As one of the largest opioid consuming countries in the world, the prevalence of opioid use disorder (OUD) during 2017 is over 5 million in the U.S. alone. The significant increase of opioids use disorder (OUD) cases during the last 2 decades may be partially attributed to our overreliance on the prescription of the opioids for the management of non-cancer chronic pain, such as osteoarthritis (OA) pain. The extensive use of opioids for pain management can be associated with a variety of side effects including constipation, nausea, dizziness, vomiting, liver damage, respiratory depression leading to brain damage due to the hypoxia, and physical dependence, tolerance and addiction. The higher dose prescription because of the physical dependence and tolerance leading to OUD and the intertwined heroin use related with the addiction have been reported. Therefore, the goals of the project are to develop, translate and commercialize a novel non-opioid therapy for sustained, effective, safe management of OA pain, and to prevent opioids use disorder among osteoarthritis patients. Through an innovative structural design, we have developed a N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone (Dex) prodrug (P-Dex-H) that is a free-flowing aqueous solution at reduced temperature, but becomes a hydrogel (ProGel) when the temperature is raised to > 30 °C. This thermoresponsive phase transition property allows the macromolecular prodrug formulation to be deposited in the synovial cavity with sustained presence for a protracted period of time. With continuous exposure to the synovial fluid, we have shown that the ProGel can then gradually solubilize and release after which it is internalized by synovial phagocytic cells and activated subcellularly to release Dex. In the preliminary studies, we have found that the P-Dex-H-based ProGel was able to provide sustained (> 1 month) amelioration to the joint pain models of adjuvant-induced arthritis (AA), monoarticular adjuvant-induced arthritis (MAA) and monoiodoacetate-induced osteoarthritis (MIA). Furthermore, typical glucocorticoid side effects, such as osteopenia, adrenal gland atrophy were not associated with ProGel treatment. Injection site reactions (e.g., arthralgia), as seen in the case of Flexion Therapeutics Zilretta (triamcinolone acetonide extended-release formulation) was also absent in animals treated with ProGel. However, ProGel formulations have not been evaluated in a clinically relevant osteoarthritis model such as the surgical destabilization of the medial meniscus (DMM) mouse model. Therefore, in the Phase I of this fast-track project, we propose to test the feasibility of using ProGel to treat arthritis pain in the DMM mouse model. A thorough physicochemical characterization, including the construction of the phase diagram for ProGel will also completed in preparation for the optimization of the formulation. For Phase II, we proposed to optimize the ProGel formulation by adjusting a variety of structural parameters with the goal of identifying an optimized formulation with the most potent and sustained joint pain amelioration and minimal toxicity. The IND enabling PK/BD study of this optimized ProGel formulation will then be performed. The successful completion of the proposed research will help the ProGel technology to become IND ready for further clinical evaluation.
Public Health Relevance Statement: NARRATIVE Osteoarthritis (OA) is the most common joint disorder, affecting over 25 million individuals in the U.S. Currently, there are no approved therapies that have been shown to alter the natural progression of OA joint pathology. Effective control of OA pain therefore remains the primary therapeutic objective. Opioids have been widely used for the treatment of OA joint pain. Given the chronic and progressive nature of OA, long-term use of opioids carries an increased risk of substance dependence and abuse. In light of the current opioid epidemic, there is an urgent need for more effective non-opioid analgesics for OA pain management. This proposal seeks to further develop, translate and commercialize a novel macromolecular dexamethasone prodrug-based thermoresponsive hydrogel (ProGel) as a novel intra-articular injection formulation for better clinical management of OA pain.
Project Terms: addiction; Adjuvant Arthritis; Adrenal Glands; Affect; Animal Model; Animals; Anti-Inflammatory Agents; aqueous; Arthralgia; arthritic pain; Arthritis; arthropathies; Atrophic; Autoimmune Diseases; base; Biodistribution; Blood Glucose; Blood Pressure; Body Weight; bone quality; Brain Injuries; Cells; Chronic; clinical application; clinical efficacy; Clinical Management; clinical translation; clinically relevant; commercialization; Constipation; copolymer; Country; Degenerative polyarthritis; Deposition; design; Development; Dexamethasone; disability; Disease; Dizziness; Dose; Drug Kinetics; Evolution; Exposure to; Extravasation; FDA approved; Feasibility Studies; Formulation; functional disability; gait examination; Gamma counter; Glucocorticoids; Goals; Guidelines; Half-Life; heroin use; Histology; Hydrogels; Hyperalgesia; Hypoxia; Immunoglobulin G; improved; improved functioning; In Vitro; in vivo; Individual; Inflammatory; Inflammatory Arthritis; Injection Site Reaction; Injections; innovation; International; Intra-Articular Injections; joint destruction; joint injury; Joints; Knee Osteoarthritis; knee pain; Label; Lead; Lesion; Light; liquid chromatography mass spectrometry; liver function; liver injury; Lupus Nephritis; Mechanics; Medial meniscus structure; Mediating; Mental Depression; methacrylamide; methyl tert-butyl ether; Modeling; Molecular Weight; Motion; mouse model; Mus; Nature; Nausea; new technology; non-cancer chronic pain; non-opioid analgesic; novel; Operative Surgical Procedures; Opioid; opioid epidemic; opioid sparing; opioid use; opioid use disorder; Organ; osteoarthritis pain; Osteopenia; Pain; pain behavior; Pain management; pain model; pain relief; Pathology; patient subsets; Patients; Phagocytes; Pharmacologic Substance; Phase; Phase Transition; Physical Dependence; Preparation; prescription opioid; Prevalence; prevent; Prodrugs; Property; Quality of life; Renal function; repaired; Reporting; Research; research clinical testing; Rheumatoid Arthritis; Risk; Safety; Series; Serum; side effect; Sleep disturbances; Small Business Innovation Research Grant; Societies; Sol-Gel Phase Transitions; Structure; Substance abuse problem; Substance Addiction; Surveys; Synovial Fluid; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Triamcinolone Acetonide; United States; Ventilatory Depression; Vomiting; Weight; Weight-Bearing state; Work
