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Biomedical subjects

A T Florence

Publications and source records attributed to A T Florence.

At least 37 records · Page 2Linked to original sources
PubMed1999

Nanospheres of cyclosporin A: poor oral absorption in dogs.

The cyclic undecapeptide cyclosporin A (CYA) used as first-line therapy in the prevention of xenograft rejection following organ transplantation, is extremely hydrophobic. Marketed formulations employ solubilising agents to facilitate absorption in the gastrointestinal tract. In this study, cyclosporin A nanospheres were prepared by precipitation in an aqueous surfactant solution. The particle matrix consists of the drug itself. Drug was dissolved in acetone and mixed rapidly with an aqueous solution of polysorbate 80 and sodium dodecyl sulphate (SDS). The acetone was evaporated to give a colloidal precipitate of spherical particles. Particle size could be controlled by varying the quantity of starting materials to give nanospheres of Z-average diameters in the range 250-900 nm with low polydispersity. The oral absorption of CYA from these nanospheres was compared to absorption from a microemulsion formulation in the dog. The relative bioavailability of cyclosporin A from nanospheres was only 3%, based on comparison of the area under the blood concentration-time curve (AUC) values for the two formulations.

Administration, Oral↗
PubMed1999

Studies on the uptake of tomato lectin nanoparticles in everted gut sacs.

Tomato lectin (TL) is a bioadhesive glycoprotein that has been shown to bind selectively to the small intestine epithelium. When bound to polystyrene microspheres, intestinal uptake occurs not only through the gut associated lymphoid tissue (GALT) but also through normal enterocytes. In this study, the everted gut sac model was used to compare the rates and quantities of intestinal uptake of tomato lectin and that of TL coupled to microspheres. Using bovine serum albumin (BSA) and BSA coupled to microspheres as comparators. Uptake is time and concentration dependent. Transfer of TL from the lumen to the serosa was 3.9 ng/mg per h whereas that of BSA was 0.5 ng/mg per h. Hence uptake of tomato lectin was 7-fold higher than BSA. The rate of uptake of TL coupled microspheres was 41.5 ng/mg per h, which was 4-fold higher than microspheres coupled to BSA (11.8 ng/mg per h). The uptake of TL conjugated microspheres was shown to be inhibited by N-acetyl-d-glucosamine tetramer [GlcNac]4.

Animals↗
PubMed1999

Interaction of a nonionic surfactant-based organogel with aqueous media.

In an attempt to explain the rather short half-life of molecules at the injection site after their intra-muscular administration in a sorbitan monostearate organogel, in vitro studies were carried out to study the effects of an aqueous medium (simulating interstitial fluid at injection site) on the physical form of the organogel. When the gel mass comes in contact with an aqueous phase, the latter penetrates into the organic gel via the sorbitan monostearate tubular network, resulting in gel breakdown into smaller fragments. The surfactant tubular network act as a conduit for water penetration into the gel. Meanwhile, emulsification, aided by the surfactants present in the gel, also occurs at the gel surface between the organogel and the aqueous phase. This leads to a gradual erosion of the gel as oil droplets bud off from the gel mass. From these in vitro observations, we speculate that after gel administration in vivo, dynamic interactions occur between the local interstitial fluid and the gel mass: fluid penetration into the gel and emulsification at the gel surface is thus responsible for gel breakdown and so a relatively short duration of drug at the injection site.

Coloring Agents↗
PubMed1999

Sorbitan monostearate/polysorbate 20 organogels containing niosomes: a delivery vehicle for antigens?

Multi-component organogels formed using the non-ionic surfactant sorbitan monostearate as gelator have been formulated to contain niosomes. The purpose of this study was to evaluate the potential of these vesicle-in-water-in-oil (v/w/o) gels as delivery vehicles for vaccines. Bovine serum albumin (BSA) and haemagglutinin (HA) were used as model antigens in depot and immunogenicity studies respectively. The complex gels were prepared by the addition of a hot (60 degrees C) aqueous niosome suspension (v/w) to the sol phase (o, an organic solution of the gelator); a vesicle-in-water-in-oil (v/w/o) emulsion was produced which cools to an opaque, semi-solid, thermoreversible v/w/o gel. Light microscopy of the organogel revealed that the microstructure consists of a tubular network of surfactant aggregates in the organic medium, the niosome suspension being dispersed in these surfactant tubules. Therefore, in such gels, the vaccine is thought to be entrapped in the niosomes, themselves located within the sorbitan monostearate tubular network in the organic medium. In vivo, a depot effect was observed following intramuscular administration of the gel containing the entrapped bovine serum albumin, cleared from the injection site over a period of days. The relatively short-lived nature of the depot was thought to arise due to interactions between the gel and the local interstitial fluid which results in gel disintegration in situ. Thus, the niosomes containing antigens are believed to be released from the organic gel. Immunogenicity studies showed that the v/w/o gel as well as one of the controls, the water-in-oil (w/o) gel, possess immunoadjuvant properties and enhance the primary and secondary antibody titres (of total IgG, IgG1, IgG2a and IgG2b) to haemagglutinin antigen. As far as humoral immunity is concerned, the w/o gel showed stronger immunoadjuvant properties compared to the v/w/o gel, being effective at a lower antigen dose i.e 0.1 microg HA.

