Transdermal delivery of 2-Arachidonoyl glycerol (2-AG) for the treatment of arthr

描述(申请人提供)：这项研究建议改进2-花生四烯酸甘油(2-AG)的经皮给药，用于辅助治疗骨关节炎、类风湿性关节炎(RA)和继发于其他自身免疫性疾病的关节疼痛，如炎症性肠道疾病、多发性硬化症和系统性红斑狼疮。目前针对这些疾病的治疗方法并不总是对许多患者提供足够的疼痛缓解，或者与成瘾、各种副作用和/或患者不依从有关。在过去的十年中，全身性类风湿关节炎的治疗有了很大的改善；然而，许多患者仍然有大量未缓解的关节疼痛和僵硬，即使他们的关节恶化可以被新的生物制剂阻止。因此，迫切需要开发治疗关节疼痛的新型药物。2-AG是一种内源性大麻素，已被证明通过CB2受体在减轻炎性疼痛中发挥重要作用。最近的一项研究表明，在关节炎疼痛的临床前模型中，关节内注射2-AG可以减轻关节疼痛。在提供局部治疗益处方面，局部产品比痛苦的局部注射更好，同时降低全身不良反应的风险。此外，该产品不会有一些患者用来治疗关节疼痛的阿片类药物的滥用责任问题。因此，我们假设含有2-AG前体药物的透皮凝胶或贴片将是治疗与自身免疫性疾病相关的关节炎和关节疼痛的重要辅助疗法，并将显著改善患者的护理和生活质量。在我们对无毛豚鼠皮肤的初步扩散研究中，发现2-AG通量为137.7127.1 ng/cm~2/h，皮肤(上层)药物含量为965.21516 5g/g皮肤。已发表的数据显示，由于角质层难以分离，疏水化合物在真皮中的浓度可能仅达到表层皮肤的25%-50%左右。在最近发表的一项2-AG研究中，关节液中需要大约1 mg/ml的初始浓度来治疗关节疼痛，疗效为50%。因此，需要将2-AG的扩散增强至少2-4倍，才能在更深的组织层和滑膜中达到这个浓度。我们的目标是合成2-AG的亲水性前体药物，以促进经皮渗透到滑液中。前药应提高2-AG在皮肤中的释放速度，因为它具有更快扩散的最佳物理化学性质。如果前药不能改善2-AG的通量，将进行微针辅助递送2-AG的盐类或其前药。本项目的具体目标包括：(1)合成一系列用于透皮通量优化的2-AG前药，(2)表征药物的理化参数，包括在选定溶剂中的溶解度和稳定性，(3)测定前药在无毛豚鼠和人皮肤中的渗透和同时生物转化，(4)比较2-AG前药与甲胺和安非他胺的稳定类似物O-1812的透皮吸收。 与公共卫生相关：自身免疫性疾病是一种免疫系统缺陷，会导致身体攻击自己的器官、组织和细胞，由80多种慢性病组成，影响着2000多万美国人。类风湿性关节炎(RA)是一种自身免疫性疾病，影响约130万关节炎和相关疾病，如RA，每年给美国经济造成近1280亿美元的医疗和间接费用，包括工资和生产力损失。目前针对这些疾病的治疗方法并不总是对许多患者提供足够的疼痛缓解，或者与各种副作用、药物成瘾潜力和/或患者不依从性有关。这项研究建议改进2-花生四烯基甘油(2-AG)的经皮给药，以辅助治疗骨关节炎、类风湿性关节炎(RA)和继发于其他自身免疫性疾病的关节疼痛，如炎症性肠病、多发性硬化症和系统性红斑狼疮。透皮系统可以在使用部位提供更多的局部药物作用，也可以减少全身药物副作用。

DESCRIPTION (provided by applicant): This research proposes to improve the transdermal delivery of 2-arachidonoylglycerol (2-AG) for the adjunct treatment of osteoarthritis, rheumatoid arthritis (RA) and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus. Current methods of treatment for these conditions do not always provide adequate pain relief in many patients, or are associated with addiction, various side effects and/or patient noncompliance. Systemic RA treatments have drastically improved over the last decade; however, many patients still have substantial unrelieved joint pain and stiffness, even though their joint deterioration may be arrested by new biological agents. Thus, there is a strong need for the development of novel drug treatments for joint pain. 2-AG, an endocannabinoid, has been shown to play a strong role in alleviation of inflammatory pain via CB2 receptors. A recent study has shown that intra-articular injection of 2-AG in a preclinical model of arthritic pain decreased joint pain. Topical products are better than painful local injections in providing local therapeutic benefit, while reducing the risk of systemic adverse effects. Additionally, this product would not have the abuse liability problems of opioids that some patients use to treat joint pain. Thus, we hypothesize that a transdermal gel or patch containing a prodrug of 2-AG will be an important adjunct treatment in arthritis and joint pain associated with autoimmune diseases, and would be a significant improvement in patient care and quality of life. In our preliminary diffusion studies with hairless guinea pig skin, 2-AG flux was found to be 137.7127.1 ng/cm2/h and the drug content in the skin (upper layer) was 965.21516 5g of drug/g of skin. Published data shows that the dermis concentration of hydrophobic compounds may reach only about 25-50% compared to the upper skin layer because of the difficulty in partitioning out of the stratum corneum. In a recently published 2-AG study, an initial concentration of about 1 mg/ml was needed in synovial fluid to treat joint pain with 50% efficacy. Hence, an enhancement of 2-AG diffusion by at least 2-4 fold will be needed to reach this concentration in the deeper layers of tissue and into the synovium. We aim to synthesize hydrophilic prodrugs of 2-AG to improve permeation across the skin into synovial fluid. Prodrugs should improve the delivery rates of 2-AG across the skin because of optimized physiochemical properties for faster diffusion. If prodrugs fail to improve the flux of 2-AG, microneedle assisted delivery of salts of 2-AG or its prodrugs will be carried out. The specific aims of this project include: (1) to synthesize a series of 2-AG prodrugs for transdermal flux optimization, (2) to characterize the physicochemical parameters of the drugs, including solubilities and stabilities in select solvents, (3) to measure the penetration and concurrent bioconversion of the prodrugs in hairless guinea pig and human skin in vitro, and (4) to compare the transdermal delivery of 2-AG prodrugs with methanandamide, and O-1812, the stable analogs of anandamide. PUBLIC HEALTH RELEVANCE: Autoimmune diseases, immune system defects that cause the body to attack its own organs, tissues, and cells, consist of more than 80 chronic diseases and affect more than 20 million Americans. Rheumatoid arthritis (RA) is an autoimmune disease which affects approximately 1.3 million Arthritis and related conditions, such as RA, cost the U.S. economy nearly $128 billion per year in medical care and indirect expenses, including lost wages and productivity. Current methods of treatment for these conditions do not always provide adequate pain relief in many patients, or are associated with various side effects, drug addiction potential, and/or patient noncompliance. This research proposes to improve the transdermal delivery of 2-arachidonoylglycerol (2-AG) for the adjunct treatment of osteoarthritis, rheumatoid arthritis (RA) and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus. A transdermal system can provide more local drug effect at the site of application and also have fewer systemic drug side effects.