abstract: A simple X-ray powder diffractometric (XRD) method with artificial neural networks (ANNs) for data modelling was developed to recognize and quantify two crystal modifications of ranitidine HCl in mixtures and thus, provide information about the solid state of the bulk drug. The method was also used to quantify ranitidine HCl from tablets in the presence of other components. An ANN consisting of three layers of neurons was trained by using a back-propagation learning rule. A sigmoid output function was used in the hidden layer to facilitate non-linear fitting. Unlike other techniques the ANN method described here employed pattern recognition on the entire XRD pattern. Correct classification was mainly influenced by the XRD pattern resolution. It was shown that data transformations improved the quantitative performance when the XRD patterns were not contaminated by other components. Only smoothed X-ray diffractograms were required to distinguish between the two crystalline forms in a mixture. In the case of ranitidine-HCl quantification from tablets, where significant interference with tablet excipients was present, better results were obtained without data transformations. The trained ANN perfectly quantified ranitidine HCI polymorphic forms from mixtures (mean sum of squared error was less than 0.02%) and ranitidine HCl form 1 from tablets (recovery = 98.65). Excellent quantification performance of the ANN analysis. demonstrated in this study, serves as an indication of the broad potential of neural networks in pattern analysis. While the system described has been developed to interpret XRD patterns, peak detection has implications in every chemical application where the recognition of peak-shaped signals in analytical data is important.
Publisher: Elsevier BV
Date: 05-2002
DOI: 10.1016/S0939-6411(01)00245-4
Abstract: This study demonstrates the effect of drug properties and method of loading (sorption and encapsulation) on entrapment within poly(alkyl cyanoacrylate) nanocapsules prepared by interfacial polymerisation of biocompatible water-in-oil microemulsions. For small molecular weight compounds ( neutral compound > anionic compound. Only minimal differences for entrapment efficiency were noted between sorption (addition of the compound 4 h after initiation of the polymerisation) and encapsulation (addition of the compound to microemulsion prior to polymerisation). For high molecular weight compounds, the method used for entrapment however, is very important. For hydrophilic macromolecules such as proteins, high entrapment efficiencies can only be achieved by encapsulation. Entrapment of such compounds seems to be independent of the net charge of the compound being encapsulated but depended on the molecular weight. For nanocapsules prepared by interfacial polymerisation of water-in-oil microemulsions, these findings are useful as a foundation in the development of nanocapsules with desired properties.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.BMC.2009.05.043
Abstract: Immunostimulatory saponin based colloidal antigen delivery systems show promise as adjuvants for subunit vaccines. For this reason, allyl oleanolate was glycosylated at the 3-position using trichloroacetimidate donors to give monodesmodic saponins following deprotection. Bisdesmodic saponins were synthesized by double glycosylation at the 3- and 28-positions of oleanolic acid. When formulated together with cholesterol and phospholipids, ring-like, helical and rod-like nanostructures were formed depending on the saponin concentrations used. As an indication of adjuvant activity, the ability of these formulations, and the saponins by themselves, to induce dendritic cell maturation was measured, but no significant activity was observed.
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: Wiley
Date: 30-09-2015
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: Informa UK Limited
Date: 2001
Abstract: The aim of this study was to investigate the use of small-scale fusion experiments and the Gordon-Taylor (GT) equation to predict whether melt extrusion of a drug with an amorphous polymer produces a stable amorphous dispersion with increased drug dissolution. Indomethacin, lacidipine, nifedipine, piroxicam, and tolbutamide were used as poorly soluble drugs. Drug olyvinylpyrrolidone (PVP) blends were prepared at a 1:1 mass ratio. Small-scale fusion experiments were performed in a differential scanning calorimeter (DSC) and in stainless steel beakers. Extrusion was performed in a Brabender Plasti-corder. The glass transition temperatures Tg were determined by DSC. Taking an average Tg from the DSC melt, beaker melt, and GT equation accurately predicted the extrudate Tg. Physical stability of beaker melt and extrudate s les was tested by X-ray powder diffraction (XRPD) and DSC after storage at 30 degrees C (beaker melt) or 25 degrees C (extrudate) and less than 10%, 60%, and 75% relative humidity, (RH). Beaker melts were amorphous, apart from some residual crystallinity. Extrudates were amorphous after preparation. Except for indomethacin/PVP, which remained amorphous, the crystallinity of beaker melts and extrudates increased only at 75% RH. Recrystallization occurred even when the Tg of the s le was well above the storage temperature. Chemical stability of the beaker melts and extrudates was tested by capillary electrophoresis and high-performance liquid chromatography (HPLC). Stability was slightly improved in the extrudate compared to the beaker melt. In general, the order for rate of dissolution was crystalline drug was less than the physical mixture, which was less than the drug/PVP beaker melt, which was approximately equal to the extrudate. The use of beaker melts allows a conservative estimate of the potential to melt extrude a drug. To predict physical stability, analysis of the Tg must be combined with physical stability experiments.
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.EJPB.2010.12.034
Abstract: Different delivery strategies to improve the immunogenicity of peptide rotein-based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG(200)) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system.
