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Recent emergence of biotherapeutic treatment such as protein or antibody administration led to novel challenges for the pharmaceutical industry such as thermal and chemical stability (pH-dependence, heat-induced denaturation, enzyme degradation) and control of drug release.1 To improve therapeutic protein release, mainly solvent-based entrapment processes were proposed especially through the formulation of liposomes1,2. In order to minimize solvent consumption, supercritical carbon dioxide (scCO2) technology was applied as alternative to biotherapeutic encapsulation as by the formulation of liposomes3 or by the entrapment of active molecule into polymeric excipients4. Among the supercritical process of polymeric encapsulation, the Particles from Gas Saturated Solutions (PGSS) offers the advantage to dispense with the use of organic solvents and to achieve yields approaching 100%. In this study, bovine serum albumin (BSA) well described in literature, was selected as a biomolecule model for its encapsulation through the PGSS process. Biodegradable polycaprolactone PCL as well as biodegradable/biocompatible polyester/polyether PCL blends (PCL/PLGA, PCL/PEG) were formulated for drug delivery applications and to investigate the influence of BSA/polymer ratio (1, 10 20 %).To prevent BSA thermal degradation, PGSS process was performed close to the human body temperature. High pressure differential scanning calorimetry and high-pressure visualization cell were coupled to select experimental conditions of pressure and temperature. The drug/polymer particles were compacted into implants prior to characterize by bicinchonic acid assay (BCA) the encapsulation yield and BSA loading and its release (up to 72h) in a PBS media. The obtained high particle recovery (close to 100 %), high drug precipitation yields (up to 81 %) and reproducible drug delivery profiles highlight the potential of PGSS process for sensitive biotherapeutic encapsulation.

International audience

International audience

Aerogel-like nanostructured materials present a wide set of potential application fields. Among these materials, silica aerogels are known in particular for their thermal super-insulation capability and their transparency in the visible range. Their integration in double-glazing should offer an energetic gain in the building sector, especially through the reduction of heat consumption. For such an application, silica gels synthesised through a sol-gel process, should be dried supercritically in order to obtain large dimensions transparent and monolithic aerogel sheets. This thesis work aims to contribute to the amelioration of the supercritical CO2 drying process efficacity while focusing particularly on the supercritical CO2 washing phase. The phenomena occurring during this phase were studied by coupling experimental and theoretical approaches. The experimental approach is based on the instrumentation of a drying system and notably the implementation of an analysis loop. This metrological tool makes it possible to monitor on line the degree of advancement of the washing phase. The theoretical approach is based on an analytical model coupling diffusion phenomena through the nanoporosity of the gels and mass transfer phenomena in the autoclave. This double approach has allowed firstly to quantify the diffusion phenomena in reference experimental conditions. The effective diffusion coefficient of a model gel nanostructure was so determined. A first estimation of the washing phase duration was also obtained. Secondly, the influence of the variation of silica aerogel nanostructure on the diffusion phenomena was studied. The obtained results have led to a first correlation between the materials permeability and the effective diffusion coefficient. This study has also underlined the interest of an aging treatment by dissolution-reprecipitation phenomena prior to drying in order to shorten the supercritical washing phase duration.; Les matériaux nanostructurés de type aérogels présentent des domaines d'applications potentielles très variés. Parmi ces matériaux, les aérogels de silice sont connus, notamment, pour leurs propriétés thermiques super-isolantes et leur transparence dans le domaine visible. Leur intégration au sein de double vitrage peut ainsi permettre d'envisager un gain énergétique dans le secteur du bâtiment, notamment au travers de la réduction des charges de chauffage. Pour une telle application, les gels de silice synthétisés par procédé sol-gel, doivent être séchés par voie supercritique afin d'obtenir des aérogels sous forme de blocs monolithiques transparents de grandes dimensions. L'objectif de ce travail de thèse est de contribuer à l'amélioration de l'efficacité du procédé de séchage dans les conditions du CO2 supercritique en s'attachant tout particulièrement à la phase de lavage au CO2 supercritique. Les phénomènes mis en jeu lors de cette phase ont été étudiés en couplant une approche expérimentale et une approche théorique. L'approche expérimentale repose sur l'instrumentation d'un banc de séchage notamment en implémentant une boucle d'analyse. Cet outil métrologique a permis de suivre en ligne le degré d'avancement de la phase de lavage. L'approche théorique repose sur l'utilisation d'un modèle analytique couplant les phénomènes de diffusion à travers la nanoporosité des gels et les phénomènes de transfert de masse dans l'autoclave. Cette double approche a permis dans un premier temps de quantifier les phénomènes de diffusion dans des conditions expérimentales de référence. Le coefficient de diffusion effectif d'une nanostructure modèle de gels de silice a été ainsi déterminé. Une première estimation de la durée de la phase de lavage a également été obtenue. Dans un second temps, l'influence de la variation de la nanostructure des aérogels de silice sur les phénomènes de diffusion a été étudiée. Les résultats obtenus ont permis d'aboutir à une première corrélation entre la perméabilité des matériaux et le coefficient de diffusion effectif. Cette étude a également souligné l'intérêt d'un traitement de vieillissement des gels par phénomènes de dissolution-reprécipitation préalablement au séchage en vue d'écourter la durée de la phase de lavage supercritique.

