Transdermal Cannabinoid Prodrug Treatment for Cannabis Withdrawal and Dependence

大麻使用障碍影响大约1.5%的美国人口，超过一半的大麻成瘾者在试图戒烟时会出现明显的戒断症状，这有助于大麻使用的复发和维持。AllTranz正在寻求资金来创建Delta-9-四氢大麻酚（THC）的透皮递送系统，作为大麻戒断和依赖的辅助治疗。虽然批准的THC（Marinol）胶囊为大麻使用障碍提供了潜在有效的治疗，但由于峰值血浆水平相关的副作用和短的作用持续时间，口服药物递送是不期望的。透皮系统将是具有最终剂量/持续时间灵活性的非侵入性非口服剂型，并且还具有较少的药物副作用（即，没有THC血浆峰值水平相关的欣快）。最初积极的初步数据鼓励AllTranz寻求资金开发新的THC前药，并通过透皮给药系统优化其使用。前药是化学修饰的母体药物，其比母体药物更具有皮肤渗透性，并且一旦它们穿过角质层就迅速分离回母体药物和前药部分。透皮制剂还提供比立即释放剂型更多的滥用威慑。经皮递送系统提供了优于其它递送系统的许多改进。贴片和凝胶不需要吞咽，消除了口腔副作用和苦味问题;它们也不需要用针刺穿皮肤，消除了疼痛和患者就医。通过皮肤的渗透允许药物直接进入体循环并避免首过效应，从而减少肝损害药物滥用者的胃副作用和肝损伤效应。具体而言，我们的目标是合成THC的皮肤可渗透前药。然后，我们的目标是评估其在体外人体皮肤渗透的最佳流量。将评价最佳前药的化学稳定性和粘合贴剂制剂的性能。最佳前药候选物将进行合成放大优化，原型贴剂将被制造，并将完成临床前毒理学测试。IND将提交给FDA，以便完成I期临床试验。根据这一为期两年的计划，可以完成大麻戒断概念研究的证明。我们将创造一种可销售的透皮药物，这将大大有助于治疗大麻依赖和戒断。 公共卫生相关性：大麻使用障碍影响大约1.5%的美国人口，超过一半的大麻成瘾者在试图戒烟时会出现明显的戒断症状，这有助于大麻使用的复发和维持。AllTranz正在寻求资金，以创建一个THC的经皮给药系统，作为大麻戒断和依赖的辅助治疗。透皮系统将是具有最终剂量灵活性的非侵入性非口服剂型，并且还具有较少的药物副作用（即，没有THC血浆峰值水平相关的欣快症）。

DESCRIPTION (provided by applicant): Cannabis use disorders affect approximately 1.5% of the United States population, and more than half of the individuals addicted to marijuana experience significant withdrawal symptoms if they try to quit, which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking funding to create a transdermal delivery system of delta-9-tetrahydrocannabinol (THC) as an adjunct treatment for marijuana withdrawal and dependence. While the approved THC (Marinol) capsule provides potentially effective treatment for cannabis use disorders, oral drug delivery is not desirable because of the peak plasma level related side effects and short duration of action. The transdermal system would be a non-invasive non-oral dosage form with ultimate dosing/duration flexibility, and also have fewer drug side effects (i.e. no THC plasma peak level related euphoria). Initial positive preliminary data has encouraged AllTranz to seek funding to develop new THC prodrugs and optimize their use through a transdermal drug delivery system. 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. Transdermal formulations also provide more abuse deterrence than immediate release dosage forms. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches and gels do not require swallowing, eliminating oral side effects and bitter taste concerns; nor do they require skin puncture by needles, eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect, decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers. Specifically we aim to synthesize skin permeable prodrugs of THC. We then aim to assess their in vitro human skin permeation for optimum flux. The optimal prodrugs will be evaluated for chemical stability and performance in adhesive patch formulations. The best prodrug candidate will undergo synthesis scale-up optimization, prototype patches will be manufactured, and preclinical toxicology testing will be completed. An IND will be submitted to the FDA so that a Phase I clinical trial can be completed. A proof of concept study in marijuana withdrawal can be completed under this two-year plan. We will create a marketable transdermal drug that will significantly aid in the treatment of marijuana dependence and withdrawal. PUBLIC HEALTH RELEVANCE: Cannabis use disorders affect approximately 1.5% of the United States population, and more than half of the individuals addicted to marijuana experience significant withdrawal symptoms if they try to quit, which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking funding to create a transdermal delivery system of THC as an adjunct treatment for marijuana withdrawal and dependence. The transdermal system would be a non-invasive non-oral dosage form with ultimate dosing flexibility, and also have fewer drug side effects (i.e. no THC plasma peak level-related euphoria).