Controlled Delivery of Insulin

描述(申请人提供)：摘要：在美国，有2080万人患有糖尿病。约有176,500名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，约75%发生在18岁以下的人群中。1型糖尿病患者必须每天注射胰岛素才能活下去。治疗所有I型糖尿病患者和许多II型糖尿病患者都需要频繁注射胰岛素。在健康人中，基础胰岛素在两餐之间和夜间以0.5-1单位/小时的速度持续分泌。尽管基础胰岛素水平较低，但它调节过夜肝脏葡萄糖的比率和两餐之间较长时间的葡萄糖输出。这使得睡前有足够的葡萄糖水平来产生大脑能量。可注射聚合物给药系统可用于胰岛素的持续释放，以满足一段时间内基础胰岛素的需求。这项工作的长期目标是开发能够在单次注射后以构象以及化学稳定和生物活性的形式持续释放胰岛素的控释制剂。我们提出的假设是，温度敏感的生物降解聚合物可以控制胰岛素以生物活性、构象和化学稳定的形式在体外和体内释放，并且所提出的基于聚合物的递送系统是生物相容的。为了验证我们的假设，我们计划进行以下具体目标的研究：[1]合成温度敏感型三嵌段共聚物，并用凝胶渗透色谱表征它们的临界凝胶浓度、凝胶转变温度、重均相对分子质量和数均相对分子质量。[2]。利用温敏性聚合物制备胰岛素原位凝胶控释系统。[3]。研究胰岛素缓释系统的体外释药特性，并评价影响其释药的因素。[4].用高效液相色谱-质谱法评价胰岛素缓释片的化学稳定性。[5]。用差示扫描量热法(DSC)评价释放胰岛素的构象稳定性。[6]。通过四甲基偶氮唑盐比色法和光镜组织学分析评价缓释系统的体内外生物相容性。[7]。目的：研究胰岛素在糖尿病大鼠体内的吸收和生物活性。这项拟议的研究将对开发一种在单次注射后以受控速度提供更长时间(~2个月)胰岛素的可注射形式做出重大贡献。这种递送系统的开发将提高患者的生活质量，并减少与糖尿病相关的长期并发症。建议的努力将对基于聚合物溶液的给药系统的开发做出重大贡献，以便在单次皮下注射后以受控速度更长时间地给药胰岛素。开发这样一种新的治疗系统对于糖尿病的成功治疗和患者生活质量的改善至关重要。

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.