Adjuvants, Immunologic↗
PubMed1999

Preparation and in vitro/in vivo evaluation of luteinizing hormone releasing hormone (LHRH)-loaded polyhedral and spherical/tubular niosomes.

Niosomes are vesicles formed by the self-assembly of nonionic surfactants in aqueous dispersions. They can entrap drugs and have been used experimentally as sustained drug delivery systems. Apart from conventional spherical niosomes, various types of vesicle ultrastructures can be formed by varying the composition of the vesicle membrane. Hexadecyl diglycerol ether (C16G2), cholesterol, and poly-24-oxyethylene cholesteryl ether (Solulan C24) in the ratio 91:0:9 gave polyhedral niosomes, whereas spherical and tubular niosomes are produced at a composition ratio of 49:49:2. The mean size of both polyhedral and spherical/tubular niosomes were within the range of 6 to 9 microm. Both types of vesicle were visualized by cryo-scanning electron microscopy. The properties of the two forms of niosomes were studied using luteinizing hormone releasing hormone (LHRH) as a model peptide. Analysis by high-performance liquid chromatography demonstrated high entrapment of LHRH acetate in polyhedral niosomes when prepared by remote loading methods using pH or (NH4)2SO4 gradients; in contrast, only low entrapment was achieved by passive loading methods (direct hydration at pH 7.4 or pH 3.0, dehydration-rehydration, and reversed-phase evaporation). In vitro studies demonstrated that both polyhedral and spherical/tubular niosomes were more stable in 5% rat skeletal muscle homogenate than in rat plasma. Also, polyhedral niosomes released more radiolabeled LHRH ([125I]LHRH) than spherical/tubular niosomes in both muscle homogenate and plasma. In clearance experiments in the rat, following intramuscular injection, both polyhedral and spherical/tubular niosomes gradually released [125I]LHRH into the blood, but some radioactivity remained at the injection site for 25 and 49 h, respectively. In contrast, [125I]LHRH in phosphate buffered saline was completely cleared from the injection site at 2 h. The release of drug is sustained by both niosome formulations, but spherical/tubular niosomes possess more stable membranes than polyhedral niosomes due to the presence of cholesterol.

Animals↗
PubMed1999

Novel sorbitan monostearate organogels.

Sorbitan monostearate, a hydrophobic nonionic surfactant, gels a number of organic solvents such as hexadecane, isopropyl myristate, and a range of vegetable oils. Gelation is achieved by dissolving/dispersing the organogelator in hot solvent to produce an organic solution/dispersion, which, on cooling sets to the gel state. Cooling the solution/dispersion causes a decrease in the solvent-gelator affinities, such that at the gelation temperature, the surfactant molecules self-assemble into toroidal inverse vesicles. Further cooling results in the conversion of the toroids into rod-shaped tubules. Once formed, the tubules associate with others, and a three-dimensional network is formed which immobilizes the solvent. An organogel is thus formed. Sorbitan monostearate gels are opaque, thermoreversible semisolids, and they are stable at room temperature for weeks. The gels are affected by the presence of additives such as the hydrophilic surfactant, polysorbate 20, which improves gel stability and alters the gel microstructure from a network of individual tubules to star-shaped "clusters" of tubules in the liquid continuous phase. Another solid monoester in the sorbitan ester family, sorbitan monopalmitate, also gels organic solvents to give opaque, thermoreversible semisolids. Like sorbitan monostearate gels, the microstructure of the palmitate gels comprise an interconnected network of rodlike tubules. Unlike the stearate gels, however, the addition of small amounts of a polysorbate monoester causes a large increase in tubular length instead of the "clustering effect" seen in stearate gels. The sorbitan stearate and palmitate organogels may have potential applications as delivery vehicles for drugs and antigens.

