Microstructured Intestinal Retentive Devices for Sustained Oral Delivery

用于持续口服给药的微结构肠保留装置

• 批准号: 9808615
• 负责人: Christopher John Bettinger
• 金额: $ 21.21万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808615
• 关键词: Adherence; Adhesions; Adhesives; Adopted; Benign; Biological; Biological Availability; Cessation of life; Characteristics; Clinical; Complex; Contrast Media; Custom; Data; Devices; Diagnostic radiologic examination; Disease; Disease Management; Dose; Drug Delivery Systems; Elastomers; Family suidae; Film; Frequencies; Friction; Gastrointestinal Transit; Gastrointestinal tract structure; Geometry; Glycerol; Healthcare Industry; Healthcare Systems; High Pressure Liquid Chromatography; In Vitro; Inflammatory Bowel Diseases; Intestines; Kinetics; Knowledge; Liquid substance; Measurement; Measures; Mechanics; Memory; Metabolic Diseases; Miniature Swine; Modeling; Modulus; Molds; Molecular; Molecular Weight; Mucins; Mucous Membrane; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Oral Administration; Outcome; Patients; Peptides; Performance; Peristalsis; Pharmaceutical Preparations; Physical Function; Pigments; Polymers; Property; Pylorus; Radial; Regimen; Roentgen Rays; Route; Shapes; Small Intestines; Stomach; Structure; System; Technology; Testing; Texture; Therapeutic; Thinness; Time; TimeLine; Tissues; UV Radiation Exposure; Vancomycin; Villus; Work; base; compliance behavior; controlled release; cost; cost effective; crosslink; design; elastomeric; gastrointestinal; improved; in vivo; innovation; instrument; microdevice; monomer; novel; particle; premature; pressure; residence; response; small molecule; success; translational impact

PROJECT SUMMARY / ABSTRACT Compliance with oral medications is often poor, which costs the US healthcare industry billions of dollars and contributes to ~100,000 premature deaths each year. The likelihood for compliance is greatly increased for medications that are administered as once-weekly medications compared to once-daily regimens. This transformation can be accomplished by increasing the residence time of drug delivery devices within the GI tract. Previous strategies aimed at increasing the residence time of devices (e.g. buoyant gastric devices, expandable gastroretention devices, and mucoadhesive materials) have achieved only partial success, to date. This project will leverage in-house expertise in biodegradable elastomers, polymer processing, and pigment- based underwater adhesives to produce a device-based oral delivery system that can increase the residence time within the small intestine of the GI tract by 10X from 20 h to > 200h. The key innovation in this approach is the use of textured device-based mucoadhesives. Specifically, a conformal expandable device will mechanically interlock with the villi of the small intestine. Mechanical interlocking increases mucoadhesion at the tissue-device interface, which will resist peristalsis and therefore increase the characteristic residence time for devices transiting the GI track. Devices will be composed of dual-crosslinked biodegradable elastomeric networks that are packaged into a temporary form factor for facile transit through the stomach using a pH- sensitive polymer encapsulant. Upon reaching the small intestine, the pH-sensitive polymer will dissolve and the drug-loaded device will expand to anchor the device within the lumen. This project will quantify in vitro device performance by measuring figures of merit such as friction forces and the work of adhesion as a function of physical parameters and device geometry. The timeline for gastric transit will be quantified using X- ray imaging to measure the in vivo gastric transit of devices loaded with X-ray contrast agent in minipigs. The oral bioavailability of a model peptide will also be measured. This project has the potential to advance a transformative device-based mucoadhesive that can increase patient compliance for orally administered medications. Furthermore, a controlled release device that stably resides in the GI tract could enable the delivery of bioactive therapeutics with poor bioavailability or extremely short half-lives such as low molecular weight peptides. Taken together, this technology could improve the administration of many orally administered therapeutics to manage disease states such as inflammatory bowel disease, obesity, or Type 2 diabetes.

项目摘要/摘要 口服药物的依从性往往很差，这给美国医疗行业造成了数十亿美元的损失 每年导致约10万人过早死亡。遵守的可能性大大增加，因为 每周给药一次的药物，而不是每天一次的药物。这 可以通过增加药物输送设备在GI中的停留时间来实现转换 一条小路。先前的策略旨在增加装置的停留时间(例如浮力胃装置， 可膨胀的胃保留装置和粘附性材料)到目前为止只取得了部分成功。 该项目将利用内部在可生物降解弹性体、聚合物加工和颜料方面的专业知识。 以水下粘合剂为基础，生产一种基于设备的口腔递送系统，可以增加居住地 在胃肠道内的时间从20小时到200小时增加了10倍。这种方法的关键创新是 使用质感设备为基础的粘合剂。具体地说，共形可扩展装置将 机械性地与小肠绒毛相连。机械互锁可增加粘附性 组织-设备界面，它将抵抗蠕动，从而增加特征停留时间 适用于通过GI轨道的设备。设备将由双交联型可生物降解弹性体组成 网络被包装成临时的形状因数，以便使用pH通过胃进行便捷的传输- 敏感的聚合物密封剂。当到达小肠时，对pH敏感的聚合物将溶解并 装载药物的装置将膨胀以将装置固定在管腔内。这个项目将在体外进行量化 通过测量摩擦力和粘附功等品质因数来衡量装置的性能 物理参数和器件几何形状的函数。胃转运的时间线将使用X- 用射线成像技术测量装有X射线造影剂的装置在小型猪体内的胃转运。这个 还将测量模型多肽的口服生物利用度。这个项目有可能推动 基于变革性设备的粘附剂，可以提高患者口服的依从性 药物。此外，稳定地驻留在胃肠道中的受控释放装置可以使 生物利用度差或半衰期极短的生物活性药物的输送，如低分子 重量级多肽。总而言之，这项技术可以改善许多口服给药的管理 治疗，以管理疾病状态，如炎症性肠道疾病，肥胖，或2型糖尿病。