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.

项目总结/摘要 口服药物的依从性通常很差，这使美国医疗保健行业花费了数十亿美元， 每年导致约10万人过早死亡。遵守的可能性大大增加， 与每日一次方案相比，每周一次给药的药物。这 可以通过增加药物递送装置在GI内的停留时间来实现转化 道。先前的策略旨在增加装置（例如浮力胃装置， 可膨胀胃滞留装置和粘膜粘附材料）迄今为止仅取得部分成功。 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，以生产基于装置的口服给药系统， 胃肠道小肠内的时间增加10倍，从20小时到> 200小时。这种方法的关键创新在于 使用纹理化的基于装置的粘膜粘合剂。具体地，适形可扩张装置将 与小肠的绒毛机械地互锁。机械联锁增加粘膜粘附， 组织-装置界面，其将抵抗腐蚀，因此增加特征停留时间 用于通过GI轨道的设备。器械将由双重交联的可生物降解弹性体 网络被包装成一个临时的形状因子，用于使用pH- 敏感的聚合物密封剂。在到达小肠后，pH敏感性聚合物将溶解， 装载药物的装置将膨胀以将该装置锚在管腔内。该项目将在体外定量 通过测量摩擦力和粘附功等品质因数， 物理参数和器件几何形状的函数。胃转运的时间轴将使用X- 射线成像，以测量小型猪体内装载有X射线造影剂的装置的体内胃转运。的 还将测量模型肽的口服生物利用度。该项目有可能推动一个 可增加患者对口服给药的顺应性的基于变革性装置的粘膜粘附剂 药物治疗此外，稳定地驻留在胃肠道中的控释装置可以使得能够在胃肠道中释放药物。 生物利用度差或半衰期极短的生物活性治疗剂的递送 重量肽。总的来说，这项技术可以改善许多口服给药的管理。 治疗剂，以管理疾病状态，如炎症性肠病、肥胖症或2型糖尿病。