Transmucosal Intra-Oral Drug Delivery System for THC

THC 经粘膜口腔内给药系统

• 批准号: 7406567
• 负责人: MAHMOUD A ELSOHLY
• 金额: $ 34.47万
• 依托单位: ELSOHLY LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406567
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Adjuvant; Adverse drug effect; Aluminum; Animal Model; Antioxidants; Anxiety; Biological Assay; Biological Availability; Blood; Blood flow; Butyrates; Bypass; Cancer Patient; Cannabinoids; Cannabis; Clinical Trials; Condition; Cyclic GMP; Daily; Data; Desire for food; Development; Dose; Drug Delivery Systems; Drug Formulations; Enhancers; Environment; Esters; Ethanol; Evaluation; Exhibits; Family suidae; Figs - dietary; Gelatin; Glaucoma; Goals; Grant; Guanosine Monophosphate; Hand; Human; Humidity; In Vitro; Institute of Medicine (U.S.); Intestinal Mucosa; Lead; Lethal Dose 50; Life; Light; Maintenance; Metabolism; Modeling; Mucous Membrane; Mus; Nausea and Vomiting; Nitrogen; Oral; Oral mucous membrane structure; Oryctolagus cuniculus; Pain management; Parents; Patients; Permeability; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Plants; Plasma; Polyethylene Glycols; Preparation; Process; Prodrugs; Production; Property; Qualifying; Range; Rate; Reporting; Research Project Grants; Resources; Salts; Sampling; Screening procedure; Sodium Chloride; Solutions; Study Section; Sus scrofa; System; Temperature; Testing; Tetrahydrocannabinol; Therapeutic; Time; Toxic effect; Treatment Efficacy; United States; United States Food and Drug Administration; Wasting Syndrome; Water; Work; Xerostomia; absorption; aqueous; base; butyrate; capsule; chemotherapy; chronic pain; concept; controlled release; day; hydrophilicity; improved; in vivo; interest; melting; microbial alkaline proteinase inhibitor; packaging material; planetary Atmosphere; pre-clinical; prototype; psychologic; rectal; research clinical testing; vitamin E succinate

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).

描述（由申请人提供）： Delta-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。该药物已获得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，以及刺激患有消耗综合征的艾滋病患者的食欲。其他治疗方法包括疼痛管理（慢性疼痛）、青光眼（降低眼压）和焦虑。美国唯一可用的配方是软明胶口服胶囊。该制剂存在一些缺点，包括生物利用度低且不稳定，以及首过效应，导致 11-OH-THC 水平相对较高，这是一种具有更突出的心理特性的代谢物，会导致药物的副作用。此外，需要每日多次剂量才能达到治疗效果。正如 1999 年医学研究所 (IOM) 报告中所建议的那样，人们对 THC（和其他大麻素）治疗活性的兴趣日益浓厚，因此需要寻找替代的输送系统。因此，我们开始开发一种基于热熔延伸 (HME) 从经粘膜基质贴片 (TMP) 输送 THC。在第一阶段期间以及此后进行的努力（为本申请做准备）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 TMP 中的 THC 具有令人鼓舞的稳定性、生物粘附性和渗透性，但未观察到兔子动物模型中的生物利用度。研究了 THC 的前药 THC-半琥珀酸酯（或 THC-HS），并开发了一种用于掺入 TMP 系统的制剂，该制剂具有良好的稳定性、生物粘附性和渗透性。 THC-HS 制剂在兔子模型中的体内测试显示出非常有希望的结果，其中血液浓度达到 6 ng/mL THC 和 17 ng/mL THC 酸性代谢物，几乎不含 11-OH-THC，显示出药物真正的跨粘膜吸收并绕过第一道。第二阶段申请的目标是利用第一阶段获得的结果，并开发一种制剂，用于从包含最合适的 THC 前药的 TMP 系统中有效、持续地输送 THC。因此，将在第二阶段合成不同的前药，并根据稳定性、生物粘附性和体外渗透特性进行评估，以选择最佳的前药/制剂。体内评估将包括每种前药的 LD50 测定，只有 LD50 与 THC 相当或更高的前药才有资格进行进一步研究。然后将在体内评估有前景的配方，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（至少三个月），以支持使用 API 为 I 期临床评估准备 TMP 系统供应。 叙述：该 II 期申请旨在开发跨粘膜贴片 (TMP) 系统，以有效且持续地输送 THC。这种输送系统对于患有 THC 有效药物的疾病的患者（癌症患者的恶心和呕吐，艾滋病患者的食欲刺激，慢性疼痛、青光眼和焦虑的治疗）具有很大的价值。