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，有 2080 万人患有糖尿病。大约 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 岁以下的个体中。 1 型糖尿病患者必须每天注射胰岛素才能维持生命。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，但它可以调节夜间肝葡萄糖的速率和长时间两餐之间的葡萄糖输出。这使得睡前大脑有足够的葡萄糖水平产生能量。可注射的聚合物递送系统可用于连续释放胰岛素，以满足所需时间段内基础胰岛素的需要。这项工作的长期目标是开发控释制剂，能够在单次注射后以构象、化学稳定和生物活性的形式持续较长时间地持续输送胰岛素。我们建议测试以下假设：温度敏感的可生物降解聚合物可以控制生物活性、构象和化学稳定形式的胰岛素的体外和体内释放，并且所提出的基于聚合物的递送系统具有生物相容性。为了检验我们的假设，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，并通过凝胶渗透色谱法表征其数均分子量。核磁共振氢谱。 [2]。使用温度敏感聚合物制备原位凝胶形成的胰岛素控释系统。 [3]。研究胰岛素从递送系统的体外释放曲线并评估可能影响释放的因素。 [4].采用HPLC-MS技术评价释放胰岛素的化学稳定性。 [5]。通过差示扫描量热法（DSC）评估释放的胰岛素的构象稳定性。 [6]。分别通过 MTT 测定和使用光学显微镜的组织学分析评估递送系统的体外和体内生物相容性。 [7]。研究糖尿病大鼠体内胰岛素输送系统的吸收和生物活性。拟议的研究将对注射剂型的开发做出重大贡献，该注射剂型在单次注射后以受控速率提供较长持续时间（约 2 个月）的胰岛素。这种输送系统的开发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。所提出的努力将为基于聚合物溶液的输送系统的开发做出重大贡献，以在单次皮下注射后以受控速率长时间输送胰岛素。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。