Gastrointestinal safety and therapeutics of oil-based Phosphatidylcholine-NSAIDS

描述（由申请人提供）：在STTR第二期资助的竞争延续中，我们建议在前两个资助周期取得的重大进展的基础上，开发一种新的磷脂酰胆碱（PC）相关非甾体抗炎药（NSAIDs）家族。在此期间，我们继续开发我们的前导化合物，布洛芬-PC和阿斯匹林-PC，其中我们将非甾体抗炎药与大豆PC化学关联，并证明这些配方可以降低胃肠道毒性，同时保持或增强药物在啮齿动物模型系统中的治疗活性。基于这些证据，以及我们的合同研究组织（synergy, Inc.）和制造商（Cardinal Health）提供的证据，FDA已经为ibuprofen-PC颁发了IND，并批准了加速的505(b)(2)生物等效性监管路径，这得到了健康受试者I/II和III期人体药代动力学数据的支持。同时进行了一项II期试验，在该试验中，骨关节炎（OA）患者被放置在布洛芬或布洛芬- pc上，为期6周的研究期，以提供测试药物的GI安全性和治疗活性的信息。如修订后的申请中所述，这些由小型企业和NIH的R03资助的临床研究表明，ibuprofen- pc与ibuprofen具有相似的生物利用度和治疗活性，但对最易受nsaid诱导的胃肠道副作用的OA患者（年龄在55岁至55岁之间）的胃十二指肠黏膜的伤害明显更小。在这份修订后的拨款申请中，我们提议继续这一有希望的研究方向，并在OA患者中进行为期12周的内镜试验，这将为布洛芬- pc的胃肠道安全性和抗炎/镇痛活性提供确凿的证据。我们还提出了一系列的实验室实验，在这些实验中，我们将与我们在Cardinal Health的项目团队密切合作，优化目前的布洛芬- pc配方，使其符合FDA的生产指南，并进一步开发一种制备pc - nsaid的新方法，这种方法似乎可以获得纯化的布洛芬- pc复合物，作为油。该纯化的ibuprofen-PC在啮齿类动物模型系统中具有优越的GI安全性和治疗活性，我们还建议在修改后的IND下评估其在健康人类受试者中的生物利用度，以加速获得该产品的监管批准。我们还建议申请阿司匹林- pc的IND，并建议在健康受试者中进行药代动力学研究，以确定其是否与阿司匹林具有生物等效性，这将使我们能够寻求505(b)(2)监管途径。最后，我们提出了一系列临床前和试点临床研究，以证实阿司匹林- pc与西乐葆共同给药时毒性远低于阿司匹林的初步证据。上述研究的成功完成将允许我们对ibuprofen-PC和aspirin-PC的一种或两种制剂提交NDA，最初是为了生物等效性，最终是为了增强胃肠道安全性和治疗活性。完成这些里程碑将使我们处于一个非常有竞争力的位置，以吸引企业合作伙伴来促进布洛芬-PC和阿斯匹林-PC的商业化，也许整个PC-NSAID的授权，使这类新型药物向公众开放，这是非常需要一种安全有效的NSAID。非甾体抗炎药（NSAIDs）由于其有效的抗炎和镇痛作用，被美国人大量使用，尤其是患有骨关节炎（OA）的老年人。然而，非甾体抗炎药的使用受到其严重副作用的限制，即在易感个体中诱发胃肠道溃疡和出血，每年有103,000例住院治疗和16,500例死亡。在这项拨款提案中开发的技术涉及通过非甾体抗炎药与表面活性脂质磷脂酰胆碱（PC）的化学关联来预防非甾体抗炎药诱导的胃肠道溃疡和出血。与pc相关的非甾体抗炎药的开发将为数百万OA患者提供更安全的药物，用于缓解疼痛和炎症，以及其他潜在用途，如预防癌症和阿尔茨海默病。

DESCRIPTION (provided by applicant): In this Competing Continuation of our STTR Phase II grant, we propose to build upon the considerable progress made during the previous two funding cycles in our effort to develop a new family of phosphatidylcholine (PC)-associated nonsteroidal anti-inflammatory drugs (NSAIDs). During this period we have continued to develop our lead compounds, ibuprofen-PC and aspirin-PC, in which we chemically associate the NSAIDs with soy PC, and have demonstrated that these formulations have reduced GI toxicity while maintaining or enhancing the drugs therapeutic activity in rodent model systems. Based upon this evidence, and that provided by our Contract Research Organization (Synergos, Inc.) and manufacturer (Cardinal Health), the FDA has issued an IND for the ibuprofen-PC and has approved an accelerated 505(b)(2) regulatory path for bioequivalence, which was supported by human pharmacokinetic data in Phase I/II and III trials on healthy subjects, together with a Phase II trial in which osteoarthritic (OA) patients were placed on either ibuprofen or ibuprofen-PC for a 6 week study period, to provide information on the GI safety and therapeutic activity of the test drugs. As described in the revised application, these clinical studies, that were funded by the small business and a R03 grant from NIH, demonstrated that ibuprofen-PC had similar bioavailability and therapeutic activity to ibuprofen, but was significantly less injurious to the gastroduodenal mucosa of OA patients most susceptible to NSAID-induced GI side effects, those who were > 55 years of age. In this revised grant application, we propose to continue this promising line of investigation, and perform a 12 week endoscopic trial in OA patients, which should provide confirmatory evidence on the GI safety and anti- inflammatory/analgesic activity of ibuprofen-PC. We also propose a series of laboratory experiments in which we will be working closely with our project team at Cardinal Health to optimize the current ibuprofen-PC formulation, so that it can meet FDA's manufacturing guidelines, and to further develop a new method of preparing PC-NSAIDs, which appears to result in obtaining a purified ibuprofen-PC complex, as an oil. This purified ibuprofen-PC possesses superior GI safety and therapeutic activity in rodent model systems and we also propose in this grant to evaluate its bioavailability in healthy human subjects under a modified IND, to obtain accelerated regulatory approval for this product. We also propose to file an IND for aspirin-PC and propose pharmacokinetic studies in healthy subjects to determine if it is bioequivalent to aspirin, which would allow us to pursue a 505(b)(2) regulatory pathway. Lastly, we propose a series of preclinical and pilot clinical studies to confirm preliminary evidence that aspirin-PC is far less toxic than aspirin when co-administered to animals with Celebrex. The successful completion of the above studies will allow us to file an NDA on one or both formulations of ibuprofen-PC and aspirin-PC, initially for bioequivalence, and ultimately for enhanced GI safety and therapeutic activity. Accomplishing these milestones should place us in a very competitive position to attract a corporate partner to facilitate the commercialization of both ibuprofen- PC and aspirin-PC, and perhaps the entire PC-NSAID franchise, making this novel class of drugs available to the public, that is in great need for a safe and effective NSAID. Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly consumed by Americans, especially older members of our population suffering from osteoarthritis (OA), due to their potent anti- inflammatory and analgesic actions. However, the use of NSAIDs is limited by their serious side effect of inducing gastrointestinal (GI) ulceration and bleeding in susceptible individuals, being responsible for 103,000 hospitalizations and 16,500 deaths a year. The technology to be developed in this grant proposal relates to prevention of NSAID-induced GI ulceration and bleeding by chemical association of NSAIDs with the surface-active lipid, phosphatidylcholine (PC). Development of PC-associated NSAIDs will provide drugs that can be more safely used by millions with OA for relief of pain and inflammation, and for other potential uses like prevention of cancer and Alzheimer's disease.