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

描述（由申请人提供）：本研究旨在改善2-花生四烯酸甘油（2-AG）的透皮给药，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（如炎症性肠病、多发性硬化症和系统性红斑狼疮）的关节疼痛。目前治疗这些病症的方法并不总是在许多患者中提供足够的疼痛缓解，或者与成瘾、各种副作用和/或患者不依从性相关。在过去的十年中，全身性RA治疗有了很大的改善;然而，许多患者仍然有大量的未缓解的关节疼痛和僵硬，即使他们的关节恶化可能会被新的生物制剂阻止。因此，迫切需要开发用于关节疼痛的新型药物治疗。 2-AG是一种内源性大麻素，已被证明通过CB 2受体在缓解炎症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可减轻关节疼痛。局部产品在提供局部治疗益处方面优于疼痛的局部注射，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于治疗关节疼痛的阿片类药物的滥用问题。因此，我们假设含有2-AG前药的透皮凝胶或贴剂将是与自身免疫性疾病相关的关节炎和关节疼痛的重要辅助治疗，并且将显著改善患者护理和生活质量。 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137.7 ± 27.1 ng/cm ~ 2/h，皮肤（上层）中的药物含量为965.21516 5g药物/g皮肤。公开的数据显示，与上皮肤层相比，疏水化合物的真皮浓度可能仅达到约25-50%，因为难以从角质层中分离出来。在最近发表的2-AG研究中，滑液中需要约1 mg/ml的初始浓度才能以50%的疗效治疗关节疼痛。因此，需要将2-AG扩散增强至少2-4倍，以在组织的深层中达到该浓度并进入滑膜。我们的目标是合成2-AG的亲水性前药，以改善通过皮肤渗透到滑液中。前药应改善2-AG通过皮肤的递送速率，因为优化的理化性质可实现更快的扩散。如果前药不能改善2-AG的通量，则将进行2-AG或其前药的盐的微针辅助递送。该项目的具体目标包括：（1）合成一系列用于经皮通量优化的2-AG前药，（2）表征药物的物理化学参数，包括在所选溶剂中的溶解度和稳定性，（3）测量前药在无毛豚鼠和人皮肤中的体外渗透和同时生物转化，（4）比较2-AG前体药物与花生四烯酸甲酯胺和O-1812（花生四烯酸甲酯胺的稳定类似物）的透皮递送。

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.