Transdermal Cannabinoid Prodrug Treatment for Cannabis Withdrawal and Dependence

描述（由申请人提供）：大麻使用障碍影响了大约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，这导致了大麻使用的复发和维持。AllTranz正在寻求资金，以创建一种德尔塔-9-四氢大麻酚（THC）的透皮给药系统，作为大麻戒断和依赖的辅助治疗。虽然经批准的四氢大麻酚胶囊对大麻使用障碍提供了潜在的有效治疗，但由于与血浆峰值水平相关的副作用和作用时间短，口服药物不可取。透皮系统将是非侵入性的非口服剂型，具有最终剂量/持续时间的灵活性，并且也具有更少的药物副作用（即没有THC血浆峰值水平相关的快感）。初步积极的初步数据鼓励AllTranz寻求资金来开发新的四氢大麻酚前药，并通过透皮给药系统优化其使用。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。透皮制剂也提供更多的滥用威慑比立即释放剂型。透皮给药系统比其他给药系统有许多改进。贴片和凝胶不需要吞咽，消除了口服副作用和苦味问题；它们也不需要用针头刺穿皮肤，从而消除了疼痛和病人看医生的时间。通过皮肤渗透使药物直接进入体循环，避免了首过效应，减少了肝损害药物滥用者的胃副作用和肝损害作用。具体来说，我们的目标是合成四氢大麻酚的皮肤渗透性前药。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。最佳的前药将被评价为化学稳定性和粘合贴剂配方的性能。最佳前药候选药物将进行合成放大优化，原型贴片将生产，临床前毒理学测试将完成。IND将提交给FDA，以便完成I期临床试验。在这个为期两年的计划中，可以完成大麻戒断的概念验证研究。我们将创造一种可销售的透皮药物，它将显著帮助治疗大麻依赖和戒断。

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).