Development of cGMP Manufacturing Process for CBD

描述（由申请人提供）：医用大麻现在在20个州和哥伦比亚特区被批准用于几种医疗条件，如恶病质、癌症、慢性疼痛、癫痫和其他以癫痫发作为特征的疾病、青光眼、艾滋病毒、艾滋病、多发性硬化症、肌肉痉挛和恶心。在将大麻素用于医疗用途方面，在若干方面取得了进展，例如通过患者倡导团体的特别开发，将夏洛特网用于儿童癫痫。Sativex¿（GW Pharmaceuticals, England）是一种含有同等比例Δ9-THC和CBD的药物，最近在加拿大、新西兰和8个欧洲国家被批准作为多发性硬化症（MS）相关痉挛的二线治疗药物。按照cGMP指南生产的药用级CBD和标准化CW产品的现成可用性，将促进NIH研究人员和其他研究人员对癫痫、多发性硬化症和其他中枢神经系统疾病的临床评估。开发的工艺还将用于制造Δ9-THC，已经用于治疗癌症疼痛和恶心以及艾滋病相关的恶病质，以及其他正在开发的大麻素。本研究计划的主要目标是开发一种符合美国FDA现行良好生产规范（cGMP）的制药级CBD生产工艺，用于NIH和其他研究人员用于儿童癫痫和其他中枢神经系统适应症的临床试验。我们的第二个目标是开发一种标准化的、富集的CBD成分，类似于夏洛特网（CW）用于儿童癫痫。我们假设，利用超临界流体技术可以从高CBD含量的大麻中经济有效地生产CBD和CW，并且这种工艺也可以生产其他生物活性大麻素混合物，用于未来的研究和治疗用途。我们建议使用超临界流体和近临界流体（含或不含极性共溶剂，如醇），按照cGMP指南生产药用级CBD（98.5%和< 0.3% Δ9-THC）和标准化CW馏分（30% CBD和< 0.3% Δ9-THC） （superfluid¿）。这些流体是二氧化碳等气体，压缩后表现出增强的热力学性质，可以“微调”，快速、选择性地提取生物活性分子。我们将从科罗拉多州、缅因州或马萨诸塞州和/或NIDA的种植者那里获得足够数量的高CBD含量的大麻，以进行拟议的研究。根据奥巴马总统最近签署的新通过的农业法案，大麻的种植和州内运输（< 0.3% Δ9-THC）现在不受毒品执法机构附表1要求的限制。自2002年以来，Aphios已被批准为附表1研究机构，DEA许可号码为：RC0288058研发DEA附表1产品。我们的许可证每年更新一次。我们一期的具体目标是：(1)建立大麻选择性超流体分离的最佳条件，以分离绝对纯度为bb0 30%和< 0.3% Δ9-THC的CBD；(2)确定了进一步纯化CBD的superfluid色谱纯化条件，绝对纯度为bb0 ~ 80%， < 0.3% ~ 9-THC；(3)建立CBD绝对纯度>98.5% < 0.3% Δ9-THC最终纯化CBD的下游色谱条件。我们的II期具体目标如下：(4)设计大麻superfluid¿CXP和大麻分段色谱的cGMP流程，以生产标准化的CW和药用级CBD；(5)对现有的superfluid¿CXP装置进行改造，构建分段色谱系统，并对设备进行升级，以生产符合cGMP要求的标准化CW和药用级CBD；(6)按照cGMP指南和批号记录和产品放行文件，生产至少3个连续的大批量CW和CBD；(7)在CMC（化学、制造和控制）中记录IND申请的生产过程，并与FDA建立药物主文件（DMF）。在第三阶段，我们将生产药用级CBD供NIH和其他制药公司临床评估，并标准化CW供马萨诸塞州和其他州的医用大麻药房使用。为了避免与联邦政府的州内贩运问题，我们将向其他有医用大麻配药法律的州出售小型CXP制造单元、工艺条件和制造标准化CW产品的支持文件。大麻在几种医学适应症中的合法使用远远超过了对大麻和用于不同医疗用途的特定大麻素的医学和临床评估。1997年，美国国立卫生研究院召集了一个特设专家小组，讨论目前对大麻医疗用途的了解。该报告讨论了其他大麻素的重要性及其对四氢大麻酚的潜在相互作用，并指出：“大麻中也存在不同比例的其他大麻素，主要是大麻二酚（CBD）和大麻酚（CBN），有时其数量可能会改变四氢大麻酚的药理学或引起它们自己的影响。CBD没有精神活性，但具有显著的抗惊厥、镇静和其他可能与四氢大麻酚相互作用的药理活性。”医学研究所（IOM, 1999）得出结论，科学数据表明大麻素药物的潜在治疗价值，主要是Δ9-THC，缓解疼痛，控制恶心和呕吐，刺激食欲，应该进行大麻素药物用于症状管理的临床试验。我们建议生产药用级CBD，供NIH和其他制药公司用于多发性硬化症和其他中枢神经系统疾病的临床评估，以及一种标准化的夏洛特网（CW）产品，供马萨诸塞州和其他州的医用大麻药房用于儿童癫痫。

DESCRIPTION (provided by applicant): Medical marijuana is now approved in 20 states and the District of Columbia for several medical conditions such as cachexia, cancer, chronic pain, epilepsy and other disorders characterized by seizures, glaucoma, HIV, AIDS, Multiple Sclerosis, muscle spasticity and nausea. Progress has been made on several fronts on the use of cannabinoids for medical use such as Charlotte's Web (CW) being used for childhood epilepsy through ad hoc development by patient advocacy groups. Sativex¿ (GW Pharmaceuticals, England), a drug containing equal proportions of Δ9-THC and CBD, was recently approved as a second-line treatment for Multiple Sclerosis (MS) associated spasticity in Canada, New Zealand and 8 European countries. The ready availability of pharmaceutical-grade CBD and a standardized CW product, manufactured following cGMP guidelines, will facilitate clinical evaluation by NIH investigators and other researchers for epilepsy, MS and other CNS diseases. The developed process will also be utilized for the manufacturing of Δ9-THC, already in use for cancer pain and nausea and AIDS-related cachexia, and other cannabinoids in development. The primary goal of this research program is to develop a process for manufacturing pharmaceutical grade CBD following current Good Manufacturing Practices (cGMP) of the US FDA for use in clinical trials for childhood epilepsy and other CNS indications by the NIH and other researchers. Our secondary goal is to develop a standardized, enriched CBD fraction, similar to Charlotte's Web (CW) for use in childhood epilepsy. We hypothesize that CBD and CW can be cost-effectively manufactured from high CBD content Cannabis sativa (hemp) utilizing supercritical fluid technology, and that such a process could also produce other bioactive cannabinoid mixtures for future research and therapeutic use. We propose to manufacture pharmaceutical-grade CBD (>98.5% and < 0.3% Δ9-THC) and a standardized CW fraction (30% CBD and < 0.3% Δ9-THC) both following cGMP guidelines by