Localized Delivery of Sirolimus to Vascular Grafts

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，以防止组织的异常向内生长（内膜增生），这种组织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）的流动，并恢复通过下肢病变动脉的血流。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主要由于阻塞性组织向内生长而失效的较小直径移植物的性能。这些移植物通常在手术放置后几个月至几年内失效。每年大约有30亿美元用于移植物的维护。该公司开发了一种通过临床血管移植物的多孔壁直接输注药物的方法，例如膨胀型聚四氟乙烯（ePTFE），因此药物仅沿移植物壁沿着最慢移动的血液层输注。因此，药物向远端运输，定位于发生异常组织增殖的麻烦的静脉吻合部位。这种方法-基于众所周知的工程原理-被证明是非常有效的定位药物输送。最近在俄勒冈州国家灵长类动物研究中心完成的非人灵长类动物研究中证实了这种方法的概念验证，表明通过ePTFE移植物局部输注非常低剂量的西罗莫司可以有效且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可接受的西罗莫司注射制剂，该制剂：1）在体温下可溶且稳定至少30天2）与市售低流量、可再填充的内部泵、管道和移植物套囊生物相容，和3）证明了适当的药代动力学特征，可提供有效局部药物浓度的西罗莫司，以抑制ePTFE移植物失效而不会引起全身性免疫抑制。 公共卫生相关性：该拨款申请的目标是开发FDA可接受的西罗莫司注射制剂，该制剂：1）在体温下可溶并稳定至少30天2）与市售低流量、可再填充的内部泵、管道和移植物套囊生物相容，和3）这证明了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移植物衰竭，引发全身性免疫抑制。

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.