Oya Alpar
School of Pharmacy, UCL, Pharmaceutics, Faculty Member
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The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA... more
The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA microparticles were produced adopting water-in-oil-in-water (W/O/W) solvent evaporation technique and were investigated for surface morphology, particle size, encapsulation efficiency (EE%) and in-vitro release profile. Porous surface morphologies with a narrow size distribution were observed when employing 0.5 ml internal aqueous phase; 23.04 µm (±0.98), 15.05 µm (±0.27) and 22.89 µm (±0.41) for PVA, Tween 80 and oleic acid. Porous microparticles exhibited increased size and reduction in EE% with increasing internal aqueous phase, with non-porous microparticles produced when adopting 2.0 ml internal aqueous phase. The selection of stabilizer influences the size of the pores formed thus offers potential for the aerodynamic properties of the microparticles to be manipulated to achieve suitable aerosolization characteristics for pulmonary delivery of proteins.
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In the present work, DNaseI loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for pulmonary delivery were prepared using emulsion solvent evaporation. The effects of the various formulation and experimental variables on the... more
In the present work, DNaseI loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for pulmonary delivery were prepared using emulsion solvent evaporation. The effects of the various formulation and experimental variables on the size and morphological characteristics of the particles as well as on the encapsulation efficiency were investigated. The stability of the encapsulated DNaseI was evaluated and the respirable fraction was determined. Cytotoxicity of the NPs was evaluated on lung epithelial cells. The results showed that by using leucine and dipalmito-phosphatidyl-choline (DPPC), discrete NPs with 76% retained biological activity were prepared. A high respirable fraction (particles below 6 μm) reaching 71.3% was achieved after nebulization of the NP suspension. The results revealed the suitability of the prepared particles for pulmonary delivery and highlighted the role of excipients in the stabilization of DNaseI against the stresses encountered during preparation.
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In this study, the spray drying technique was used to prepare ciprofloxacin microparticles (CFX-MPs) for pulmonary administration. By virtue of its amphoteric properties, CFX was dissolved in either a slightly alkaline or acidic solution... more
In this study, the spray drying technique was used to prepare ciprofloxacin microparticles (CFX-MPs) for pulmonary administration. By virtue of its amphoteric properties, CFX was dissolved in either a slightly alkaline or acidic solution depending on the used polymer. Dextran and chitosan were used to prepare the MPs and modify the release characteristics of the drug. Particle surface modification was done with either DPPC or PEG. The effects of the manufacturing and formulation parameters on the drug-polymer interactions were investigated by thermal analysis and infrared spectroscopy. CFX-MPs showed improved aerosolisation properties and the encapsulated drug possessed high antimicrobial activity against two of the common and resistant respiratory pathogens: Pseudomonas aeruginosa and Staphylococus aureus. MPs were safe on the lung epithelial cells. Modulation of particle characteristics and drug release was possible by altering not only the polymer but also the type of the acid from which the powders were spray dried. MPs prepared with glutamic and aspartic acids showed better characteristics than those prepared with acetic and hydrochloric acids. Dextran modified particles showed improved aerosolisation properties and safety on lung epithelial cells.
Research Interests: Chitosan, Aerosols, Pharmaceutics, Cell line, Humans, and 14 moreStaphylococcus aureus, Drug Delivery Systems, Lung, Pseudomonas aeruginosa, Anti-Bacterial Agents, Epithelial cells, Pseudomonas Aeruginosa, Ciprofloxacin, Microspheres, Drug Carriers, Excipients, Drug Compounding, Hydrogen-Ion Concentration, and Polyethylene Glycols
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The iron uptake systems of pathogenic bacteria provide potential targets for immunological intervention. We have partially purified the high molecular mass, iron-regulated outer membrane proteins (IROMPs) from Pseudomonas aeruginosa and... more
The iron uptake systems of pathogenic bacteria provide potential targets for immunological intervention. We have partially purified the high molecular mass, iron-regulated outer membrane proteins (IROMPs) from Pseudomonas aeruginosa and used them to prepare a panel of monoclonal antibodies (mAbs). Five mAbs reacted with an 85 kDa IROMP separated by SDS-PAGE, but gave only low-level binding to whole cells by immunogold electron microscopy. However, iodination of whole cells indicated that the 85 kDa IROMP is surface-exposed. The mAbs were only cross-reactive with clinical isolates representing eight of the 17 International Antigenic Typing Scheme serotypes of P. aeruginosa, suggesting significant heterogeneity with respect to this IROMP.
