Vancomycin encapsulation in biodegradable poly(epsilon-caprolactone) microparticles for bone implantation. Influence of the formulation process on size, drug loading, in vitro release and cytocompatibility.

Vancomycin encapsulation in biodegradable poly(epsilon-caprolactone) microparticles (200 microm mean diameter) was most efficient with a simple emulsion technique that dispersed 122.5 mg/g of polymer. Scanning electron micrographs showed smooth or pitted particles. Dissolution studies were correlated with microparticle morphology, indicating higher release with pitted particles when vancomycin was encapsulated in a dissolved state. The cytocompatibility of these poly(epsilon-caprolactone) microparticles was demonstrated by a direct contact cytotoxic assay. This material can be considered as an efficient drug delivery system for bone implantation.

Antifungal chromans inhibiting the mitochondrial respiratory chain of pea seeds and new xanthones from Calophyllum caledonicum.

Two new xanthones, caledonixanthone M 1 and caloxanthone L 2, and one new acid, caledonic acid 6 were isolated from the hexane-soluble extract of the stem bark of Calophyllum caledonicum. In the course of this phytochemical study, seven other known compounds - calothwaitesixanthone, calozeyloxanthone, allanxanthone, isoapetalic acid 3, calolongic acid 4, apetalic acid 5 and isocalolongic acid 7 - were isolated. Their antifungal activity against the growth of the human pathogenic fungus Aspergillus fumigatus was then investigated. The results indicated that the crude extract, calolongic acid 4 and isocalolongic acid 7 exhibited strong inhibitory effects with MIC (80) values of 8, 4, 2 microg/mL, respectively. Besides, calolongic acid 4, its lactone derivative 4a and isocalolongic acid 7 markedly reduced the respiration of pea seed mitochondria.

A new injectable bone substitute combining poly(epsilon-caprolactone) microparticles with biphasic calcium phosphate granules.

Previous studies have shown the effectiveness of an injectable bone substitute (IBS) composed of biphasic calcium phosphate in 2% hydroxypropyl methylcellulose gel (50/50 w/w). A therapeutic agent in the form of a drug can be added to the biomaterial by encapsulation into microparticles to protect the active agent, control its release and preserve the material rheological properties. Poly(epsilon-caprolactone) was used in this study because of its biocompatibility and resorbability, as tested in orthopaedic implants and surgical sutures. Particles (80-200 microm) were manufactured by a solvent evaporation-extraction process (1 g of polymer, 11-15 ml methylene chloride, with a stirring speed of 400-600 rpm) and introduced into the IBS in a 5-50% (V/V) range. Injectability was evaluated by texture analysis. With less than 45% of particles, the material had rheological properties similar to those of the reference IBS, whereas injectability decreased markedly with more than 45% of particles. A preliminary in vitro release study showed that this type of triphasic IBS could be efficient for drug delivery systems with osteoconduction properties.

Influence of isostatic compression on the stability of vancomycin loaded with a calcium phosphate-implantable drug delivery device.

It is essential to prevent microbial infections after osteoarticular trauma or prosthesis implantation. As an alternative to antibiotic parenteral administration, antibiotic-loaded biomaterials allow high concentrations to be obtained in situ without systemic toxicity. Although the formulation of biphasic calcium-phosphate (BCP)-vancomycin granules by isostatic compression has recently been used to produce drug-delivery devices, the stability of vancomycin needs to be proven. In this study, vancomycin was associated with BCP powders by isostatic compression at 100, 140, or 200 MPa and then extracted or released by a rotating paddle system for 24 h. Vancomycin assays were performed by spectrophotometric and microbiological methods. The results show that all vancomycin associated with the material was recovered after extraction without degradation. Thus, vancomycin was not denaturated after application of 100, 140, or 200 MPa of isostatic compression. The results for vancomycin released from granules compressed at the three pressures were not significantly different (p =.01) whether assays were performed microbiologically or spectrophotometrically, indicating a good correlation between the two methods. This process involving high pressure appears to be a good means of developing drug delivery devices loaded with therapeutic agents without denaturating the components.

Development of a "continuous-flow adhesion cell" for the assessment of hydrogel adhesion.

The purpose of this study was to develop an in vitro perfusion technique or "continuous-flow adhesion cell" model to predict the in vivo performances of different mucoadhesive drug delivery systems based on hydrogels. Two studies were performed, either using a rabbit small intestine or a polyethylene surface; the adhesion of four gels--two poly(acrylic acid)s (PAAs) (carbomer [CM] and polycarbophil [PC]), an ethyleneoxide-propyleneoxide block copolymer (Poloxamer 407 [PM]), and a polysaccharide (scleroglucane [SG])--were evaluated. In this respect, scleroglucane was used as a control. The adhesiveness of the different gels for both supports is in accordance with that described in the literature, that is, polycarbophil adhered more strongly than carbomer, which itself adhered more strongly than poloxamer. This study proved that the gels adhere more strongly to the polyethylene tube than to the rabbit small intestine, thus indicating that evidence for adhesion properties does not need any presence of mucus. Therefore, our in vitro model could be a good method, more precise and more simple than an ex vivo technique, to predict the bioadhesion of gelified devices.

End-chain radiolabeling and in vitro stability studies of radiolabeled poly(hydroxy acid) nanoparticles.

In order to study the tissue distribution of biodegradable nanoparticles after oral administration in animals, end-chain-radiolabeled poly(D,L-lactides) were prepared. Two groups of polymers (Mn = 7500, I = 2.4 and Mn = 28000, I = 1.4 as determined by organic size-exclusion chromatography) were chemically modified by reaction of [14C]acetic anhydride with hydroxyl end-chain groups. The activities of both resulting radioactive poly(D,L-lactides) varied from 57 to 1140 microCi/g. Poly(D,L-lactide) or poly(D,L-lactide-co-glycolide) nanoparticles containing various amounts of radioactive polymer were prepared according to the solvent evaporation process with acetone as cosolvent with methylene chloride in the organic phase. Their mean diameter was 133 +/- 25 nm, measured by photon correlation spectroscopy. The radiolabeled-end-group stability of these particles in buffer solutions was found to be greater when the matrix was made from the radiolabeled poly(D,L-lactide) having the highest molecular weight and the lowest polydispersity index. The polymer-chain stability was totally retained for at least 1 week in a phosphate buffer, pH 7.4, i.e. for the selected experiment time.