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Biomedical subjects

S S Davis

Publications and source records attributed to S S Davis.

At least 55 records · Page 3Linked to original sources
PubMed1999

Detection and determination of surface levels of poloxamer and PVA surfactant on biodegradable nanospheres using SSIMS and XPS.

The surface chemical characterisation of sub-200 nm poly(DL-lactide co-glycolide) nanospheres has been carried out using the complementary analytical techniques of static secondary ion mass spectrometry (SSIMS) and X-ray photoelectron spectroscopy (XPS). The nanospheres, which are of interest for site-specific drug delivery, were prepared using an emulsification-solvent evaporation technique with poly(vinyl alcohol), Poloxamer 407 and Poloxamine 908 respectively as stabilisers. The presence of surfactant molecules on the surface of cleaned biodegradable colloids was confirmed and identified on a qualitative molecular level (SSIMS) and from a quantitative elemental and functional group analysis (XPS) perspective. SSIMS and XPS data were also used in combination with electron microscopy to monitor the effectiveness of cleaning procedures in removing poorly bound surfactant molecules from the surface of nanospheres. The findings are discussed with respect to the development of nanoparticle delivery systems, particularly the composition of the surface for extending blood circulation times and achieving site-specific deposition.

Adsorption↗
PubMed1999

Biodegradable lamellar particles of poly(lactide) induce sustained immune responses to a single dose of adsorbed protein.

The adjuvanticity of lamellar particles of poly(L-lactide) (PLA) towards adsorbed ovalbumin (OVA) was investigated. The aim of vaccine formulation was to maximise the amount of antigen retained on the particles and the time of retention during incubation of the formulations in PBS at 37 degrees C. Unmodified PLA lamellae were capable of adsorbing large quantities of OVA (up to 12.5% w/w) but major and rapid desorption occurred in PBS at 37 degrees C (80% released in 24 h). Retention of OVA on PLA lamellae was improved (25% released in 24 h) by precipitating the particles using aqueous sodium deoxycholate solution (DOC-modified PLA lamellae and lyophilising the lamellae-protein preparation after adsorption. Sustained immune responses were elicited in mice to a single sub-cutaneous injection of OVA adsorbed onto DOC-modified PLA lamellae. The level of antibodies induced and the pattern of response was similar to that induced by an alum-adsorbed OVA formulation. Normally boosting is required to obtain high levels of antibody when OVA is adsorbed on poly(DL-lactide co-glycolide) (PLG) microspheres. The lamellar forms of PLA may function as an efficient immunomodulator by effectively retaining adsorbed antigen and by activating immune cells due to their irregular shape. PLA lamellae have potential to stimulate enhanced immune responses to a variety of adsorbed antigens.

Adjuvants, Immunologic↗
PubMed1999

In vitro cytotoxicity of poly(amidoamine)s: relevance to DNA delivery.

We have examined the cytotoxicity of a number of poly(amidoamine) polymers which have been proposed for use as DNA delivery systems and compared them to the charged polyamino acid polylysine. Most of the poly(amidoamine)s tested were shown to be remarkably non-toxic to both HepG2 and HL60 cell lines. However, one of the structures (NG30, co-monomers methylene bisacrylamide, dimethylethylene diamine) did show cytotoxicity similar to that of polylysine. A second PAA structure (NG37, NG38, NG39, co-monomers bisacryloyl piperazine, 2-methyl piperazine) showed mild cytotoxicity towards both cell lines, related to the degree of polymerisation. The results support the idea that the cytotoxicity of polycations has a strong structural basis rather than being an effect due only to charge. As a consequence of their general reduced level of cytotoxicity, poly(amidoamine)s appear to have possible advantages for complexation with DNA over some other cationic polymers as a key component of DNA delivery systems.

Cation Exchange Resins↗
PubMed1999

Induction of cellular immunity to a mycobacterial antigen adsorbed on lamellar particles of lactide polymers.