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Several advantages have been proposed for administering antitubercular drugs in particulate carriers including a reduction in the dose and frequency of administration, increasing patient compliance as well as targeting the drug to... more
Several advantages have been proposed for administering antitubercular drugs in particulate carriers including a reduction in the dose and frequency of administration, increasing patient compliance as well as targeting the drug to macrophages that harbour Mycobacterium tuberculosis. An important characteristic responsible for mucosal adsorption and translocation of particles through the mucosa is surface charge. In these investigations chitosan was used as an emulsion stabiliser in the preparation of rifampicin loaded PLGA, PCL and combined PLGA+PCL microspheres. Chitosan not only imparted a positive charge to the surface of the microspheres but was also able to increase their loading efficiency. Combined PLGA+PCL microspheres display substantially altered release kinetics which may be useful in the delivery of rifampicin and other agents that may benefit from sustained and controlled delivery profiles.
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ABSTRACT The aim of this study was to prepare stable liposomes coated or loaded with bioadhesive polymers and test their efficacy following oral, nasal (IN) or intramuscular (IM) delivery of diphtheria toxoid (DT) in raising systemic... more
ABSTRACT The aim of this study was to prepare stable liposomes coated or loaded with bioadhesive polymers and test their efficacy following oral, nasal (IN) or intramuscular (IM) delivery of diphtheria toxoid (DT) in raising systemic antibody responses. The stability of these liposomes in three different media mimicking gastrointestinal (GI) fluids of the stomach and small intestine was also examined. Fluorescence microscopy of the rat small intestine showed preferential adsorption/association of polymer-coated liposomes versus free FITC-BSA. Finally, the efficacy liposomes composed of dipalmitoylphosphatidylcholine, dicetyl phosphate and cholesterol (DPPC:DCP:CH, 7:3:2 molar ratio) for delivery of DT to mice was assessed. Immunisation through the IM route with these liposomes produced the highest DT specific serum IgG antibody titres; liposomes loaded with chitosan chloride were the only formulation to elicit a specific measurable IgG response when delivered orally with the present protocol. IN delivery of liposomes loaded with PVA resulted in a significantly better IgG antibody response (p < 0.05) when compared to uncoated liposomes.
1. Biochem Soc Trans. 1992 Nov;20(4):316S. Poly(lactic acid) microspheres as immunological adjuvants for orally delivered cholera toxin b subunit. Almeida AJ, Alpar HO, Williamson D, Brown MR. Department of Pharmaceutical Sciences, Aston... more
1. Biochem Soc Trans. 1992 Nov;20(4):316S. Poly(lactic acid) microspheres as immunological adjuvants for orally delivered cholera toxin b subunit. Almeida AJ, Alpar HO, Williamson D, Brown MR. Department of Pharmaceutical Sciences, Aston University, Birmingham, UK. ...
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The aim of this study was to further investigate the interactions between cholesterol (CH) and mixed bile salts (BS) (sodium cholate and sodium deoxycholate) and their suitability for drug and vaccine delivery. Insulin was used as a model... more
The aim of this study was to further investigate the interactions between cholesterol (CH) and mixed bile salts (BS) (sodium cholate and sodium deoxycholate) and their suitability for drug and vaccine delivery. Insulin was used as a model protein to assess the ability of CH:BS vesicles to entrap a therapeutically relevant macromolecule. The association of protein (FITC-insulin) with the CH:BS structure was confirmed with fluorescence microscopy, and the overall morphology of the vesicles was examined with atomic force microscopy (AFM). Results demonstrate that the nature of the vesicles formed between CH and BS is dependent not only on the concentration of BS but also on the increasing CH concentration leading to CH crystal formation.
