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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

基本信息

批准号：
7339966
负责人：
NICHOLAS A PEPPAS
金额：
$ 3.75万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-12-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7339966
关键词：
Acids Adverse effects Applications Grants Behavior Binding Biological Availability Brush Border Carboxylic Acids Characteristics Class Coculture Techniques Complex Condition Dissociation Dose Drug Formulations Endopeptidases Enhancers Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Ethers Ethyl Ether Ethylene Glycols Evaluation Exhibits Gastrointestinal tract structure Gel Glucose Grant Hydrogels Hydrogen Bonding Hypoglycemia Hypoglycemic Agents Insulin Intestinal Mucosa Intestines Investigation Liquid substance Membrane Molecular Structure Mucins Mucous body substance Oral Oral Administration Oxygen Pathway interactions Penetration Peptide Hydrolases Peptides Permeability Pharmaceutical Preparations Polymers Property Proteins Protons Purpose Range Rate Reporting Research Personnel Resistance Route Series Simulate Small Intestines Stomach Structure Swelling System Transferrin Vertebral column Wistar Rats Work absorption base copolymer crosslink cytotoxicity design diabetic rat ethylene glycol improved in vivo insulin, polyethylene glycol(B1)-ionization light scattering methacrylic acid monolayer novel polymethacrylic acid programs uptake

项目摘要

Hydrogels of poly(methaerylie acid) (PMAA) grafted with poly(ethylene glycol) (PEG) are used as carriers for oral (transmucosal) protein delivery. These gels exhibit reversible, pH-dependent swelling behavior due to the formation or dissociation of interpolymer complexes between the acidic pendant groups and the ether groups of the grafted chains. These delivery characteristics are due to large changes in the network mesh over a relatively narrow range of pH values due to the formation of the interpolymer complexes. The formation of the interpolymer complexes serves to protect the drugs from binding with the polymeric carrier. Our systems are advantageous over other designs because we have been able to obtain strong, dose- dependent hypoglycemic effects. We have observed bioavailabilities of 12.8 %, based on insulin release. Our new hypothesis is that insulin conjugates (PEG-insulin and transferrin-insulin) in association with the improved protein release carriers can increase bioavailability significantly. Additionally, the bioavailability may also be increased by elevating the transition pH of our network structures by the addition of more crosslinking agent in our system. When only insulin is released from the microparticles adhering to the mucus, the majority of the entrapped insulin is released within the microenvironment of the brush border. In the systems proposed here, part of the entrapped insutin-transferrin conjugates that are released into the lumen will be further protected from degradation. One important advantage of these systems is that the conjugates cross the intestinal barrier via transcellular pathways. These systems do not change the structure of the paracellular junctions and hence avoid the various adverse effects associatedwith use of penetration enhancers or enzyme inhibitors. In the present grant we will focus on the investigation of release of PEG- insulin and transferrin-insulin conjugates from the complexation hydrogels. Specifically, we will focus on the investigation of the release profile of transferrin molecule from the complexation hydrogel under dynamic pH conditions, the structural analysis of PEG-insulin and insulin-transferrin conjugates by dynamic light scattering, complete analysis of release of the drug conjugate from the pH responsive complexation hydrogels, investigation of the conjugate delivery and transport from the formulations developed above through HT29-MTX/CaCo-2 cocultures, and in vivo studies of delivery of the conjugated insulin by the complexation hydrogels

以聚乙二醇（PEG）接枝的聚甲基酸（PMAA）水凝胶为载体