Microspheres prepared from synthetic, biodegradable poly (L-lactide) [PLA] and copolymers of lactide and glycolide such as poly (DL lactide co-glycolide) [PLG] have been widely investigated for controlled delivery of encapsulated vaccine antigens. In this study we describe novel lamellar microparticles produced from PLA to which protein antigens can be adsorbed. These particles when administered to mice, induced strong Th1-type T cell responses to the adsorbed 38 kDa protein antigen from M. tuberculosis characterised by high levels of Interferon-gamma. In addition to proteins, we were also able to adsorb synthetic peptides resulting in specific T cell proliferation. Induction of strong cellular immunity together with the versatility of antigen adsorption to these particles should make such lamellae a useful tool to deliver protective antigens from intracellular pathogens.

Adsorption↗
PubMed1999

The stability and immunogenicity of a protein antigen encapsulated in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol.

Protein-loaded microparticles were produced from blends of poly(ethylene glycol) (PEG) with poly(L-lactide) (PLA) homopolymer or poly(DL-lactide co-glycolide) copolymers (PLG) using a water-in oil-in oil method. The stability of ovalbumin (OVA) associated with microparticles prepared using PEG and 50:50 PLG, 75:25 PLG and PLA, respectively, was analysed by SDS-PAGE and quantified by scanning densitometry following incubation in PBS at 37 degrees C for up to 1 month. Fragmentation and aggregation of OVA was detected with all 3 formulations. The extent of both processes correlated with the degradation rate of the lactide polymer used and decreased in the order PLA < 75:25 PLG < 50:50 PLG. Extensive degradation of the PLG/PEG microparticles also occurred over 4 weeks whereas the use of PLA/PEG blends resulted in a stable microparticle morphology and much reduced fragmentation and aggregation of the associated protein. Following a single sub-cutaneous immunisation, high levels of specific serum IgG antibody were elicited by OVA associated with the PLA/PEG particles. Injection of OVA associated with the 75:25 PLG/PEG microparticles resulted in very low levels of specific antibody. A higher response was induced by the 50:50 PLG/PEG formulation but there was very large inter-animal variation in this group. Antibody levels elicited by all 3 formulations were significantly higher than those elicited by a single injection of soluble OVA. Analysis of antigen specific IgG1 and IgG2a antibody subtype levels also revealed the greater efficacy of the PLA/PEG microparticles as an adjuvant system. The use of PLA/PEG microparticles shows improved protein loading and delivery capacity while maintaining a high level of stability of the associated protein. These results indicate a strong correlation between the stability of microencapsulated antigen and the magnitude of the immune response following sub-cutaneous immunisation.

Animals↗
PubMed1999

PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug.

The nanoprecipitation technique for preparation of nanoparticles suffers the drawback of poor incorporation of water soluble drugs. The aim of this study was therefore to assess various formulation parameters to enhance the incorporation of a water soluble drug (procaine hydrochloride) into poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared by this technique. Approaches investigated for drug incorporation efficiency enhancement included the influence of aqueous phase pH, replacement of procaine hydrochloride with procaine dihydrate and the inclusion of excipients: poly(dl-lactide) (PLA) oligomers, poly(methyl methacrylate-co-methacrylic acid) (PMMA-MA) or fatty acids into the formulation. The nanoparticles produced were submicron size (<210 nm) and of low polydispersity. It was found that an aqueous phase pH of 9.3, replacement of procaine hydrochloride with procaine dihydrate and the incorporation of PMMA-MA, lauric and caprylic acid into the formulation could enhance drug incorporation efficiency without the size, morphology and nanoparticle recovery being adversely influenced. For instance changing the aqueous phase pH from 5.8 to 9.3 increased nanoparticle recovery from 65.1 to 93.4%, drug content from 0.3 to 1.3% w/w and drug entrapment from 11.0 to 58.2%. However, the presence of high ratios of lauric acid and procaine dihydrate in the formulation adversely affected the morphology and size of the nanoparticles. Also, PLA oligomers were not considered a feasible approach since it decreased drug entrapment from 11.0 to 8.4% and nanoparticle recovery from 65.1 to 19.6%. Drug release from nanoparticles appears to consist of two components with an initial rapid release followed by a slower exponential stage. This study has demonstrated that formulation variables can be exploited in order to enhance the incorporation of a water soluble drug into PLGA nanoparticles by the nanoprecipitation technique.

