Some priorities in maximizing access to and quality of contraceptive services.
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Contraception↗
Biomedical subjects
S S Davis
Publications and source records attributed to S S Davis.
Single dose, polymeric, microparticle-based vaccines: the influence of formulation conditions on the magnitude and duration of the immune response to a protein antigen.
Ovalbumin-loaded poly (D,L-lactide co-glycolide) [OVA-loaded PLG] microparticles, produced by emulsion/solvent evaporation stimulated the production of high serum IgG antibody levels after a single subcutaneous (s.c.) administration in mice and the duration of the immune response paralleled the degradation rate of the carrier. Formulations based on slow resorbing PLG maintained relatively constant peak antibody levels for 26 weeks and high titres for over 1 year at a level approximating the peak response to the faster resorbing, OVA-loaded particles which was of lower duration. Vaccine formulations prepared by simple mixing of blank PLG microparticles and OVA exhibited low primary immune responses which were only elevated by boosting. OVA-loaded PLG microparticles exhibited a substantial surface protein component amounting to ca 40% and 60% of the total protein loading for slow resorbing and fast resorbing PLG, respectively. These findings suggest that sustained presentation of surface protein to the immune system was a major factor in the induction and long-term maintenance of high antibody titres following a single s.c. administration of OVA-loaded microparticles.
Alum Compounds↗
European Commission COST/STD Initiative. Report of the expert panel VII. Vaccine delivery systems.
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Drug Delivery Systems↗
Evidence for the formation of amphotericin B-phospholipid complexes in Langmuir monolayers.
PURPOSE: To study the interaction of the polyene antifungal amphotericin B with phospholipid Langmuir monolayers and to correlate with stability of phospholipid-stabilized drug emulsions. METHODS: Pressure-area isotherms of mixed monolayers of amphotericin B (0-20 mol%) and different phospholipid types were recorded using conventional Langmuir trough methods. Emulsion stability of amphotericin B-containing lipid emulsions was measured using dynamic light scattering. RESULTS: Incorporation of amphotericin B into monolayers composed of saturated phospholipids (Lipoid E80-3) had a profound effect on the shape of the isotherm. This effect was directly related to the concentration of amphotericin B in the monolayer. At high drug concentrations, the shape of the isotherms became progressively similar to that of pure DPPC, thus exhibiting regions attributable to phospholipid in different phase states. This effect on isotherm shape was not observed following incorporation of the drug into monolayers composed of the equivalent unsaturated lecithin (Lipoid E80). CONCLUSIONS: These results are interpreted as indicating the formation of an amphotericin B-phospholipid complex, resulting in phase separation within the monolayer. The extent and nature of this phase separation was dependent on both the concentration of drug in the system, and the saturation state of the phospholipid component. The relevance of these observations to the stability of amphotericin B drug emulsions stabilised by saturated and unsaturated phospholipid emulsifiers is discussed. These observations may also be relevant to the toxicity of these, and other novel amphotericin B formulations.
1,2-Dipalmitoylphosphatidylcholine↗
Improving protein delivery from microparticles using blends of poly(DL lactide co-glycolide) and poly(ethylene oxide)-poly(propylene oxide) copolymers.
PURPOSE: Microparticles containing ovalbumin as a model for protein drugs were formulated from blends of poly(DL lactide-co-glycolide) and poly(ethylene oxide)-poly(propylene oxide) copolymers (Pluronic). The objectives were to achieve uniform release characteristics and improved protein delivery capacity. METHODS: The water- in oil -in oil emulsion/solvent extraction technique was used for microparticle production. RESULTS: A protein loading level of over 40% (w/w) was attained in microparticles having a mean diameter of approximately 5 microns. Linear protein release profiles over 25 days in vitro were exhibited by certain blend formulations incorporating hydrophilic Pluronic F127. The release profile tended to plateau after 10 days when the more hydrophobic Pluronic L121 copolymer was used to prepare microparticles. A delivery capacity of 3 micrograms OVA/mg particles/ day was achieved by formulation of microparticles using a 1:2 blend of PLG:Pluronic F127. CONCLUSIONS: The w/o/o formulation approach in combination with PLG:Pluronic blends shows potential for improving the delivery of therapeutic proteins and peptides from microparticulate systems. Novel vaccine formulations are also feasible by incorporation of Pluronic L121 in the microparticles as a co-adjuvant.
Chemistry, Pharmaceutical↗
Vaccinia virus-expressed bovine ephemeral fever virus G but not G(NS) glycoprotein induces neutralizing antibodies and protects against experimental infection.
