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.

项目摘要 /摘要 遵守口服药物通常很差，这使美国医疗保健行业花费了数十亿美元， 每年造成约100,000例过早死亡。合规的可能性大大增加 与每天一次的治疗方案相比，每周服用一次药物。这 可以通过增加GI中药物输送设备的停留时间来实现转化 道。以前的策略旨在增加设备的停留时间（例如浮力胃设备， 迄今为止，可扩展的胃食装置和粘附材料仅取得了部分成功。 该项目将利用可生物降解的弹性体，聚合物加工和色素的内部专业知识 - 基于水下胶粘剂，以生产基于设备的口服输送系统，该系统可以增加住宅 从20 h到> 200h，在胃肠道小肠内的时间在10倍。这种方法的关键创新是 使用基于纹理的粘膜粘附力。具体而言，可提供的可扩展设备将 机械地与小肠的绒毛互锁。机械互锁会增加粘液粘附 组织设备界面，该界面将抵抗蠕动，因此增加了特征的停留时间 用于传输GI轨道的设备。设备将由双交联的可生物降解弹性体组成 通过pH-包装成临时外形的网络，可通过pH- 灵敏的聚合物封装。到达小肠后，pH敏感的聚合物将溶解并 加载药物的设备将扩展以将设备固定在管腔内。该项目将在体外量化 通过测量摩擦力等优点数字和粘附的工作来表现设备的性能 物理参数和设备几何形状的功能。将使用X-来量化胃运输的时间表 射线成像以测量在Minipigs中装有X射线对比剂的设备的体内胃转运。这 也将测量模型肽的口服生物利用度。该项目有可能提高 基于转化设备的粘附性可以提高口服的患者依从性 药物。此外，稳定居住在胃肠道中的受控释放设备可以使 提供生物活性疗法的生物活性疗法较差或极短的半衰期，例如低分子 重量肽。综上所述，这项技术可以改善许多口服管理的管理 治疗疾病状态（例如炎症性肠病，肥胖症或2型糖尿病）的治疗剂。