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The aim of this study was to investigate the effect of size and charge on the permeation of nanoparticles through the skin as the first step in designing a transdermal vaccine delivery system. Fluorescent particles ranging in size and... more
The aim of this study was to investigate the effect of size and charge on the permeation of nanoparticles through the skin as the first step in designing a transdermal vaccine delivery system. Fluorescent particles ranging in size and charge were applied to the surface of full thickness pig skin in a diffusion chamber and the receptor fluid was assayed to determine permeation. Fluorescence microscopy was used to visualise the skin after experiments. The results showed that only 50 and 500 nm particles that were negatively charged were able to permeate the skin. This provides evidence of the potential of nanoparticles as delivery vectors for antigens and DNA for the purpose of transdermal vaccination protocols. The results would indicate that negative particles with sufficient charge may be ideal carriers for this purpose.
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Many novel therapeutic agents are proteins and peptides which need stabilisation due to their inherent instability in aqueous solution. Freeze-drying is an established method for protein stabilisation, although the use of additives is... more
Many novel therapeutic agents are proteins and peptides which need stabilisation due to their inherent instability in aqueous solution. Freeze-drying is an established method for protein stabilisation, although the use of additives is often necessary in order to preserve protein structure and activity during lyophilisation itself. The molecular interactions between protein and protective additive are as yet unclear. In this study, we examined the use of a range of saccharide additives to stabilise the model multi-subunit enzyme L-asparaginase during lyophilisation, assessed post-drying enzyme activity and quaternary structure, and related the extrapolated levels of additive necessary to provide full stabilisation to the theoretical levels predicted from an existing hypothesis using molecular modelling. It was found that each of the saccharides tested here displayed similar levels of protection towards L-asparaginase under the conditions used. Amounts of additive required to give ful...
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ABSTRACT Biodegradable microspheres of polylactide have been prepared for the controlled release of model proteins. Studies have shown that release from these microspheres is dependent on properties of the polymer and the protein... more
ABSTRACT Biodegradable microspheres of polylactide have been prepared for the controlled release of model proteins. Studies have shown that release from these microspheres is dependent on properties of the polymer and the protein encapsulated. The combination of two proteins will have an effect on the characteristics of the particles produced and the release profiles obtained.Using a solvent evaporation technique, low molecular weight poly(L)lactide microspheres were produced, loaded with different ratios of a number of model proteins. The effects on loading efficiency, particle size, surface charges and release were examined.The results suggest that the outcome of the presence of carrier proteins, and co-encapsulated adjuvants on the properties of the microspheres produced must be studied for each combination employed.
Streptococcus equi subsp. equi is the causative agent of Strangles, which is one of the most costly and widespread infectious diseases, affecting the respiratory tract of Equidae. In this work, polyvinyl alcohol, alginate and chitosan... more
Streptococcus equi subsp. equi is the causative agent of Strangles, which is one of the most costly and widespread infectious diseases, affecting the respiratory tract of Equidae. In this work, polyvinyl alcohol, alginate and chitosan were used in formulations of surface modified poly-epsilon-caprolactone microspheres which were evaluated after adsorption of S.equi enzymatic extract for physicochemical characteristics and in vivo immune responses in mice. After subcutaneous immunisation, the formulations induced higher lymphokines levels, in accordance with cellular and humoral immune responses, as compared to the free antigen, successfully activating the paths leading to Th1 and Th2 cells. The obtained results highlight the role of these microspheres as an adjuvant and their use to protect animals against strangles.
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Streptococcus equi subspecies equi affects animals of Equidae family and is the causative agent of strangles, an acute, extremely contagious and deadly disease. Prolonged periods of protection associated to absence of serious adverse... more
Streptococcus equi subspecies equi affects animals of Equidae family and is the causative agent of strangles, an acute, extremely contagious and deadly disease. Prolonged periods of protection associated to absence of serious adverse reactions were not yet achieved. Thus, this experimental work is focused on the study of mucosal, humoral and cellular immune responses developed in a mouse model, after the intranasal administration of S. equi antigens associated by adsorption or encapsulation to poly(lactic acid) nanospheres, modified by mucoadhesive polymers and absorption enhancers. Particles fitted the nanometer range and proteins integrity and antigenicity were not affected. PLA nanospheres induced a mixed Th1 and Th2 response, being therefore potential carriers for the delivery of S. equi antigens.
