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Biomedical subjects

S S Davis

Publications and source records attributed to S S Davis.

At least 109 records · Page 6Linked to original sources
PubMed1994

Optimizing gastrointestinal delivery of drugs.

There is currently a great deal of effort being aimed at achieving effective delivery of novel therapeutic drugs, such as peptides, by the oral route. Opportunities have been identified which could lead to more convenient delivery systems for this class of drug. It is likely that a polypeptide given unprotected into the gastrointestinal environment will be degraded significantly. However, it is well known that small quantities of dietary proteins can be absorbed, even though these may have little or no physiological effect. It is felt that the colon may provide an advantageous absorption site for peptides. As a consequence there has been considerable interest, not only in the development of colonic delivery systems, but also in the establishment of strategies designed to maximize peptide absorption from the colon. Traditionally, vaccine research has been concerned with producing systemic immunity by parenteral immunization. However, the gradual acceptance of the importance of IgA in protecting mucosal surfaces against infection from numerous pathogenic organisms has led to an increased interest in oral immunization. Because of the existence of the CMIS, oral immunization induces secretory immunity in both the genital and respiratory tracts. Therefore, oral immunization offers the possibility for development of easily administered vaccines that will be effective in prevention against important respiratory and genital tract infections. The recent advances in recombinant DNA technology and the development of antigen delivery systems have given rise to optimism that several new and improved oral vaccines may be available by the next millennium.

Administration, Oral↗
PubMed1994

Evaluation of 153Sm-diethylenetriaminepentaacetic acid for radiolabelling of pharmaceutical dosage forms by neutron activation.

153Sm-DTPA provides a suitable alternative to 99mTc-DTPA and 111In-DTPA as a water soluble tracer for the evaluation of pharmaceutical preparations. The chelate was handled biologically in a similar way to 99mTc-DTPA and 111In-DTPA. The chelate can be incorporated into the formulation as a non-radioactive excipient and the intact dosage form can then be neutron activated to produce 153Sm.

Administration, Inhalation↗
PubMed1994

Chitosan as a novel nasal delivery system for peptide drugs.

A nasal solution formulation of the cationic material chitosan was shown to greatly enhance the absorption of insulin across the nasal mucosa of rat and sheep. The absorption promoting effect was concentration dependent with the optimal efficacy obtained for concentrations higher than 0.2% and 0.5% in rats and sheep, respectively. The absorption promoting effect was reversible with time in a "pulse-chase" study. Histological examination of the nasal mucosa of rats exposed to a chitosan solution for 60 minutes showed little change.

Absorption↗
PubMed1994

Surface modification of poly(lactide-co-glycolide) nanospheres by biodegradable poly(lactide)-poly(ethylene glycol) copolymers.

The modification of surface properties of biodegradable poly(lactide-co- glycolide) (PLGA) and model polystyrene nanospheres by poly(lactide)-poly(ethylene glycol) (PLA:PEG) copolymers has been assessed using a range of in vitro characterization methods followed by in vivo studies of the nanospheres biodistribution after intravenous injection into rats. Coating polymers with PLA:PEG ratio of 2:5 and 3:4 (PEG chains of 5000 and 2000 Da. respectively) were studied. The results reveal the formation of a PLA:PEG coating layer on the particle surface resulting in an increase in the surface hydrophilicity and decrease in the surface charge of the nanospheres. The effects of addition of electrolyte and changes in pH on stability of the nanosphere dispersions confirm that uncoated particles are electrostatically stabilized, while in the presence of the copolymers, steric repulsions are responsible for the stability. The PLA:PEG coating also prevented albumin adsorption onto the colloid surface. The evidence that this effect was observed for the PLA:PEG 3:4 coated nanospheres may indicate that a poly(ethylene glycol) chain of 2000 Da can provide an effective repulsive barrier to albumin adsorption. The in vivo results reveal that coating of PLGA nanospheres with PLA:PEG copolymers can alter the biodistribution in comparison to uncoated PLGA nanospheres. Coating of the model polystyrene nanospheres with PLA:PEG copolymers resulted in an initial high circulation level, but after 3 hours the organ deposition data showed values similar to uncoated polystyrene spheres. The difference in the biological behaviour of coated PLGA and polystyrene nanospheres may suggest a different stability of the adsorbed layers on these two systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Polystyrene-poly (ethylene glycol) (PS-PEG2000) particles as model systems for site specific drug delivery. 2. The effect of PEG surface density on the in vitro cell interaction and in vivo biodistribution.

