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:
    10326409
  • 负责人:
  • 金额:
    $ 84.04万
  • 依托单位:
  • 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 2023-12-31
  • 项目状态:
    已结题

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 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) 2017年仅在美国就超过500万。阿片类药物使用障碍(OUD)病例的显著增加 在过去的20年中,部分原因可能是我们过度依赖阿片类药物的处方, 治疗非癌症慢性疼痛,如骨关节炎(OA)疼痛。阿片类药物在疼痛中的广泛应用 管理可能与各种副作用有关,包括便秘,恶心,头晕,呕吐, 肝损伤、由于缺氧导致的呼吸抑制导致脑损伤,以及身体依赖, 宽容和成瘾。由于身体依赖性和耐受性, 导致OUD和与成瘾相关的交织的海洛因使用的报道。因此 该项目的目标是开发,翻译和商业化一种新的非阿片类药物疗法, 有效、安全地管理OA疼痛,并预防骨关节炎患者的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),其是在还原温度下自由流动的水溶液。 在室温下,水凝胶可以是水凝胶,但是当温度升高到> 30 °C时,水凝胶变成水凝胶(ProGel)。这 热响应相变性质允许大分子前药制剂沉积在 滑膜腔持续存在一段时间。持续暴露在 滑液,我们已经表明,ProGel可以逐渐溶解和释放后,它是 通过滑膜吞噬细胞内化并在亚细胞内活化以释放Dex。在初步研究中, 我们已经发现,基于P-Dex-H的ProGel能够提供持续(> 1个月)的改善, 关节疼痛模型的抗炎药诱导的关节炎(AA),单关节抗炎药诱导的关节炎(MAA)和 单碘乙酸盐诱导的骨关节炎(MIA)。此外,典型的糖皮质激素副作用,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),如在CalpionTherapeutics的Zilretta™(曲安奈德缓释剂)的情况下所见 在用ProGel处理的动物中也不存在。然而,ProGel制剂还没有被广泛应用。 在临床相关的骨关节炎模型中进行评价,例如内侧半月板的手术失稳 (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 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 的提法。对于第二阶段,我们建议通过调整各种因素来优化ProGel配方。 结构参数,目的是确定具有最有效和最持久的 关节疼痛改善和最小毒性。该优化ProGel制剂的IND启用PK/BD研究 将被执行。拟议研究的成功完成将有助于ProGel技术 成为IND准备进一步的临床评价。

项目成果

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STEVEN GOLDRING其他文献

STEVEN GOLDRING的其他文献

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{{ truncateString('STEVEN GOLDRING', 18)}}的其他基金

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:
    10013068
  • 财政年份:
    2020
  • 资助金额:
    $ 84.04万
  • 项目类别:
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:
    10281291
  • 财政年份:
    2020
  • 资助金额:
    $ 84.04万
  • 项目类别:
CELLULAR RESPONSES TO INORGANIC PARTICULATES
细胞对无机颗粒的反应
  • 批准号:
    6375146
  • 财政年份:
    1999
  • 资助金额:
    $ 84.04万
  • 项目类别:
CELLULAR RESPONSES TO INORGANIC PARTICULATES
细胞对无机颗粒的反应
  • 批准号:
    6511933
  • 财政年份:
    1999
  • 资助金额:
    $ 84.04万
  • 项目类别:
CELLULAR RESPONSES TO INORGANIC PARTICULATES
细胞对无机颗粒的反应
  • 批准号:
    6171148
  • 财政年份:
    1999
  • 资助金额:
    $ 84.04万
  • 项目类别:
CELLULAR RESPONSES TO INORGANIC PARTICULATES
细胞对无机颗粒的反应
  • 批准号:
    6607019
  • 财政年份:
    1999
  • 资助金额:
    $ 84.04万
  • 项目类别:
CELLULAR RESPONSES TO INORGANIC PARTICULATES
细胞对无机颗粒的反应
  • 批准号:
    2904798
  • 财政年份:
    1999
  • 资助金额:
    $ 84.04万
  • 项目类别:
FUNCTION OF CALCITONIN RECEPTORS
降钙素受体的功能
  • 批准号:
    6100313
  • 财政年份:
    1997
  • 资助金额:
    $ 84.04万
  • 项目类别:
CALCITONIN RECEPTORS IN DEVELOPMENT
降钙素受体的发育
  • 批准号:
    6100314
  • 财政年份:
    1997
  • 资助金额:
    $ 84.04万
  • 项目类别:
GORDON CONFERENCE ON CELL AND MOLECULAR BIOLOGY OF BONES
骨骼细胞和分子生物学戈登会议
  • 批准号:
    2083284
  • 财政年份:
    1995
  • 资助金额:
    $ 84.04万
  • 项目类别:

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