pH Sensitive Complex Hydrogels for Protein Drug Release

用于蛋白质药物释放的 pH 敏感复合水凝胶

• 批准号: 8433421
• 负责人: Anthony M Lowman
• 金额: $ 37.12万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433421
• 关键词: Acids; Adhesives; Advanced Development; Agreement; Applications Grants; Attention; Bacterial Adhesins; Belief; Biological Availability; Blood Circulation; Calcitonin; Carbohydrates; Carrier Proteins; Cell model; Complex; Development; Drug Delivery Systems; Drug Design; Drug Formulations; Drug Transport; Engineering; Environment; Epithelial; Epithelial Cells; Ethylene Glycols; Exhibits; Gastrointestinal Transit; Gastrointestinal tract structure; Gel; Glucose; Goals; Grant; Hydrogels; In Vitro; Insulin; Intestinal Mucosa; Intestines; Isoelectric Point; Lead; Legal patent; Liquid substance; Membrane; Methodology; Molecular; Nature; Oral; Oral Administration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Polymers; Property; Proteins; Pyrrolidinones; Research; Research Design; Resistance; Rodent Model; Route; Series; Simulate; Small Intestines; Solubility; Somatotropin; Stomach; Structure; System; Testing; Time; Transferrin; Universities; Vertebral column; Work; absorption; commercialization; compliance behavior; controlled release; cytotoxicity; diabetic rat; enzyme activity; ethylene glycol; gastrointestinal; improved; in vivo; methacrylic acid; monolayer; novel; novel strategies; novel therapeutics; public health relevance; residence; success; therapeutic protein

DESCRIPTION (provided by applicant): This is a resubmission of a competing renewal proposal of grant RO1 EB000246-17 for the continuation of our studies on the fundamental understanding of transmucosal delivery of drugs, peptides and proteins using a series of novel biopolymeric complexation carriers with unique properties and in advanced controlled release systems. It has generally been believed that peptides and proteins such as insulin cannot be administered via the oral route because of their degradation by the proteolytic enzymes in the gastrointestinal tract and their extremely slow rate of transport across the mucosal membrane. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy. Our group has developed a new class of polymeric complexation hydrogels comprised of poly (ethylene glycol) (PEG) chains grafted on poly (methacrylic acid) (PMAA) backbone chain. The new systems, henceforth designated as P (MAA-g-EG), have shown extreme promise as oral delivery vehicles for insulin, calcitonin, and growth hormone. Prior studies have established that these systems are promising candidates for oral delivery of insulin. Yet, our more recent work and attention is now focused on continued strategies for enhancing the bioavailability of oral delivered proteins, in addition to insulin. The methodologies we intend to pursue in this competing renewal proposal include: (i) developing further strategies for protection of the protein in the GI lumen; (ii) enhancing transport of the proteins across the GI lumen; and (iii) increasing the residence times in the upper small intestine through enhanced bioadhesion. While some strategies have been previously investigated with moderate success using insulin, in this work, we will pursue novel strategies that may provide significant advances over our prior studies with insulin. Additionally, we intend to further develop these complexation hydrogels for oral delivery of other therapeutic proteins such as calcitonin and growth hormone.

描述（由申请人提供）：这是对授予RO 1 EB 000246 -17的竞争性更新提案的重新提交，用于继续我们对使用一系列具有独特性质的新型生物聚合物络合载体和先进控释系统进行药物、肽和蛋白质经粘膜递送的基本理解的研究。一般认为，肽和蛋白质如胰岛素不能通过口服途径给药，因为它们在胃肠道中被蛋白水解酶降解，并且它们穿过粘膜的转运速率极慢。一个成功的蛋白质药物口服给药系统可能会导致新的治疗方法的发展，增加患者的依从性和疗效。 本课题组开发了一类新型的聚合物络合水凝胶，它是由聚乙二醇（PEG）链接枝到聚甲基丙烯酸（PMAA）主链上而成。新的系统，此后指定为P（MAA-g-EG），已显示出作为胰岛素，降钙素和生长激素的口服递送载体的极端前景。先前的研究已经确定，这些系统是口服递送胰岛素的有希望的候选者。然而，我们最近的工作和注意力现在集中在持续的策略，以提高口服递送的蛋白质，除了胰岛素的生物利用度。我们打算在这一竞争性更新提案中追求的方法包括：（i）开发进一步的策略以保护GI腔中的蛋白质;（ii）增强蛋白质穿过GI腔的转运;以及（iii）通过增强生物粘附来增加在小肠上部的停留时间。虽然一些策略以前已经使用胰岛素进行了适度的成功研究，但在这项工作中，我们将寻求新的策略，这些策略可能会比我们以前的胰岛素研究取得重大进展。此外，我们打算进一步开发这些复合水凝胶，用于口服递送其他治疗性蛋白质，如降钙素和生长激素。