Transmucosal Intra-Oral Drug Delivery System for THC

说明（由申请人提供）：δ-9-四氢大麻酚（THC）是大麻植物中的活性成分，具有广泛的治疗价值药理特性。该药物已被美国食品和药物管理局（FDA）批准（Marinol（r）软明胶胶囊）用于治疗与化疗相关的恶心和呕吐，并用于刺激患有消耗综合征的艾滋病患者的食欲。其他可能的治疗包括疼痛管理（慢性疼痛），青光眼（降低眼内压）和焦虑。在美国唯一可用的配方是软明胶口服胶囊。该制剂具有几个缺点，包括低的和不稳定的生物利用度和首过效应，其导致相对高水平的11-OH-THC，其是具有更突出的心理特性的代谢物，其有助于药物的副作用。此外，需要每日多次给药以获得治疗效果。对四氢大麻酚（和其他大麻素）治疗活性的兴趣日益增加，有必要寻找替代的输送系统，如1999年医学研究所报告所建议的那样。因此，我们已着手开发一种基于热熔延伸（HME）的新配方，以从三氯甲烷基质贴剂（TMP）中释放THC。在I期期间，以及在此后进行的努力中（在本申请的准备中），制备并测试了几种含有THC或其前药的制剂。尽管体外研究显示出令人鼓舞的稳定性、生物粘附性和TMP中THC的渗透结果，但在兔动物模型中未观察到生物利用度。研究了THC的前药THC-半琥珀酸酯（或THC-HS），并开发了用于掺入TMP系统的制剂，其具有积极的稳定性、生物粘附性和渗透性。在兔模型中对THC-HS制剂的体内测试证明了非常有希望的结果，其中血液水平达到高达6 ng/mL THC和17 ng/mL THC酸代谢物，几乎没有11-OH-THC，显示了药物的真正的经粘膜吸收和首过旁路。该II期申请的目标是利用I期期间获得的结果，并开发用于从掺入最合适的THC前药的TMP系统有效持续递送THC的制剂。因此，将在II期期间合成不同的前药，并基于稳定性、生物粘附性和体外渗透特性评价最佳前药/制剂的选择。体内评价将包括每种前药的LD 50测定，只有那些具有与THC相当或高于THC的LD 50的前药才有资格进行进一步的研究。然后将在体内评价有前景的制剂，首先在兔模型中，然后在猪模型中（更能预测人体的全身吸收）。最后，选定的前药将采用cGMP生产，并将生成稳定性数据（至少3个月），以支持使用API制备TMP系统供应，用于I期临床评价。 叙述：该第二阶段申请旨在开发一种用于有效和持续递送THC的甘草酸贴剂（TMP）系统。这种递送系统对于患有THC将是有效药物的病症（癌症患者的恶心和呕吐、AIDS患者的食欲刺激、慢性疼痛、青光眼和焦虑的治疗）的患者将具有很大的价值。

DESCRIPTION (provided by applicant): Delta-9-Tetrahydrocannabinol (THC), the active ingredient in the cannabis plant, has a wide range of pharmacological properties of therapeutic value. The drug has been approved by the Food and Drug Administration (FDA) (Marinol(r) soft gelatin capsules) for the treatment of nausea and vomiting associated with chemotherapy and for appetite stimulation in AIDS patients suffering from the wasting syndrome. Other therapeutic possibilities include pain management (chronic pain), glaucoma (lowering the intraocular pressure), and anxiety. The only formulation available in the United States is the soft gelatin oral capsule. This formulation suffers from several shortcomings including low and erratic bioavailability and first pass effect which results in relatively high levels of 11-OH-THC, a metabolite with much more prominent psychological properties which contribute to the side effects of the drug. In addition, multiple daily doses are required for therapeutic efficacy. The increased interest in THC (and other cannabinoids) therapeutic activities necessitated the search for alternative delivery systems, as was recommended in the Institute of Medicine (IOM) Report of 1999. We have, therefore, embarked on the development of a new formulation based on Hot Melt Extension (HME) to deliver THC from a Transmucosal Matrix Patch (TMP). During the Phase I period, and in efforts carried out thereafter (in preparation for this application), several formulations were prepared and tested that contained THC or a prodrug thereof. Although in vitro studies exhibited encouraging stability, bioadhesive, and permeation results for THC from TMP, bioavailability in the rabbit animal model was not observed. A prodrug of THC, THC-hemisuccinate (or THC-HS), was investigated, and a formulation for incorporation into a TMP system was developed with positive stability, bioadhesive, and permeability profile. In vivo testing of the THC-HS formulation in the rabbit model demonstrated extremely promising results, where blood levels reached up to 6 ng/mL THC and 17 ng/mL of THC acid metabolite, with almost no 11-OH-THC, showing a true transmucosal absorption of the drug and bypassing of the first pass. The goal of this Phase II application is to capitalize on the results obtained during Phase I, and to develop a formulation for the effective, sustained delivery of THC from a TMP system incorporating the most suitable THC prodrug. Therefore, different prodrugs will be synthesized during Phase II and evaluated for the selection of the best prodrug/formulation(s) based on stability, bioadhesive, and permeation in vitro profiles. In vivo evaluation will include LD50 determinations for each prodrug, with only those having LD50 comparable to or higher than that of THC qualifying for further studies. Promising formulations will then be evaluated in vivo, first in the rabbit model and then in the pig model (more predictive of systemic absorption in humans). Finally, the selected prodrug will be cGMP produced, and stability data (at least three months) will be generated to support the use of the API in preparing TMP systems supply for Phase I clinical evaluation. Narrative: This Phase II application is directed toward the development of a Transmucosal Patch (TMP) System for the effective and sustained delivery of THC. Such delivery system will be of great value for patients suffering from conditions for which THC would be an effective drug (nausea and vomiting in cancer patients, appetite stimulation in AIDS patients, treatment of chronic pain, glaucoma, and anxiety).