The effect of differing densities of poly (ethylene glycol-2000) (PEG2000) at the particle surface of polystyrene-poly (ethylene glycol-2000) (PS-PEG2000) particles was assessed in terms of hydrophobic interaction chromatography (HIC) and the in vitro and in vivo behaviour of the particles. The particles, with different surface densities of PEG, were prepared by varying the copolymerizing reaction of styrene with a PEG macromonomer. There is a clear relationship between the surface density of PEG as determined by X-ray photoelectron spectroscopy and surface hydrophobicity as assessed by hydrophobic interaction chromatography (HIC). Similarly, the interaction of the particles with non-parenchymal liver cells in in vitro studies was shown to decrease as the surface density of PEG increases. The in vivo study investigating the biodistribution of the PS-PEG particles after intravenous injection into rats reveals that a relationship exists between the surface density of PEG and the extent to which the particles remain in the circulation, avoiding recognition by the reticuloendothelial system. Particles with the higher surface densities show increased circulatory times which compared well with data for particles prepared with the surface adsorbed PEO-PPO block copolymer, Poloxamine 908.

Animals↗
PubMed1994

Preparation of sterically stabilized human serum albumin nanospheres using a novel Dextranox-MPEG crosslinking agent.

Human serum albumin (HSA) nanospheres with a size less than 200 nm in diameter were prepared using a modified coacervation method and crosslinking with methyl polyethylene glycol modified oxidized Dextram (Dextranox-MPEG) which created a sterically stabilizing polyethylene oxide surface layer surrounding the nanospheres. The crosslinking efficiency and the surface characteristics of glutaraldehyde and Dextranox-MPEG crosslinked HSA nanospheres were determined and compared. The zeta potential of the Dextranox-MPEG crosslinked particles was significantly lower than that of glutaraldehyde stabilized particles. The existence of a hydrated steric barrier surrounding the nanospheres was confirmed by an electrolyte and pH induced flocculation test. The Dextranox-MPEG crosslinked nanospheres showed a significantly reduced plasma protein adsorption on the particle surface compared with glutaraldehyde crosslinked nanospheres.

Chemistry, Pharmaceutical↗
PubMed1994

Nasal absorption of desmopressin in rats and sheep. Effect of a bioadhesive microsphere delivery system.

The nasal absorption of desmopressin was studied in two animal models, the rat and the sheep. The bioavailability after nasal administration was found to be 13 times higher in the rat model. This discrepancy is suggested to be due to the impaired mucociliary clearance mechanism in the rat model and possibly differences in enzymatic degradation and elimination rates of the drug. The effect of the addition of L-alpha-lysophosphatidylcholine (LPC) to the formulations as an absorption enhancer was most pronounced in the sheep model. The use of the bioadhesive starch microsphere delivery system, especially in combination with LPC, had a profound effect on the absorption of desmopressin in sheep, with bioavailabilities reaching nearly 10% compared with 1.2% for a simple nasal solution of desmopressin.

Absorption↗
PubMed1994

Innovations in avoiding particle clearance from blood by Kupffer cells: cause for reflection.

Therapeutic applications of drug carrier systems following intravenous administration have been limited because of the pronounced tendency of these carriers to localize primarily in Kupffer cells. Recently, attempts have been made to design colloids and drug carrier systems that can be disguised as "self" and remain unrecognizable, at least to a certain extent, by the hepatic macrophages. This review is designed to provide a critical view on fundamentals, current progress, limitations, and future prospects of such engineered colloids and drug carrier systems for intravenous route of administration.

