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

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：白宫发起了一场积极的运动，以打击目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来自多个方面。其中 在各个方面，手术后继续使用类阿片是一种日益增长的成瘾风险。现任员额 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（NSAID）。这两种治疗策略具有显著的医疗保健成本影响，因为它们 不良事件和成瘾风险。阿片类药物有严重的副作用，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 口服和胃肠外制剂的NSAID是多模式术后疼痛的重要组成部分 管理策略，以提高他们的阿片类药物节约能力。然而，NSAID（环氧合酶（考克斯）-1/2 抑制剂）具有严重的不良事件，如GI出血、心血管事件和全身出血。 这种现状已经产生了对用于急性术后镇痛的有效的肠胃外/口服镇痛剂的未满足的需求。 没有阿片类药物成瘾风险的手术疼痛管理。双水杨酸酯，二聚体或水杨酸，虽然 非FDA批准的药物，目前可用于治疗骨关节炎和类风湿性关节炎的口服剂量 关节炎双水杨酸在多个层面上发挥作用，以沿着手术疼痛途径的多个步骤为目标。双水杨 通过其活性代谢产物水杨酸（SA），通过IKK-激酶β抑制降低NF-κB活化， 不与环氧化酶1（考克斯-1）直接结合;因此，不影响血小板功能， 更安全的血液学和胃肠道安全性特征1. RH Nanopharmaceuticals（RH Nano）成功地 通过FDA 505（B）（2）监管途径提交当前口服双水杨酸盐的IND前申请审查 在接下来的几个月里。FDA已确认双水杨酸可能被视为一种新的化学品 实体（NCE）申请新药初始申请（NDA）。RH Nano还开发了一种微粉化版本的 双水杨酸酯（M-双水杨酸酯）用于口服和肠胃外给药。我们的初步测试表明， 对于目前的口服双水杨酸盐，M-双水杨酸盐具有改善的药代动力学特征，包括较短的Tmax， 更高的Cmax和更大的曲线下面积（AUC），导致增强的生物分布。预计将 与口服双水杨酸具有相同的安全性。总统“打击吸毒成瘾”委员会 和阿片类药物危机”已建议美国总统，“个人与急性或 慢性疼痛必须获得非阿片类药物疼痛管理选择”，国家药物研究所 滥用（NIDA）对“治疗门诊受试者疼痛的非阿片类药物，包括 阿片类药物节约战略”。考虑到这些需求，RH Nano提出了一个制造和预处理计划， 在两种动物模型中进行肠外间水杨酸盐的临床试验，以评估治疗的有效性和安全性 急性术后疼痛管理。在本提案（第一阶段）中，我们将与粒子科学公司合作， 在严格的化学生产和控制（CMC）指导方针下开发最佳配方。同相 第二部分，我们拟在两种动物中进行间水杨酸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。我们还将使用动物疼痛模型， 临床前疗效研究和动物脑组织中的体内受体占据（RO）测定，以评估 通过与Melior Discovery的合作，开发了M-salsalate的阿片类药物保留特性。的结果 这些实验将使我们能够为Pre-IND FDA会议提供足够的数据， 人体临床试验。