Novel Controlled Delivery Systems for Contraceptives

描述(申请人提供)：近年来，用于控制释放避孕激素的皮下埋植剂因在使用者中造成各种问题而成为诉讼的目标。这些问题包括据称在插入和取出过程中出现的严重副作用和并发症。一个完善的避孕激素输送系统必须限制注射的突发效应，在治疗期间内释放激素，易于给药，可生物降解，并具有制造工艺的成本效益。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制释放系统，以便在以预定的速度进行单次皮下注射后，以更长的持续时间传递避孕激素。我们建议验证这样的假设，即相和温度敏感、可逆凝胶形成、可生物降解的智能聚合物可以控制激素的体外和体内释放，并且所提出的基于智能聚合物的递送系统具有生物相容性。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(即较低的临界溶液温度)、凝胶渗透层析的重均相对分子质量和1H核磁共振的数均相对分子质量；(2)利用相敏感和温度敏感的聚合物制备基于原位凝胶形成的智能聚合物溶液的左旋诺孕酮和睾酮的控释系统；(3)研究左炔诺孕酮和睾酮的体外释放曲线；(4)用4-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴化法评价上述给药系统的体外生物相容性；(5)研究上述激素在兔体内的吸收。我们相信，本研究有可能为避孕激素的肠外控释释放系统带来新的和改进的方法。开发这样一种新的治疗系统对于激素相关疾病的成功治疗和患者生活质量的改善至关重要。

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.