Binding Sites↗
PubMed1993

Coating particles with a block co-polymer (poloxamine-908) suppresses opsonization but permits the activity of dysopsonins in the serum.

The surfaces of polystyrene microspheres (60 nm in diameter) and colloidal gold particles (17 nm in diameter) were coated with a polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymer; poloxamine-908. The polymer adsorb strongly to the microspheres via its relatively hydrophobic POP segments. This leaves the POE chains in a mobile state as they extend outward from the surface and thereby provide stability to the particle suspension by suppressing aggregation. The blood clearance and biodistribution of uncoated vs. poloxamine-908-coated 125I-labelled polystyrene microspheres were compared 1 h after intravenous administration into rats. Poloxamine coating dramatically reduced liver accumulation of microspheres and kept them within the systemic circulation. These observations were further confirmed by electron microscopy, demonstrating that Kupffer cells were loaded with uncoated latex but had ingested few if any of the poloxamine-908-coated particles. The interaction of uncoated and poloxamine-coated gold particles with freshly isolated rat liver sinusoidal cells was examined by electron microscopy. The accumulation in Kupffer cells of gold particles after opsonization with autologous plasma was in accordance with previous observations where the dominant opsonizing activity had been identified as fibronectin. In contrast, coating of gold particles with poloxamine-908 prior to plasma opsonization prevented the adsorption of fibronectin onto their surface. Simultaneously, Kupffer cells failed to recognize poloxamine-908-coated gold particles before and after opsonization. Unlike Kupffer cells, liver endothelial cells endocytosed poloxamine-908-coated gold particles prior to opsonization but failed to recognize them after the opsonization process. This was taken as an indication of the presence of dysopsonic activity in plasma. This dysopsonic activity was studied using polystyrene latex microspheres, where the uptake of such particles by phagocytes is known to be independent of opsonization. The coating of 125I-labelled polystyrene microspheres with poloxamine-908 dramatically reduced their interaction with liver sinusoidal cells. This interaction was further reduced in the presence of either autologous plasma or serum. A heat-stable (60 degrees C for 15 min) serum component of molecular mass > 100 kDa was found to mediate this suppressive effect. Thus, we demonstrate that organ-specific receptors, opsonin activities and plasma dysopsonins regulate the in vivo clearance of particulate materials from the circulation. Poloxamine-908 coating modulates particle clearance by effectively blocking opsonization but still allowing for dysopsonization.

Animals↗
PubMed1993

An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen.

Earlier we demonstrated that coating the surface of large model polystyrene microspheres (220-300 nm in diameter) with the block co-polymer polyoxyethylene/polyoxypropylene poloxamine-908 triggered their accumulation in the rat spleen by a filtration mechanism following intravenous administration [Moghimi, S.M., Porter, C.J.H., Muir, I.S., Illum, L. and Davis, S.S. (1991) Biochem. Biophys. Res. Commun. 177, 861-866]. We have now demonstrated that the macrophages of the red-pulp can effectively phagocytose the filtered poloxamine-coated microspheres 24 h post-administration. This could be the result of either the loss of the surface absorbed poloxamine, and hence the steric barrier, or 'neutralization' of the effect of the anti-phagocytic material poloxamine-908 within the spleen. In order to assess the capacity of the splenic uptake mechanism(s), rats received daily intravenous administration of unlabelled large poloxamine-908 coated microspheres (220 nm in diameter) for 4 days (daily-dosed animals). Control rats received daily saline injection. On the fifth day all animals were injected with either radiolabelled large (220 nm) or small (60 nm in diameter) poloxamine-coated polystyrene microspheres. Predosing dramatically decreased the splenic uptake of the large test microspheres but had no effect on the uptake of small test-microspheres. The failure of the spleen to take up particles was not associated with an increased circulatory level of microspheres. Surprisingly, both small and large coated microspheres were sequestered by the liver and accumulated in Kupffer cells as demonstrated by electron microscopy in daily-dosed animals. In contrast, the liver of control animals did not effectively sequester poloxamine-coated microspheres. Here, microspheres predominantly remained in blood. Sequestration of poloxamine-908 coated microspheres by Kupffer cells of the liver of daily-dosed animals was the result of opsonization by an unknown serum component.

