Localized Delivery of Sirolimus to Vascular Grafts

描述（由申请人提供）：公司的业务和研究重点是开发和商业化一种新的药物递送方法，以防止组织的异常生长（内膜增生），这种组织可以阻断血液通过人工血管（血管移植物）的流动，广泛用于血液透析患者，并恢复下肢病变动脉的血液流动。虽然大动脉内的人工血管移植表现良好，但仍有迫切需要改善小直径血管移植的性能，这些小直径血管移植的失败主要是由于组织向内生长受阻。这些移植物通常在手术植入后的几个月到几年内失效。每年大约有30亿美元花费在嫁接维护上。本公司开发了一种通过临床血管移植物的多孔壁（如膨胀聚四氟乙烯（ePTFE））直接输注药物的方法，使药物仅输注到沿移植物壁移动最慢的血液层中。因此，药物被远端运输，定位在麻烦的静脉吻合口，异常组织增生发生。这种基于众所周知的工程原理的方法被证明对药物的局部递送非常有效。俄勒冈国家灵长类动物研究中心最近完成的非人类灵长类动物研究证实了这种方法的概念证明，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申请的目标是开发一种FDA可接受的可注射西罗莫司制剂，该制剂具有以下特点：1)在体温下可溶且稳定至少30天；2)与市上可获得的低流量、可再填充的内泵、管和移植物袖带具有生物相容性；3)证明适当的药代动力学特征，以有效的局部药物浓度提供西罗莫司，以抑制ePTFE移植物失败，而不会引起全身免疫抑制。

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.