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：
10281291
负责人：
STEVEN GOLDRING
金额：
$ 84.04万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10281291
关键词：
Adjuvant Arthritis Adrenal Glands 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 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 base bone quality clinical application clinical efficacy clinical translation clinically relevant commercialization copolymer design disability feasibility testing 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.

抽象的作为世界上最大的阿片类药物消费国之一，阿片类药物使用障碍（OUD）的患病率 2017 年，仅美国就有超过 500 万例阿片类药物使用障碍 (OUD) 病例显着增加。在过去的 20 年中，这可能部分归因于我们过度依赖阿片类药物的处方。治疗非癌症慢性疼痛，例如骨关节炎 (OA) 疼痛广泛使用阿片类药物治疗疼痛。管理可能与多种副作用相关，包括便秘、恶心、头晕、呕吐、肝损伤、呼吸抑制导致缺氧导致脑损伤、身体依赖性，耐受性和成瘾性由于身体依赖性和耐受性，处方剂量较高。据报道，导致 OUD 和与成瘾相关的海洛因相互交织。该项目的目标是开发、转化和商业化一种新型非阿片类药物疗法，用于持续、有效、安全地管理骨关节炎疼痛，并预防骨关节炎患者阿片类药物使用障碍。通过创新的结构设计，我们开发了N-(2-羟丙基)甲基丙烯酰胺(HPMA) 共聚物地塞米松 (Dex) 前药 (P-Dex-H)，是一种在还原条件下自由流动的水溶液温度，但当温度升高到 > 30 °C 时会变成水凝胶 (ProGel)。热响应相变特性允许大分子前药制剂沉积在滑膜腔持续存在较长时间。滑液中，我们已经证明 ProGel 可以逐渐溶解并释放，然后在初步研究中，被滑膜吞噬细胞内化并在亚细胞内激活以释放 Dex。我们发现基于 P-Dex-H 的 ProGel 能够持续（> 1 个月）改善佐剂诱发的关节炎 (AA)、单关节佐剂诱发的 (关节炎MAA) 和单碘乙酸诱发的骨关节炎（MIA）此外，典型的糖皮质激素副作用，例如骨质减少、肾上腺萎缩与 ProGel 治疗无关（例如，关节痛），如 Flexion Therapeutics 的 Zilretta™（曲安奈德缓释剂）用 ProGel 治疗的动物中也不存在这种情况。然而，ProGel 制剂尚未出现。在临床相关的骨关节炎模型中进行评估，例如内侧半月板的手术不稳定因此，在这个快速通道项目的第一阶段，我们建议测试其可行性。使用 ProGel 治疗 DMM 小鼠模型中的关节炎疼痛彻底的理化特性，包括ProGel相图的构建也将完成，为优化做准备对于第二阶段，我们建议通过调整各种参数来优化 ProGel 配方。结构参数，旨在确定具有最有效和持续性的优化配方关节疼痛减轻且毒性最小。 IND 可以对这种优化的 ProGel 制剂进行 PK/BD 研究。然后将进行拟议研究的成功完成将有助于 ProGel 技术为进一步的临床评估做好 IND 准备。