Calorimetry, Differential Scanning↗
PubMed1999

Water-in-sorbitan monostearate organogels (water-in-oil gels).

Novel multicomponent organogels containing an aqueous phase are described, and some properties which influence their potential as delivery devices for hydrophilic drugs and vaccines are discussed. The gel is produced by preparing a hot water-in-oil (w/o) emulsion using sorbitan monostearate, a nonionic surfactant which is also the organogelator, as the principal emulsifying agent. On cooling at room temperature, the w/o emulsion sets to an opaque, semisolid, thermoreversible organic gel. Cooling the emulsion results in a reduced solubility of the sorbitan monostearate in the oil, with a corresponding decrease in solvent-surfactant affinities, causing surfactant self-assembly into aggregates. The microstructure of the w/o gel is seen by light microscopy to consist of a network of tubules and fibrils (containing the aqueous phase) dispersed in the organic medium. X-ray diffraction and freeze-fracture studies suggest that the tubular aggregates in the w/o gel are made up of surfactant molecules arranged in inverted bilayers and that the aqueous phase is accommodated within these inverted bilayers, bound by the polar headgroups of the surfactant molecules. The presence of water in the tubular skeleton of the organic gels results in the establishment of percolating electroconductive aqueous channels in the organogel. Increasing the water content of a w/o gel causes the surfactant tubules to swell with a corresponding increase in conductivity until the tubules are saturated. Further increase in the water content results in the excess water accumulating in droplets within the organic medium and a decrease in conductivity as the gel integrity is compromised. The w/o gels (containing a model antigen, radiolabeled bovine serum albumin, in the aqueous phase) have demonstrated depot properties after intramuscular administration to mice, entrapped antigen being released over a period of days.

Animals↗
PubMed1999

Osmotic behaviour of polyhedral non-ionic surfactant vesicles (niosomes).

In addition to common spherical non-ionic surfactant vesicles (niosomes), disc-like, tubular, and polyhedral niosomes have also been reported. The permeability and osmotic activity of niosomes are important in determining their use as controlled-release drug-delivery systems. These properties have been compared for polyhedral niosomes prepared by hydrating a mixture of a hexadecyl diglycerol ether (C16G2), a poly(24)oxyethylene cholesteryl ether (Solulan C24), 91:9 or 98:2, and conventional spherical niosomes prepared from the same surfactants but with cholesterol. When subjected to osmotic gradients, polyhedral niosomes, the membranes of which are in the gel phase, swell and shrink less than their spherical counterparts and they are more permeable to the hydrophilic solute 5(6)-carboxyfluorescein. In 2 M NaCl the rate of release of carboxyfluorescein from polyhedral niosomes (both containing 9% Solulan C24) into either a hypotonic (water) or an isotonic medium (2 M NaCl) was low. This contrasted with similarly loaded spherical niosomes and polyhedral niosomes containing 2% Solulan C24, from which release was high in hypotonic media (e.g. water) but less in an isotonic medium (2 M NaCl). For both polyhedral and spherical niosomes encapsulating carboxyfluorescein (pKa = 6.4), release rates were higher at pH 8 than at pH 5. Polyhedral niosomes are thus, in general, less osmotically active than spherical niosomes because of their rigid but highly permeable membranes. The unusual polyhedral membrane impermeability to carboxyfluorescein co-entrapped with salt in hypotonic media is a function of Solulan C24 content, and is possibly a result of salting out of the polyoxyethylene chains; this is, therefore, a property that might be manipulated in the design of a drug-delivery system.

Drug Delivery Systems↗
PubMed1998

Synthesis and physicochemical properties of lipophilic polyamide dendrimers.

PURPOSE: To synthesise symmetrical dendritic macromolecules with external lipid surfaces, to investigate their behaviour at the air-water interface and their ability to form supramolecular aggregates, and to gain an understanding of their potential as drug carriers. METHODS: Dendrimeric compounds were synthesised with molecular weights ranging from 737 (1st generation dendrimer) to 25,246 (6th generation dendrimer) with carbon numbers ranging from 40 to 1404. The surface behaviour of these compounds was determined using spread films at the air/water interface on a Langmuir trough, and transmission electron microscopy was used to study the supramolecular aggregates formed by the more hydrophobic members of the series. RESULTS: Dendrimers up to a maximum of 6 generations were synthesised. Surface saturation did not allow the completion of the synthesis of the 7th generation. The limiting surface areas at the air/water interface ranged from 0.4 nm2 to 16.1 nm2 values in good agreement with the areas derived from computer generated molecular models (0.5 nm2 to 14 nm2). CONCLUSIONS: The synthesised dendrimers exhibited a linear relationship between area per molecule and the molecular weight of the compounds. A dendrimer with 16 lipoamino acid branches formed tubular supramolecular aggregates with a helical structure and dimensions in the long axis of 140-200 nm.