Animals↗
PubMed1993

Enhanced hepatic clearance of intravenously administered sterically stabilized microspheres in zymosan-stimulated rats.

The blood clearance and organ deposition of sterically stabilized (poloxamine-908 coated) polystyrene microspheres of two different sizes (60 and 220 nm in diameter) were compared in control and zymosan-stimulated rats 3 h after intravenous administration. Poloxamine coating dramatically decreased the uptake of 60-nm microspheres by organs of the reticuloendothelial system and, concomitantly, kept microspheres in the blood. Large poloxamine-coated microspheres (220 nm) initially remained in the blood, but eventually a large fraction of these microspheres was filtered by the spleen. Daily administration of zymosan produced a marked increase in the intravascular clearance of the large, but not the small, poloxamine-coated microspheres. The enhanced intravascular clearance of large poloxamine-coated microspheres in zymosan-treated rats was the result of hepatic sequestration. On the other hand, the splenic filtration of these microspheres was depressed by 225% below the control values, despite the dramatic increase in spleen size of zymosan-treated rats. Preincubation of large poloxamine-coated microspheres in serum derived from both the control and zymosan-treated animals suggested that the enhanced hepatic uptake of large sterically stabilized microspheres following zymosan stimulation was not the result of "specific opsonization" processes. Instead, the changes in the proliferative as well as the phagocytic response of Kupffer cells appeared to be responsible for these observations. The preferred hepatic uptake of large poloxamine-coated microspheres, as opposed to smaller particles, is suggested to be due to differences in surface characteristics and the properties of microspheres. These may include differences in polymer density and the surface conformation of the polyoxyethylene segments of the polymer in the biological environment and the way they interact with both plasma components and the macrophage surface. These observations could be of importance in the use of sterically stabilized drug carriers for delivery of therapeutic agents to sites other than the reticuloendothelial system in clinical conditions associated with globally or regionally enhanced reticuloendothelial activity.

Animals↗
PubMed1993

Characterization of colonic transit of nondisintegrating tablets in healthy subjects.

The transit of pharmaceutical dosage forms through the colon has been shown to be highly variable. The amount of fiber in the diet is known to alter gastrointestinal transit; however, the dietary intake of the subjects in previous studies was not adequately controlled. Using the technique of gamma scintigraphy, we have therefore characterized the variability in the colonic transit of nondisintegrating tablets, by strictly controlling the dietary fiber intake of the subjects. Eight healthy male subjects followed a diet containing 25 g dietary fiber per day, for six days prior to dosing. Each subject received five 6-mm nondisintegrating tablets on three consecutive days. Mouth-to-anus transit times exhibited a high degree of variability. Regional differences in colonic transit were evident. Tablet stasis appeared to occur mainly in the ascending colon and hepatic flexure. Despite the diets of the volunteers being identical, colonic transit was still observed to be highly variable, which suggests that this variability is intrinsic.

Adult↗
PubMed1993

Long-term antibody responses in mice following subcutaneous immunization with ovalbumin entrapped in biodegradable microparticles.