utilizing supercritical fluids and near- critical fluids with or without polar co-solvents such as alcohols (SuperFluids¿). These fluids are gases such as carbon dioxide which when compressed, exhibit enhanced thermodynamic properties that can be "fine-tuned" for rapid and selective extraction of bioactive molecules. We will obtain sufficient quantities of high CBD content Cannabis sativa from growers in Colorado, Maine or Massachusetts and/or NIDA to conduct the proposed research. Under the newly passed Farm bill, recently signed by President Obama, the farming and intra-state transportation of hemp (< 0.3% Δ9-THC) are now exempt from the Schedule 1 requirements of the Drug Enforcement Agency. Since 2002, Aphios has been an approved Schedule 1 research facility with DEA license No. RC0288058 to research and develop DEA Schedule 1 products. Our license is renewed annually. Our Phase I Specific Aims are as follows: (1) Establish optimum conditions for the selective SuperFluids¿ fractionation of Cannabis sativa to Isolate CBD with absolute purities >30% and < 0.3% Δ9-THC; (2) Define SuperFluids¿ chromatographic purification conditions for the further purification of CBD with absolute purities >80% and < 0.3% ¿9-THC; and (3) Establish downstream chromatographic conditions for the final purification of CBD with absolute purities of CBD >98.5% and < 0.3% Δ9-THC. Our Phase II Specific Aims are as follows: (4) Design cGMP processes for SuperFluids¿ CXP and segmentation chromatography of Cannabis sativa to produce standardized CW and pharmaceutical-grade CBD; (5) Modify extant SuperFluids¿ CXP Unit, construct segmentation chromatography systems and upgrade facility to manufacture standardized CW and pharmaceutical-grade CBD following cGMP; (6) Manufacture a minimum of 3 back-to-back large scale batches of CW and CBD following cGMP guidelines and document in batch records and product release; and (7) Document manufacturing process in a CMC (chemistry, manufacturing and controls) for IND applications to the FDA, and establish a Drug Master File (DMF) with the FDA. In Phase III, we will manufacture pharmaceutical-grade CBD for clinical evaluation by the NIH and other pharmaceutical companies, and standardized CW for use by medical marijuana dispensaries in Massachusetts and other states. In order to avoid intra-state trafficking issues with the Federal government, we will sell small scale CXP manufacturing units, process conditions and supporting documentation for manufacturing standardized CW products to other state with medical marijuana dispensing laws. The legitimate use of marijuana for several medical indications has far outpaced the medical and clinical evaluation of marijuana and specific cannabinoids for different medical uses. In 1997, the National Institutes of Health convened an Ad Hoc Expert Panel to discuss current knowledge of the medical uses of Cannabis. The report discussed the importance of other cannabinoids and their potential interaction effects upon THC, stating: "Varying proportions of other cannabinoids, mainly cannabidiol (CBD) and cannabinol (CBN), are also present in Cannabis, sometimes in quantities that might modify the pharmacology of THC or cause effects of their own. CBD is not psychoactive but has significant anticonvulsant, sedative, and other pharmacological activity likely to interact with THC." The Institute of Medicine (IOM, 1999) concluded that scientific data indicate the potential therapeutic value of cannabinoid drugs, primarily Δ9-THC, for pain relief, control of nausea and vomiting, and appetite stimulation and clinical trials of cannabinoid drugs for symptom management should be conducted. We propose to manufacture pharmaceutical-grade CBD for clinical evaluation by the NIH and other pharmaceutical companies for Multiple Sclerosis and other CNS diseases, and a standardized Charlotte's Web (CW) product for use by medical marijuana dispensaries in Massachusetts and other states for childhood epilepsy.