Localized Delivery of Sirolimus to Vascular Grafts

西罗莫司局部递送至血管移植物

• 批准号: 8251068
• 负责人: Ronald J. Shebuski
• 金额: $ 22.48万
• 依托单位: CYLERUS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251068
• 关键词: Applications Grants; Arteries; Award; Biocompatible; Biological Assay; Blood; Blood Substitutes; Blood Vessels; Blood flow; Body Temperature; Businesses; Caliber; Cities; Clinical; Data; Development; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Stability; Engineering; Excipients; Freezing; Goals; Hemodialysis; Hyperplasia; Ice; Immunosuppression; Immunosuppressive Agents; Implant; Infusion procedures; Injectable; Iowa; Lead; Longevity; Lower Extremity; Maintenance; Methods; Obstruction; Operative Surgical Procedures; Oral; Oregon; Patients; Performance; Peripheral; Pharmaceutical Preparations; Pharmacy (field); Pharmacy facility; Phase; Plasma; Polytetrafluoroethylene; Prevention; Primates; Pump; Research; Sampling; Shipping; Ships; Sirolimus; Site; Small Business Innovation Research Grant; Solvents; System; Time; Tissues; Transplant Recipients; Universities; Vascular Graft; Veins; Venous; Whole Blood; base; college; graft failure; implantation; improved; new technology; nonhuman primate; novel; prevent; subcutaneous

DESCRIPTION (provided by applicant): The Company's business and research efforts are focused on developing and commercializing a novel drug delivery approach to prevent the abnormal ingrowth of tissue (intimal hyperplasia) that can block the flow of blood through artificial blood vessels (vascular grafts) that are widely used in hemodialysis patients, and to restore blood flow through diseased arteries in the lower limbs. Although synthetic grafts in larger arteries perform well, there remains a compelling need to improve the performance of smaller diameter grafts that fail primarily as a result of obstructive tissue ingrowth. These grafts typically fail within a few months-to-years after surgical placement. Approximately $3B annually is spent on graft maintenance. The Company has developed a method for infusing drugs directly through the porous wall of clinical vascular grafts, such as expanded polytetrafluoroethylene (ePTFE), so that drug is infused only into the slowest moving blood layers along the graft wall. Consequently, drug is transported distally, localizing at troublesome venous anastomotic sites where abnormal tissue proliferation occurs. This method - based on well-known engineering principles - turns out to be extremely efficient for localizing drug delivery. Proof-of- concept with this approach has recently been confirmed in non-human primate studies, completed at the Oregon National Primate Research Center, showing that very low doses of sirolimus, locally infused through ePTFE grafts, can effectively and safely abolish the tissue ingrowth that would otherwise lead to graft obstruction. The goals of this Phase I SBIR application are to develop a FDA acceptable injectable sirolimus formulation that is: 1) soluble and stable for at least 30 days at body temperature 2) biocompatible with a commercially available low flow, refillable internal pump, tubing and graft cuff, and 3) that demonstrates the appropriate pharmacokinetic profile to provide sirolimus at effective local drug concentrations to suppress ePTFE graft failure without eliciting systemic immunosuppression. PUBLIC HEALTH RELEVANCE: The goals of this grant application are to develop a FDA acceptable injectable sirolimus formulation that is: 1) soluble and stable for at least 30 days at body temperature 2) biocompatible with a commercially available low flow, refillable internal pump, tubing and graft cuff, and 3) that demonstrates the appropriate pharmacokinetic profile to provide sirolimus at effective local drug concentrations to suppress ePTFE graft failure without eliciting systemic immunosuppression.

描述（由申请人提供）：公司的业务和研究工作着重于开发和商业化一种新型的药物输送方法，以防止组织（内膜增生）的异常向内生长（可通过人造血管（血管移植）（血管移植物）来阻止血液流动（血管移植物），这些血管被广泛用于血液溶解患者，以恢复血液中的血液流动较低。尽管较大动脉中的合成移植物的表现良好，但仍有迫切需要提高直径较小的移植物的性能，而直径移植物主要是由于阻塞性组织内部而导致的。这些移植物通常在手术放置后几个月内失败。每年大约花费$ 3B用于移植维护。该公司开发了一种直接通过临床血管移植物的多孔壁注入药物的方法，例如扩展的聚氟乙烯（EPTFE），因此仅将药物注入沿移植壁的最慢的血液层中。因此，在远端运输药物，位于发生异常组织增殖的麻烦静脉吻合部位。根据众所周知的工程原则，这种方法对于本地化药物的定位非常有效。最近在俄勒冈国家灵长类动物研究中心完成的非人类灵长类动物研究中证实了使用这种方法的证明证明，这表明，通过EPTFE移植物局部注入的非常低剂量的Sirolimus可以有效而安全地废除组织内核，否则会导致移植阻塞。该阶段I SBIR应用的目标是开发一种可接受的可接受的注射蛋白蛋白素配方：1）在体温下至少30天，在体温下至少30天2）生物兼容，可与可供不顾的内部泵，可加入的内部泵，管道和嫁接的型兼容，并没有提供适当的药物浓度，以抑制过时的药物浓度，以抑制siracokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokokok,,,,系统性免疫抑制。 公共卫生相关性：本赠款应用的目标是开发一种可接受的可接受的西罗里木素公式，即：1）在体温下至少30天，在体温下至少稳定30天2）生物兼容，可与可口可用的内部泵，管道，管道和移植式cuff提供适当的药物浓度，以抑制药物的素食，以抑制si象塞象与塞象药物的特征，以提供有效的药物，以有效地抑制药物的特征。系统性免疫抑制。