Publisher: MDPI AG
Date: 22-04-2022
DOI: 10.3390/PHARMACEUTICS14050919
Abstract: Clove oil (CO), an essential oil of Syzygium aromaticum, has been reported as an anesthetic for many fish species. However, its insoluble properties require a suitable delivery system for its application. In the present study, nanoformulations of CO as a nanoemulsion (CO-NE), a self-microemulsifying drug-delivery system (CO-SMEDDS), and a self-nanoemulsifying drug-delivery system (CO-SNEDDS) were prepared for delivering CO. Zebrafish were used as a fish model to investigate oil pathways. The result shows fluorescence spots of fluorescence-labeled CO accumulate on the gills, skin, and brain. All CO nanoformulations significantly increased penetration flux compared to CO ethanolic solution. Investigation of the anesthetic mechanism of action using a rat brain γ-aminobutyric acid subtype A (GABAA) receptor-binding test demonstrates that CO and its major compound, eugenol, modulate [3H]muscimol binding. CO-NE exhibited a concentration-dependent binding activity with an EC50 value of 175 µg/mL, significantly higher than CO solution in dimethyl sulfoxide. In conclusion, CO enters the fish through the skin and gills. The anesthetic mechanism of action of CO is based on modulation of [3H] muscimol binding to GABAA receptors. Among three nanoformulations tested, CO-NE is the most effective at increasing permeability and enhancing the receptor-binding activity of the oil.
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: Elsevier BV
Date: 03-2000
DOI: 10.1016/S0378-5173(99)00408-1
Abstract: The aim of the current study was to investigate the effect of different co-surfactants on the phase behaviour of the pseudoternary system water:ethyl oleate:nonionic surfactant blend (sorbitan monolaurate olyoxyethylene 20 sorbitan mono-oleate). Four aliphatic alcohols (1-propanol, 1-butanol, 1-hexanol and 1-octanol) and four 1, 2-alkanediols (1,2-propanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol) were used. The co-surfactant-free system forms two different colloidal structures, a water-in-oil microemulsion (w/o ME) and lamellar liquid crystals (LC) and two coarse dispersions, water-in-oil (w/o EM) and oil-in-water (o/w EM) emulsions. Microemulsion region area (%ME), liquid crystalline region area (%LC), amount of hiphile blend required to produce a balanced microemulsion (%AMPH) and amount of water solubilised (%W) were used as assessment criteria to evaluate the co-surfactants. Seven calculated physico-chemical descriptors were used to represent the different co-surfactants. 1-butanol, 1,2-hexanediol and 1, 2-octanediol produced balanced MEs capable of solubilising a high percentage of both oil and water. A similarity was observed between the descriptors attributed to 1-butanol and 1,2-hexanediol. The requirements of a co-surfactant molecule to produce a balanced microemulsion were: HLB value 7.0-8.0, a carbon backbone of 4-6 atoms, percentage carbon of 60-65%, percentage oxygen of 20-30%, logP value 0.2-0.9 and log 1/S (S: aqueous solubility) close to zero.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JCONREL.2018.09.001
Abstract: Liposomes are phospholipid bilayer vesicles that have been explored in pharmaceutical research as drug delivery systems for >50 years. Despite being important to their morphology and drug release pattern, the physical state of the drug within liposomes (liquid, solid, crystalline form) is often overlooked. This review focuses on precipitation of drug within liposomes, which can result in the formation of confined nanocrystals, and consequent changes in liposome morphology and drug release patterns. The type of drugs that form nanocrystals within liposomes, preparation and characterisation of liposomal drug nanocrystals, and the in vitro drug release behaviour from these systems are communicated, with a discussion of their potential as drug delivery systems.
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: To prepare poly(ethyl 2-cyanoacrylate) nanocapsules containing insulin by interfacial polymerization of spontaneously forming, biocompatible microemulsions. A pseudo-ternary phase diagram of a mixture of medium chain glycerides (caprylic/capric triglycerides and mono-/diglycerides), a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) and water was constructed. Polarizing light microscopy was used to identify combinations forming microemulsions. Microemulsions were characterized by conductivity and viscosity to select systems suitable for the preparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacial polymerization. Nanocapsules were prepared by addition of 100 mg of ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsion containing 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. The nanocapsules formed were characterized by photon correlation spectroscopy, freeze fracture transmission and scanning electron microscopy. Insulin nanocapsules were prepared by using an aqueous solution of insulin (100 units/ml) as the dispersed phase of the microemulsion. The entrapment and the release of insulin from the nanocapsules were determined. Three regions were identified in the pseudo-ternary phase diagram a microemulsion region, a region in which liquid crystalline structures were present and a coarse emulsion region. All systems in the microemulsion region were water-in-oil dispersions. Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nm were formed upon interfacial polymerization of the microemulsion. Nanocapsules were found to have a central cavity surrounded by a polymer wall. In excess of 80% of the insulin present in the microemulsion was encapsulated upon interfacial polymerization. Interfacial polymerization of spontaneously forming water-in-oil microemulsions represents a convenient method for the preparation of poly(alkylcyanoacrylate) nanocapsules suitable for the entrapment of bioactive peptides.
Publisher: Informa UK Limited
Date: 12-2009
DOI: 10.1080/00480169.2009.64731
Abstract: To investigate polymeric nanoparticles as an oral delivery system for protein biocontrol agents for control of the brushtail possum, Trichosurus vulpecula. Insulin-loaded poly(ethyl 2-cyanoacrylate) (PECA) nanoparticles were prepared using interfacial polymerisation, and characterised for size, zeta potential, and efficiency of encapsulation of insulin. In-vitro release of insulin-loaded PECA nanoparticles was quantified using reverse-phase high-pressure liquid chromatography (HPLC). The in-vivo pharmacokinetics of insulin in PECA nanoparticles was investigated following I/V administration, and when injected directly into the caecum alone or in conjunction with the permeation enhancer EDTA. Blood s les were collected at intervals from -5 to 180 minutes, and the concentration of insulin in plasma was quantified using a radioimmunoassay (RIA) validated for possum plasma. Poly(ethyl 2-cyanoacrylate) nanoparticles were produced with a uniform particle size of 200-300 nm, and the mean entrapment of insulin was 78%. In-vitro release of insulin from the PECA nanoparticles was controlled, although incomplete, and approximately 30% of the insulin remained entrapped. The bioavailability of insulin when administered in a PECA nanoparticulate formulation injected directly into the caecum was <1%, and was not increased by addition of the permeation enhancer. The nanoparticulate formulations investigated as part of this study resulted in low bioavailability of the peptide insulin in the brushtail possum.
Publisher: Elsevier BV
Date: 04-2019
Publisher: American Chemical Society (ACS)
Date: 15-02-2021
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.JCONREL.2012.10.020
Abstract: New generation vaccines increasingly utilize highly purified peptides and proteins as the target antigen, however these are often poorly immunogenic. One of the most promising strategies for improving immunogenicity of such subunit vaccines is through incorporation into particulate carriers. Here we report the preparation, physicochemical characterization and in vivo immunological activity of cubosomes, a novel lipid-based nanostructured particulate carrier, modified to include the Toll-like receptor agonists monophosphoryl lipid A and imiquimod. The immunological activity of cubosome formulations was compared to that of liposome and alum formulations. Sustained release of the model antigen ovalbumin (Ova) was observed in vitro and in vivo from cubosomes. Cubosomes+adjuvants induced robust CD8⁺ and CD4⁺ T cell proliferation and interferon-γ production, as well as the production of Ova-specific antibodies. Cubosomes+adjuvants were more efficient at generating Ova-specific cellular responses and were equally as effective in generating humoral responses when compared to liposomes+adjuvants and alum. Overall, the results show that cubosomes have the potential to act as effective sustained release vaccine delivery systems.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.IJPHARM.2013.10.012
Abstract: Coalescence of polymer particles in polymer matrix tablets influences drug release. The literature has emphasized that coalescence occurs above the glass transition temperature (Tg) of the polymer and that water may plasticize (lower Tg) the polymer. However, we have shown previously that nonplasticizing water also influences coalescence of Eudragit RLPO so there is a need to quantify the different types of water in Eudragit RLPO. The purpose of this study was to distinguish the types of water present in Eudragit RLPO polymer and to investigate the water loss kinetics for these different types of water. Eudragit RLPO was stored in tightly closed chambers at various relative humidities (0, 33, 56, 75, and 94%) until equilibrium was reached. Fourier transform infrared spectroscopy (FTIR)-DRIFTS was used to investigate molecular interactions between water and polymer, and water loss over time. Using a curve fitting procedure, the water region (3100-3,700 cm(-1)) of the spectra was analyzed, and used to identify water present in differing environments in the polymer and to determine the water loss kinetics upon purging the s le with dry compressed air. It was found that four environments can be differentiated (dipole interaction of water with quaternary ammonium groups, water cluster, and water indirectly and directly binding to the carbonyl groups of the polymer) but it was not possible to distinguish whether the different types of water were lost at different rates. It is suggested that water is trapped in the polymer in different forms and this should be considered when investigating coalescence of polymer matrices.
Publisher: Oxford University Press (OUP)
Date: 04-2002
Abstract: This study evaluated the potential of poly(iso-butyl cyanoacrylate) (PBCA) nanocapsules dispersed in a biocompatible microemulsion to facilitate the absorption of insulin following intragastric administration to diabetic rats. Insulin-loaded PBCA nanocapsules were prepared in-situ in a biocompatible water-in-oil microemulsion by interfacial polymerisation. The microemulsion consisted of a mixture of medium-chain mono-, di- and tri-glycerides as the oil component, polysorbate 80 and sorbitan mono-oleate as surfactants and an aqueous solution of insulin. Resulting nanocapsules were approximately 200 nm in diameter and demonstrated a high efficiency of insulin entrapment (& 80%). In-vitro release studies showed that PBCA nanocapsules could suppress insulin release in acidic media and that release at near neutral conditions could be manipulated by varying the amount of monomer used for polymerisation. Subcutaneous administration of insulin-loaded nanocapsules to diabetic rats demonstrated that the bioactivity of insulin was largely retained following this method of preparing peptide-loaded nanocapsules and that the pharmacodynamic response was dependent on the amount of monomer used for polymerisation. The intragastric administration of insulin-loaded nanocapsules dispersed in the biocompatible microemulsion resulted in a significantly greater reduction in blood glucose levels of diabetic rats than an aqueous insulin solution or insulin formulated in the same microemulsion. This study demonstrates that the formulation of peptides within PBCA nanocapsules that are administered dispersed in a microemulsion can facilitate the oral absorption of encapsulated peptide. Such a system can be prepared in-situ by the interfacial polymerisation of a water-in-oil biocompatible microemulsion.
Publisher: MDPI AG
Date: 16-03-2022
DOI: 10.3390/PHARMACEUTICS14030650
Abstract: The anesthetic effect of Alpinia galanga oil (AGO) has been reported. However, knowledge of its pathway in mammals is limited. In the present study, the binding of AGO and its key compounds, methyl eugenol, 1,8-cineole, and 4-allylphenyl acetate, to gamma-aminobutyric acid type A (GABAA) receptors in rat cortical membranes, was investigated using a [3H]muscimol binding assay and an in silico modeling platform. The results showed that only AGO and methyl eugenol displayed a positive modulation at the highest concentrations, whereas 1,8-cineole and 4-allylphenyl acetate were inactive. The result of AGO correlated well to the amount of methyl eugenol in AGO. Computational docking and dynamics simulations into the GABAA receptor complex model (PDB: 6X3T) showed the stable structure of the GABAA receptor–methyl eugenol complex with the lowest binding energy of −22.16 kcal/mol. This result shows that the anesthetic activity of AGO and methyl eugenol in mammals is associated with GABAA receptor modulation. An oil-in-water nanoemulsion containing 20% w/w AGO (NE-AGO) was formulated. NE-AGO showed a significant increase in specific [3H]muscimol binding, to 179% of the control, with an EC50 of 391 µg/mL. Intracellular studies show that normal human cells are highly tolerant to AGO and the nanoemulsion, indicating that NE-AGO may be useful for human anesthesia.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.JCONREL.2005.11.020
Abstract: Water-in-oil microemulsions (w/o ME) capable of undergoing a phase-transition to lamellar liquid crystals (LC) or bicontinuous ME upon aqueous dilution were formulated using Crodamol EO, Crill 1 and Crillet 4, an alkanol or alkanediol as cosurfactant and water. The hypothesis that phase-transition of ME to LC may be induced by tears and serve to prolong precorneal retention was tested. The ocular irritation potential of components and formulations was assessed using a modified hen's egg chorioallantoic membrane test (HET-CAM) and the preocular retention of selected formulations was investigated in rabbit eye using gamma scintigraphy. Results showed that Crill 1, Crillet 4 and Crodamol EO were non-irritant. However, all other cosurfactants investigated were irritant and their irritation was dependent on their carbon chain length. A w/o ME formulated without cosurfactant showed a protective effect when a strong irritant (0.1 M NaOH) was used as the aqueous phase. Precorneal clearance studies revealed that the retention of colloidal and coarse dispersed systems was significantly greater than an aqueous solution with no significant difference between ME systems (containing 5% and 10% water) as well as o/w emulsion containing 85% water. Conversely, a LC system formulated without cosurfactant displayed a significantly greater retention compared to other formulations.
Publisher: American Chemical Society (ACS)
Date: 15-03-2022
Publisher: Springer Science and Business Media LLC
Date: 21-06-2006
DOI: 10.1007/S11095-006-0272-Z
Abstract: The purpose of this study was to investigate the immunogenicity of liposomes containing mannosylated lipid core peptide (manLCP) constructs, both in vitro and in vivo, with or without the addition of the immune stimulating adjuvant Quil A. Mouse bone marrow dendritic cells (BMDC) were cultured with liposome formulations for 48 h, and the resulting level of BMDC activation was determined by flow cytometry. BMDC pulsed with liposome formulations were incubated with 5,6-carboxyfluoroscein diacetate succinimidyl ester-labeled T cells for 72 h and the resulting T cell proliferation was determined by flow cytometry. To investigate the immunogenicity of formulations in vivo, groups of C57Bl/6J mice were immunized by subcutaneous injection, and the resulting antigen-specific cytotoxic and protective immune responses toward tumor challenge evaluated. Despite being unable to demonstrate the activation of BMDC, BMDC pulsed with liposomes containing manLCP constructs were able to stimulate the proliferation of naïve T cells in vitro. However, in vivo only liposomes containing both manLCP and Quil A were able to stimulate a strong antigen-specific cytotoxic immune response. Liposomes containing manLCP and Quil A within the same particle were able to protect against the growth of tumor cells to a similar level as if the antigen was administered in alum with CD4 help. ManLCPs administered in liposomes are able to stimulate strong cytotoxic and protective immune responses if Quil A is also incorporated as an adjuvant.
Publisher: American Chemical Society (ACS)
Date: 27-06-2019
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.IJPHARM.2009.09.047
Abstract: Coalescence of polymer particles has been identified as a crucial step in film formation on tablets, pellets and granules. Though the significance of thermal treatment on matrix dosage forms is well established the process of coalescence in matrix formation and the forces driving it remain unexplored. The aim of this study was to investigate whether stresses in tablets, caused by deformation of excipient during compression, provide a driving force for polymer matrix formation. Polymer matrix tablets containing Eudragit-RLPO, a pH independent and permeable polymer at two levels 10 and 40% (w/w) were prepared by direct compression. Either lactose monohydrate (brittle) or mannitol (plastic) was used as a diluent at 80 or 50% (w/w) and indomethacin, a model drug was present at 10% (w/w). Tablets from each formulation type were prepared at two compression pressures either 221 MPa (above the yield pressure of both excipients) or 74 MPa (below the yield pressure of both excipients). Tablets from each formulation type compressed at the two compression pressures were thermally treated at 40 degrees C (below Tg) or 70 degrees C (above Tg) for 24 h. The rotating basket (100 rpm) method was used for the release studies conducted at 37 degrees C in 900 ml phosphate buffer (0.2 M) pH 7.2 as the dissolution medium. Morphological characteristics of the tablets were observed by scanning electron microscopy. Differences in tablet structure due to the formulation and processing variables were further evaluated by disintegration and tensile strength testing. Data from this factorial study were analysed by analysis of variance. Excipient mechanical properties determine matrix properties only at low polymer level independent of curing temperature and at high polymer level cured at 40 degrees C only. Though lactose and mannitol have different mechanical properties and therefore different deformation behaviors, this did not influence the properties of tablets containing 40% (w/w) polymer cured at 70 degrees C, suggesting stresses in these tablets are not a significant driving force for matrix formation.
