BIOERODABLE NARCOTIC ANTAGONIST DELIVERY DEVICE

本研究的主要目的是开发一种可注射的， 将释放麻醉剂拮抗剂的生物可侵蚀的药物递送装置 纳洛酮通过接近零的动力学的侵蚀控制过程 秩序由于尺寸限制，设计寿命将 30天。该系统将使用类似软膏的 生物可蚀性聚（原酸酯），最近在我们的实验室开发。的 这种聚合物的水解是非常好理解的， 降解产物是毒理学上良性的1，2，6-己三醇， 羧酸。 聚合物的软膏状稠度允许 通过简单混合掺入高浓度的纳洛酮 在室温下不使用溶剂，因此 最小化潜在不利的纳洛酮-聚合物相互作用， 使可掺入聚合物中的药物量最大化。 实际的输送系统将由聚合物药物混合物组成， 微囊化在生物可侵蚀的大孔膜内。这 封装将软膏状材料限制为固定的几何形状， 允许通过常规皮下注射器给药，和 防止患者取出。我们选择了一种界面 通过缩聚过程，用大孔聚合物包围聚合物， 由二胺和二酸缩合制备的聚酰胺膜 氯化首先将软膏状材料与干冰混合， 磨碎产生细粉。然后将其加入乙醇中， 在-40 °C下，加入二胺，并且该混合物分散在正- 含有二酰氯的己烷也保持在-40 ℃。 因为聚酰胺基本上是不可降解的， 二胺，由L-α-丙氨酸和二醇制备的特殊二胺， 做好准备该二胺由于酯基而可降解， 是基于一种无毒的胺。所得90微摩尔胶囊可以是 通过18号针头注射毒理学和药代动力学数据 以显示系统的生物相容性和功能性。 拟定的具体研究是致突变性试验、静脉注射 聚合物水解产物在大鼠中的生物沉积研究， 在兔中的生物相容性和在兔中的药代动力学研究。

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.