A NOVEL APPROACH TO POLYMERIC NARCOTIC ANTAGONISTS

二十年来一直在寻找一种成功的麻醉剂拮抗剂。 的 拮抗剂环佐辛和纳洛酮的发现导致 加快该领域的研究。 一种较新的拮抗剂，纳洛酮， 已被证明是一种有效的拮抗剂， 实验 还期望获得长效药物，因此 减轻成瘾者定期服药的需要， 以最小的剂量提供最大的功效。 已经进行了几次尝试来开发能够递送药物的药物递送系统。 提供长效麻醉拮抗作用。 他们没有被 由于药物 浓度在延长释放时耗尽。 我们的方法来 控释基于可生物降解的聚合物主链， 药物分子通过不稳定基团共价结合。 药物释放 主要由不稳定键的水解速率控制，而不是由 扩散过程。 聚合物骨架的分解要慢得多 比聚合物-药物不稳定的键长得多。 免疫 由这些聚合物主链引起的动物反应， 发现碎片极少。 我们实验室的初步研究是 支持这一主张。 该建议包括使用麻醉剂拮抗剂纳洛酮， 各种聚氨基酸作为骨架药物载体。 基础研究的目的 为了在体外和体内获得恒定的释放速率 使用聚氨基酸主链的各种组合的动物实验， 间隔基团和不稳定键。 从拟议的数据中获得的数据 研究将为设计长期的， 皮下注射的、可生物降解的纳洛酮递送系统。

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.