Controlled Delivery of Insulin

胰岛素的控制输送

• 批准号: 7294461
• 负责人: Jagdish Singh
• 金额: $ 7.13万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-20 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294461
• 关键词: Affect; Age-Years; Autoimmune Diseases; Biocompatible; Biological; Biological Assay; Breathing; Calorimetry; Cerebrum; Chemicals; Child; Daily; Development; Diabetes Mellitus; Differential Scanning Calorimetry; Drug Formulations; Exubera; Food; Forms Controls; Gel; Gel Chromatography; Glucose; Goals; Hepatic; In Situ; In Vitro; Individual; Injectable; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Length; Molecular Weight; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Patients; Polymers; Population; Powder dose form; Production; Quality of life; Rate; Scanning; Solutions; Subcutaneous Injections; System; Techniques; Temperature; Testing; Transition Temperature; United States; United States Food and Drug Administration; Weight; Work; absorption; basal insulin; base; biodegradable polymer; biomaterial compatibility; chemical stability; controlled release; copolymer; desire; diabetic; diabetic rat; glucose output; improved; in vivo; insulin secretion; light microscopy; novel therapeutics; response; young adult

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.

描述（由申请人提供）：摘要：在美国，2080万人患有糖尿病。约有176，500名20岁以下的人患有糖尿病。所有新诊断的I型糖尿病病例中约有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都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晚上以0.5-1单位/小时的速率持续分泌。尽管基础胰岛素水平较低，但它可调节夜间肝葡萄糖和两餐之间长时间葡萄糖输出的速率。这允许足够的葡萄糖水平用于睡前的大脑能量生产。可注射聚合物递送系统可用于胰岛素的连续释放，以满足基础胰岛素持续所需时间的需要。这项工作的长期目标是开发控释制剂，其可以在单次注射后以构象以及化学稳定和生物活性形式持续更长时间地递送胰岛素。我们建议测试的假设，温度敏感的生物可降解聚合物可以控制在体外和体内释放的胰岛素在生物活性，构象和化学稳定的形式和建议的聚合物为基础的输送系统是生物相容性。[1].合成温度敏感性三嵌段共聚物，并用凝胶渗透色谱法表征其临界凝胶浓度、凝胶转变温度、重均分子量和数均分子量。[2]的文件。利用温度敏感聚合物制备胰岛素原位凝胶控释系统。[3]的文件。目的研究胰岛素从给药系统中的体外释放特性，并评价影响释放的因素。[4]采用HPLC-MS技术评价释放胰岛素的化学稳定性。[5]的文件。采用差示扫描量热法（DSC）评价释放胰岛素的构象稳定性。[6]的文件。分别采用MTT法和光镜组织学方法评价其体外和体内生物相容性。[7]的文件。研究胰岛素缓释系统在糖尿病大鼠体内的吸收和生物活性。拟定的研究将显著有助于开发一种注射剂型，该注射剂型在单次注射后以受控速率持续更长时间（约2个月）递送胰岛素。开发这种输送系统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。所提出的努力将显著有助于开发基于聚合物溶液的递送系统，以在单次皮下注射后以受控速率递送胰岛素持续更长时间。开发这种新型治疗系统对于成功治疗糖尿病和改善患者的生活质量至关重要。