Two related glycoproteins (G and G(NS)) encoded in the bovine ephemeral fever virus (BEFV) genome were expressed from recombinant vaccinia viruses (rVV). Both proteins were detected in lysates of rVV-infected cells by labelling with D-[6-3H]glucosamine or by immuno-blotting. The recombinant G protein (mol. mass 79 kDa) appeared slightly smaller than the native G protein but reacted with monoclonal antibodies directed against all defined neutralizing antigenic sites (G1, G2, G3a, G3b and G4). The recombinant G(NS) protein (mol. mass 90kDa) was identical in size to the native G(NS) protein and failed to react by immuno-fluorescence with anti-G protein monoclonal or poly-clonal antibodies. Antisera raised in rabbits against rVV-G or rVV-G(NS) both reacted strongly by immuno-fluorescence and immuno-electron microscopy with BEFV-infected cells. The G protein was localized intracellularly in the endoplasmic reticulum/Golgi complex and at the cell surface associated with budding and mature virus particles. The G(NS) protein also localized intracellularly in the endoplasmic reticulum/Golgi complex; however, at the cell surface it was associated with amorphous structures and not with budding or mature virions. Rabbits vaccinated with rVV-G developed high levels of antibodies which neutralized BEFV grown in either mammalian or insect cells. Cattle vaccinated with rVV-G also produced neutralizing antibodies and were protected against experimental BEFV infection. In contrast, rVV-G(NS) vaccinated rabbits and cattle failed to produce neutralizing antibodies and, after challenge, BEFV was isolated from two-thirds of the vaccinated cattle.
Aedes↗
Particle uptake and translocation across epithelial membranes.
Oral delivery of drugs and vaccines has many advantages over other routes of administration. For example, for vaccination, enteric delivery may result in the induction of a mucosal immune response against pathogens which colonise and invade the mucosa. However, the oral delivery of peptide or protein drugs or antigens is beset with problems, such as gastrointestinal breakdown of labile molecules, low level of macromolecular absorption and, for vaccines, the poor immune response usually elicited by orally administered soluble antigens. Investigations are therefore in progress to develop means of increasing intestinal absorption and decreasing digestion of orally administered molecules. Molecules can be incorporated into biodegradable microparticles to reduce the effect of gut secretions and to enable the absorption of bioactive agents in an unaltered form. The uptake of microparticulates through the gut wall is accepted as a true biological phenomenon but the mechanism and route of uptake have not been established. Furthermore, in general, only small numbers of microparticles are translocated across epithelial membranes, possibly making these systems inappropriate for drug or vaccine delivery. This paper reviews particle uptake across the gastrointestinal tract and describes studies carried out to determine whether a humoral response can be elicited following oral administration of an antigen associated with biodegradable poly(DL lactide-coglycolide) microparticles. The use of lipid delivery vehicles to enhance microparticle uptake and the selective transport of microspheres across M cells is also described.
Administration, Oral↗
Comments concerning 'The penetration of amphotericin B from an Intralipid formulation into fibrin loci in a rabbit model of candidiasis'.
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Amphotericin B↗
The effect of mannitol on the oral bioavailability of cimetidine.
The aim of the study was to investigate whether mannitol at amounts relevant to pharmaceutical formulations would alter the oral bioavailability of cimetidine, a drug primarily absorbed from the small bowel. Seven healthy male subjects each received four formulations, a chewable tablet or a solution, containing 0.200 g of cimetidine and either 2.264 g of mannitol or sucrose, in a randomized four-way cross-over study. Frequent blood samples were taken over a 24 h period to allow a cimetidine plasma profile to be obtained for each formulation. Transit of the radiolabeled formulations was followed by gamma scintigraphy. Statistically significant reductions in the AUC0-24 and maximum plasma concentration values were observed with the mannitol dosage forms compared to the sucrose controls. The mean small intestinal transit times were shortened after administration of the mannitol solution and tablet; the transit time of the solution was significantly shorter with values 23% of those for the sucrose solution. The implication of the study findings is that excipients cannot always be regarded as "inert" substances that can be incorporated into a formulation without having any deleterious effect on the overall in vivo behaviour of the product.
Administration, Oral↗
Influence of surface coverage with poly(ethylene oxide) on attachment of sterically stabilized microspheres to rat Kupffer cells in vitro.
