A NOVEL APPROACH TO POLYMERIC NARCOTIC ANTAGONISTS

20年来，人们一直在寻找一位成功的麻醉剂拮抗剂。这个 拮抗剂环佐辛和纳洛酮的发现导致了 加快了该领域的研究。最近的一种拮抗剂，纳曲酮， 已被证明是一种有效的拮抗剂，基于广泛的临床 实验。还希望获得一种长效药物，因此 减轻吸毒成瘾者定期服药的需要 以最小的剂量提供最大的疗效。 已经进行了几次尝试来开发能够 提供长效的麻醉性拮抗作用。他们还没有被 成功地实现了恒定释放，这是由于药物 浓度在长时间释放后就会耗尽。我们的方法是 控释是基于一种可生物降解的聚合物骨架 药物分子通过不稳定的基团共价结合。药物释放是 主要由不稳定键的水解率控制，而不是由 这是一个扩散过程。聚合物主干的分解速度要慢得多。 而不是聚合物-药物在几个月内不稳定的键。免疫 这些聚合物骨架在动物体内引起的反应并被降解 碎片被发现是最小的。我们实验室的初步研究是 支持这一说法。 该提案包括使用麻醉性拮抗剂纳曲酮和 多种多氨基酸作为主干药物载体。基础研究的目的 用于在体外和体内获得恒定的释放速率 动物实验使用不同组合的多氨基酸骨架， 间隔基和不稳定键。从建议中获得的数据 研究将提供有价值的信息，在设计长期， 可皮下注射、可生物降解的纳曲酮给药系统。

A successful narcotic antagonist has been sought for two decades. The discoveries of the antagonists cyclozocine and naloxone have led to accelerated research in the area. A more recent antagonist, naltrexone, has been shown to be an effective antagonist based on extensive clinical experiments. It is also desirable to obtain a long-acting drug, thus alleviating the need for an addicted person to take regular medication and provide maximum efficacy with minimum dose. Several attempts have been made to develop drug delivery systems capable of providing long-acting narcotic antagonistic effects. They have not been succaessful in achieving constant release due to the fact that drug concentration is depleted upon prolonged release. Our approach to controlled release is based on a biodegradable polymer backbone to which drug molecules are covalently bound via labile groups. Drug release is primarily controlled by the rate of hydrolysis of the labile bonds, not by a diffusion process. The polymer backbone breaks down much more slowly than the polymer-drug labile bond over a period of months. Immune reactions in animals caused by these polymer backbones and degraded fragments were found to be minimal. Initial studies in our laboratory are supportive of this claim. This proposal includes the use of the narcotic antagonist naltrexone and various polyamino acids as backbone drug carriers. The basic studies aim for the attainment of a constant release rate in both in vitro and in vivo animal experiments using various combinations of polyamino acid backbones, spacer groups and labile bonds. The data obtained from the proposed studies would provide information valuable in the design of long-term, hypodermically injectable, biodegradable naltrexone delivery systems.