Publisher: American Chemical Society (ACS)
Date: 16-09-2021
Publisher: American Chemical Society (ACS)
Date: 16-11-2017
Publisher: American Chemical Society (ACS)
Date: 06-2022
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0378-5173(01)00801-8
Abstract: The aim of this study was to determine the miscibility of drug and excipient to predict if glass solutions are likely to form when drug and excipient are melt extruded. Two poorly water-soluble drugs, indomethacin and lacidipine, were selected along with 11 excipients (polymeric and non-polymeric). Estimation of drug/excipient miscibility was performed using a combination of the Hoy and Hoftzyer/Van Krevelen methods for Hansen solubility parameter calculation. Miscibility was experimentally investigated with differential scanning calorimetry (DSC) and hot stage microscopy (HSM). Studies were performed at drug/excipient ratios, 1:4, 1:1 and 4:1. Analysis of the glass transition temperature (T(g)) was performed by quench cooling drug/excipient melts in the DSC. Differences in the drug/excipient solubility parameters of 10 MPa(1/2) were expected to indicate a lack of miscibility and not form glass solutions when melt extruded. Experimentally, miscibility was shown by changes in drug/excipient melting endotherms and confirmed by HSM investigations. Experimental results were in agreement with solubility parameter predictions. In addition, drug/excipient combinations predicted to be largely immiscible often exhibited more than one T(g) upon reheating in the DSC. Melt extrusion of miscible components resulted in amorphous solid solution formation, whereas extrusion of an "immiscible" component led to amorphous drug dispersed in crystalline excipient. In conclusion, combining calculation of Hansen solubility parameters with thermal analysis of drug/excipient miscibility can be successfully applied to predict formation of glass solutions with melt extrusion.
Publisher: Elsevier BV
Date: 03-1999
DOI: 10.1016/S0731-7085(98)00232-5
Abstract: The aim of the present work was to develop a method for predicting the phase behaviour of four component systems consisting of oil, water and two surfactants from a limited number of screening experiments. Investigations were conducted to asses the potential of artificial neural networks (ANNs) with back-propagation training algorithm to predict the phase behaviour of four component systems. Three inputs only (percentages of oil and water and HLB of the surfactant blend) and four outputs (oil in water emulsion, water in oil emulsion, microemulsion, and liquid crystals containing regions) were used. S les used for training represented about 15% of the s ling space within the tetrahedron body. The network was trained by performing optimization of the number and size of the weights for neuron interconnections. The lowest error was obtained with 15 hidden neurons and after 4,500 training cycles. The trained ANN was tested on validation data and had an accuracy of 85.2-92.9%. In most cases the errors in the prediction were confined to points lying along the boundaries of regions and for the extrapolated predictions outside the ANNs 'experience'. This approach is shown to be highly successful and the ANNs have proven to be a useful tool for the prediction of the phase behaviour of quaternary systems with less experimental effort.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.IJPHARM.2012.08.018
Abstract: Liposomes are generally well tolerated drug delivery systems with a potential use for the oral route. However, little is known about the fate of liposomes during exposure to the conditions in the gastro-intestinal tract (GIT). To gain a better understanding of liposome stability in the intestine, a dynamic in vitro lipolysis model, which so far has only been used for the in vitro characterisation of other lipid-based drug delivery systems, was applied to different liposomal formulations. Liposome size and phospholipid (PL) digestion were determined as two markers for liposome stability. In addition, the effect of PL degradation on the ability to maintain liposomally incorporated danazol in solution during lipolysis was evaluated in order to address the feasibility of liposomes designed for oral administration. Rate and extend of hydrolysis of PLs mediated by pancreatic enzymes was determined by titration and HPLC. Size of liposomes was determined by dynamic light scattering during incubation in lipolysis medium (LM) and during lipolysis. SPC-based (soy phosphatidylcholine) liposomes were stable in LM, whereas for EPC-3-based (hydrated egg phosphatidylcholine) formulations the formation of aggregates of around 1 μm in diameter was observed over time. After 60 min lipolysis more than 80% of PLs of the SPC-liposomes were digested, but dependent on the liposome concentration only a slight change in size and size distribution could be observed. Although EPC-3 formulations did form aggregates during lipolysis, the lipids exhibited a higher stability compared to SPC and only 30% of the PLs were digested. No direct correlation between liposome integrity assessed by vesicle size and PL digestion was observed. Danazol content in the liposomes was around 5% (mol/mol danazol/total lipid) and hardly any precipitation was detected during the lipolysis assay, despite pronounced lipolytic degradation and change in vesicle size. In conclusion, the tested dynamic in vitro lipolysis model is suitable for the assessment of liposome stability in the intestine. Furthermore, liposomes might be a useful alternative to other lipid based delivery systems for the oral delivery of poorly soluble drugs.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1002/JPS.21366
Publisher: American Chemical Society (ACS)
Date: 04-09-2020
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.IJPHARM.2011.10.028
Abstract: Coalescence of polymer particles on thermal treatment plays an important role in effective control of drug release from these matrix systems. The water content of the polymer may influence coalescence since it is well established that sorbed water may act as a plasticizer, or cause other changes in mechanical properties. However, these effects depend on the amount and type (plasticizing/nonplasticizing) of water present. The purpose of this study was to determine the accuracy of different methods used to determine moisture content of a polymer (Eudragit RLPO) and to determine the types water present. The polymer powder was stored at various relative humidities (33, 56, 75, 94%). Four water determination methods, [weight loss on drying, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and Karl Fischer titration (KFT)] were utilized to determine moisture content. DSC was used to study the thermal behaviour of moist and dry s les. The Gordon-Taylor equation was used to calculate the amount of plasticizing water. Scanning electron microscopy was employed to examine the morphology of the polymer particles after thermal analyses. It is concluded that KFT accurately determines the total water content but that the thermal methods underestimate total water content. However KFT does not indicate the type of water present. The Gordon-Taylor model suggests that only about 25% of the water in the polymer containing 10% water was acting as a plasticizer. Complementary methods should be used to measure the water content of pharmaceutical polymers.
