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

2-花生四烯酰甘油 (2-AG) 经皮给药治疗关节炎

• 批准号: 8279206
• 负责人: Audra L. Stinchcomb
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279206
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Adverse drug effect; Adverse effects; Affect; American; Animals; Arthralgia; Arthritis; Autoimmune Diseases; Binding; Biological Products; CNR1 gene; CNR2 gene; Caring; Cavia; Cells; Chronic Disease; Combined Modality Therapy; Data; Defect; Degenerative polyarthritis; Dermis; Deterioration; Development; Diffusion; Dosage Forms; Drug Addiction; Endocannabinoids; Future; Gel; Human; Immune system; In Vitro; Inflammatory Bowel Diseases; Injection of therapeutic agent; Intra-Articular Injections; Joints; Measures; Medical; Methods; Multiple Sclerosis; Opioid; Oral; Organ; Pain; Pain-Free; Pathway interactions; Patient Care; Patient Noncompliance; Patients; Penetration; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Play; Population; Pre-Clinical Model; Prodrugs; Productivity; Property; Publishing; Quality of life; Research; Rheumatoid Arthritis; Risk; Role; Route; Salts; Secondary to; Series; Site; Skin; Solubility; Solvents; Stratum corneum; Structure; Synovial Fluid; Synovial Membrane; System; Systemic Lupus Erythematosus; TRPV1 gene; Testing; Therapeutic; Tissues; United States; United States National Institutes of Health; Vanilloid; Wages; addiction; analog; anandamide; compliance behavior; cost; effective therapy; improved; in vivo; inflammatory pain; joint stiffness; methanandamide; novel; receptor; tool

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.

描述（由申请人提供）：本研究提出改善 2-花生四烯酰甘油 (2-AG) 的透皮递送，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）的关节痛。目前治疗这些病症的方法并不总能为许多患者提供足够的疼痛缓解，或者与成瘾、各种副作用和/或患者不依从性有关。过去十年，系统性 RA 治疗取得了巨大进步；然而，许多患者的关节疼痛和僵硬仍然严重未缓解，尽管新的生物制剂可能会阻止他们的关节恶化。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，已被证明可通过 CB2 受体在缓解炎性疼痛方面发挥强大作用。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。局部产品比痛苦的局部注射更能提供局部治疗效果，同时降低全身不良反应的风险。此外，该产品不会存在一些患者用来治疗关节疼痛的阿片类药物的滥用倾向问题。因此，我们假设含有2-AG前药的透皮凝胶或贴剂将成为与自身免疫性疾病相关的关节炎和关节痛的重要辅助治疗，并且将显着改善患者护理和生活质量。 在我们对无毛豚鼠皮肤进行的初步扩散研究中，发现 2-AG 通量为 137.7127.1 ng/cm2/h，皮肤（上层）中的药物含量为 965.21516 5g 药物/g 皮肤。已发表的数据显示，由于难以从角质层中分离出来，真皮层中疏水性化合物的浓度仅达到皮肤上层的约25-50%。在最近发表的一项 2-AG 研究中，滑液中需要约 1 mg/ml 的初始浓度才能治疗关节疼痛，疗效达 50%。因此，需要将 2-AG 扩散增强至少 2-4 倍才能在组织深层和滑膜中达到此浓度。我们的目标是合成 2-AG 的亲水性前药，以改善穿过皮肤进入滑液的渗透性。由于优化的理化特性可实现更快的扩散，前药应提高 2-AG 穿过皮肤的递送速率。如果前药不能提高2-AG的通量，则将进行微针辅助递送2-AG或其前药的盐。该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）测量前药在无毛豚鼠和人体皮肤中的体外渗透和同时生物转化，以及（4）比较 2-AG 前药与 Methanandamide 和 O-1812（Anandamide 的稳定类似物）的透皮递送。