SBIR-STTR Award

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-?B 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.

Public Health Relevance Statement:
NARRATIVE: A parenteral formulation of micronized salsalate (M-salsalate) has a potential to be a safe and effective post-operative analgesic without the risks of current opioids and non-opioid based medications. We propose to use M-salsalate as an alternative to current NSAIDs in the multimodal approach for post-operative pain management. The purpose of this proposal is to characterize the attributes of M-salsalate and to show the stable formulation, pharmacokinetics, dose tolerability, and complete the toxicological and opioid sparing profile in preclinical animal models.

NIH Spending Category:
Brain Disorders; Chronic Pain; Neurosciences; Opioid Misuse and Addiction; Opioids; Pain Research; Substance Abuse

Project Terms:
Acute; Acute Pain; addiction; Address; Adverse effects; Adverse event; Affect; American; Analgesics; Animal Model; animal pain; Animals; Area; Area Under Curve; base; Binding; Biodistribution; Biological Assay; brain tissue; Canis familiaris; Cardiovascular system; Carrageenan; Chemicals; Chemistry; chronic pain; Clinical Research; combat; Cutaneous; Cyclic GMP; cyclooxygenase 1; Data; Degenerative polyarthritis; dimer; dosage; Dose; Drug Addiction; Drug Kinetics; efficacy study; Event; Experimental Animal Model; experimental study; Financial Hardship; Formulation; gastrointestinal; Gastrointestinal Hemorrhage; Goals; Guidelines; Health Care Costs; Healthcare Systems; Hematology; Hemorrhage; high risk; Human; Humidity; Hyperalgesia; Hypersensitivity; Hypotension; illicit opioid; improved; in vivo; Individual; Inflammation; inhibitor/antagonist; interest; Intravenous; Life; Light; Maximum Tolerated Dose; meetings; Methods; Mind; Modeling; multimodality; nanodrug; National Institute of Drug Abuse; Nausea and Vomiting; Neurologic; non-opioid analgesic; Non-Steroidal Anti-Inflammatory Agents; novel therapeutics; Nuclear; Operative Surgical Procedures; Opiate Addiction; Opioid; opioid abuse; opioid epidemic; opioid mortality; opioid overdose; opioid sparing; opioid use; Oral; Oral Administration; Organ; Outcome; Outpatients; Pain; Pain management; parenteral administration; particle; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacotherapy; Phase; Phosphotransferases; platelet function; Population; Postoperative Pain; Postoperative Period; pre-clinical; Pre-Clinical Model; Preclinical Testing; prescription opioid; Process; Property; Prostaglandin-Endoperoxide Synthase; Rattus; receptor; Regulatory Pathway; Reproducibility; research clinical testing; Respiration; Rheumatoid Arthritis; Risk; Rodent; Rodent Model; Role; Safety; Salicylic Acids; salicylsalicylic acid; Savings; Scheme; Science; Serious Adverse Event; small molecule; social; surgical pain; surgical risk; Temperature; Testing; Toxic effect; Toxicology; treatment strategy; United States; Urinary Retention; Ventilatory Depression; Work

The White House has initiated an aggressive campaign to combat the current opioid crisis that isaffecting all levels of the American way of life. The opioid crisis has emerged from multiple fronts. Among thesevarious 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 theiradverse 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 asNSAIDs, both in oral and parenteral formulations, are an essential part of a multimodal post-operative painmanagement strategy for their opioid sparing capabilities. However, NSAIDs (Cyclooxygenase (Cox)-1/2inhibitors) 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 anon-FDA-approved drug, is currently available in oral dosage for the treatment of osteoarthritis and rheumatoidarthritis. Salsalate works at multiple levels to target multiple steps along the surgical pain pathway. Salsalatethrough its active metabolite, salicylic acid (SA), reduces NF-κB activation via IKK-kinase beta inhibition, andhas no direct binding to cyclooxygenase 1 (Cox-1); therefore, does not affect function of platelets, resulting in asafer hematological and gastrointestinal safety profile 1. RH Nanopharmaceuticals (RH Nano) had a successfulPre-IND application review for current oral salsalate through the FDA 505(b)(2) regulatory pathway to submitan IND in the next few months. FDA has confirmed that salsalate is likely to be considered a new chemicalentity (NCE) for an initial New Drug Application (NDA). RH Nano has also developed a micronized version ofsalsalate (M-salsalate) for oral and parenteral administration. Our preliminary testing shows that in comparisonwith 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 tohave the same safety profile as the oral salsalate. The President's Commission on "Combating Drug Addictionand the Opioid Crisis" has recommended to the President of the United States that "individuals with acute orchronic pain must have access to non-opioid pain management options", and the National Institute on DrugAbuse (NIDA) has a strong interest on "non-opioid medications to treat pain in outpatient subjects, includingopioid 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 treatmentof acute postoperative pain management. In this proposal (Phase I), we will partner with Particle Sciences todevelop the optimal formulation under strict Chemistry Manufacturing and Control (CMC) guidelines. In PhaseII, 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 forpreclinical efficacy studies, and an in vivo Receptor Occupancy (RO) assay in animal brain tissues to assessthe opioid sparing properties of M-salsalate through a partnership with Melior Discovery. The results fromthese experiments will enable us to generate adequate data for a Pre-IND FDA meeting for discussion ofclinical testing in humans.

Public Health Relevance Statement:
NARRATIVE: A parenteral formulation of micronized salsalate (M-salsalate) has a potential to be a safe and effective post-operative analgesic without the risks of current opioids and non-opioid based medications. We propose to use M-salsalate as an alternative to current NSAIDs in the multimodal approach for post-operative pain management. The purpose of this proposal is to characterize the attributes of M-salsalate and to show the stable formulation, pharmacokinetics, dose tolerability, and complete the toxicological and opioid sparing profile in preclinical animal models.

Project Terms:
<2-Hydroxybenzoic Acid>