Topical Cyclosporin A Treatment for Psoriasis

描述（由申请人提供）： 口服环孢素A（CsA）是一种有效的治疗方法，用于严重银屑病患者。局部CsA治疗的可用性可以为银屑病患者提供显着的好处。有效的局部CsA制剂可以减轻这种强效药物的副作用，包括肾毒性和高血压，从而增加可能从CsA中获益的银屑病患者人群基础的广度，包括具有轻度或中度症状的患者。过去开发局部CsA治疗的尝试在很大程度上无效。皮肤是大多数分子量超过500 Da的分子的极好屏障，并且已经论证了CsA的相对高的分子量（1，200 Da）阻碍了药物穿过角质层的转运。最近，Mitragotri及其同事开发了新型渗透促进剂组合（SCOPE制剂），能够大大改善角质层的渗透性。SCOPE组合物已被证明在递送分子量高达5，000Da的分子方面是有效的，具有最低水平的皮肤刺激。我们建议在这些发现的基础上，开发局部制剂，有效地治疗银屑病使用环孢素A。在该提案的第一阶段，将使用一种新型高通量实验系统来鉴定基本上无刺激性的制剂，与标准制剂相比，该制剂能够使可递送至皮肤的CsA的量提高50倍。在该项目的第二阶段，第一阶段开发的主要配方将进行动物试验和小规模人体试验。能够递送CsA的局部制剂也可用作施用该药物用于其它适应症（例如特应性皮炎）的基础。

DESCRIPTION (provided by applicant): Orally delivered cyclosporin A (CsA) is an effective treatment that is used in patients with severe psoriasis. The availability of a topical CsA treatment could provide significant benefit to psoriasis patients. An effective topical CsA formulation could mitigate the side effects of this powerful drug, which include nephrotoxicity and hypertension thereby increasing the breadth of the psoriasis patient population base who might benefit from CsA to include those with mild or moderate symptoms. Past attempts to develop a topical CsA treatment have been largely ineffective. The skin is an excellent barrier for most molecules with a molecular weight of more than 500 Da and has been argued that the relatively high molecular weight of CsA (1,200 Da) hinders the transport of the drug across the stratum corneum. Recently, Mitragotri and coworkers have developed novel combinations of penetration enhancers (SCOPE formulations) that are able to greatly improve the permeability of the stratum corneum. SCOPE compositions have been shown to be effective in delivering molecules with molecular weight of up to 5,000 Da, with minimal levels of skin irritation. We propose here to build on these discoveries to develop topical formulations that are effective in treatment of psoriasis using CsA. In Phase I of the proposal a novel high throughput experimentation system will be used to identify substantially non-irritating formulations that are capable of producing a fifty-fold improvement in the amount of CsA that can be delivered to the skin compared to a standard formulation. In Phase II of the project the leading formulations developed in Phase I will be subjected to animal testing and a small-scale human trial. A topical formulation capable of delivering CsA might also find use as a basis for administering this drug for other indications such as, for example, atopic dermatitis.