Controlled Delivery of Insulin

概述：在美国，有2080万人患有糖尿病。大约有17.65万20岁以下的人患有糖尿病。在所有新诊断的I型糖尿病病例中，大约75%发生在18岁以下的个体中。1型糖尿病患者必须每天注射胰岛素以维持生命。所有I型糖尿病患者和许多II型糖尿病患者的治疗需要频繁注射胰岛素。在健康个体中，基础胰岛素在两餐之间和整个夜间以0.5-1单位/小时的速率持续分泌。虽然基础胰岛素水平很低，但它可以调节隔夜肝脏葡萄糖的速率和两餐之间较长时间的葡萄糖输出。这就保证了睡眠时大脑产生足够能量所需的葡萄糖水平。可注射聚合物递送系统可用于胰岛素的持续释放，以满足所需时间的基础胰岛素的需要。这项工作的长期目标是开发控释制剂，使其能够在单次注射后以构象、化学稳定和生物活性的形式连续递送胰岛素，持续时间更长。我们建议测试温度敏感的可生物降解聚合物可以控制胰岛素在体外和体内以生物活性、构象和化学稳定的形式释放的假设，以及提出的基于聚合物的递送系统是生物相容性的。为了验证我们的假设，我们计划研究以下具体目标：合成温度敏感型三嵌段共聚物，并用凝胶渗透色谱法表征其临界凝胶浓度、凝胶转变温度、质量平均分子量和H - NMR表征其数量平均分子量。[2]。利用温度敏感聚合物制备胰岛素原位凝胶形成控制递送系统。[3]。目的：研究胰岛素从给药系统的体外释放情况，并评价影响释放的因素。[4]。采用高效液相色谱-质谱技术评价胰岛素释放物的化学稳定性。[5]。用差示扫描量热法（DSC）评价释放胰岛素的构象稳定性。[6]。通过MTT法和光镜组织学分析分别评价两种给药系统的体内和体外生物相容性。[7]。目的：研究胰岛素在糖尿病大鼠体内的吸收和生物活性。拟议的研究将为开发一种注射形式做出重大贡献，该形式在单次注射后以可控速率递送胰岛素，持续时间更长（约2个月）。这种给药系统的发展将改善患者的生活质量，并减少与糖尿病相关的长期并发症。所提出的努力将对基于聚合物溶液的递送系统的发展做出重大贡献，该系统可以在单次皮下注射后以可控的速率递送胰岛素，持续时间更长。这种新型治疗系统的开发对于成功治疗糖尿病和改善患者的生活质量至关重要。

DESCRIPTION (provided by applicant): Summary: In the United States, 20.8 million people suffer from diabetes. About 176,500 people under 20 years of age have diabetes. About 75% of all newly diagnosed cases of type I diabetes occurs in individuals younger than 18 years of age. People with Type1diabetes must take daily insulin injections to stay alive. Frequent injection of insulin is required for the treatment of all patients with type I and many patients with type II diabetes. In healthy individuals, basal insulin is secreted continuously between meals and throughout the night at a rate of 0.5-1 Unit/h. Although the basal insulin level is low, it modulates the rate of overnight hepatic glucose and glucose output during prolonged periods between meals. This allows for sufficient glucose level for cerebral energy production at bedtime. Injectable polymeric delivery systems can be used for continuous release of insulin to meet the need of basal insulin for a desired period. The long-term goal of this work is to develop controlled release formulations which can deliver insulin continuously in a conformationally as well as chemically stable and biologically active form for longer duration after a single injection. We propose to test the hypotheses that the temperature sensitive biodegradable polymers can control the in vitro and in vivo release of insulin in biologically active, conformationally and chemically stable form and the proposed 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 their critical gel concentration, gel transition temperature, weight average molecular weight by gel permeation chromatography, and number average molecular weight by H NMR. [2]. To prepare in situ gel-forming controlled delivery systems for insulin, using temperature sensitive polymers. [3]. To study in vitro release profiles of insulin from the delivery systems and to evaluate factors that can affect the release. [4].To evaluate the chemical stability of released insulin using HPLC-MS technique. [5]. To evaluate the conformational stability of released insulin by differential scanning calorimetry (DSC). [6]. To evaluate the in vitro and in vivo biocompatibility of the delivery systems by MTT assay and histological analysis using light microscopy, respectively. [7]. To study in vivo absorption and bioactivity of insulin from the delivery systems in diabetic rats. The proposed study will contribute significantly to the development of an injectable form which delivers insulin at a controlled rate for longer duration (~ 2 months) after a single injection. Development of such a delivery system will improve patients' quality of life, and decrease the long term complications associated with diabetes. The proposed efforts will contribute significantly for the development of polymer solution based delivery systems to deliver insulin at a controlled rate for longer duration after single subcutaneous injection. Development of such a novel therapeutic system is critical for successful treatment of diabetes and improvement in the patients' quality of life.