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1016/S0731-7085(01)00375-2
Abstract: The identification, characterization and quantification of crystal forms are becoming increasingly important within the pharmaceutical industry. A combination of different physical analytical techniques is usually necessary for this task. In this work solid-state techniques, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and X-ray powder diffractometry (XRPD) were combined to analyze polymorphic purity of crystalline ranitidine-HCl, an antiulcer drug, H2 receptor antagonists. A series of 12 different mixtures of Form 1 and 2 was prepared by geometric mixing and their DRIFT spectra and XRD powder patterns were obtained and analyzed, either alone or combined together, using Artificial Neural Networks (ANNs). A standard feed-forward network, with back-propagation rule and with multi layer perceptron architecture (MPL) was chosen. A working range of 1.0-100% (w/w) of crystal Form 2 in Form 1 was established with a minimum quantifiable level (MQL) of 5.2% and limit of detection of 1.5% (w/w). The results demonstrate that DRIFTS combined with XRPD may be successfully used to distinguish between the ranitidine-HCl polymorphs and to quantify the composition of binary mixtures of the two.
Publisher: Elsevier BV
Date: 07-1999
DOI: 10.1016/S0378-5173(99)00104-0
Abstract: A simple X-ray powder diffractometric method was developed for the qualitative and quantitative assay of the two crystalline modifications of ranitidine-HCl. The main purpose of the present work was to investigate if artificial neural networks (ANNs) could be applied in quantitative X-ray diffractometric analyses. The ANN approach was compared with a conventional mixture design method. The results obtained by the ANN had a smaller standard deviation and relative error and a better precision at lower concentrations. ANNs provide a simple alternative to conventional statistical modelling methods to identify the non-linear relationship without complex equations.
Publisher: American Chemical Society (ACS)
Date: 27-02-2019
DOI: 10.1021/ACS.MOLPHARMACEUT.8B01308
Abstract: The use of electron microscopy techniques in the understanding of shape and size of nanoparticles are commonly applied to drug nanotechnology, but the type of microscopy and suitability for the particles of interest can have a significant impact on the result. The size and shape of the nanoparticles are crucial in clinical applications however, direct comparison of the results from standard transmission electron microscopy (TEM) and cryo-TEM have rarely been reported. As a useful case for comparison, liposomal drug nanocrystals are studied here. In this study, the effect of thawing temperature on the size and shape of the ciprofloxacin nanocrystals was determined. A quantitative standard TEM assay was developed to allow for high-throughput particle size analysis. These results were compared to size and shape information obtained using the cryo-TEM method. The results showed broad agreement between the two TEM methods and that ciprofloxacin nanocrystals formed shorter and thinner crystals inside the liposomes at higher thawing temperatures. The results provide confidence in the use of standard TEM to determine the size and shape distribution of solid nanoparticles (in this case, encapsulated inside liposomes) from aqueous media without fear of s le preparation altering the conclusions.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1002/JPS.21724
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.EJPS.2019.104961
Abstract: A crystalline adduct of the anti-tubercular drug, moxifloxacin and trans-cinnamic acid (1:1 molar ratio (MCA
Publisher: Elsevier BV
Date: 03-2015
Publisher: Elsevier BV
Date: 03-2009
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: Springer Science and Business Media LLC
Date: 21-11-2012
Publisher: American Institute of Mathematical Sciences (AIMS)
Date: 2009
Publisher: Elsevier BV
Date: 03-2002
DOI: 10.1016/S0378-5173(02)00002-9
Abstract: The effect of several formulation variables on some of the physico-chemical characteristics of poly (ethyl cyanoacrylate) (PECA) nanocapsules prepared by the interfacial polymerisation of biocompatible water-in-oil microemulsions was investigated. In all cases, yields were high (>90%) and the polydispersity in size of nanocapsules was narrow. The molecular weight of the nanocapsules formed was influenced by the pH of the aqueous component of the microemulsion, increasing with increasing pH. The size of the nanocapsules formed (ranging from around 130 to 180 nm) was a function of the ratio of the mass of monomer used to the water weight fraction of the microemulsion, increasing as this ratio was increased. This is due to the formation of a thicker polymer wall resulting from the increased mass of monomer available per unit interfacial area as this ratio is increased. The rate of release of insulin from nanocapsules was also influenced by this ratio, in agreement with its effect on wall thickness. This study demonstrates that many pharmaceutically relevant physico-chemical properties of poly (alkyl cyanoacrylate) (PACA) nanocapsules prepared by interfacial polymerisation of microemulsions can readily be manipulated by changing either the pH of the aqueous component, the water weight fraction of the microemulsion or the mass of monomer used for polymerisation.
