Transdermal Cannabidiol Prodrug Delivery

描述（由申请人提供）：超过8.5%的美国人口和全世界7500万人符合酒精使用障碍（AUDs）的诊断标准，酒精滥用是美国和世界三大可预防的公共卫生问题之一。AUDs通常被称为酒精中毒，其病因复杂，慢性酒精相关的神经变性、戒断相关的焦虑和持续的酒精渴望是高复发和不良临床结果的预测因素。AUDs的治疗将受益于药理学方法，可以解决这些被忽视的终点，以改善临床结果。然而，目前fda批准用于治疗过度饮酒的三种药物中，没有一种是针对神经变性、戒断或焦虑的。大麻二酚（CBD）是一种可以改善这三种综合征的药物。经皮给药大麻素是一个可行的替代口服剂量。大多数大麻素在肝脏中被高度代谢。CBD的口服生物利用度仅为6%左右，在CBD口服剂量临床试验中检测到血浆药物水平很低。患者口服大麻素的临床试验很可能由于药物剂型选择不当而产生不一致的结果。我们假设可以开发一种CBD透皮剂型，并且这种剂型可以在未来的酒精患者临床研究中提供治疗水平的药物。整个项目的长期假设是，CBD将减少戒断相关的焦虑和控制酒精渴望，从而通过调节内源性大麻素系统降低酗酒者的高复发易感性。在实现这一目标的第一步，将对通过透皮微针给药的CBD前药进行概念验证评估。CBD本身不会以治疗速率渗透皮肤，除非将其作为凝胶应用于较大的皮肤表面积，因为透皮应用的面积与递送速率成正比。前药是经过化学修饰的母体药物，比母体药物更具有皮肤渗透性，一旦穿过角质层，它们就会迅速分离回母体药物和前药部分。AllTranz的初步数据显示，CBD前药单独使用并不能改善皮肤渗透，除非前药是专门为微针设计的。此外，与优化后的CBD前药微针递送相比，单独使用微针递送CBD并没有显著增强。具体来说，我们的目标是合成CBD的前药，结合微针装置，它将非常具有皮肤渗透性。然后，我们的目标是评估他们的体外人体皮肤渗透的最佳通量。在未来的研究中，我们将开发原型产品并申请IND，并在健康对照和酗酒者中开始I期临床试验。未来的CBD透皮系统也可以在II期临床试验中进行测试，用于阿片类药物成瘾、镇痛作用、炎症缓解（关节炎）和恶心呕吐治疗，因为有大量的临床前/临床数据证明CBD对这些适应症的治疗效用。

DESCRIPTION (provided by applicant): With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol abuse is among the top three preventable public health problems in the U.S. and the world. AUDs, commonly referred to as alcoholism, have a complex etiology where chronic alcohol associated neurodegeneration, withdrawal-related anxiety and persistent alcohol craving are predictive of high relapse and poor clinical outcomes. The treatment of AUDs would benefit from a pharmacological approach that could address these overlooked endpoints to improve clinical outcomes. However, of the three drugs currently FDA-approved for the treatment of excessive alcohol consumption, none address neurodegeneration, withdrawal or anxiety. Cannabidiol (CBD) is a drug that could improve these three syndromes. Transdermal drug delivery of cannabinoids is a viable alternative to oral dosing. Most of the cannabinoids are highly metabolized in the liver. The oral bioavailability of CBD is only about 6%, and very low plasma drug levels were detected in CBD oral dose clinical trials. It is highly possible that clinical trials of oral dose cannabinoids in patients have given inconsistent results because of a poor choice of drug dosage form. We hypothesize that a CBD transdermal dosage form can be developed, and that this dosage form could provide therapeutic levels of drug in a future clinical study with alcoholic patients. The long-term hypothesis of the overall project is that CBD will decrease withdrawal related anxiety and control alcohol craving, thereby decreasing high relapse susceptibility in alcoholics by modulating the endocannabinoid system. In the first step towards this goal, a proof of concept evaluation of CBD prodrugs delivered via transdermal microneedles will be conducted. CBD itself does not permeate the skin at a therapeutic rate, unless it is applied as a gel to a large skin surface area, as the area of transdermal application is directly proportional to the delivery rate. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent, and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. AllTranz has preliminary data showing that CBD prodrugs alone do not improve skin permeation, unless the prodrugs are specifically designed for use with microneedles. Additionally, CBD delivery with microneedles alone is not significantly enhanced, as compared to optimized CBD prodrugs for microneedle delivery. Specifically we aim to synthesize prodrugs of CBD that will be very skin permeable in combination with a microneedle device. We then aim to assess their in vitro human skin permeation for optimum flux. In future studies we will develop the prototype product and apply for an IND and begin Phase I clinical trials in healthy controls and alcoholics. The future CBD transdermal system could also be tested in Phase II clinical trials for opiate addiction, analgesic effect, inflammation relief (arthritis), and nausea and vomiting treatment, as there is substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications. PUBLIC HEALTH RELEVANCE: With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol abuse is among the top three preventable public health problems in the U.S. and the world. Currently approved pharmacological treatments in the treatment of alcoholism and other types of drug addiction are limited in that they do not address multiple aspects of addiction: craving, neurodegeneration, withdrawal and anxiety. The proposed preclinical research will accelerate testing of cannabidiol (CBD) in an appropriate delivery system to assess its potential benefits as a lead candidate in the search for novel alcoholism and other drug addiction pharmacotherapies. The future CBD transdermal system could also be tested in Phase II clinical trials for analgesic effect, inflammation relief, and nausea and vomiting treatment, as there is also substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications.