Novel Controlled Delivery Systems for Contraceptives

描述（由申请人提供）：近年来，用于控制递送避孕激素的皮下植入物因给使用者造成各种问题而成为诉讼的目标。这些问题包括在插入和取出过程中据称的严重副作用和并发症。一个完善的避孕激素递送系统必须限制注射时的爆发效应，在治疗期间的治疗要求内释放激素，易于给药，可生物降解，以及制造过程的成本效益。基于智能聚合物溶液的输送系统将满足所有上述要求。该项目的长期目标是开发基于智能聚合物溶液的控释系统，以在单次皮下注射后以预定速率更长时间地递送避孕激素。我们建议测试的假设，相和温度敏感，可逆凝胶形成，可生物降解，智能聚合物可以控制在体外和体内释放的激素和建议的智能聚合物为基础的交付系统是生物相容性。为了验证我们的假设，我们计划研究以下具体目标：（1）合成温度敏感的三嵌段共聚物并表征它们的临界凝胶浓度，凝胶转变温度（即，（2）采用相敏和温敏高分子材料制备了左炔诺孕酮和睾酮的原位凝胶型智能高分子溶液控释系统，（3）研究了左炔诺孕酮和睾酮的体外释放特性，并对释放系统的性能进行了评价。（4）采用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四氮唑（MTT）比色法评价上述药物的体外生物相容性;（5）研究上述药物在家兔体内的吸收情况。我们相信，本研究有可能导致新的和改进的方法，胃肠外控制释放给药系统的避孕激素。这种新型治疗系统的开发对于成功治疗乳腺癌相关疾病和改善患者的生活质量至关重要。

DESCRIPTION (provided by applicant): Subdermal implants for controlled delivery of contraceptive hormones have become the target of litigation in recent years for causing a variety of problems in users. These problems include purported serious side effects and complications during insertion and removal. A well-developed contraceptive hormone delivery system must limit the burst effect on injection, release the hormone within the therapeutic requirements for the duration of treatment, ease of administration, biodegradable, and cost effectiveness of the manufacturing process. Smart polymer solution based delivery systems would meet all the above requirements. The long-term goal of this project is to develop smart polymer solution based controlled delivery systems to deliver contraceptive hormones after single subcutaneous injection at predefined rate for longer duration. We propose to test the hypotheses that phase and temperature sensitive, reversibly gel forming, biodegradable, smart polymers can control the in vitro and in vivo release of hormone and the proposed smart polymer based delivery systems are biocompatible. To test our hypotheses, we plan to study the following specific aims: (1) To synthesize temperature sensitive triblock copolymers and characterize them for critical gel concentration, gel transition temperature (i.e., lower critical solution temperature), weight average molecular weight by gel permeation chromatography, and number average molecular weight by 1H NMR; (2) To prepare in situ gel forming smart polymer solution based controlled delivery systems for levonorgestrel and testosterone, using phase sensitive and temperature sensitive polymers; (3) To study in vitro release profiles of levonorgestrel and testosterone from delivery systems; (4) To evaluate the biocompatibility of the above delivery systems in vitro, using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay; and (5) To study in vivo absorption of the above hormones from delivery systems in rabbits. We believe that the present study has potential to result in novel and improved approaches for parenteral controlled release delivery systems for contraceptive hormones. Development of such a novel therapeutic system is critical for successful treatment of hormone-related diseases and improvement in the patients' quality-of-life.