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Induction of systemic immune responses after intraperitoneal inoculation of poly(L)lactide microspheres containing the V antigen of Yersinia pestis co-encapsulated with IFN-gamma were investigated. Serum antibody responses and T cell... more
Induction of systemic immune responses after intraperitoneal inoculation of poly(L)lactide microspheres containing the V antigen of Yersinia pestis co-encapsulated with IFN-gamma were investigated. Serum antibody responses and T cell proliferative responses were measured in groups of Balb/c mice which were injected intraperitoneally with single or double emulsion preparations of either V/IFN-gamma or V alone in a range of dose levels. Groups which received V antigen co-encapsulated with IFN-gamma produced higher V-specific antibody responses, predominantly of the IgG1 isotype. Administration of 25 micrograms V/IFN-gamma in a single emulsion resulted in a significantly increased (p < 0.05) splenic T cell proliferative response to V antigen compared with other formulations. It was concluded that IFN-gamma co-encapsulated with V antigen in poly(L)lactide microspheres acted as an adjuvant and increased antigen specific systemic immune responses. Therefore, co-encapsulation with IFN-gamma may result in effective single dose vaccines by increasing the immunogenicity of the formulations.
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The characterization of the immunological cascades of the innate immune system activated by pathogen associated molecular patterns (PAMP) recognized by pattern recognition receptors (PRR) have allowed the elucidation of the mechanisms... more
The characterization of the immunological cascades of the innate immune system activated by pathogen associated molecular patterns (PAMP) recognized by pattern recognition receptors (PRR) have allowed the elucidation of the mechanisms underlying the immunomodulatory properties of adjuvants. Thus, the combinatorial use of adjuvants with specific, complementary functions is investigated to achieve tailored immune responses to subunit vaccines. We have previously shown how combinatorial administration of chitosan and cholera toxin B or muramyl-di-peptide (MDP) intranasally, but not intramuscularly, can allow small doses of MDP which, when administered alone cannot adjuvantise Helicobacter pylori urease (rUre), achieve an immunomodulatory effect through the specific physiological effect of chitosan. The aim of this study was to investigate if in the context of rUre the adjuvantising effect of MDP could be realized via the intramuscular route by combination with aluminium hydroxide, as compared with the routinely used veterinary adjuvant combination of alum and Quil-A. Serum IgG kinetics were comparable between the two adjuvant combination groups. However, the alum + MDP combination afforded higher antigen-specific recall responses in splenocyte cultures, associated with elevated release of the type I immune response cytokines IFN-gamma and IL-2. This data suggests that the adjuvanticity of MDP can be modulated in the context of alum in a manner dissimilar to that of Quil-A, achieving a balancing effect on the responses elicited by alum adjuvantisation.
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Poly-(epsilon-caprolactone) (PCL), a poly(lactide-co-glycolide) (PLGA)-PCL blend and co-polymer nanoparticles encapsulating diphtheria toxoid (DT) were investigated for their potential as a mucosal vaccine delivery system. The... more
Poly-(epsilon-caprolactone) (PCL), a poly(lactide-co-glycolide) (PLGA)-PCL blend and co-polymer nanoparticles encapsulating diphtheria toxoid (DT) were investigated for their potential as a mucosal vaccine delivery system. The nanoparticles, prepared using a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation method, demonstrated release profiles which were dependent on the properties of the polymers. An in vitro experiment using Caco-2 cells showed significantly higher uptake of PCL nanoparticles in comparison to polymeric PLGA, the PLGA-PCL blend and co-polymer nanoparticles. The highest uptake mediated by the most hydrophobic nanoparticles using Caco-2 cells was mirrored in the in vivo studies following nasal administration. PCL nanoparticles induced DT serum specific IgG antibody responses significantly higher than PLGA. A significant positive correlation between hydrophobicity of the nanoparticles and the immune response was observed following intramuscular administration. The positive correlation between hydrophobicity of the nanoparticles and serum DT specific IgG antibody response was also observed after intranasal administration of the nanoparticles. The cytokine assays showed that the serum IgG antibody response induced is different according to the route of administration, indicated by the differential levels of IL-6 and IFN-gamma. The nanoparticles eliciting the highest IgG antibody response did not necessarily elicit the highest levels of the cytokines IL-6 and IFN-gamma.
