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: 10021658
• 负责人: Christopher John Bettinger
• 金额: $ 17.43万
• 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/10021658
• 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.

项目概要/摘要 口服药物的依从性往往很差，这给美国医疗保健行业造成了数十亿美元的损失 每年导致约 100,000 人过早死亡。合规的可能性大大增加 与每日一次的治疗方案相比，每周一次的药物治疗。这 可以通过增加药物输送装置在胃肠道内的停留时间来完成转化 道。以前的策略旨在增加装置的停留时间（例如浮胃装置、 迄今为止，可扩张的胃滞留装置和粘膜粘附材料仅取得了部分成功。 该项目将利用可生物降解弹性体、聚合物加工和颜料方面的内部专业知识 基于水下粘合剂来生产基于设备的口腔输送系统，可以增加停留时间 胃肠道小肠内的时间从 20 小时延长至 > 200 小时 10 倍。该方法的关键创新在于 使用基于纹理装置的粘膜粘合剂。具体来说，保形可扩张装置将 与小肠绒毛机械连锁。机械互锁增加了粘膜粘附 组织-装置界面，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。装置将由双交联的可生物降解弹性体组成 网络被包装成临时形状因子，以便使用 pH 值轻松通过胃 敏感聚合物封装剂。到达小肠后，pH 敏感聚合物会溶解并 载药装置将膨胀以将装置锚定在管腔内。该项目将在体外量化 通过测量摩擦力和粘附功等品质因数来衡量设备性能 物理参数和设备几何形状的函数。胃转运的时间线将使用 X- 进行量化 射线成像测量小型猪体内装载 X 射线造影剂的装置的体内胃传输。这 还将测量模型肽的口服生物利用度。该项目有潜力推动 基于变革性装置的粘膜粘附剂，可以提高患者口服给药的依从性 药物。此外，稳定地驻留在胃肠道中的控释装置可以使 提供生物利用度差或半衰期极短的生物活性治疗药物，例如低分子药物 重量肽。总而言之，这项技术可以改善许多口服药物的管理 控制炎症性肠病、肥胖或 2 型糖尿病等疾病状态的疗法。