Publisher: Informa UK Limited
Date: 2001
Abstract: Two pseudoternary phase diagrams were constructed using ethyl oleate, water, and a surfactant blend containing poly (oxyethylene 20) sorbitan monooleate and sorbitan monolaurate with or without the cosurfactant 1-butanol. Two colloidal regions were identified in the cosurfactant-free phase diagram a microemulsion (ME) and a region containing lamellar liquid crystals (LC). The addition of 1-butanol increased the area in which systems formed microemulsions and eliminated the formation of any liquid crystalline phases. S les that form the colloidal regions of both systems were investigated by freeze-fracture transmission electron microscopy and by viscosity and conductivity measurements. The three techniques were compared and evaluated as characterisation tools for such colloidal systems and also to identify transitions between the colloidal systems formed. A droplet ME was present at a low water volume fraction (phi w) in both systems (phi w < 0.15) as revealed by electron microscopy. At higher phi w values, LC structures were observed in micrographs of s les taken from the cosurfactant-free system while the structure of s les from the cosurfactant-containing system was that of a bicontinuous ME. The viscosity of both systems increased with increasing phi w to 0.15 and flow was Newtonian. However, formation of LC in the cosurfactant-free system resulted in a dramatic increase in viscosity that was dependent on phi w and a change to pseudoplastic flow. In contrast, the viscosity of the bicontinuous ME was independent of phi w. Three different methods were used to estimate the percolation threshold from the conductivity data for the cosurfactant-containing system. The use of nonlinear curve fitting was found to be most useful yielding a value close to 0.15 for the phi w.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1002/JPS.23054
Publisher: CSIRO Publishing
Date: 2006
DOI: 10.1071/WR06028
Abstract: The common brushtail possum (Trichosurus vulpecula) is the most significant vertebrate pest in New Zealand, being a major ecological threat to the indigenous bio ersity and an economic threat as a vector for bovine tuberculosis. Novel and effective strategies to reduce the population of T. vulpecula are needed urgently. Several biocontrol agents are currently being assessed and from research to date it is likely that the biocontrol agents will be peptide or protein molecules. It is not possible to administer such biocontrol agents alone because they would be degraded rapidly in the animal, especially if delivered orally. Technologies used in the pharmaceutical industry to design efficacious drug-delivery systems for humans and animals can be applied to the design of delivery systems for biocontrol agents used in wildlife management, although there are some unique challenges that must be overcome.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6FO00158K
Abstract: The aim of this study was to find a surrogate for Human Gastric Lipase (HGL), since the development of gastrointestinal lipolysis models are h ered by the lack of a lipase with similar digestive properties as HGL.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCIS.2019.08.007
Abstract: The distribution of three cell-penetrating peptides (CPPs) with different architectures (short, long linear and branched) on poly(lactic-co-glycolic) acid (PLGA) nanoparticles depends on the conjugation approach. Here, we explore the utilization of a zero-length crosslinking reaction for the covalent attachment of CPPs to PLGA nanoparticles and the translation of the reaction into a microfluidic platform. A microfluidic device with a staggered herringbone mixer was used for the formulation of CPP-tagged PLGA nanoparticles. CPP-tagged PLGA nanoparticles were labeled with gold nanoparticles (AuNPs) and transmission electron microscopy (TEM) and small angle X-ray scattering (SAXS) were used to elucidate the distribution of CPPs. The SAXS scattering profiles for the CPP-tagged PLGA nanoparticles prepared with the in situ microfluidics conjugation approach indicated a distribution of the Au-labeled CPPs throughout the PLGA nanoparticles. For the post-microfluidics conjugation approach, the SAXS scattering profiles did not show the feature of the Au-labeled CPPs distributed throughout the PLGA nanoparticles and an arrangement of the Au-labeled CPP on the surface was support by TEM micrographs. The distribution of the CPPs was highly dependent on the conjugation approach and was not influenced by the architecture of the CPPs. The results provided insight for the rational design of CPP-tagged PLGA nanoparticles using microfluidics.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2014
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.IJPHARM.2010.01.031
Abstract: Tartaric acid, metoprolol free base and metoprolol tartrate act as plasticisers for Eudragit RL, in the dry but also in the wet state. Fitting analytical solutions of Fick's second law of diffusion allowed for the determination of the apparent diffusivities of water and of tartaric acid, metoprolol free base and metoprolol tartrate upon exposure of thin films to 0.1M HCl, phosphate buffer pH 7.4 and distilled water. Based on these calculations, it could be shown that water penetration into the systems is predominantly controlled by pure diffusion, irrespective of the type of bulk fluid. Interestingly, the plasticising effect of metoprolol tartrate was much more pronounced than that of tartaric acid, resulting in monotonically increasing diffusion coefficients with increasing initial drug content. In contrast, the plasticising activity of metoprolol free base was very limited in the wet state, due to drug precipitation in aqueous environments. Partially observed film shrinking (after an initial system swelling) could be attributed to the leaching of the plasticising compound into the release medium, resulting in less flexible polymeric networks and squeezing out of water. Also the release of tartaric acid, metoprolol free base and metoprolol tartrate into the investigated bulk fluids was predominantly diffusion controlled. However, the precipitation of the free base in wet films rendered the mass transport mechanisms more complex, at moderate and high initial drug loadings. The obtained new insight into the underlying drug release mechanisms in Eudragit RL networks can help to facilitate the optimisation of this type of dosage forms.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.JCONREL.2012.02.027
