In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease

Article Article scientifique Article In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease eng 2012 author Rodriguez Aller Marta Ruth 670131 author Kaufmann Béatrice 87539 author Guillarme Davy 623637 author Deutsch-Stella Cinzia 506323 author Furrer Pascal 42164 author Rudaz Serge 28978 author El Zaoui I. author Valamanesh F. author Di Tommaso Claudia 636997 author Behar-Cohen F. author Veuthey Jean-Luc 22317 author Gurny Robert 24779 544-552 10.1016/j.ejpb.2011.11.017 0939-6411 http://linkinghub.elsevier.com/retrieve/pii/S0939641111003353 Cyclosporine A (CsA) has been demonstrated to be effective for the treatment of a variety of ophthalmological conditions, including ocular surface disorders such as the dry eye disease (DED). Since CsA is characterised by its low water solubility, the development of a topical ophthalmic formulation represents an interesting pharmaceutical question. In the present study, two different strategies to address this challenge were studied and compared: (i) a water-soluble CsA prodrug formulated within an aqueous solution and (ii) a CsA oil-in-water emulsion (Restasis), Allergan Inc., Irvine, CA). First, the prodrug formulation was shown to have an excellent ocular tolerance as well as no influence on the basal tear production; maintaining the ocular surface properties remained unchanged. Then, in order to allow in vivo investigations, a specific analytical method based on ultra high pressure liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC–MS/MS) was developed and optimised to quantify CsA in ocular tissues and fluids. The CsA ocular kinetics in lachrymal fluid for both formulations were found to be similar between 15 min and 48 h. The CsA ocular distribution study evidenced the ability of the prodrug formulation to penetrate into the eye, achieving therapeutically active CsA levels in tissues of both the anterior and posterior segments. In addition, the detailed analysis of the in vivo data using a icompartmental model pointed out a higher bioavailability and lower elimination rate for CsA when it is generated from the prodrug than after direct application as an emulsion. The interesting in vivo properties displayed by the prodrug solution make it a safe and suitable option for the treatment of DED. Cyclosporine A Prodrug Precorneal kinetic UHPLC-MS/MS quantification Ophthalmic formulation Dry eye Dewey 615 31 Section des sciences pharmaceutiques 17 false European journal of pharmaceutics and biopharmaceutics 80 3 db89857c-6d95-4cd3-944f-259237710637 Article (Published version) Restricted 2012 - in vivo characterization of cyclosporine, EJPB 2012, 80, 544-552.pdf 896843 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

Title	Published in	Year	Views	Downloads

In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease	European journal of pharmaceutics and biopharmaceutics	2012	633	0
A novel cyclosporin A micelle formulation for topical ophthalmic applications: development, biocompatibility, corneal penetration, and efficacy studies		2011	862	1 652

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