Micronized salsalate in a parenteral formulation is a safe and effective analgesic for acute postoperative pain management

肠外制剂中的微粉化水杨酸是一种安全有效的止痛药，用于急性术后疼痛管理

• 批准号: 10394982
• 负责人: Izhar Hasan
• 金额: $ 70.14万
• 依托单位: RH NANOPHARMACUETICALS L.L.C.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394982
• 关键词: Acute; Acute Pain; Address; Adverse effects; Adverse event; Affect; American; Analgesics; Animal Model; Animals; Area; Area Under Curve; Binding; Biodistribution; Biological Assay; Canis familiaris; Cardiovascular system; Carrageenan; Chemicals; Chemistry; Clinical Research; Cutaneous; Cyclic GMP; Data; Degenerative polyarthritis; Dose; Drug Addiction; Drug Kinetics; Event; Experimental Animal Model; Financial Hardship; Formulation; Gastrointestinal Hemorrhage; Goals; Guidelines; Health Care Costs; Healthcare Systems; Hematology; Hemorrhage; Human; Humidity; Hyperalgesia; Hypersensitivity; Hypotension; Individual; Inflammation; Intravenous; Life; Light; Maximum Tolerated Dose; Methods; Mind; Modeling; National Institute of Drug Abuse; Nausea and Vomiting; Neurologic; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Operative Surgical Procedures; Opiate Addiction; Opioid; Oral; Oral Administration; Organ; Outcome; Outpatients; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacotherapy; Phase; Phosphotransferases; Population; Postoperative Pain; Postoperative Period; Pre-Clinical Model; Preclinical Testing; Process; Property; Prostaglandin-Endoperoxide Synthase; Rattus; Regulatory Pathway; Reproducibility; Respiration; Rheumatoid Arthritis; Risk; Rodent; Rodent Model; Role; Safety; Salicylic Acids; Savings; Scheme; Science; Serious Adverse Event; Temperature; Testing; Toxic effect; Toxicology; United States; Urinary Retention; Ventilatory Depression; Work; addiction; animal pain; base; brain tissue; chronic pain; combat; cyclooxygenase 1; dimer; dosage; efficacy study; experimental study; gastrointestinal; high risk; illicit opioid; improved; in vivo; inhibitor; interest; meetings; multimodality; nanodrug; non-opioid analgesic; novel therapeutics; opioid abuse; opioid epidemic; opioid mortality; opioid overdose; opioid sparing; opioid use; parenteral administration; particle; platelet function; pre-clinical; prescription opioid; receptor; research clinical testing; salicylsalicylic acid; small molecule; social; surgical pain; surgical risk; treatment strategy

SUMMARY: The White House has initiated an aggressive campaign to combat the current opioid crisis that is affecting all levels of the American way of life. The opioid crisis has emerged from multiple fronts. Among these various fronts, the continued use of opioids in the post-operative area is a growing addiction risk. Current post- operative pain management utilizes a multimodal pain management strategy, which includes opioids and non- opioids (NSAIDs). These two treatment strategies have significant health care cost implications due to their adverse events and addiction risks. Opioids have serious adverse effects such as nausea, vomiting, respiratory depression, urinary retention, hypotension, and long-term addiction risks. Non-opioids such as NSAIDs, both in oral and parenteral formulations, are an essential part of a multimodal post-operative pain management strategy for their opioid sparing capabilities. However, NSAIDs (Cyclooxygenase (Cox)-1/2 inhibitors) have serious adverse events such as GI bleeding, cardiovascular events, and systemic bleeding. This current state of affairs has created an unmet need for an effective parenteral/oral analgesic for acute post- operative pain management without the risks of opioid addiction. Salsalate, a dimer or salicylic acid, although a non-FDA-approved drug, is currently available in oral dosage for the treatment of osteoarthritis and rheumatoid arthritis. Salsalate works at multiple levels to target multiple steps along the surgical pain pathway. Salsalate through its active metabolite, salicylic acid (SA), reduces NF-κB activation via IKK-kinase beta inhibition, and has no direct binding to cyclooxygenase 1 (Cox-1); therefore, does not affect function of platelets, resulting in a safer hematological and gastrointestinal safety profile 1. RH Nanopharmaceuticals (RH Nano) had a successful Pre-IND application review for current oral salsalate through the FDA 505(b)(2) regulatory pathway to submit an IND in the next few months. FDA has confirmed that salsalate is likely to be considered a new chemical entity (NCE) for an initial New Drug Application (NDA). RH Nano has also developed a micronized version of salsalate (M-salsalate) for oral and parenteral administration. Our preliminary testing shows that in comparison with current oral salsalate, M-salsalate has an improved pharmacokinetic profile including a shorter Tmax, higher Cmax, and larger area under the curve (AUC), resulting in enhanced biodistribution. It is expected to have the same safety profile as the oral salsalate. The President’s Commission on “Combating Drug Addiction and the Opioid Crisis” has recommended to the President of the United States that “individuals with acute or chronic pain must have access to non-opioid pain management options”, and the National Institute on Drug Abuse (NIDA) has a strong interest on “non-opioid medications to treat pain in outpatient subjects, including opioid sparing strategies”. With these needs in mind, RH Nano proposes a plan for manufacturing and pre- clinical testing of parenteral M-salsalate in two animal models to assess the efficacy and safety in the treatment of acute postoperative pain management. In this proposal (Phase I), we will partner with Particle Sciences to develop the optimal formulation under strict Chemistry Manufacturing and Control (CMC) guidelines. In Phase II, we propose to conduct the pharmacokinetics and toxicology studies of M-salsalate in two species of animals (rodent and non-rodent) through a partnership with Calvert Labs. We will also use an animal pain model for preclinical efficacy studies, and an in vivo Receptor Occupancy (RO) assay in animal brain tissues to assess the opioid sparing properties of M-salsalate through a partnership with Melior Discovery. The results from these experiments will enable us to generate adequate data for a Pre-IND FDA meeting for discussion of clinical testing in humans.

