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Gastrointestinal safety and therapeutics of oil-based Phosphatidylcholine-NSAIDS

油基磷脂酰胆碱-NSAIDS 的胃肠道安全性和治疗作用

基本信息

批准号：
8009629
负责人：
LENARD M LICHTENBERGER
金额：
$ 3.75万
依托单位：
PLX OPCO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8009629
关键词：
Adverse effects Adverse event Age Age-Years Alzheimer&apos s Disease American Animals Anti Inflammatory Analgesics Applications Grants Arthritis Aspirin Biological Availability Biological Models Businesses Cardiovascular system Cessation of life Characteristics Chemicals Chronic Clinical Clinical Data Clinical Research Clinical Trials Complex Coxibs Critiques Data Degenerative polyarthritis Development Dose Drug Formulations Drug Kinetics Drug user Economics Family Funding Gastrointestinal Injury Goals Grant Guidelines Health Hemorrhage Hospitalization Human Ibuprofen Individual Inflammation Investigation Label Laboratories Lead Learning Lecithin Left Link Lipids Manufacturer Name Marketing Methods Minor Mucous Membrane Non-Steroidal Anti-Inflammatory Agents Oils Osteoarthrosis Deformans PTGS2 gene Pain Patients Pharmaceutical Preparations Pharmacia brand of valdecoxib Pharmacologic Substance Phase Phase II Clinical Trials Plague Population Positioning Attribute Prevention Product Approvals Prophylactic treatment Published Comment Rattus Regulatory Pathway Research Research Contracts Research Personnel Rodent Rodent Model Rofecoxib Safety Series Small Business Technology Transfer Research Source Surface System Technology Testing Therapeutic Therapeutic Equivalency Time TimeLine Toothache Toxic effect Treatment Efficacy Ulcer United States National Institutes of Health Withdrawal Work base cancer prevention celecoxib chemical association commercialization drug efficacy drug market drug testing gastrointestinal human subject improved inhibitor/antagonist irritation meetings member novel phase 1 study phase 3 study pre-clinical preclinical study prevent programs research study response soy

项目摘要

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.

描述（由申请人提供）：在我们的STTR第二阶段补助金的竞争延续中，我们建议在前两个资助周期取得的相当大的进展的基础上，努力开发一种新的磷脂酰胆碱（PC）相关非甾体抗炎药（NSAID）。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，其中我们将NSAID与大豆PC化学结合，并证明这些制剂在啮齿动物模型系统中降低了GI毒性，同时保持或增强了药物的治疗活性。根据该证据以及我们的合同研究组织（Synergos，Inc.）和制造商（Cardinal Health），FDA已经发布了布洛芬-PC的IND，并批准了生物等效性的加速505（B）（2）监管路径，这得到了健康受试者的I/II期和III期试验中的人体药代动力学数据以及骨关节炎（OA）患者接受布洛芬或布洛芬-PC 6周研究期的II期试验的支持，提供关于试验药物的GI安全性和治疗活性的信息。如修订后的申请中所述，这些由小企业和NIH的R 03资助的临床研究表明，布洛芬-PC具有与布洛芬相似的生物利用度和治疗活性，但对最易受NSAID诱导的GI副作用影响的OA患者（> 55岁）的胃十二指肠粘膜损伤明显较小。在本修订的资助申请中，我们建议继续进行这一有前景的研究，并在OA患者中进行为期12周的内窥镜试验，该试验应提供关于布洛芬-PC的GI安全性和抗炎/镇痛活性的确证性证据。我们还提出了一系列实验室实验，我们将与Cardinal Health的项目团队密切合作，以优化目前的布洛芬-PC制剂，使其符合FDA的生产指南，并进一步开发制备PC-NSAID的新方法，这似乎导致获得纯化的布洛芬-PC复合物，作为油。这种纯化的布洛芬-PC在啮齿动物模型系统中具有上级GI安全性和治疗活性，我们还在本授权中提议在修改的IND下评估其在健康人类受试者中的生物利用度，以获得该产品的加速监管批准。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，我们提出了一系列的临床前和试点临床研究，以确认初步证据表明，阿司匹林-PC是远远低于阿司匹林的毒性时，共同管理的动物与西乐葆。上述研究的成功完成将使我们能够对布洛芬-PC和阿司匹林-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GI安全性和治疗活性。实现这些里程碑应该使我们处于非常有竞争力的地位，以吸引企业合作伙伴，以促进布洛芬- PC和阿司匹林-PC的商业化，也许还有整个PC-NSAID特许经营权，使这类新型药物可供公众使用，这是非常需要安全有效的非甾体抗炎药。非甾体类抗炎药（NSAID）由于其强效抗炎和镇痛作用而被美国人，尤其是患有骨关节炎（OA）的老年人大量消耗。然而，NSAID的使用受到其在易感个体中诱导胃肠道（GI）溃疡和出血的严重副作用的限制，每年导致103，000例住院和16，500例死亡。本资助提案中开发的技术涉及通过NSAID与表面活性脂质磷脂酰胆碱（PC）的化学结合来预防NSAID诱导的GI溃疡和出血。PC相关的NSAID的开发将提供药物，可以更安全地被数百万OA患者用于缓解疼痛和炎症，以及其他潜在的用途，如预防癌症和阿尔茨海默病。