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Mécanismes d'adsorption du risédronate par des phosphates de calcium biologiques: applications aux biomatériaux

Abstract : Our work is focused on the reactivity of biomimetic calcium phosphate towards a therapeutic agent from Bisphosphonates family: risedronate. This drug is currently marketed under the name of "Actonel" and used in the treatment of several diseases related to bone tissue such as osteoporosis. We purpose in this paper to elucidate the mechanisms of interaction occurring at the interface between apatite and risedronate. In order to do that, the physico-chemical properties of materials examined and the characteristics of the solution were taken as experimental variables. The study of adsorption led us initially to develop calcium phosphates with different physico-chemical characteristics. For this the experimental synthesis conditions are varied (degree of saturation, temperature, maturation time, pH...). In order to specify the nature of the interactions between risedronate molecules and calcium ions in solution, a calcium risedronate salt are prepared. To clarify the physico-chemical characteristics of the precipitates (cristallinity index, structural and morphological changes, formation of insoluble salts) several complementary physico-chemical techniques are used ( XRD, FTIR, Raman, solide state NMR, SEM, TEM, DTA/TGA, BET, chemical analysis and complexometric study). The precipitated solids are calcium phosphate apatites wich have variable chemical compositions (atomic ration Ca/P from 1,33 to 1,65) as well as different structural and microstructural properties. Their specific surface area covers the range from 49 to 201 m²/g. The solids synthesized under physiological conditions of pH and temperature are nanocrystalline apatites of low crystallinity, similar to bone mineral. One of the most interesting characteristics of these biomimetic apatite nanocrystals is the existence of a surface hydrated layer essentially formed of non-apatitic environments of phosphate and carbonate ions. These labile species are not observed on well crystallized hydroxyapatite. In all cases, the adsorption data were well described by a Langmuir adsorption isotherm. The rate of risedronate adsorption is extremely rapid, witch attests to the high interaction between calcium phosphate surface and bisphosphonate species. The reactivity of solids examined versus the adsorbate molecules was discussed on the basis of the physico-chemical system characteristics. Then, various factors are taken into consideration to explain the difference in behaviour of these materials (chemical composition of both adsorbents and solution, surface reactivity and existence of non-apatitic environments, microstructure,...). The overall analysis of results from the solution composition influence on the risedronate binding and adsorption effect on the apatite dissolution shows a correlation between the phosphonate groups of the solution and phosphate ions from the surface of the supports. This observation reflects the existence of an exchange process involving these species in mineral-interface environment. The study of poorly crystalline at different stages of maturation confirms the involvement of this surface substitution reaction. However, the evolution of calcium content during the adsorption suggests that other phenomena may intervene. Thus at higher concentrations of adsorbate the uptake curve increase steeply, indicating the existence of complex processes at the mineral surface. In addition, a study conducted by Raman and Infrared spectroscopy and NMR, on supports after contact with the adsorbate molecules, attests to the presence of strong interactions involving the functional groups of the adsorbate and calcium sites on apatite surface. The study compared with risedronate salts of calcium precipitates confirmed the formation of amorphous phase typical of Ca2BP compound. The evolution of apatite nanocrystals in the presence of risedronate molecules affects very little the composition of surface hydrated layer and inhibits therefore their maturation process. Biologically, the location of these drugs on the surface of bone mineral may be beneficial to the extent that these species can block the aging process of bone tissue and maintaining its reactivity. To minimize the side effects of bisphosphonates molecules and improve their local bioavailability in order to broaden their scope of treatment, a local diffusion approach seems an interesting way. All results from this work are a platform for the development of biomaterials as a risedronate delivery system.
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Submitted on : Tuesday, February 7, 2012 - 4:31:06 PM
Last modification on : Wednesday, October 5, 2022 - 4:16:15 PM
Long-term archiving on: : Tuesday, May 8, 2012 - 2:32:29 AM


  • HAL Id : tel-00667418, version 1


Farid Errassifi. Mécanismes d'adsorption du risédronate par des phosphates de calcium biologiques: applications aux biomatériaux. Matériaux. Faculté des Sciences Semlalia-Marrakech, 2011. Français. ⟨NNT : ⟩. ⟨tel-00667418⟩



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