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国之一，阿片类药物使用障碍（OUD）的患病率 2017 年，仅在美国这一数字就超过 500 万。阿片类药物使用障碍（OUD）病例显着增加 过去 20 年来，部分原因可能是我们过度依赖阿片类药物处方。 治疗非癌症慢性疼痛，例如骨关节炎 (OA) 疼痛。阿片类药物广泛用于止痛 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使用。因此， 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)。这 热响应相变特性允许大分子前药制剂沉积在 滑膜腔持续存在很长一段时间。随着持续暴露于 滑液中，我们已经证明 ProGel 可以逐渐溶解并释放，然后 被滑膜吞噬细胞内化并在亚细胞内激活以释放 Dex。在初步研究中， 我们发现基于 P-Dex-H 的 ProGel 能够持续（> 1 个月）改善 佐剂性关节炎（AA）、单关节佐剂性关节炎（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。注射部位反应（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 配方尚未被 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 (DMM) 小鼠模型。因此，在这个快速通道项目的第一阶段，我们建议测试以下项目的可行性： 使用 ProGel 治疗 DMM 小鼠模型中的关节炎疼痛。彻底的物理化学表征， 包括ProGel相图的构建也将完成，为优化做准备 配方的。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最持久的优化配方 改善关节疼痛且毒性最小。 IND 能够对这种优化的 ProGel 配方进行 PK/BD 研究 然后将被执行。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。