Research Interests: Immune response, Polymers, Atomic Force Microscopy, Spleen, Methods, and 23 moreHumans, Mice, Endocytosis, Female, Animals, Nanostructures, Drug Delivery Systems, Vaccination, Clinical Sciences, Caco-2 cells, Particle Size, Delivery System, Surface Properties, Intranasal Administration, Polyesters, Caco 2 Cell, Lactic Acid, Antigens, Static Electricity, Nasal Mucosa, immunoglobulin G, Interleukin, and Interferon gamma
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Free hydrocortisone, hydrocortisone incorporated into microspheres and empty microspheres have been administered orally to rats with carrageenan-induced hindpaw inflammation. Hydrocortisone administered in particles was effective at a... more
Free hydrocortisone, hydrocortisone incorporated into microspheres and empty microspheres have been administered orally to rats with carrageenan-induced hindpaw inflammation. Hydrocortisone administered in particles was effective at a lower dose than free steroid in reducing inflammation. Inflammatory exudates were able to release steroid from the microspheres by proteolytic degradation.
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Microcapsules of phenethicillin potassium as a model water-soluble drug, coated with ethyl cellulose, have been prepared (core: wall ratios 1:1, 1:2 and 1:3) in which the taste has been masked, the odour almost eliminated and the release... more
Microcapsules of phenethicillin potassium as a model water-soluble drug, coated with ethyl cellulose, have been prepared (core: wall ratios 1:1, 1:2 and 1:3) in which the taste has been masked, the odour almost eliminated and the release retarded. Sieve analysis showed that with decreasing core: wall ratios there was a trend towards increasing amounts of larger sized microcapsules. At constant core:wall ratios in vitro release of drug was generally greatest from the larger microcapsules. This result correlated with the surface areas of the microcapsules which became less as the asymmetry of the microcapsules diminished with decrease in microcapsule size. There was a linear relation between the amount of ethyl cellulose and the time for 60% release of drug, and the release pattern was analogous to that from insoluble porous matrices. Scanning electron micrographs showed the microcapsules to be irregularly shaped with circular surface pores, and they did not alter in shape or size during dissolution. Tableting of 1:1 core: wall ratio microcapsules significantly further retarded the dissolution.
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The distribution of latex microspheres (1.1 microns diam) has been investigated in-vivo, as a potential passive targeted system for the treatment of inflammation. Microspheres administered orally were found in the circulation and in... more
The distribution of latex microspheres (1.1 microns diam) has been investigated in-vivo, as a potential passive targeted system for the treatment of inflammation. Microspheres administered orally were found in the circulation and in inflamed tissues and exudates of inflammatory air pouches in rats. Oral absorption was also found in a rabbit. Particles administered directly into the circulation also penetrated into the air pouch tissues and fluids. The possibility of using microspheres as a passive targeted system for the treatment of inflammation is discussed.
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Tetanus toxoid was adsorbed onto poly(L-lactic acid) microspheres. Analyses by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blotting suggest that the formulation procedure does not affect the stability or the... more
Tetanus toxoid was adsorbed onto poly(L-lactic acid) microspheres. Analyses by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blotting suggest that the formulation procedure does not affect the stability or the antigenic properties of the protein. After nasal administration to guinea-pigs, the resulting preparation enhanced the immune response to the tetanus toxoid when compared with the free antigen. The increase in systemic immunoglobulin G titre was almost immediate in the group treated with the adsorbed tetanus toxoid (time zero, 140; week 2, 1550; week 4, 2760), reaching 36,000 two weeks after the booster (week 7), whereas the free antigen produced an immune response similar to that found in non-treated animals. In a parallel experiment, latex particles of a similar size to poly(L-lactic acid) microspheres, administered to both rats and rabbits, were detected in the blood stream. These findings with tetanus toxoid demonstrate the use of microsphere delivery systems for nasal application of antigens. These had a profound effect on the immune response, and indicate possibilities for overcoming some of the barriers to drug absorption in general.