Buffers↗
PubMed1999

Evaluation of the clearance characteristics of bioadhesive systems in humans.

This paper describes the characterisation, radiolabelling and clearance characteristics of three bioadhesive nasal delivery systems; starch microspheres, chitosan microspheres and chitosan solution. The time taken for 50% of these bioadhesive materials and a control to be cleared from the nasal cavity, after nasal administration to human volunteers, was evaluated using gamma scintigraphy. The data show that the control was cleared rapidly, with a half life of 21 min, whereas the bioadhesive delivery systems had much longer half lives. The clearance of the chitosan solution almost doubled to 41 min, whilst the half life of clearance for the starch microspheres more than tripled to 68 min and for the chitosan microspheres the half life of clearance quadrupled to 84 min. From the results reported in this study it is possible to determine that both chitosan systems and the starch microspheres have good bioadhesive characteristics. The results have supported the hypothesis that chitosan delivery systems can reduce the rate of clearance from the nasal cavity, thereby increasing the contact time of the delivery system with the nasal mucosa, providing the potential for increasing the bioavailability of drugs incorporated into these systems.

Adhesiveness↗
PubMed1999

Potential of polymeric lamellar substrate particles (PLSP) as adjuvants for vaccines.

In recent years microspheres or microparticles produced from biodegradable polymers such as poly(D,L-lactide) (PLA) and poly(D, L-lactide-co-glycolide) (PLGA) containing encapsulated vaccine antigens have been investigated for administration via parenteral, oral, and intranasal routes. These microparticles allow the controlled release of vaccines with an aim to reduce the number of doses for primary immunisation or to develop single dose vaccines. The polymer materials have been widely regarded as being of minimal toxicity. Evaluation of candidate systems in animal studies have shown antibody levels and cell responses similar to or greater than those observed with adjuvants such as alum. However, there are concerns regarding the integrity and immunogenicity of the antigen during the encapsulation process when the antigen is exposed to organic solvents, high shear stresses and the exposure of antigen to low pH which is caused by polymer degradation. An alternative approach would be to adsorb antigens to the surface of biodegradable polymer particles. Polymeric lamellar substrate particles (PLSP), produced by a simple precipitation of PLA, are suitable for this purpose. The adsorption of antigens onto these particles is a simple procedure. It avoids pH changes due to bulk polymer degradation and the use of solvents and therefore will be less damaging to the vaccine. Moreover, such systems will be much easier to scale up for a clinical study and eventual manufacture. The aim of this article is to discuss the preparation and physical characteristics of PLSP, antigen adsorption, in vivo efficacy of PLSP antigen systems and to consider the potential of PLSP as controlled release adjuvants for protein, peptide or viral vaccines.

Adjuvants, Immunologic↗
PubMed1999

Dextran cross-linked gelatin microspheres as a drug delivery system.

This paper describes the use of oxidized dextran as a cross-linker for the preparation of gelatin microspheres. Microspheres were obtained by a thermal gelation method and their dissolution kinetic was examined. In order to find evidence of sugar mediated cross-linking, swelling tests and gelatin microspheres dissolution experiments were performed. The obtained results indicated that oxidized dextran can form a cross-linked gelatin network which can reduce the dissolution of gelatin. More interestingly, gelatin microspheres treated by both native and oxidized dextran slow down, even if to a different extent, the release of the antitumor drug TAPP-Br used as a model compound. Taken together, our results suggest that oxidized dextran could be an interesting means to cross-link gelatin microspheres allowing the use of this delivery formulation for controlled release of drugs.

Dextrans↗
PubMed1999

The effect of oleic acid on the human ileal brake and its implications for small intestinal transit of tablet formulations.

