SR Drug Delivery for the Treatment of Drug Abuse

描述（由申请人提供）：本项目的长期目标是开发一种新的药物滥用治疗方法。 丁丙诺啡是一种高度亲脂性的部分μ-阿片激动剂，正在进行阿片维持计划的测试。 为了提供长期恒定的丁丙诺啡递送，期望开发可皮下植入的持续释放制剂。 为了在长时间内以恒定速率递送丁丙诺啡，我们提出开发持续释放微胶囊。 我们假设，皮下注射丁丙诺啡微胶囊将提供长期治疗血浆浓度的丁丙诺啡。 本提案的具体目的是：（1）开发丁丙诺啡的缓释微囊，（2）评价微囊的体外药物释放特性，（3）评价微囊的体内性能，以及（4）评价微囊的长期稳定性。 丁丙诺啡微胶囊将使用聚（丙交酯-共-乙交酯）通过一种新的微胶囊化技术制备。 这种独特的微胶囊化技术是在PI的实验室中开发的，其中活性成分被掺入水凝胶中，然后在合成的可生物降解的聚合物中进行微胶囊化。 在我们实验室刚刚完成的初步实验表明，在微胶囊化之前使用交联水凝胶可以显著增加载药量。 它还揭示了药物以溶解状态存在于水凝胶内。 结果，水凝胶的掺入显著降低了药物的突释效应和总体溶解。 将在家兔中测试丁丙诺啡微胶囊的体内释放和生物相容性。 还将在大鼠模型中测试微胶囊的激动剂效应和海洛因剂量效应。 在兔和大鼠中成功进行临床前评价后，这种新型的递送系统将来可用于猴评价，然后进行人体临床试验。

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop a novel treatment for drug abuse. Buprenorphine is a highly lipophilic partial mu-opiate agonist, which is being tested for opiate maintenance program. In order to provide long-term constant buprenorphine delivery, it is desirable to develop a sustained release formulation, which could be implanted subcutaneously. In order to deliver buprenorphine at a constant rate over a prolonged period, we propose to develop sustained release microcapsules. We hypothesize that subcutaneous administration of buprenorphine microcapsules will deliver long-term therapeutic plasma concentrations of buprenorphine. The specific aims of this proposal are to: (1) develop sustained release microcapsules of buprenorphine, (2) evaluate in vitro drug release characteristics of the microcapsules, (3) evaluate in vivo performance of the microcapsules, and (4) evaluate the long-term stability of the microcapsules. Buprenorphine microcapsules will be prepared using poly(lactide-co-glycolide) by a novel microencapsulation technique. This unique microencapsulation technique has been developed in the PI's laboratory, where the active ingredients are incorporated within a hydrogel followed by microencapsulation within a synthetic biodegradable polymer. Preliminary experiments just completed in our laboratory revealed that the use of a crosslinked hydrogel, before the microencapsulation, could significantly increase the drug loading. It also revealed that the drug was present within the hydrogel in the dissolved state. As a result, incorporation of the hydrogel significantly reduced the burst effect and overall dissoluation of the drug. The buprenorphine microcapsules will be tested in rabbits for in vivo release and biocompatibility. The microcapsules will also be tested in a rat model for agonist effect and heroin dose effect. Following the successful preclinical evaluations in rabbits and rats, this novel delivery system can be used, in the future, for evaluation in monkeys followed by human clinical trials.