Aerogel-like nanostructured materials present a wide set of potential application fields. Among these materials, silica aerogels are known in particular for their thermal super-insulation capability and their transparency in the visible range. Their integration in double-glazing should offer an energetic gain in the building sector, especially through the reduction of heat consumption. For such an application, silica gels synthesised through a sol-gel process, should be dried supercritically in order to obtain large dimensions transparent and monolithic aerogel sheets. This thesis work aims to contribute to the amelioration of the supercritical CO2 drying process efficacity while focusing particularly on the supercritical CO2 washing phase. The phenomena occurring during this phase were studied by coupling experimental and theoretical approaches. The experimental approach is based on the instrumentation of a drying system and notably the implementation of an analysis loop. This metrological tool makes it possible to monitor on line the degree of advancement of the washing phase. The theoretical approach is based on an analytical model coupling diffusion phenomena through the nanoporosity of the gels and mass transfer phenomena in the autoclave. This double approach has allowed firstly to quantify the diffusion phenomena in reference experimental conditions. The effective diffusion coefficient of a model gel nanostructure was so determined. A first estimation of the washing phase duration was also obtained. Secondly, the influence of the variation of silica aerogel nanostructure on the diffusion phenomena was studied. The obtained results have led to a first correlation between the materials permeability and the effective diffusion coefficient. This study has also underlined the interest of an aging treatment by dissolution-reprecipitation phenomena prior to drying in order to shorten the supercritical washing phase duration.; Les matériaux nanostructurés de type aérogels présentent des domaines d'applications potentielles très variés. Parmi ces matériaux, les aérogels de silice sont connus, notamment, pour leurs propriétés thermiques super-isolantes et leur transparence dans le domaine visible. Leur intégration au sein de double vitrage peut ainsi permettre d'envisager un gain énergétique dans le secteur du bâtiment, notamment au travers de la réduction des charges de chauffage. Pour une telle application, les gels de silice synthétisés par procédé sol-gel, doivent être séchés par voie supercritique afin d'obtenir des aérogels sous forme de blocs monolithiques transparents de grandes dimensions. L'objectif de ce travail de thèse est de contribuer à l'amélioration de l'efficacité du procédé de séchage dans les conditions du CO2 supercritique en s'attachant tout particulièrement à la phase de lavage au CO2 supercritique. Les phénomènes mis en jeu lors de cette phase ont été étudiés en couplant une approche expérimentale et une approche théorique. L'approche expérimentale repose sur l'instrumentation d'un banc de séchage notamment en implémentant une boucle d'analyse. Cet outil métrologique a permis de suivre en ligne le degré d'avancement de la phase de lavage. L'approche théorique repose sur l'utilisation d'un modèle analytique couplant les phénomènes de diffusion à travers la nanoporosité des gels et les phénomènes de transfert de masse dans l'autoclave. Cette double approche a permis dans un premier temps de quantifier les phénomènes de diffusion dans des conditions expérimentales de référence. Le coefficient de diffusion effectif d'une nanostructure modèle de gels de silice a été ainsi déterminé. Une première estimation de la durée de la phase de lavage a également été obtenue. Dans un second temps, l'influence de la variation de la nanostructure des aérogels de silice sur les phénomènes de diffusion a été étudiée. Les résultats obtenus ont permis d'aboutir à une première corrélation entre la perméabilité des matériaux et le coefficient de diffusion effectif. Cette étude a également souligné l'intérêt d'un traitement de vieillissement des gels par phénomènes de dissolution-reprécipitation préalablement au séchage en vue d'écourter la durée de la phase de lavage supercritique.