Chromatography, High Pressure Liquid↗
PubMed1997

The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual.

This mini-review covers some of the historical and recent arguments over the experimental evidence on the uptake by and translocation from the intestinal mucosa of microparticulates after oral administration. It is concluded that there is now no dispute over the fact that this is a normal occurrence. Particulate uptake does take place, not only via the M-cells in the Peyer's patches and the isolated follicles of the gut-associated lymphoid tissue, but also via the normal intestinal enterocytes. Factors affecting uptake include particle size, surface charge and hydrophobicity and the presence or absence of surface ligands. The covalent attachment of lectin or invasion molecules to the surface of carrier particles leads to greater systemic uptake. Whether or not the route can be utilized for the routine administration of therapeutic agents which are not normally absorbed from the gut is not yet proven. Many studies show that 2-3% of the ingested dose of submicron particles can be absorbed. The increasing diversity of carrier systems, which includes dendrimers and liposomes, needs to be exploited fully. More also must be learned about the inter- and intra-subject variability of lymphoid tissue so that appropriate selectivity can be achieved through the design of specific carriers.

Administration, Oral↗
PubMed1997

Enhanced oral uptake of tomato lectin-conjugated nanoparticles in the rat.

PURPOSE: To investigate the usefulness of a surface-conjugated, bioadhesive molecule, tomato lectin, to augment intestinal uptake of orally administered inert nanoparticles. METHODS: Fluorescent 500 nm polystyrene nanoparticles with tomato lectin covalently surface coupled using a carbodiimide reaction were administered to female Wistar rats by oral gavage daily for 5 days. RESULTS: Analysis of tissue extracted polymer by gel permeation chromatography revealed a 23% systemic uptake of tomato lectin conjugated nanoparticles compared to < 0.5% of TL nanoparticles blocked with N-acetylchitotetraose thus representing an increase of almost 50 fold across the intestine. Intestinal uptake of tomato lectin-conjugated nanoparticles via the villous tissue was 15 times higher than uptake by the gut-associated lymphoid tissue. CONCLUSIONS: The application of tomato lectin as a bioadhesive agent in vivo has been demonstrated to enhance subsequent intestinal transcytosis of colloidal particulates to which it is bound.

Absorption↗
PubMed1997

Peter Howard Elworthy (1933-1995): a biographical note.

Peter Elworthy had a considerable influence on pharmaceutical science, education and practice, in the UK. He died in December 1995 at the early age of 62, but he had retired from full time academic work from his post as Professor of Pharmacy and Head of the Department of Pharmacy in the University of Manchester twelve years earlier. Concerned about his health but also not a little disillusioned by the multiple pressures placed even then on senior academics, he foresaw the era of cuts and the central oversight and restrictions. His heart was elsewhere. In his 1976 Harrison Memorial Lecture (reproduced in this issue) he said: "Looking back, I have the feeling of having been very lucky. 'Much have I travell'd in the realms of gold, and many goodly states and kingdoms seen.' My main interest has been in the phenomenon of micellization. The subject has been of absorbing interest, and continually shows new bright facets which lead to new scientific advances. Travelling in the realms of gold has nothing to do with gold, but to me it means travelling in sunlight, which illuminates things brightly, and makes visible new facts, which have been invisible before. Occasionally dark clouds form; they are the disappointments and frustrations, but we need them in order to be able to recognize the sunlight by contrast."

History, 20th Century↗
PubMed1997

Polyhedral non-ionic surfactant vesicles.

Large polyhedral (2-10 microns) non-ionic surfactant vesicles (niosomes) formed from mixtures of a hexadecyl diglycerol ether (C16G2), a cholesteryl poly-24-oxyethylene ether (solulan C24) and a low level of cholesterol are being investigated as slow-release systems for ophthalmic, subcutaneous or intramuscular administration. The phase-diagram of this three-component system has been constructed and these polyhedral vesicles are found to be in the gel (L beta) phase. Confocal laser-scanning microscopy was used to confirm the complex morphology of these vesicles. The thermo-responsive nature of release of entrapped carboxyfluorescein and nicotinamide adenine dinucleotide has been studied; release is increased with increase in temperature (37 degrees C) even though the polyhedral vesicles still maintain their polyhedral shape at this temperature. The results indicate that the thermo-responsive features of the niosomes are a result of reversible changes in bi-layer permeability caused by temperature-mediated alteration in the membrane-packing characteristics of the polyethoxylated cholesterol ether.

