Novel Controlled Delivery Systems for Contraceptives

描述（由申请人提供）：用于控制避孕激素的皮下植入物近年来因给使用者带来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严重的副作用和并发症。一个发达的避孕激素输送系统必须限制注射时的爆裂效应，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上述所有要求。该项目的长期目标是开发基于智能聚合物溶液的控制递送系统，在单次皮下注射后以预定的速率递送避孕激素，持续时间更长。我们建议测试相和温度敏感、可逆凝胶形成、可生物降解的智能聚合物可以控制体外和体内激素释放的假设，以及提出的基于智能聚合物的传递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，并通过凝胶临界浓度、凝胶转变温度（即较低的临界溶液温度）、凝胶渗透色谱法的质量平均分子量和1H NMR的数量平均分子量对其进行表征；(2)利用相敏和温敏聚合物制备左炔诺孕酮和睾酮原位凝胶形成智能聚合物溶液控制递送系统；(3)研究左炔诺孕酮和睾酮在给药系统中的体外释放情况；(4)采用3-（4,5 -二甲基噻唑-2-基）- 2,5 -二苯基溴化四唑（MTT）法评价上述给药系统的体外生物相容性；(5)研究上述激素在家兔体内通过给药系统的吸收。我们相信，目前的研究有可能导致新的和改进的方法，肠外控释输送系统的避孕激素。这种新型治疗系统的发展对于成功治疗激素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.