GI-Safer Naproxen Formulation R&D for the Treatment of Osteoarthritis and Related

胃肠道更安全的萘普生配方 R

• 批准号: 7657930
• 负责人: Upendra Marathi
• 金额: $ 74.57万
• 依托单位: PLX OPCO, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657930
• 关键词: 13-hydroxyoctadecadienoic acid; Acids; Adult; Advanced Development; Affect; Age-Years; American; Analgesics; Animal Model; Animal Testing; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Aspirin; Biological Models; Blood; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Investigator; Clinical Trials; Contracts; Data; Degenerative polyarthritis; Development; Dinoprostone; Disease; Dose; Double-Blind Method; Drug Formulations; Drug Kinetics; Eicosanoids; Endoscopy; Event; Family; Gastrointestinal Injury; Gel; Goals; Grant; Hemorrhage; Hip Osteoarthritis; Hip region structure; Hospitalization; Hydroxyeicosatetraenoic Acids; Ibuprofen; Incidence; Inflammation; Inflammatory; Injury; Investigational New Drug Application; Knee; Knee Osteoarthritis; Laboratories; Lead; Lecithin; Leukotriene B4; Manufacturer Name; Marketing; Measurement; Mediating; Methods; Morbidity - disease rate; Mucous Membrane; Myocardial Infarction; Naproxen; Naproxen sodium; Non-Steroidal Anti-Inflammatory Agents; Oils; Pain Disorder; Patients; Peptic Ulcer; Pharmaceutical Preparations; Phase; Phospholipids; Placebos; Pre-Clinical Model; Principal Investigator; Process; Property; Public Health; Randomized; Risk; Rodent Model; Route; Safety; Small Business Innovation Research Grant; Source; Stroke; Suspension substance; Suspensions; Test Result; Testing; Therapeutic Equivalency; Thrombosis; Time; Toxic effect; Treatment Efficacy; Ulcer; United States Food and Drug Administration; Upper arm; Validation; Work; analytical method; capsule; chronic pain; commercialization; comparative; comparative efficacy; gastrointestinal; healthy volunteer; improved; in vivo; interest; mortality; prototype; public health relevance; research and development; research clinical testing; scale up; sound; volunteer

DESCRIPTION (provided by applicant): ABSTRACT: This application is a Phase I/Phase II Fast-Track SBIR application. Osteoarthritis (OA), the clinical syndrome of joint pain and dysfunction caused by joint degeneration, affects more people than any other joint disease. There are no consistently effective methods for preventing OA or slowing its progression, and so symptomatic treatments represent the standard of care, the foundation of which are the non-steroidal anti-inflammatory drugs (NSAIDs). Such treatments for OA require consideration of not only gastrointestinal (GI) risk, but also cardiovascular (CV) risk; non-selective NSAIDs acting on both cyclooxygenase-1 (COX-1) and COX-2 universally increase the risk of GI injury, whereas nearly all NSAIDs, especially the selective COX-2 inhibitors, have been shown to increase the risk of serious CV events. The withdrawal of rofecoxib and valdecoxib from the market amplify the continuing need for an NSAID with minimal CV and GI risks. Naproxen has become the NSAID of choice for most mild/moderate chronic inflammatory indications, including OA, as it appears to have little or no increased risk of cardiovascular adverse events. However, in spite of its favorable CV safety profile, naproxen is well known to induce GI toxicity that is sometimes life-threatening. The activities proposed in this grant application are intended to advance a new naproxen formulation (Naproxen-PC) that not only improves the GI safety of naproxen using a non-COX mechanism, but also may enhance anti-inflammatory activity compared with naproxen. Naproxen-PC improves GI safety by increasing the lipophilicity of the NSAID via non- covalent pre-association with a surface-active phospholipid, namely phosphatidylcholine (PC). This oil-based formulation of PC-associated naproxen (Naproxen-PC) has been shown in rodent models to have remarkably lower (~85%) GI toxicity, while retaining the efficacy and general safety profile of unmodified naproxen. Recently, novel methods have been developed to profile bioactive lipids in a model of joint inflammation, including products of both cyclooxygenase (COX) and lipoxygenase (LOX). Preliminary data assaying a range of bioactive lipids suggests that Naproxen-PC may have enhanced anti-inflammatory efficacy, as reflected in the attenuation of pro-inflammatory eicosanoids (including prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 12- hydroxyeicosatetraenoic acid (12-HETE), and 5-HETE), while sparing anti-inflammatory eicosanoids (13- hydroxyoctadecadienoic acid (13-HODE)), compared with unmodified naproxen, in a rodent model of joint inflammation. The major objective of this Fast-Track SBIR application is to confirm the preliminary data described above and continue and expand the development of Naproxen-PC and initiate clinical studies. In Phase I, initial activities will focus on expanding and confirming the enhanced anti-inflammatory activity of Naproxen-PC seen in animal models. Also, in partnership with a commercial manufacturer, we propose to optimize the laboratory formulation of Naproxen-PC so that it may be softgel encapsulated and manufactured for clinical trials. Several lead prototypes resulting from this optimization will be identified that appear commercially viable, which will be tested in established animal models with both GI safety and analgesic and anti-inflammatory efficacy endpoints. The results of these experiments will allow selection of a single, validated lead Naproxen-PC formulation. In Phase II, the lead formulation will be manufactured as 250 mg Naproxen-PC gelcaps according to regulatory standards, further tested for stability, then advanced into clinical trials. Initially, a single-dose bioequivalence (BE) study, comparing Naproxen-PC with unmodified naproxen, will be completed in healthy volunteers; this pharmacokinetics study will provide BE data for Naproxen-PC FDA approval via the accelerated 505(b)(2) regulatory route, and provide data on the systemic safety of Naproxen- PC. Then, a comparative proof-of-concept clinical trial will be conducted examining analgesic efficacy, general safety and the incidence of gastrointestinal ulcers, assessed endoscopically, in patients with osteoarthritis aged 55 years or older, following administration of 500 mg Naproxen-PC or naproxen BID for 12 weeks. The development activities encompassed in this grant proposal will significantly advance the Naproxen-PC development toward commercialization. If the Naproxen-PC formulation is shown in subsequent confirmatory clinical trials to possess an improved GI safety profile, together with equivalent analgesic and perhaps superior anti-inflammatory efficacy compared with naproxen, it will represent an important new treatment for patients with osteoarthritis and related chronic inflammatory diseases.

