Biomedical subjects
Publications and source records attributed to J P Benoit.
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It is now well established that the biological activity of proteins is related not only to their mean molecular structure, but also to their intramolecular mobility. Nearly all techniques sensitive to dynamics have given evidence for intramolecular mobility in proteins: NMR, ESR, Raman spectroscopy, fluorescence quenching, Mössbauer spectroscopy, neutron scattering, measurements of elastic constants and hydrogen-deuterium exchange. The dynamics of proteins has also been approached by theoretical calculations. We report here investigations of the atomic and molecular displacements in hen egg-white lysozyme crystals using a new technique. This technique, based on the X-ray diffuse scattering analysis (scattering out of the Bragg reflections), can yield information on the atomic displacements, provided that they are correlated. Rigid-body molecular displacements, correlated along short rows of aligned molecules in two perpendicular directions, have been detected and analysed (mean square amplitude of the order of 5 X 10(-4) nm2). This technique can be also applied to the detection and analysis of intramolecular displacements.
The aim of this study was to determine the bioburden of PLGA microspheres produced by the solvent emulsion/extraction process as a means of determining an appropriate gamma-irradiation dose for sterilization. Bioburden was evaluated on the basis of ISO specifications. The analysis of initial microbial contamination was performed on blank microspheres, prepared by a non-aseptic laboratory scale process. A mean bioburden of 36.04 CFU (colony forming units)/110 mg microspheres was determined. Most of the detected germs originated from human commensal flora. According to the ISO dose-selection method, a gamma-irradiation dose of 19.6 kGy was found sufficient to ensure a sterility level of 10(-6). The effect of the selected irradiation dose on both the molecular weight of the polymer and the kinetics of 5-fluorouracil drug release from the microspheres was compared to the European Pharmacopeia recommended irradiation dose (25 kGy). This 20% reduced dose showed a lower extent of molecular weight reduction of PLGA and a better control of 5-FU release from microparticles. This can be related to reduce polymer radiation damage.
Rhizobacteria Pseudomonas fluorescens-putida were microencapsulated in Eudragit by spray-drying. These microparticles are subsequently included in seed coating or pelleting material. The survival of the bacterial cell in microparticles were studied under different levels of relative humidity (RH): 0, 33, 55 and 100%. The protective effects of silica, present in certain formulations, were demonstrated at the relative humidities of 33 and 55%. The release of the encapsulated bacteria was also studied over time. The release was fast, the bacteria being observed at 15 min immersion of the Eudragit microparticles in an aqueous-buffer medium at 20 degrees C. This result, related to the physicochemical character of the coating polymer, showed that water was the triggering element for the release of rhizobacteria. Compatibility studies between two film-forming agents used for seed coatings and the encapsulated bacteria, as well as wettability measures of tableted microparticles, were carried out. The bacterial survival was good with the seed coating agent, Sepiret 1039G, and the wettability measurements of agglomerated microparticles were in accord with the rapid release of the microencapsulated bacteria. The application of microparticles containing rhizobacteria on seeds can now be considered for preliminary trials.
Cross-linked albumin microcapsules were prepared, using a polycondensation interfacial process. Doxorubicin was incorporated in these microcapsules by simple adsorption from aqueous solution. Increasing the extent of cross-linkage of the microcapsule walls by either increasing the cross-linking agent concentration or the time of reaction significantly reduced the absorption ability of these microcapsules. Doxorubicin release kinetic evaluation revealed that the presence of a salt in the release medium was needed to enable much of the drug to be released. Furthermore, the doxorubicin displacement intensity from the microcapsules was dependent on the nature and concentration of the cations used, indicating that an ion-exchange process was involved. Analysis of the various doxorubicin release profiles, using ion-exchange kinetic equation, showed that the release kinetic process is governed by a film diffusion process at low and moderate Na+ ion concentrations in the exchanging solution, and by a particle diffusion process at high Na+ ion concentrations, sufficient to drive the doxorubicin exchange to completion.
The following work deals with ibuprofen-loaded ethylcellulose microspheres. The drug exists either in a state of molecular dispersion or in crystalline form, depending on the encapsulation ratio. The in vitro release profiles have been studied and the Higuchi model applied to the experimental results. With an appropriate treatment of the results, it has been shown that the surface crystals responsible for the observed burst effect are really encapsulated by the polymer. The calculation of the tortuosity factor clearly shows that the release kinetics are controlled by the hydrophobicity of ethylcellulose and the geometry of the porous volume resulting from the dissolution of ibuprofen crystals. It thus appears that crystals are probably differently distributed in the matrix depending on the microsphere size.
The design of a microencapsulation procedure for the preparation of biodegradable BCNU-loaded microspheres used as intracerebral implants is the aim of this work. This approach will give sustained high local concentrations of the anti-tumour drug in the brain without the associated significant systemic toxicity. The microencapsulation technique used is a solvent-evaporation process based on the formation of an oil-in-water emulsion. The stability of BCNU in methylene chloride saturated with water and its high value of partition coefficient between methylene chloride and water justifies the selection of this organic solvent as the dispersed phase in the methodology. A spectrophotometric method for the quantification of BCNU in mixtures containing PLAGA is developed which allows the evaluation of drug photodecomposition. The volume of methylene chloride and the concentration of PVA in the external aqueous phase are the two variables that induce the largest variations of the microsphere size. The two main process parameters leading to the highest microencapsulation yield are the polymer concentration in the organic phase and the volume of the external aqueous phase; whereas the pH of the external aqueous phase and the use of co-solvents in the organic phase lead only to a small improvement in microsphere payload.
This research deals with the microencapsulation of the bacteria Pseudomonas fluorescens-putida, using the spray-drying technique. These bacteria act as a plant growth stimulator and the microparticles are subsequently included in the seed coating or pelleting material. The objective was to maintain living encapsulated bacteria for a minimum of 5-6 months. Three polymers were tested: a methacrylic copolymer from the Eudragit range, an ethylcellulose and a modified starch. A silica additive to the spraying food was also examined. The granulometric distribution and the morphology of the microparticles were studied and the residual moisture was measured after each bacteria survival control test. The best results were obtained with the methacrylic copolymer Eudragit, particularly for microparticles collected in the cone of the spray-drying chamber. The mean diameter of the microspheres was 44.6 microns, 85% of these particles having a size between 6.2 and 84.4 microns. The bacterial survival time of a particular strain incorporated in these microparticles, strain M3.1, was one year. A relationship was found between the bacterial survival and the microspheres' residual moisture, the best survival of the stored bacteria being observed when the residual moisture was around 25%.
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