School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Switzerland.
Eur J Pharm Biopharm. 2012 Apr;80(3):544-52. doi: 10.1016/j.ejpb.2011.11.017. Epub 2011 Dec 3.
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 bicompartmental 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.
环孢素 A（CsA）已被证明可有效治疗多种眼科疾病，包括眼表疾病（如干眼症）。由于 CsA 的水溶性低，因此开发局部眼用制剂是一个有趣的药学问题。在本研究中，研究并比较了两种解决这一挑战的不同策略：（i）将水溶性 CsA 前药制成水溶液制剂，（ii）CsA 油包水乳液（Restasis，Allergan Inc.，Irvine，CA）。首先，前药制剂表现出极好的眼部耐受性，并且对基础泪液产生没有影响；保持眼表特性不变。然后，为了允许进行体内研究，开发了一种基于超高效液相色谱-串联三重四极杆质谱（UHPLC-MS/MS）的特定分析方法，用于定量检测眼组织和液中的 CsA。两种制剂的泪液中 CsA 的眼部动力学在 15 分钟至 48 小时之间相似。CsA 眼部分布研究表明，前药制剂能够穿透眼睛，在前节和后节组织中达到治疗性有效 CsA 水平。此外，使用双室模型对体内数据进行详细分析表明，与直接应用乳液相比，从前药生成 CsA 时具有更高的生物利用度和更低的消除率。前药溶液表现出的有趣的体内特性使其成为治疗 DED 的安全且合适的选择。
