Gastrointestinal safety and therapeutics of oil-based Phosphatidylcholine-NSAIDS

描述(由申请人提供)：在这一竞争延续我们的STTR第二阶段资助中，我们建议在前两个资助周期取得重大进展的基础上，努力开发与磷脂酰胆碱(PC)相关的非类固醇抗炎药物(NSAID)的新家族。在此期间，我们继续开发我们的先导化合物布洛芬-PC和阿司匹林-PC，在这些化合物中，我们将非类固醇抗炎药与大豆PC进行化学关联，并已证明这些制剂降低了GI毒性，同时在啮齿动物模型系统中保持或增强了药物的治疗活性。基于此证据，以及我们的合同研究组织(Synergos，Inc.)提供的证据美国食品药品监督管理局已经为布洛芬-PC和制造商(红衣主教健康)颁发了IND，并批准了加速的505(B)(2)生物等效性监管路径，该路径得到了健康受试者I/II和III期试验中人体药代动力学数据的支持，以及一项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上进行为期6周的研究，以提供有关测试药物的胃肠道安全性和治疗活性的信息。正如修订后的申请中所描述的，这些临床研究由小型企业资助，并得到NIH的R03拨款，表明布洛芬-PC具有与布洛芬相似的生物利用度和治疗活性，但对最容易受到非类固醇激素引起的胃肠道副作用的OA患者的胃十二指肠粘膜的损害显著较小，这些患者年龄在55岁。在这项修订的拨款申请中，我们建议继续这一有希望的研究路线，并在OA患者中进行12周的内窥镜试验，这将为布洛芬-PC的胃肠道安全性和抗炎/止痛活性提供确凿证据。我们还提出了一系列实验室实验，在这些实验中，我们将与红衣主教健康公司的项目团队密切合作，优化目前的布洛芬-PC配方，使其能够满足FDA的制造指南，并进一步开发一种新的制备PC-NSAIDs的方法，其结果似乎是获得纯化的布洛芬-PC复合体，作为一种油。这种纯化的布洛芬-PC在啮齿动物模型系统中具有优异的胃肠道安全性和治疗活性，我们还在这项拨款中建议在改良的IND下评估其在健康受试者中的生物利用度，以加速该产品的监管批准。我们还建议提交阿司匹林-PC的IND，并建议在健康受试者中进行药代动力学研究，以确定它是否与阿司匹林生物等效，这将使我们能够追求505(B)(2)调节途径。最后，我们提出了一系列临床前和试点临床研究，以证实初步证据表明，当阿司匹林-PC与Celebrex联合给药时，毒性远低于阿司匹林。上述研究的成功完成将使我们能够就布洛芬-PC和阿司匹林-PC中的一种或两种制剂提交保密协议，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非常有竞争力的地位，以吸引企业合作伙伴促进布洛芬-PC和阿司匹林-PC的商业化，也许是整个PC-NSAID专营权的商业化，使这一新型药物可供公众使用，这是安全和有效的NSAID的迫切需要。非类固醇抗炎药(NSAIDs)因其强大的抗炎和止痛作用，被美国人，特别是患有骨关节炎(OA)的老年患者大量消耗。然而，非甾体抗炎药的使用受到严重副作用的限制，这些副作用会导致易感人群胃肠道(GI)溃疡和出血，每年导致103,000人住院和16,500人死亡。这项赠款提案中将要开发的技术涉及通过非类固醇抗炎药与表面活性脂质磷脂酰胆碱(PC)的化学结合来预防非类固醇抗炎药引起的胃肠道溃疡和出血。PC相关非类固醇抗炎药的开发将提供更安全的药物，数百万患有OA的人可以更安全地使用这些药物来缓解疼痛和炎症，并用于其他潜在用途，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.