Cholesterol↗
PubMed1997

The effect of monomers and of micellar and vesicular forms of non-ionic surfactants (Solulan C24 and Solulan 16) on Caco-2 cell monolayers.

Measurements of transepithelial electrical resistance (TEER), the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) test and monitoring of poly(ethylene glycol) (PEG) transport have been used to study the effects of the non-ionic surfactants Solulan C24 and Solulan 16, either free in solution or as an integral part of niosome bi-layers, on intestinal epithelial cells from man (Caco-2 cell monolayers). The effects on epithelial integrity and on the transport of the hydrophilic drug metformin depend on the concentration of the surfactants. At concentrations above 1% the effect on TEER of the surfactant in niosomal form and free in solution were equivalent whereas cell viability was preserved to a higher concentration of Solulans when the Solulans were present in the niosomal form. It was concluded that the toxic effect of niosomes arises from free surfactant present in the niosome suspension.

Caco-2 Cells↗
PubMed1996

Adverse drug events related to dosage forms and delivery systems.

While some of the adverse events caused by the administration of medicines are specifically attributable to the drug molecule, a proportion arises because of the chemical, biological and physical nature of the formulation. The effects may be compounded by certain patient factors, an incomplete understanding of the behaviour of the formulation or the coadministration of other drugs. This review examines adverse drug reactions and other adverse events arising from the nature of the dosage form or formulation used. These adverse effects may be the result of local irritation/toxicity, hypersensitivity or allergic reactions, systemic effects from essentially local therapies, or idiosyncratic reactions in a small number of individuals. In certain cases where the exact nature of the formulation is unknown, adverse events cannot be attributed to any single ingredient. In addition, the total of all ingredients of a formulation, even where details of the formulation are clear, may give rise to abnormal behaviour of the formulation in vivo. Often the desired objective of a particular specialised formulation leads to an unforseen but related adverse effect, and in certain instances these events are completely unpredictable and at variance with the perceived objectives of the formulation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

The activity of doxorubicin niosomes against an ovarian cancer cell line and three in vivo mouse tumour models.

Demonstration of the improved doxorubicin pharmacokinetics and tumoricidal activity, after a single intravenous dose of 10mg kg-1 doxorubicin sorbitan monostearate (Span 60) based niosomes in the mouse adenocarcinoma (MAC) tumour model (Uchegbu et al., 1995) preceded the present study in which the activity of doxorubicin C16G2 (a hexadecyl diglycerol ether) based niosomes was evaluated against naive and established MAC tumour models. C16G2 niosomes were equiactive with doxorubicin solution. It is concluded that while in some tumour models, niosomal formulations demonstrate some advantages over the free drug, caution is advocated in the extrapolation of these results. The activity of doxorubicin C16G2 and Span 60 niosomes was also studied against a human ovarian cancer cell line and its doxorubicin resistant subline. There was a slight reduction in the IC50 against the resistant cell line when the drug was encapsulated in Span 60 niosomes in comparison to the drug in solution. Taking into account the in-vitro release characteristics of the various niosomal formulations, it is concluded that the use of niosomal formulations against multidrug resistance shows sufficiently encouraging results to warrant further study.

Adenocarcinoma↗
PubMed1996

Biliary excretion of polystyrene microspheres with covalently linked FITC fluorescence after oral and parenteral administration to male Wistar rats.

To further our understanding of microspheres as a drug delivery system, the biliary excretion of covalently linked FITC fluorescence polystyrene microspheres of various diameters was investigated after oral and parenteral administration to male Wistar rats. About 36%, 16% 3% and 1% of the dose was excreted into the bile after parenteral injection of 50 nm, 500 nm, 1 micron and 3 microns diameter microspheres, respectively, over 24 h. In addition, about 30%, 11%, 1%, and 1% of the dose, respectively, was found in the blood at 24 h. After oral administration of 50 nm, 500 nm, and 1 micron microspheres, the recovery was about 18%, 8% and 1% of the dose in the bile and about 9%, 1%, and 0% in the blood, respectively. No 3 microns microspheres were detected in the bile or blood after oral administration. Particles were not detected in the urine of any group tested. Thus, the present study demonstrated that biliary excretion plays an important role in the disposition of microspheres administered by the oral or parenteral routes, and there is a size-related excretion of microspheres into the bile.

Administration, Oral↗