A water-soluble prodrug of cyclosporine A for ocular application: a stability study.
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 degrees 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 x 10(-3) and 26.0 x 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 microm at 7 and 14 days, respectively. The hydrolysis mechanism was partially elucidated by identification of the intermediate pSer-Sar-CsA.
Laboratory of Pharmaceutical Technology and Biopharmaceutics, School of Pharmacy, University of Geneva, Quai E. Ansermet 30, 1211 Geneva 4, Switzerland.
Frederic
F
Lallemand
Philippe
P
Perottet
Olivia
O
Felt-Baeyens
Werner
W
Kloeti
Florence
F
Philippoz
Judith
J
Marfurt
Kamel
K
Besseghir
Robert
R
Gurny
D000287:Administration, Topical; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000737:chemistry* / Q000378:metabolism; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000378:metabolism; D013058:Mass Spectrometry; D009883:Ophthalmic Solutions; D010316:Particle Size; D017785:Photons; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013057:Spectrum Analysis / Q000379:methods; D013696:Temperature; D013997:Time Factors
D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D011355:Prodrugs; D016572:Cyclosporine