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: 10377820
• 负责人: Joel Steven Ross
• 金额: $ 100万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377820
• 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/antagonist; 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; 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/antagonist; 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.

摘要：白宫发起了一项激进的运动，以应对当前的阿片类药物危机 影响美国生活方式的各个层面。阿片类药物危机已经从多个方面出现。其中 各种方面，在术后区域继续使用阿片类药物是成瘾风险的日益增长的风险。当前职位 - 手术疼痛管理采用多模式疼痛管理策略，其中包括阿片类药物和非 - OOPIOIDS（NSAIDS）。这两种治疗策略由于其 不利事件和成瘾风险。阿片类药物具有严重的不良反应，例如恶心，呕吐， 呼吸道抑郁，泌尿率保留，低血压和长期成瘾风险。非阿片类药物，例如 NSAID在口头和父母公式中都是多模式后疼痛的重要组成部分 其阿片类药物保留能力的管理策略。但是，NSAIDS（环氧合酶（COX）-1/2 抑制剂）具有严重的不良事件，例如胃肠道出血，心血管事件和全身性出血。 这种当前的状况使对有效的肠胃外/口服镇痛药的需求未满足 - 急性后 手术疼痛管理没有阿片类药物成瘾的风险。 salsalate，二聚体或水杨酸，尽管 非FDA批准的药物目前可用于口服剂量用于治疗骨关节炎和类风湿病 关节炎。 Salsalate在多个级别上工作，沿着手术疼痛途径靶向多个步骤。 salsalate 通过其活性代谢物水杨酸（SA），通过IKK-激酶β抑制作用降低NF-κB的激活，并且 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 更安全的血液学和胃肠道安全概况1。RH纳米药物（RH NANO）成功 通过FDA 505（b）（2）提交的监管途径 在接下来的几个月中。 FDA已确认salsalate可能被认为是一种新化学物质 初始新药应用（NDA）的实体（NCE）。 RH Na​​no还开发了一个微粉化版本 口服和肠胃外给药的盐酸盐（M-salsalate）。我们的初步测试表明，相比之下 使用当前的口服盐酸，M-盐盐具有改进的药代动力学特征，包括较短的Tmax， 较高的CMAX和曲线下较大的面积（AUC），导致生物分布增强。期望 具有与口服萨尔萨酸盐相同的安全性。总统委员会“打击吸毒成瘾 并且已向美国总统推荐阿片类药物危机。 慢性疼痛必须可以使用非阿片类疼痛管理选择”，以及国家药物研究所 虐待（NIDA）对“治疗门诊受试者的疼痛的非阿片类药物，包括 阿片类药物的保留策略”。考虑到这些需求，RH Na​​no提出了制造和预先制造计划的计划 在两个动物模型中对父母M-六盐的临床测试，以评估治疗的效率和安全性 急性后疼痛管理。在此提案（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）指南下制定最佳配方。在阶段 ii，我们建议在两种动物中进行M-六酸酯的药代动力学和毒理学研究 通过与Calvert Labs建立合作伙伴关系（啮齿动物和非变形物）。我们还将使用动物疼痛模型进行 临床前效率研究以及动物脑组织中的体内受体占用（RO）评估 通过与Melior Discovery建立合作伙伴关系，M-Salalate的阿片类药物保留特性。结果 这些实验将使我们能够生成足够的数据，以进行预先指示的FDA会议，以讨论 人类的临床测试。