描述(由申请人提供)：摘要：本申请为第一阶段/第二阶段快速通道SBIR应用程序。骨性关节炎(OA)是由关节退行性变引起的关节疼痛和功能障碍的临床综合征，比任何其他关节疾病影响更多的人。目前尚无一贯有效的方法来预防或减缓其进展，因此对症治疗代表了护理的标准，其基础是非类固醇抗炎药(NSAIDs)。这样的治疗不仅需要考虑胃肠道(GI)风险，也需要考虑心血管(CV)风险；同时作用于环氧合酶-1(COX-1)和COX-2的非选择性NSAIDs普遍增加GI损伤的风险，而几乎所有的NSAIDs，特别是选择性COX-2抑制剂，都被证明增加了严重CV事件的风险。罗非昔布和valdecoxib从市场上撤出，放大了对心血管和胃肠道风险最小的非甾体抗炎药的持续需求。萘普生已成为包括骨关节炎在内的大多数轻/中度慢性炎症适应症的非甾体抗炎药的选择，因为它似乎很少或没有增加心血管不良事件的风险。然而，尽管它具有良好的心血管安全性，但众所周知，萘普生会引起胃肠道毒性，有时甚至危及生命。在这项赠款申请中建议的活动旨在促进一种新的萘普生制剂(NAPROXEN-PC)，该制剂不仅利用非COX机制改善NAPROXEN的胃肠道安全性，而且与NAPROXEN相比还可以增强抗炎活性。萘普生-PC通过与表面活性磷脂，即磷脂酰胆碱(PC)非共价预结合，增加非类固醇抗炎药的亲脂性，从而改善胃肠道的安全性。在啮齿动物模型中，这种PC相关的油基制剂(NAPROXEN-PC)具有显著较低的GI毒性(~85%)，同时保持了未经修饰的NAPROXEN的有效性和总体安全性。最近，已经发展了新的方法来描述关节炎症模型中的生物活性脂类，包括环氧合酶(COX)和脂氧合酶(LOX)的产物。初步数据分析表明，在关节炎症的啮齿动物模型中，与未经修饰的萘普生相比，促炎二十烷类化合物(包括前列腺素E2(PGE2)、白三烯B4(LTB4)、12-羟基二十碳四烯酸(12-HETE)和5-羟基二十碳四烯酸(5-HETE))的减弱反映了萘普生-PC可能具有增强的抗炎效果，而抗炎二十烷类化合物(13-羟基十八碳二烯酸(13-HODE))则较少。这项快速跟踪SBIR应用的主要目标是确认上述初步数据，并继续和扩大萘普生-PC的开发，并启动临床研究。在第一阶段，最初的活动将集中在扩大和证实在动物模型中看到的萘普生-PC增强的抗炎活性。此外，我们与一家商业制造商合作，建议优化萘普生-PC的实验室配方，以便将其制成软胶囊并生产用于临床试验。这项优化将确定几个似乎具有商业可行性的领先原型，这些原型将在具有GI安全性以及止痛和消炎功效终点的已建立的动物模型中进行测试。这些实验的结果将允许选择单一的、有效的萘普生-PC铅配方。在第二阶段，根据监管标准，铅配方将被制造为250毫克的萘普生-PC胶帽，进一步进行稳定性测试，然后进入临床试验。最初，将在健康志愿者中完成单剂量生物等效性(BE)研究，比较萘普生-PC和未经修饰的NAPROXEN；这项药代动力学研究将通过加速的505(B)(2)调控路线为FDA批准NAPROXen-PC提供BE数据，并提供关于NAPROXen-PC系统安全性的数据。然后，将进行一项比较的概念验证临床试验，在服用500毫克萘普生-PC或NAPROXEN BID 12周后，通过内窥镜评估55岁或55岁以上的骨关节炎患者的止痛有效性、一般安全性和胃肠道溃疡的发生率。这项赠款提案中包含的开发活动将极大地推动萘普生-PC的开发走向商业化。如果在随后的验证性临床试验中证实该制剂具有更好的胃肠道安全性，再加上与萘普生相当的止痛药和可能更好的抗炎功效，它将成为治疗骨性关节炎和相关慢性炎症性疾病患者的一种重要的新疗法。