School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
J Control Release. 2013 Aug 28;170(1):153-9. doi: 10.1016/j.jconrel.2013.04.019. Epub 2013 May 3.
Cyclosporine A is a poorly water-soluble, immunosuppressive drug used to treat a variety of ocular diseases. Its limited solubility makes challenging the development of a cyclosporine A-based eye drop for ocular topical application. Based on the prodrug strategy, the practically insoluble cyclosporine A was converted into a freely soluble prodrug. Such a water-soluble prodrug made it possible to develop water-based concentrated eye drops. The prodrug formulations were tested for their ex vivo permeation and in vivo distribution at three concentrations (equivalent to 0.05%, 0.50% and 2.00% w/v cyclosporine A). The ex vivo permeation experiments were performed on corneal and conjunctival epithelia. The in vivo distribution evaluated the total cyclosporine A present in the ocular structures as well as in serum, spleen and cervical lymphatic ganglions. Each prodrug formulation was compared to conventionally used cyclosporine A eye drops at an equivalent concentration. The experimental results showed that the tested eye drops behaved differently. The prodrug formulation was characterized by the following: i) preferential conjunctival penetration, ii) an interesting capacity to create large tissue deposits and iii) a lower risk of systemic complications and immunosuppression. The prodrug aqueous eye drop was demonstrated to be a patient-friendly option for the treatment of ocular diseases requiring high ocular levels of cyclosporine A, pushing the boundaries of the current therapeutic arsenal.
环孢素 A 是一种水溶性差的免疫抑制剂，用于治疗多种眼部疾病。其有限的溶解度使得开发用于眼部局部应用的环孢素 A 滴眼剂具有挑战性。基于前药策略，将实际上不可溶的环孢素 A 转化为可自由溶解的前药。这种水溶性前药使开发水基浓缩滴眼剂成为可能。对三种浓度（相当于 0.05%、0.50%和 2.00%w/v 环孢素 A）的前药制剂进行了体外渗透和体内分布测试。体外渗透实验在角膜和结膜上皮上进行。体内分布评估了眼组织结构中以及血清、脾脏和颈部淋巴结中存在的总环孢素 A。将每种前药制剂与等效浓度的常规使用的环孢素 A 滴眼剂进行比较。实验结果表明，测试的滴眼剂表现不同。前药制剂的特点如下：i）优先穿透结膜，ii）具有在组织中形成大量药物储存的有趣能力，iii）发生全身并发症和免疫抑制的风险较低。前药水性滴眼剂被证明是一种适合患者的选择，可用于治疗需要高眼部环孢素 A 水平的眼部疾病，推动了当前治疗武器库的发展。
