BIOERODABLE NARCOTIC ANTAGONIST DELIVERY DEVICE

这项研究的主要目标是开发一种可注射的， 释放麻醉性拮抗剂的可生物侵蚀的药物输送装置 通过接近于零的动力学控制侵蚀过程的纳曲酮 秩序。主要由于尺寸限制，设计寿命将 是30天。这个系统的开发将使用类似于药膏的 可生物侵蚀的聚(邻苯二甲酸酯)，最近在我们的实验室开发。这个 这种聚合物的水解是非常清楚的，最终的 降解产物是毒性无害的1，2，6-己三醇和 一种羧酸。聚合物的膏状稠度允许 用简单混合法掺入高浓度纳曲酮 在室温下不使用溶剂的程序，因此 最大限度地减少潜在的不利纳曲酮-聚合物相互作用和 最大限度地增加可并入聚合物中的药物数量。 实际的输送系统将由聚合物药物混合物组成， 微胶囊化在可生物侵蚀的大孔膜中。这 封装会将软膏状材料限制为固定的几何形状， 允许通过传统的皮下注射器给药，以及 防止被病人取出。我们已经选择了一个界面 用大孔包围聚合物的缩聚过程 由二胺和二元酸缩合而成的聚酰胺膜 氯化物。这种药膏状的材料首先与干冰混合，然后 研磨成细粉。然后将其添加到乙醇中，保持 在-40摄氏度下，加入二胺，这种混合物分散在n- 含有二酸氯化物的己烷也保持在零下40摄氏度。 因为聚酰胺基本上是不可降解的，并且含有有毒的 二胺，一种由L-α-丙氨酸和二元醇制备的特殊二胺 做好准备。这种二胺可通过酯基和 是基于一种无毒的胺。由此得到的90微摩尔胶囊可以 通过18号针头注射。毒理学和药代动力学数据 将被获得以显示该系统的生物兼容性和功能。 建议的具体研究是突变测试，一种静脉注射 大鼠组织中聚合物水解物的生物沉积研究 兔体内生物相容性和兔体内药代动力学研究。

The principal objective of this research is to develop an injectable, bioerodible drug delivery device that will release the narcotic antagonist naltrexone by an erosion-controlled process by kinetics that approach zero order. Primarily because of size constraints, the designed lifetime will be 30 days. This system will be developed using an ointment-like bioerodible poly(ortho ester), recently developed in our laboratories. The hydrolysis of this polymer is very well understood, and the ultimate degradation products are the toxicologically benign 1,2,6-hexanetriol and a carboxylic acid. The ointment-like consistency of the polymer allows incorporation of high concentrations of naltrexone by a simple mixing procedures at room temperature without the use of solvents, thus minimizing potentially adverse naltrexone-polymer interactions and maximizing the amount of drug that can be incorporated into the polymer. The actual delivery system will consist of a polymer drug mixture, microencapsulated within a bioerodible, macroporous membrane. This encapsulation will confine the ointment-like material to a fixed geometry, allow administration by means of a conventional hypodermic syringe, and prevent removal by the patient. We have selected an interfacial polycondensation procedure to surround the polymer with a macroporous polyamide membrane produced by the condensation of a diamine and a diacid chloride. The ointment-like material is first mixed with dry ice and then ground to produce a fine powder. This is then added to ethanol, maintained at -40 degrees C, the diamine added, and this mixture dispersed in n- hexane, containing the diacid chloride, also maintained at -40 degrees C. Because polyamides are essentially nondegradable and contain a toxic diamine, a special diamine prepared from L-alpha-alanine and a diol will be prepared. This diamine is degradable by virtue of the ester groups and is based on a nontoxic amine. The resulting 90 micromoles capsules can be injected through an 18-gauge needle. Toxicology and pharmacokinetic data will be obtained to show biocompatibility and functionality of the system. The specific studies proposed are mutagenicity testing, an intravenous biodeposition study with polymer hydrolysate in rats, a tissue biocompatibility in rabbits, and a pharmacokinetic study in rabbits.