ProGel Technology for Better Management of Osteoarthritis Pain

ProGel 技术可更好地治疗骨关节炎疼痛

• 批准号: 10326409
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326409
• 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; 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

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者国家之一，阿片类药物使用障碍的普遍性（OUD） 仅在美国，2017年期间就超过500万。阿片类药物使用障碍（OUD）病例的显着增加 在过去的20年中，可能部分归因于我们对阿片类药物处方的过度依赖 非癌慢性疼痛的治疗，例如骨关节炎（OA）疼痛。广泛使用阿片类药物来疼痛 管理可以与各种副作用有关，包括便秘，恶心，头晕，呕吐， 肝脏损伤，呼吸道抑郁，导致由于缺氧引起的脑损伤和身体依赖性， 宽容和成瘾。由于身体依赖性和耐受性，较高的剂量处方 已经报道了导致OUD和与成瘾相关的相互交织的海洛因使用。因此， 该项目的目标是开发，翻译和商业化一种新型的非阿片类药物疗法，以持续， 有效，安全地治疗OA疼痛，并防止骨关节炎患者使用阿片类药物疾病。 通过创新的结构设计，我们开发了N-（2-羟基丙烯）甲基丙烯酰胺（HPMA） 共聚物 - 塞米松（DEX）前药（p-dex-H），是一种自由流动的水溶液 温度，但是当温度升高到> 30°C时变为水凝胶（progel）。这 热响应期过渡特性允许大分子前药公式沉积在 持续存在的滑腔长期存在。不断暴露于 滑液，我们已经表明，前卫可以逐渐溶解并释放，之后是 通过滑膜细胞内部化并在下激活以释放DEX。在初步研究中 我们发现，基于P-DEX-H的Progel能够为该持续的（> 1个月）提供缓解 调节引起的关节炎（AA），单关节调节引起的关节炎（MAA）和的关节疼痛模型 单二乙酸盐诱导的骨关节炎（MIA）。此外，典型的糖皮质激素副作用，例如 骨质减少症，肾上腺萎缩与Progel治疗无关。注射部位反应（例如， Arthralgia），如Flexion Therapeutics的Zilretta™（Triamcinolone acotonide Extendend-Release）所见 在用progel处理的动物中也没有配方奶。但是，前卫公式尚未 在临床上相关的骨关节炎模型中进行了评估，例如内侧半月板的手术不稳定 （DMM）鼠标模型。因此，在这个快速轨道项目的第一阶段，我们建议测试 使用Progel治疗DMM小鼠模型中的关节炎疼痛。彻底的身体特征， 包括构造前曲的相图还将完成以准备优化 公式。对于第二阶段，我们建议通过调整各种 结构参数的目的是确定具有最潜力和持续的优化公式 关节疼痛的缓解和最小的毒性。该优化的Progel公式的IND启用PK/BD研究 然后将执行。拟议研究的成功完成将有助于Progel技术 准备好进行进一步的临床评估。