综述：白宫发起了一场咄咄逼人的运动，以应对当前的阿片类药物危机 影响着美国生活方式的各个层面。阿片类药物危机是从多个方面出现的。其中包括 在各个方面，术后继续使用阿片类药物是一个越来越大的成瘾风险。现任职位- 手术疼痛管理采用多模式疼痛管理策略，包括阿片类药物和非阿片类药物 阿片类药物(非类固醇抗炎药)。这两种治疗策略具有重大的医疗成本影响，因为它们 不良事件和成瘾风险。阿片类药物有严重的不良反应，如恶心、呕吐、 呼吸抑制、尿潴留、低血压和长期成瘾风险。非阿片类药物，如 非甾体类抗炎药，无论是口服制剂还是非甾体抗炎药，都是多模式术后疼痛的重要组成部分 他们的阿片类药物储备能力的管理战略。然而，非类固醇抗炎药(环氧合酶-1/2 抑制剂)有严重的不良反应，如胃肠道出血、心血管事件和全身出血。 目前的情况产生了对有效的肠外/口服止痛剂治疗急性后遗症的需求，但尚未得到满足 无阿片成瘾风险的手术疼痛管理。水杨酸，二聚体或水杨酸，尽管 非FDA批准的药物，目前以口服剂量提供，用于治疗骨关节炎和类风湿 关节炎。水杨酸盐在多个水平上发挥作用，靶向手术疼痛通路上的多个步骤。水杨酸盐 通过其活性代谢物水杨酸(SA)，通过抑制IKK-κβ来降低NF-KK B的激活，以及 与环氧合酶1(COX-1)没有直接结合；因此，不影响血小板的功能，导致 更安全的血液和胃肠道安全性简介1.RH纳米药物(RH Nano)成功地 通过FDA 505(B)(2)监管途径提交的当前口服水杨酸盐的IND前申请审查 在接下来的几个月里。FDA已经证实，水杨酸盐很可能被视为一种新的化学物质 首次新药申请实体(NCE)(NDA)。Rh Nano还开发了微粉化版本的 用于口服和非肠道给药的水杨酸盐(M-水杨酸盐)。我们的初步测试表明，相比之下， 在目前口服沙柳酸盐的情况下，M-沙柳酸盐具有改善的药动学曲线，包括更短的Tmax， 更高的Cmax和更大的曲线下面积(AUC)，导致生物分布增强。预计它将 具有与口服水杨酸盐相同的安全性。总统关于“打击毒瘾”的委员会 和阿片类药物危机“已向美国总统建议，”急性或非传染性疾病患者 慢性疼痛必须有机会获得非阿片类疼痛管理选择“，以及国家药物研究所 滥用(NIDA)对门诊受试者治疗疼痛的非阿片类药物有浓厚的兴趣，包括 阿片类药物节约策略“。考虑到这些需求，RH Nano提出了一项制造和预 在两种动物模型上进行M-水杨酸盐肠外注射的临床试验，以评估其疗效和安全性 急性术后疼痛管理。在本计划(第一阶段)中，我们将与粒子科学合作 在严格的化学制造和控制(CMC)指导下开发最佳配方。同相 II，我们建议进行M-水杨酸盐在两种动物体内的药代动力学和毒理学研究 (啮齿动物和非啮齿动物)通过与卡尔弗特实验室的合作伙伴关系。我们还将使用动物疼痛模型来 临床前疗效研究，以及动物脑组织体内受体占有率(RO)分析以评估 通过与梅里奥尔发现公司的合作，M-水杨酸盐的阿片类药物节省特性。结果来自于 这些实验将使我们能够为IND前FDA会议生成足够的数据，以讨论 在人体上进行临床试验。