The attachment to rat Kupffer cells of polymeric microspheres, sterically stabilized with different amounts of pendant poly(ethylene oxide) (PEO), was assessed in vitro. Four types of copolymer polystyrene (PS) microspheres were synthesized by variation of four possible monomer ratios that included styrene, methoxy-PEO-methacrylate (750 and 2000 mol. wt PEO) and allylurea. This produced poly(styrene-(methoxy-PEO)methacrylate) microspheres with hydrophilic side-groups of either urea (PS-U-PEO) and/or mixed molecular weight (750/2000 mol. wt) PEO (PS-U-M-PEO, PS-M-PEO), or single molecular weight (2000) PEO (PS-PEO) at their surfaces. The hypothesis was tested that increasing the total content of PEO comprising the steric barrier reduces attachment to cell surfaces. Attachment of PEO microspheres bearing the urea spacer and/or mixed molecular weight PEO was found to be intermediate between charge stabilized control PS and PEO (2000 mol. wt) bearing particles. Post-adsorption of different Poloxamer (PEO-poly(propylene oxide)-PEO) surfactants to the microspheres further decreased attachment. Significant negative linear correlations between surface PEO content, measured by electron spectroscopy for chemical analysis (ESCA), and attachment to Kupffer cells were demonstrated. Decreases in attachment also resulted with all graft PEO particles bearing adsorbed sodium dodecyl sulphate (SDS), whilst the attachment of SDS-treated PS control particles increased. It is proposed that trains of adsorbed graft PEO are displaced by the SDS to increase the effective fraction of graft PEO within the steric layer. Overall, increasing the amount of hydrophilic PEO in the steric layer, from graft and adsorbed sources, reduces the attachment of these particles to Kupffer cells in vitro.
Analysis of Variance↗
Synthetic delivery system for tuberculosis vaccines: immunological evaluation of the M. tuberculosis 38 kDa protein entrapped in biodegradable PLG microparticles.
Tuberculosis remains a major public health burden which could be ameliorated by effective and well-defined subunit vaccines, particularly because the protective efficacy of current M. bovis BCG vaccines is both unpredictable and variable. The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly (DL-lactide co-glycolide) (PLG) microparticles which served as a delivery system. Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund's adjuvant (IFA). Vaccination of mice with a single dose of antigen-loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund's adjuvant (IFA). T-cell responses were found to be superior to those induced with antigen/IFA. The T- and B-cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA. Differences in adjuvanticity were revealed by measuring antigen-specific IgG1, IgG2a and antigen-induced IFN-gamma secretion in vitro: substantially higher titres of IgG2a were observed following immunization with antigen/microparticles than with 38 kDa protein/IFA. This was paralleled by a tenfold higher secretion of IFN-gamma in mice injected with antigen/microparticles. Reduction in colony-forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli. Taken together these results indicate that biodegradable PLG microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis.
Amino Acid Sequence↗
The effect of different concentrations of mannitol in solution on small intestinal transit: implications for drug absorption.
The aim of the present study was to investigate the effect that different concentrations of mannitol have on small intestinal transit, and whether any observed effect was concentration dependent. Eight, healthy male subjects each received 200ml of radiolabelled purified water, or a 200ml solution of mannitol at three different concentrations; 0.755g/200ml, 1.509g/200ml and 2.264g/200ml, in a randomised, four way cross-over study. Transit of the radiolabelled solutions was followed by gamma scintigraphy. The study demonstrated no significant differences between the gastric emptying times of the four solutions. Rapid gastric emptying was observed in most cases. The mean small intestinal transit times for the 0.755g/200ml, 1.509g/200ml and 2.264g/200ml mannitol solutions was reduced by 11%, 23% and 34% respectively, when compared to the control solution. The intestinal transit data of the four solutions demonstrate that mannitol has a concentration dependent effect on small intestinal transit. Small concentrations of mannitol included in a pharmaceutical formulation could therefore lead to reduced uptake with any drug exclusively absorbed from the small intestine.
Adult↗
Structure and toxicity of amphotericin B/triglyceride emulsion formulations.
This paper investigates the relationship between the in-vitro toxicity of amphotericin B/triglyceride emulsion formulations, and their phospholipid composition and method of manufacture. Emulsion toxicity, as measured by the erythrocyte potassium leakage assay, was found to be dependent on the transition temperature of the phospholipid emulsifier, and the thermal history of the emulsion. Emulsions made using unsaturated phospholipids showed a low toxicity irrespective of the method of manufacture. Emulsions made using phospholipids with phase transition temperatures above the maximum process temperature displayed a toxicity comparable to the deoxycholate-solubilized formulation. This toxicity was significantly reduced when such formulations were heated to a temperature above the phase transition temperature for the phospholipid. We interpret these data as demonstrating that the amphotericin molecule must be inserted fully into the phospholipid emulsifier in order to produce a low toxicity emulsion, and that this insertion is critically dependent on the composition of the emulsifier and its phase transition properties.
Amphotericin B↗
The effects of pharmaceutical excipients on small intestinal transit.