Abstract: Novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) containing the poorly water-soluble drug halofantrine above equilibrium solubility (150% S(eq)) were compared in vitro and in vivo with conventional SNEDDS containing the drug below equilibrium solubility (75% S(eq)). Pre-concentrates comprising of either medium chain lipids (Captex 300/Capmul MCM) or long chain lipids (soybean oil/Maisine), Cremophor RH40 and ethanol were formulated maintaining the lipid-to-surfactant-to-cosolvent ratio constant (55:35:10, w/w %). The ability of super-SNEDDS to increase the absorption of halofantrine in dogs, as well as the predictivity of the dynamic in vitro lipolysis model was studied. In vitro lipolysis of SNEDDS and super-SNEDDS showed rapid drug precipitation from all formulations while the same drug concentrations in the digestion medium were found during digestion of equal amounts of SNEDDS and super-SNEDDS. Elevated halofantrine solubilisation during in vitro lipolysis was observed only when multiple capsules of conventional SNEDDS were subjected to in vitro digestion. After lipolysis the isolated super-SNEDDS pellets were characterised by XRPD revealing no crystalline halofantrine from any of the investigated formulations. Subsequent dissolution studies of the super-SNEDDS pellet in the lipolysis medium demonstrated enhanced dissolution of halofantrine suggesting that halofantrine in the pellet was amorphous. The enhanced dissolution of the amorphous halofantrine was also reflected in vivo since two capsules of conventional SNEDDS were needed to achieve similar AUC and C(max) as obtained after dosing of a single capsule of super-SNEDDS. The study demonstrated that the absorption of halofantrine was not h ered by drug precipitation. Super-SNEDDS lead to precipitation of halofantrine in an amorphous form, which can be the driving force for enhanced absorption. Since super-SNEDDS were also physically stable for at least 6 months they represent a potential novel oral lipid-based drug delivery system for low aqueous soluble compounds.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.NANO.2019.102022
Abstract: Anti-biofilm peptides are a subset of antimicrobial peptides and represent promising broad-spectrum agents for the treatment of bacterial biofilms, though some display host toxicity in vivo. Here we evaluated nanogels composed of modified hyaluronic acid for the encapsulation of the anti-biofilm peptide DJK-5 in vivo. Nanogels of 174 to 194 nm encapsulating 33-60% of peptide were created. Efficacy and toxicity of the nanogels were tested in vivo employing a murine abscess model of a Pseudomonas aeruginosa LESB58 high bacterial density infection. The dose of DJK-5 that could be administered intravenously to mice without inducing toxicity was more than doubled after encapsulation in nanogels. Upon subcutaneous administration, the toxicity of the DJK-5 in nanogels was decreased four-fold compared to non-formulated peptide, without compromising the anti-abscess effect of DJK-5. These findings support the use of nanogels to increase the safety of antimicrobial and anti-biofilm peptides after intravenous and subcutaneous administration.
Publisher: American Chemical Society (ACS)
Date: 29-11-2018
DOI: 10.1021/ACS.MOLPHARMACEUT.8B00940
Abstract: Liposomes have been widely researched as drug delivery systems however, the solid state form of drug inside the liposome, whether it is in solution or in a solid state, is often not studied. The solid state properties of the drug inside the liposomes are important, as they dictate the drug release behavior when the liposomes come into contact with physiological fluid. Recently, a new approach of making liposomal ciprofloxacin nanocrystals was proposed by the use of an additional freeze-thawing step in the liposomal preparation method. This paper aims to determine the solid state properties of ciprofloxacin inside the liposomes after this additional freeze-thawing cycle using cryo-TEM, small-angle X-ray scattering (SAXS), and cross-polarized light microscopy (CPLM). Ciprofloxacin precipitated in the ciprofloxacin hydrate crystal form with a unit cell dimension of 16.7 Å. The nanocrystals also showed a phase transition at 93 °C, which represents dehydration of the hydrate crystals to the anhydrate form of ciprofloxacin, verified by temperature-dependent SAXS measurements. Furthermore, the dependence of the solid state form of the nanocrystals on pH was investigated in situ, and it was shown that the liposomal ciprofloxacin nanocrystals retained their crystalline form at pH 6-10. Understanding the solid state attributes of nanocrystals inside liposomes provides improved understanding of drug dissolution and release as well as opening avenues to new applications where the nanosized crystals can provide a dissolution benefit.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.EJPB.2009.07.010
Abstract: The aim of this study was to better understand the interactions between metoprolol tartrate and quaternary polymethacrylate (Eudragit RL and Eudragit RS) films. For reasons of comparison, polymeric films containing the free base metoprolol or free tartaric acid were also prepared. Systems containing various amounts of the free base, free acid and the salt were characterised using polarising light microscopy, X-ray powder diffraction, differential scanning calorimetry and mechanical analysis (puncture test). The free base is the most efficient plasticiser of the three species for Eudragit RL and Eudragit RS, but with limited solubility in the polymers. Due to its hydrophobicity, it can interact with the hydrophobic polymer backbones. In contrast, in salt containing films, ionic interactions between the positively charged quaternary ammonium groups and the negatively charged tartrate anions apparently occur, this being suggested by the different effects on Eudragit RL versus RS, which have different contents of quaternary ammonium groups. Importantly, the combination of acid and base as a salt avoids drug precipitation at higher metoprolol contents. The obtained new insight into the occurring drug-polymer interactions can help to facilitate the development/optimisation of this type of dosage forms.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2012
Location: Germany
Start Date: 2009
End Date: 2012
Funder: National Health and Medical Research Council
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