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ProGel Technology for Better Management of Osteoarthritis Pain

ProGel 技术可更好地治疗骨关节炎疼痛

基本信息

批准号：
10013068
负责人：
STEVEN GOLDRING
金额：
$ 25.21万
依托单位：
ENSIGN PHARMACEUTICAL, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2020-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013068
关键词：
Adjuvant Arthritis Adrenal Glands Affect Animal Model Animals Anti-Inflammatory Agents Arthralgia Arthritis Atrophic Autoimmune Diseases Biodistribution Blood Glucose Blood Pressure Body Weight Brain Injuries Cells Chronic Clinical Management Constipation Country Degenerative polyarthritis Deposition Development Dexamethasone Disease Dizziness Dose Drug Kinetics Evolution Exposure to Extravasation FDA approved Feasibility Studies Formulation Gamma counter Glucocorticoids Goals Guidelines Half-Life Histology Hydrogels Hyperalgesia Hypoxia Immunoglobulin G In Vitro Individual Inflammatory Inflammatory Arthritis Injection Site Reaction Injections International Intra-Articular Injections Joints Knee Osteoarthritis Label Lead Lesion Light Lupus Nephritis Mechanics Medial meniscus structure Mediating Mental Depression Modeling Molecular Weight Motion Mus Nature Nausea Operative Surgical Procedures Opioid Organ Osteopenia Pain Pain management Pathology Patients Phagocytes Pharmacologic Substance Phase Phase Transition Physical Dependence Preparation Prevalence Prodrugs Property Quality of life Renal function Reporting Research Rheumatoid Arthritis Risk Safety Series Serum Sleep disturbances Small Business Innovation Research Grant Societies Sol-Gel Phase Transitions Structure Substance Addiction Substance abuse problem 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 addiction aqueous arthritic pain arthropathies base bone quality clinical application clinical efficacy clinical translation clinically relevant commercialization copolymer design disability functional disability gait examination heroin use improved improved functioning in vivo innovation joint destruction joint injury knee pain liquid chromatography mass spectrometry liver function liver injury methacrylamide methyl tert-butyl ether mouse model new technology non-cancer chronic pain non-opioid analgesic novel opioid epidemic opioid sparing opioid use opioid use disorder osteoarthritis pain pain behavior pain model pain relief patient subsets prescription opioid prevent repaired research clinical testing side effect

项目摘要

ABSTRACT 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.

摘要