1. The effect of three iso-osmotic pharmaceutical excipient solutions on gastrointestinal transit were investigated in eight healthy male volunteers. Each subject received 200 ml radiolabelled purified water, or a 200 ml solution of sodium acid pyrophosphate ((SAPP) 1.1 g/200 ml), mannitol (2.264 g/200 ml) or sucrose (4.08 g/200 ml) in a four way cross over design. On each of the study days the volunteers also received five 6 mm diameter non-disintegrating tablets. Dual isotope gamma scintigraphy was used to assess the transit behaviour of the tablets and solutions. 2. There were no significant differences between the gastric emptying times of the four solution formulations. Rapid gastric emptying was observed in all cases (mean t 50% varied from 11-14 min). 3. Small intestinal transit (SIT) times for the SAPP and mannitol solutions were reduced by 39 and 34%, respectively, when compared with the control solution (purified water = 240 min; SAPP = 147 min; mannitol = 158 min). The 95% confidence limits for the mean differences in SIT time between the control and SAPP solutions was 39-94-149 min, and 40-82-124 min between the mannitol and the control. Intestinal transit for the sucrose solution was similar to that for the control solution (sucrose = 229 min). 4. There were no significant differences in the transit times of the non-disintegrating tablet preparations, when co-administered with each solution.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Measurement of nasal mucociliary transport rates on the isolated human inferior turbinate.
The mucociliary transport rate was measured using sequential images of graphite particles moving on 17 isolated human inferior turbinates. These had been removed from 13 patients who had normal saccharin clearance tests on the day of surgery. The initial mean mucociliary transport rate was found to be 4.1 mm/min rising to 5.0 mm/min 2 h after harvesting. After 4 h it fell to 3.7 mm/min. Where the rate was measured at two different sites on the same turbinate (n = 4), there was a close correlation over 6 h (r = 0.95, P < 0.001). When the turbinates were exposed to an aqueous solution of adrenaline (1:10,000) or a 2.5% cocaine solution, the rate increased or decreased respectively by 100% and 58% but returned to within 10% of the initial level within 2 h. We believe that the isolated inferior turbinate can be considered a useful model for the study of mucociliary clearance and agents that may influence it.
Cocaine↗
Aspects of the design and delivery of microparticles for vaccine applications.
Mortality and morbidity data continue to indicate there is a compelling need for the derivation of a new generation of vaccine delivery systems that can be usefully applied via injection and also mucosally. One technology that has potential for design as an effective vaccine delivery system is the formulation of biodegradable microparticles from the polymers and poly lactide co-glycolide (PLGA) in particular. The potential advantages of the delivery of vaccines within such microparticles is discussed. The potential for eliciting and optimising immunity after the mucosal delivery of biodegradable microparticles is also discussed.
Administration, Inhalation↗
Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes.
The concept of steric stabilization as used in colloid science is applied to carefully manipulate the drainage and lymphatic distribution of subcutaneously administered model polystyrene nanospheres. A wide range of synthetic polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymers of poloxamine and poloxamer series have been used to produce sterically stabilized nanospheres. We have found a correlation between the length of the stabilizing POE chains of the block co-polymers and nanosphere drainage and passageway across tissue lymph interface in dermal lymphatic capillaries in the rat footpads; the longer the POE chains, the faster the particle drainage. Nanospheres conditioned with block co-polymers of POE chains of 5-15 ethylene oxide units are effectively opsonized in lymphatics; a process which dramatically enhances sequestration (up to 40% of the administered dose) by macrophages of the regional lymph nodes. If the dimensions of the stabilizing POE chains of the poloxamines and poloxamers exceed the range of the Van der Waals force of attraction, opsonization fails to occur and rapidly drained engineered vehicles escape clearance by macrophages of the regional nodes, reach the systemic circulation and remain in the blood for prolonged periods. These observations suggest that a lymphatic delivery composition based on polymer-coated particles will be advantageous for many applications in clinical and experimental medicine.
Animals↗
Resorbable polymeric microspheres for drug delivery--production and simultaneous surface modification using PEO-PPO surfactants.
Poly(oxyethylene)-poly(oxypropylene) (PEO-PPO) co-polymers have been used as surfactants to produce resorbable poly(DL-lactide co-glycolide) (PLG) microspheres in the 500 nm-1 micron size range by an emulsification/solvent evaporation technique based on acetone-dichloromethane mixtures. The high polydispersity of microspheres could be reduced by using low PLG concentrations of 1% (w/v). Surface analysis by static secondary ion mass spectroscopy revealed the presence of PEO-PPO at the microsphere surface after cleaning by centrifuging and resuspension in water, and after further cleaning by dialysis. Physical entrapment of PEO-PPO chains in the particle surface is indicated due to rapid collapse of the solvent swollen PLG network as acetone is extracted from the suspended droplets. Opportunities are presented for simultaneous manufacture and surface modification of microspheres.
Chemistry, Pharmaceutical↗