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International audience

International audience; Low oral bioavailability can be circumvented by the formulation of the poorly water soluble drug in ordered mesoporous silica (OMS-L-7). Fenofibrate is an orally administered, poorly water-soluble active pharmaceutical ingredient (API), used clinically to lower lipid levels. Fenofibrate was loaded into silica using two methods: incipient wetness and supercritical impregnation. This study investigates the impact of loading and the impact of varying supercritical carbon dioxide (scCO2) processing conditions. The objective is to enhance Fenofibrate loading into silica while reducing degree of the drug crystallinity, so as to increase the drug's dissolution rate and its bioavailability. The comparison of both impregnation processes was made in terms of impregnation yields and duration as well as physical characterization of the drug.While incipient wetness method led to a Fenofibrate loading up to 300 mgdrug/gsilica in 48 h of impregnation, the supercritical impregnation method yielded loading up to 485 mgdrug/gsilica in 120 min of impregnation duration, at 16 MPa and 308 K, with a low degree of crystallinity (about 1%) comparable to the crystallinity observed via the solvent method. In addition to the enhancement of impregnation efficiency, the supercritical route provides a solvent-free alternative for impregnation.

International audience; Supercritical impregnation can be used for the elaboration of controlled release systems that may be applied to pharmaceutical and medicinal fields. The present work is dedicated to the impregnation of intraocular lenses (IOLs) with antibiotics using supercritical carbon dioxide as impregnation vector. Commercially available intraocular lenses have been impregnated with cefuroxime sodium in order to obtain ophthalmic drug delivery systems dedicated to the prevention of postoperative endophthalmitis in cataract surgery.The influence of the variation of some experimental operating conditions such as the pressure (8–20 MPa), the temperature (308 and 333 K), the impregnation duration (1–5 h), the addition of a cosolvent (ethanol) or the depressurisation rate (slow and rapid depressurisation) has been studied. In certain experimental conditions, foaming phenomena have been observed.In order to evaluate the impregnation efficiency, the impregnation yields were quantified gravimetrically and the drug release profiles were determined through in vitro drug release studies carried out at 310 K and in a solution simulating the aqueous humor.At rapid depressurisation rates, controlled drug release IOLs with impregnation yields varying between 0.002 and 0.063 mgdrug/mgIOL were obtained. Increasing the pressure or adding a cosolvent were favourable to enhance the impregnation yields. However, a non desired foaming phenomenon was observed for the most favourable conditions.By carrying out slow depressurisations, foaming phenomena were avoided. Nevertheless, in these conditions, the impregnation process was less efficient.The drug partition seems to be more favourable towards the supercritical phase than towards the polymer and the impregnation phenomena governed by a deposition mechanism rather than a molecular dispersion of the active ingredient. The drug is almost deposited within the porosity created during the rapid depressurisation phase. This result was confirmed by the results of the drug release studies.