Transmucosal Intra-Oral Drug Delivery System for THC

描述（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的药理学特性。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）用于治疗化疗引起的恶心和呕吐，并用于刺激患有消瘦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（降低眼压）和焦虑。在美国唯一可用的配方是软明胶口服胶囊。这种制剂有几个缺点，包括低和不稳定的生物利用度和第一遍效应，导致相对较高水平的11-OH-THC，这是一种具有更突出的心理特性的代谢物，导致药物的副作用。此外，为了达到治疗效果，每天需要多次剂量。对四氢大麻酚（和其他大麻素）治疗活动的兴趣增加，需要寻找替代的输送系统，正如1999年医学研究所（IOM）报告所建议的那样。因此，我们已经着手开发一种基于热熔延伸（HME）的新配方，以从粘膜基质贴片（TMP）中输送四氢大麻酚。在第一阶段期间，以及之后的努力中（为本申请做准备），制备和测试了几种含有四氢大麻酚或其前体药物的配方。尽管体外研究显示了TMP中四氢大麻酚令人鼓舞的稳定性、生物粘附性和渗透结果，但没有观察到兔动物模型中的生物利用度。研究了THC的前药THC-半琥珀酸盐（THC-半琥珀酸盐），并开发了一种具有正稳定性、生物黏附性和渗透性的制剂。在兔模型中对THC- hs制剂的体内测试显示出非常有希望的结果，其血液中THC的含量高达6 ng/mL， THC酸代谢物达到17 ng/mL，几乎没有11-OH-THC，显示出药物的真正经黏膜吸收和第一次绕过。第二阶段申请的目标是利用第一阶段获得的结果，并开发一种配方，用于从TMP系统中有效、持续地递送四氢大麻酚，其中包含最合适的四氢大麻酚前药。因此，不同的前药将在II期合成，并根据稳定性、生物粘附性和体外渗透性评估选择最佳前药/配方。体内评估将包括每种前药的LD50测定，只有LD50与四氢大麻酚相当或高于四氢大麻酚的前药才有资格进行进一步的研究。有希望的配方将在体内进行评估，首先在兔子模型中，然后在猪模型中（更能预测人类的全身吸收）。最后，选定的前药将进行cGMP生产，并生成稳定性数据（至少3个月），以支持原料药在准备TMP系统供应中用于I期临床评估。

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).