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.

摘要：白宫发起了一场积极的运动，以对抗当前的阿片类药物危机