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: 8191585
• 负责人: kalpana paudel
• 金额: $ 1.52万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191585
• 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. 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.

描述（由申请人提供）：本研究旨在改善2-花生四烯醇甘油（2-AG）的经皮给药，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。目前对这些疾病的治疗方法并不总是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。在过去的十年里，系统性类风湿性关节炎的治疗得到了极大的改善；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被新的生物制剂所阻止。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受体在减轻炎症性疼痛中发挥重要作用。最近的一项研究表明，在临床前关节炎疼痛模型中关节内注射2-AG可减轻关节疼痛。局部产品比疼痛的局部注射在提供局部治疗效益方面更好，同时减少了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责任问题。因此，我们假设含有2-AG前药的透皮凝胶或贴片将成为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方法，并将显著改善患者的护理和生活质量。我们在无毛豚鼠皮肤上进行初步扩散研究，发现2-AG通量为137.7127.1 ng/cm2/h，皮肤（上层）中药物含量为965.21516 g/g。已发表的数据表明，由于角质层难以分离，真皮疏水化合物的浓度可能仅达到皮肤表层的25-50%。在最近发表的一项2-AG研究中，滑膜液中初始浓度约为1mg /ml，治疗关节疼痛的疗效为50%。因此，2-AG的扩散至少要增强2-4倍，才能在组织的较深层和滑膜中达到这个浓度。我们的目标是合成亲水的2-AG前药，以提高渗透通过皮肤滑膜液。前药可以提高2-AG在皮肤上的递送率，因为优化的理化性质可以加快扩散。如果前药不能改善2-AG的通量，将进行微针辅助递送2-AG盐或其前药。本课题的具体目的包括：(1)合成一系列2- ag前药用于透皮通量优化；(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)测定前药在体外无毛豚鼠和人皮肤中的渗透和同步生物转化；(4)比较2- ag前药与甲胺和O-1812（稳定的类似物）的透皮传递。