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）：该公司的业务和研究工作重点是开发和商业化一种新型药物输送方法，以防止组织异常向内生长（内膜增生），这种方法可以阻止血液通过广泛用于血液透析患者的人造血管（血管移植物）流动，并恢复通过下肢患病动脉的血流。尽管较大动脉中的合成移植物表现良好，但仍然迫切需要改善较小直径移植物的性能，这些移植物主要由于阻塞性组织向内生长而失效。这些移植物通常在手术放置后几个月到几年内失败。每年大约花费 3B 美元用于移植维护。该公司开发了一种直接通过临床血管移植物的多孔壁（例如膨体聚四氟乙烯（ePTFE））输注药物的方法，以便药物仅输注到沿移植物壁移动最慢的血液层中。因此，药物被输送到远端，定位于发生异常组织增殖的麻烦静脉吻合部位。这种方法基于众所周知的工程原理，事实证明对于局部药物输送非常有效。这种方法的概念验证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得到证实，表明通过 ePTFE 移植物局部注入极低剂量的西罗莫司，可以有效、安全地消除组织向内生长，否则会导致移植物阻塞。该 I 期 SBIR 申请的目标是开发 FDA 可接受的注射西罗莫司制剂，该制剂具有以下特点：1) 在体温下可溶且稳定至少 30 天 2) 与市售低流量、可再填充内部泵、管道和移植物套囊具有生物相容性，3) 具有适当的药代动力学特征，可在有效的局部药物浓度下提供西罗莫司，以抑制 ePTFE 移植物失败，而不会引发 全身免疫抑制。 公共健康相关性：本拨款申请的目标是开发 FDA 可接受的注射西罗莫司制剂，该制剂具有以下特点：1) 在体温下可溶且稳定至少 30 天 2) 与市售低流量、可再填充内部泵、管道和移植物套囊具有生物相容性，3) 具有适当的药代动力学特征，可在有效的局部药物浓度下提供西罗莫司，以抑制 ePTFE 移植物失败，而不会引起 全身免疫抑制。