Ovalbumin (OVA) was entrapped in microparticles prepared from three different poly(lactide-co-glycolide) (PLG) polymers and the microparticles were administered subcutaneously to mice as a single dose. Two weeks after immunization, the serum IgG antibody response to OVA entrapped in microparticles was significantly greater than the response to soluble OVA. The response to OVA entrapped in microparticles peaked at week 10 and remained high for the full 1-year duration of the study. In a second study, the effect of particle size on the immunogenicity of PLG microparticles with entrapped OVA was assessed. Following booster immunizations in mice, microparticles of 1.5 microns were significantly more immunogenic than microparticles of 72.6 microns. Furthermore, although enhanced serum IgG responses were induced by immunization with OVA adsorbed to microparticles (1.0 microns), entrapment of the OVA in microparticles (1.5 microns) resulted in significantly better responses.

Animals↗
PubMed1993

An in vitro study of diamorphine permeation through premature human neonatal skin.

The permeation kinetics of diamorphine through human premature neonatal cadaver skin over a range of gestational ages between 24 and 36 weeks was investigated using small diffusion cells. A strong inverse correlation was noted between the apparent permeability coefficient and the gestational age of the skin (P < 0.01; n = 26). The calculated apparent permeability coefficients decreased with gestational age from 6.0 x 10(-2) cm.hr-1 at 24 weeks' gestation to 5.2 x 10(-6) cm.hr-1 at 36 weeks' gestation. The amount of diamorphine remaining bound within the skin at the end of the in vitro experiments did not change significantly with gestational age of the skin. Diamorphine was subject to degradation over the course of the in vitro experiments to produce significant amounts of 6-monoacetylmorphine and evidence is presented to suggest that this was due to residual skin esterase activity. It is calculated that the steady-state flux rate of diamorphine through neonatal skin observed in these experiments would be sufficient to obtain a therapeutic plasma concentration of morphine assuming a 2-cm2 area for application and a delivery rate of 15 micrograms hr-1 kg-1. However, the prolonged half-life of morphine in the premature neonate would result in a delay of some hours before the attainment of this level.

Chromatography, High Pressure Liquid↗
PubMed1993

The effect of meal composition on the gastrocolonic response: implications for drug delivery to the colon.

The response of the colon to eating, the gastrocolonic response (GCR), may have important implications for the design of drug dosage forms for selective delivery to the colon. Therefore, the effect of meal composition on the GCR and its relation to the transit of nondisintegrating tablets has been investigated. Eight healthy male volunteers each received 5 x 6-mm radiolabeled nondisintegrating tablets, and the transit was followed using a gamma camera. When the tablets reached the ileocolonic region, each volunteer received a test meal (1000 kcal) containing 70% carbohydrate, 15% fat, and 15% protein. The subsequent movement of the tablets was then monitored. The study was repeated using a 70% fat meal and a 70% protein meal, so that the effects of a high-carbohydrate, a high-fat, and a high-protein meal on the GCR could be compared. The incidence of GCRs was similar after all meals. Thus, there appeared to be no effect of meal composition on the movement of the tablets into the colon. This implies that the ingestion of food may not necessarily stimulate the passage of material across the ileocecal junction and that other factors may also be involved.

Adult↗
PubMed1993

The preparation and characterization of poly(lactide-co-glycolide) microparticles. II. The entrapment of a model protein using a (water-in-oil)-in-water emulsion solvent evaporation technique.

Poly(lactide-co-glycolide) (PLG) microparticles with entrapped antigens have recently been investigated as controlled-release vaccines. This paper describes the preparation of PLG microparticles with an entrapped model antigen, ovalbumin (OVA), using a (water-in-oil)-in-water emulsion solvent evaporation technique. In a series of experiments, the effects of process parameters on particle size and OVA entrapment were investigated. It was found that smooth, spherical microparticles 1-2 microns in diameter containing up to 10% (w/w) OVA could be produced using a small volume of external aqueous phase containing a high concentration of emulsion stabilizer and a 1:5 antigen:polymer ratio. PAGE analysis, isoelectric focusing, and Western blotting of OVA released from the microparticles in vitro confirmed that the molecular weight and antigenicity of the protein remained largely unaltered by the entrapment procedure.

Blotting, Western↗