PURPOSE: A human volunteer study was carried out to investigate whether activation of the ileal brake mechanism affects the transit of tablets through the small intestine. METHODS: Oleic acid, which has previously been shown to activate the brake, was delivered to the small intestine in a modified release capsule at doses of 300 mg, 600 mg and 1200 mg. The effect of the oleic acid was determined by measuring the transit of two sets of radiolabelled tablets by gamma scintigraphy. One set of tablets was dosed with the capsule and the other one hour later. RESULTS: The results show that in the majority of the volunteers small intestinal residence time was greater with the oleic acid than control. The effect was most pronounced in the tablets given concomitantly with the capsule and with the higher doses of oleic acid. CONCLUSIONS: The ileal brake, activated by oleic acid, can slow the transit of tablets through the small intestine.

Feedback↗
PubMed1999

Complex formation between the anionic polymer (PAA) and a cationic drug (procaine HCI): characterization by microcalorimetric studies.

PURPOSE: Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl). METHODS: This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, deltaH, and N) were determined. RESULTS: As the KCl concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of deltaGobs with deltaSobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KCI concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HCl was greater than those of the electrostatic attractions. CONCLUSIONS: We have shown that the interaction between PAA and procaine HCl is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HCl molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HCl complex.

Acrylic Resins↗
PubMed1998

A poly(D,L-lactide-co-glycolide) microsphere depot system for delivery of haloperidol.

Haloperidol-loaded biodegradable poly(d,l-lactide-co-glycolide) (PLG) microspheres, with theoretical mean particle sizes of about 0. 8, 2 and 8 micrometer, have been successfully prepared by using an emulsification-solvent evaporation method. The effect of various processing parameters such as the content of polymer in dichloromethane, the content of polyvinyl alcohol in the aqueous phase, and the stirring speed of emulsification on the particle size and size distribution of microspheres has been investigated and three optimal procedures suggested. The influence of particle size on drug content and incorporation efficiency of haloperidol-loaded PLG microspheres also has been evaluated. In vitro a linear release of haloperidol from PLG microspheres over an extended period of time without a significant burst effect has been achieved; the time of 50% drug release (T50%) being around 55 days. The effect of drug content and particle size on the cumulative release of haloperidol from PLG microspheres was also studied together with the reproducibility of drug content and release profile from batch-to-batch with different particle sizes.

Antipsychotic Agents↗
PubMed1998

Structure and mucoadhesion of mussel glue protein in dilute solution.

Purified mussel adhesive protein mefp-1 (Mytilus edulis foot protein 1) has been studied regarding its state of oligomerization and gross conformation in dilute solution. Sedimentation equilibrium in the analytical ultracentrifuge of a dilute solution of protein (0.4 mg/mL) in acetate buffer at pH 4.5 and I = 0.10 M yielded an apparent molecular weight (whole distribution weight average, Mw, app) of 114 000 +/- 5000 via the "M" procedure, a value in almost exact agreement with the monomeric molecular weight obtained by MALDI mass spectrometry. At this low concentration, it is reasonable to assume thermodynamic ideality, i.e., Mw,app approximately Mw. This result, together with plots of point weight average apparent molecular weight versus concentration for three different loading concentrations (0.4, 0.8, 1.0 mg/mL), clearly demonstrates that this protein is essentially monomeric in dilute solution. Sedimentation velocity experiments yielded an estimate of the sedimentation coefficient s020,w = 2.34 +/- 0.17 S, which for M = 110 000 gives a frictional ratio f/f0 = 3.2 +/- 0.3. The interpretation of this, in terms of an extended rather than globular conformation for the structure of mefp-1 in dilute solution, is considered, within plausible limits of molecular hydration, and models for the structure in solution are considered, in light of the thermodynamic nonideality behavior of these molecules and previously published circular dichroism data. The significance of these observations in terms of the bioadhesive properties of mefp-1 is described, and the very strong interaction in dilute solution with a mucin glycoprotein is demonstrated.

Adhesiveness↗
PubMed1998

The control of protein release from poly(DL-lactide co-glycolide) microparticles by variation of the external aqueous phase surfactant in the water-in oil-in water method.

