CONTROLLED PERCUTANEOUS DELIVERY OF RETINOIDS

为减少全反式维甲酸(ATRA)慢性局部给药引起的刺激性，建议开发一种基于天然生物聚合物的经皮给药系统。由东部合作肿瘤学小组领导的一项国家第二阶段试验现在正在调查外用全反式维甲酸对黑色素瘤化学预防的效果。使用Franz扩散池的初步研究表明，这种天然生物聚合物显著减少了维甲酸通过皮肤的运输量，从而减少了全身过载。在这项第一阶段的可行性研究中，我们建议：(1)通过测定维甲酸在无毛小鼠皮肤中的渗透和分布(视黄醇剂量、生物聚合物含量和分子量的函数)来考察天然生物聚合物在受控经皮给药中的作用；(2)通过人体贴片测试来评估三种不同强度的生物聚合物凝胶的局部应用的耐受性和控制ATRA凝胶的作用。拟议应用的长期目标是开发基于天然生物聚合物的经皮给药系统，用于化学预防有黑色素瘤风险的发育不良痣患者的黑色素瘤。拟议的商业应用：一种受控的局部给药系统可以使全反式维甲酸疗法成为一种可行的黑色素瘤化学预防治疗方法，黑色素瘤是美国上升最快的癌症。在化妆品中使用具有公认安全记录的天然可生物降解生物聚合物有望提供一种更好的替代目前用于局部递送ATRA的合成聚合物的方法。

Development of a percutaneous delivery system based on a natural biopolymer is proposed for the reduction of irritation caused by the chronic topical delivery of all-trans-retinoic acid (ATRA). A national Phase II trial led by the Eastern Cooperative Oncology Group is now investigating the effects of topical ATRA for the chemoprevention of melanoma. Preliminary studies using Franz diffusion cells have shown that the natural biopolymer significantly reduces the amount of retinoid delivery across the skin, thus reducing systemic overload. In this Phase I feasibility study we propose: (1) to examine the role of the natural biopolymer for the controlled percutaneous delivery of both conventional and radiolabeled ATRA by determining the penetration and distribution of retinoid across hairless mouse skin as a function of retinoid dose, biopolymer content and molecular weight; and (2) to establish the tolerance of topical applications of biopolymer-based and control ATRA gels of three different strengths as evaluated by human patch testing. The long-term goal of the proposed application is to develop natural biopolymer-based percutaneous delivery system for the chemoprevention of melanoma in individuals with dysplastic nevi who are at risk of developing melanoma. PROPOSED COMMERCIAL APPLICATION: A controlled topical delivery system could make ATRA retinoid therapy a viable chemopreventive treatment of melanoma, which is the fastest rising cancer in the United States. The use of a natural biodegradable biopolymer with proven safety track record in cosmetic products is expected to provide a better alternative to the current use of synthetic polymers for the topical delivery of ATRA.