Research Interests: Pharmacy, Polymers, Western blotting, Adsorption, LaTeX, and 14 morePharmacology and Clinical pharmacy, Female, Animals, Male, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Rats, Particle Size, Wistar Rats, Rabbits, Microspheres, Intranasal Administration, Lactic Acid, Tetanus Toxoid, and Nasal Mucosa
Factors relating to the transfer of latex microspheres of 0.87 micron mean diameter from the gastrointestinal tract (GIT) to the circulation have been investigated. The rapidity of appearance and the number of particles increased when the... more
Factors relating to the transfer of latex microspheres of 0.87 micron mean diameter from the gastrointestinal tract (GIT) to the circulation have been investigated. The rapidity of appearance and the number of particles increased when the volume of water used as a suspending vehicle was increased. This was probably due to barrier cell integrity being compromised so that the movement of particles across the enterocytes would be enhanced. Particles were swept into these channels by the waterflow. The tonicity of the fluid was important as isotonic and hypertonic saline were not as effective as water in transferring particles. Particles were transferred from GIT segments adjacent to the stomach which may in part explain the rapid appearance of particles in the circulation. Particle uptake was blocked by cytochalasin B which suggests an active component may also be involved.
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... In the absence of an appropriate pharmaceutical preparation containing absorption-promoting adjuvants, the systemic bioavailability of interferon-a and interferon# from the gut or rectum is virtually nil (Bocci et a1 1986). Because ...
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Numerous strategies are currently available for preparing liposomes, although no single method is ideal in every respect. Two methods for producing liposomes using compressed carbon dioxide in either its liquid or supercritical state were... more
Numerous strategies are currently available for preparing liposomes, although no single method is ideal in every respect. Two methods for producing liposomes using compressed carbon dioxide in either its liquid or supercritical state were therefore investigated as possible alternatives to the conventional techniques currently used. The first technique used modified compressed carbon dioxide as a solvent system. The way in which changes in pressure, temperature, apparatus geometry and solvent flow rate affected the size distributions of the formulations was examined. In general, liposomes in the nano-size range with an average diameter of 200 nm could be produced, although some micron-sized vesicles were also present. Liposomes were characterized according to their hydrophobic drug-loading capacity and encapsulated aqueous volumes. The latter were found to be higher than in conventional techniques such as high-pressure homogenization. The second method used compressed carbon dioxide as an anti-solvent to promote uniform precipitation of phospholipids from concentrated ethanolic solutions. Finely divided solvent-free phospholipid powders of saturated lipids could be prepared that were subsequently hydrated to produce liposomes with mean volume diameters of around 5 microm.
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Hydrocortisone and its more soluble ester, hydrocortisone 21-acetate, have been incorporated into poly(D,L-lactic) acid (PDLLA) microspheres using single, double emulsion/solvent evaporation and by spray-drying techniques. This paper... more
Hydrocortisone and its more soluble ester, hydrocortisone 21-acetate, have been incorporated into poly(D,L-lactic) acid (PDLLA) microspheres using single, double emulsion/solvent evaporation and by spray-drying techniques. This paper describes the characterization of the microparticles obtained (morphology, particle size distribution, drug content, yield of production, in vitro drug release behaviour) and a comparison of the results (drug loading, drug release, size of the microspheres) obtained from the different techniques used. These results demonstrate that by using a relatively more soluble ester of an insoluble steroid, hydrocortisone, the drug content within the microspheres can be increased, together with a high efficiency of loading, irrespective of the technique employed. In the case of hydrocortisone, spray-drying produces the highest loading and encapsulation efficiency compared to both single and double emulsion methods for microspheres of similar size (about 2-4 microns) and suitable for lung delivery, but with lower yields (about 55% versus about 33%).