Poly(DL-lactide co-glycolide) microparticles below 5 microm in size and containing ovalbumin (OVA), were prepared using the water-in oil-in water (w/o/w) technique with either polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP) as stabilisers in the external aqueous phase. PVP-stabilised microparticles exhibited higher protein loading (8.2%, w/w relative to 4.0% for PVA stabilised microparticles) and increased core loading (encapsulation) of protein (70% vs. 30% for the PVA system). The use of PVP instead of PVA to prepare microparticles also resulted in reduction in the initial burst release of OVA, together with sustained protein release over 28 days and an increase in the protein delivery capacity from 35 to 45 microg/mg particles. The changes in protein loading and delivery characteristics are considered to arise in part from an increase in the viscosity of the droplets of polymer solution, constituting the primary water-in oil emulsion, by diffusion of PVP from the external aqueous phase. Variation of the external aqueous phase surfactant provides a promising approach for improving the loading of therapeutic proteins and vaccine antigens within biodegradable microparticles and for modulating their release pattern.

Drug Carriers↗
PubMed1998

The distribution of protein associated with poly(DL-lactide co-glycolide) microparticles and its degradation in simulated body fluids.

Poly(lactide co-glycolide) (PLG) microparticles with a mean size of less than 2 microns, prepared by the water-in oil-in water method, exhibited a maximum surface protein (ovalbumin) content in excess of 50% of the total loading. The surface-core distribution was found to be sensitive to stabiliser concentration and the type of albumin used in the formulation. The degradation of OVA was monitored following incubation of microparticles for 14 days in PBS and for 2 h in simulated gastric and intestinal fluids, respectively. OVA removed from the surface of particles, following incubation in PBS, was found to be intact as measured by SDS-PAGE. After 7 days in PBS at 37 degrees C, protein extracted from the microparticles was found to be partly hydrolysed with the prevalence of an antigen fragment at 36.1 kDa. The relative amount of intact OVA in 50:50 PLG microparticles decreased more rapidly than in the slower degrading 75:25 PLG microparticles. Importantly, the degradation of extracted OVA over 14 days was similar for microparticles incubated either with regular changes of release medium or in a dialysis tube. Almost all the OVA encapsulated in PLG microparticles remained intact after incubation in simulated gastric and intestinal media for 2 h. In contrast, the surface protein was rapidly degraded by trypsin and pepsin and was not detected by SDS-PAGE.

Body Fluids↗
PubMed1998

The effect of lymphatic oedema on the uptake of colloids to the lymph nodes.

The majority of pathological conditions of the lymphatic system can result in some degree of lymphoedema, which in turn causes a reduced rate of lymph flow. In some cases, such as when nodes are invaded by tumour metastases, blockage of the lymphatic vessels may occur. In order to investigate the effect of such pathology on nanosphere uptake in regional lymph nodes, the fate of model polystyrene nanospheres, surface modified with block co-polymers of the poloxamine series, was determined following subcutaneous administration in a rat model with lymphoedema (induced by the administration of lambda-carrageenan). A drastic reduction of injection site drainage and lymph node uptake of nanospheres was observed in the inflammation model compared to control animals. The observations suggest that biodegradable nanospheres based on these will be suitable for the detection of oedema in the lymphatic system.

Animals↗
PubMed1998

Sugar cross-linked gelatin for controlled release: microspheres and disks.

The aim of the present paper was to find a 'biocompatible' means to cross-link gelatin-based pharmaceutical devices. In particular, we have studied the ability of native and oxidized mono- and di-saccharides to induce the cross-linking of gelatin. To this end, gelatin discs and gelatin microspheres were produced and their dissolution kinetics at 37 degrees C were examined. In order to find evidence of sugar-mediated cross-linking, DSC and FTIR experiments were performed. The obtained results indicated that both native and oxidized sugars resulted to different extents, in the formation of a cross-linked gelatin network able to reduce the dissolution of gelatin. These results suggest that oxidized mono- and disaccharides could be an interesting method by which to cross-link gelatin thereby reducing the risk of toxic side effects arising from the use of synthetic cross-linkers.

Biocompatible Materials↗