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A water-soluble prodrug of cyclosporine A for ocular application: A stability study

Felt-Baeyens, Olivia
Kloeti, Werner
Philippoz, Florence
Marfurt, Judith
Besseghir, Kamel
Published in European Journal of Pharmaceutical Sciences. 2005, vol. 26, no. 1, p. 124-129
Abstract UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) developed for topical eye delivery. Such a prodrug has to fulfil two paradoxical requirements as it must be rapidly hydrolysed under physiological conditions but also retain a long shelf-life in aqueous media. This study has been conducted to explore the stability of UNIL088 formulated as an eyedrop solution. The stability study of the prodrug was performed over a pH range of 5–7 at 20 °C and at various ionic strengths. The molecule was more stable at pH 5 than at pH 7 with conversion rate constant of 3.2 × 10−3 and 26.0 × 10−3 days−1, respectively. The effect of temperature was studied at four different temperatures and activation energy was determined. Conversion of UNIL088 followed a pseudo-first-order kinetic with an activation energy of 79.4 kJ mol−1. Due to its low solubility, CsA generated precipitated in the solution. The average size of CsA precipitates, determined by photon spectroscopy, was 0.22 and 1.08 μm at 7 and 14 days, respectively. The hydrolysis mechanism was partially elucidated by identification of the intermediate pSer-Sar-CsA.
Keywords Cyclosporine AProdrugStabilitySolubilityConversion mechanismShelf-lifePrecipitationAdministrationTopicalChromatographyHigh Pressure LiquidDrug StabilityHydrogen-Ion ConcentrationHydrolysisImmunosuppressive AgentsMass SpectrometryOphthalmic SolutionsParticle SizePhotonsSpectrum AnalysisTemperature
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Research group Groupe Gülaçar
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LALLEMAND, Frédéric et al. A water-soluble prodrug of cyclosporine A for ocular application: A stability study. In: European Journal of Pharmaceutical Sciences, 2005, vol. 26, n° 1, p. 124-129. https://archive-ouverte.unige.ch/unige:3262

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Deposited on : 2009-09-21

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