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Prolonged release microparticles able to reduce the initial burst effect

Abstract : Multiparticular injectable dosage forms present a burst effect known to lead to i) a systemic toxicoligal critical issue if blood concentrations of the drug are too high and ii) a change in the release profile due to a lower loading charge in microparticles. In order to solve this problem, composite microparticles have been developed: they consist in nanoparticles encapsulated in microparticles. Such a concept has been demonstrated in vitro by encapsulating poly(epsiloncaprolactone) nanoparticles in a non-biodegradable polymeric matrix with two model drugs: a small molecular weight drug (ibuprofene) and a peptide (triptorelin acetate). The novelty of the research work lies on the adequate choice of polymers and solvents used for microparticles manufacturing. Indeed, the solvent used to manufacture microparticles has to be a non-solvent of the nanoparticles polymer. Ethyl acetate was a good candidate since it does not dissolve poly(epsilon-caprolactone) nanoparticles but is an excellent solvent for ethylcellulose and the polycationic polymer used in the first part of the work. Based on in vitro release studies, it was demonstrated that composite microparticles allowed the initial release to be strongly reduced together with a prolonged release. In a second part, the burst release reduction has been confirmed in vivo in rats with 2 drug models: ibuprofen and insulin. However, the microparticles polymer matrix was replaced by a biodegradable copolymer made of lactic and glycolic acids. It has been demonstrated that the novel composite microparticles were an innovative dosage form able to control the initial burst release often associated to microparticles after sub-cutaneous or intramuscular administration while still maintaining the prolonged release of the encapsulated drugs. Such a result can be associated with the more difficult diffusion of the drug through the two consecutive polymeric barriers of nanoparticles and microparticles.
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  • HAL Id : tel-01777266, version 1



Ahmed Sheikh Hassan. Prolonged release microparticles able to reduce the initial burst effect. Pharmaceutical sciences. Université Henri Poincaré - Nancy 1, 2008. English. ⟨NNT : 2008NAN10128⟩. ⟨tel-01777266⟩



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