Development of cGMP Manufacturing Process for CBD

CBD cGMP 生产工艺的开发

• 批准号: 8966448
• 负责人: TREVOR P. CASTOR
• 金额: $ 74.21万
• 依托单位: APHIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966448
• 关键词: Acquired Immunodeficiency Syndrome; Alcohols; Anticonvulsants; Back; Cachexia; Canada; Cannabidiol; Cannabinoids; Cannabinol; Cannabis; Cannabis sativa plant; Carbon Dioxide; Central Nervous System Diseases; Chemistry; Childhood; Chromatography; Chronic Cancer Pain; Clinical Trials; Colorado; Country; Data; Desire for food; Development; Disease; District of Columbia; Documentation; England; Epilepsy; European; Exhibits; Farming environment; Federal Government; Fractionation; Gases; Glaucoma; Goals; HIV; Health; Hemp; Institute of Medicine (U.S.); Internet; Knowledge; Laws; Licensing; Liquid substance; Maine; Marijuana; Massachusetts; Medical; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; National Institute of Drug Abuse; Nausea; Nausea and Vomiting; New Zealand; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Practice Guidelines; Process; Property; Records; Reporting; Research; Research Personnel; Sativex; Schedule; Seizures; Solvents; System; Technology; Therapeutic; Therapeutic Uses; Thermodynamics; Transportation; United States National Institutes of Health; cancer pain; cannabinoid drug; cost; design; manufacturing process; marijuana use; patient advocacy group; programs; research clinical testing; research facility; sedative; symptom management; trafficking

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.

描述（由申请人提供）：医用大麻现已在 20 个州和哥伦比亚特区获得批准用于治疗多种疾病，如恶病质、癌症、慢性疼痛、癫痫和其他以癫痫、青光眼、艾滋病毒、艾滋病、多发性硬化症为特征的疾病，大麻素在医疗用途方面已在多个方面取得进展，例如通过临时开发用于治疗儿童癫痫症的夏洛特网 (CW)。由患者权益团体发起。 （英格兰 GW 制药公司）是一种含有等比例 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。药品级 CBD 和标准化 CW 产品，按照 cGMP 指南生产，将有助于 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进行临床评估。开发的工艺也将用于生产。 Δ9-THC，已用于治疗癌症疼痛、恶心和艾滋病相关的恶病质，以及正在开发的其他大麻素。该研究计划的主要目标是开发一种遵循现行良好生产规范（cGMP）的药品级 CBD 的生产工艺。我们的第二个目标是开发一种标准化的、浓缩的 CBD 成分，类似于用于儿童的夏洛特网 (CW)。我们追求利用超临界流体技术从高 CBD 含量大麻（大麻）中经济高效地生产 CBD 和 CW，并且这样的过程还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。生产医药级 CBD（>98.5% 和 < 0.3% Δ9-THC）和标准化 CW 分数（30% CBD 和 < 0.3% Δ9-THC）均遵循 cGMP通过使用超临界流体和近临界流体（有或没有极性共溶剂，如醇）（SuperFluids¿这些流体是二氧化碳等气体，在压缩时表现出增强的热力学特性，可以“微调”以快速、选择性地提取生物活性分子，我们将从科罗拉多州的种植者那里获得足够数量的高 CBD 含量的大麻。 、缅因州或马萨诸塞州和/或 NIDA 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 (< 0.3% Δ9-THC) 的种植和州内运输现已豁免。根据缉毒局附表 1 的要求，Aphios 已成为经批准的附表 1 研究机构，拥有 DEA 许可证号 RC0288058，用于研究和开发 DEA 附表 1 产品。我们的许可证每年都会更新。目标如下： (1) 为选择性超级流体建立最佳条件¿分馏大麻以分离绝对纯度 >30% 和 < 0.3% Δ9-THC 的 CBD； (2) 定义 SuperFluids¿进一步纯化 CBD 的色谱纯化条件，绝对纯度 >80% 且 < 0.3% ¿ (3) 建立最终纯化 CBD 的下游色谱条件，CBD 绝对纯度 >98.5% 且 Δ9-THC < 0.3%。我们的第二阶段具体目标如下：(4) 设计超级流体的 cGMP 工艺。 CXP 和大麻分段色谱法生产标准化 CW 和医药级 CBD (5) 修改现有的 SuperFluids¿ CXP 单元，建造分段色谱系统并升级设施，以按照 cGMP 生产标准化 CW 和药品级 CBD； (6) 按照 cGMP 指南和批次记录文件生产至少 3 个连续的大规模批次 CW 和 CBD； (7) 在 CMC（化学、制造和控制）中记录向 FDA 申请 IND 的生产过程，并与 FDA 建立药物主文件 (DMF)。我们将生产药品级 CBD，供 NIH 和其他制药公司进行临床评估，并生产标准化 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发生州内贩运问题，我们将出售。小型 CXP 制造单位、工艺条件和支持文件，用于根据医用大麻分配法向其他州生产标准化 CW 产品。大麻在多种医疗适应症中的合法使用远远超过了针对不同医疗用途的大麻和特定大麻素的医学和临床评估。用途。 1997 年，美国国立卫生研究院召集了一个特设专家小组来讨论大麻医疗用途的最新知识，该报告讨论了其他大麻素的重要性及其对 THC 的潜在相互作用影响，指出：“其他大麻素的不同比例，主要是大麻二酚 (CBD) 和大麻酚 (CBN)，也存在于大麻中，有时其含量可能会改变 THC 的药理学或引起 CBD 本身的影响。没有精神活性，但具有显着的抗惊厥、镇静和其他可能与 THC 相互作用的药理活性。”医学研究所（IOM，1999）得出的结论是，科学数据表明大麻素药物（主要是 Δ9-THC）对于缓解疼痛具有潜在的治疗价值，控制恶心和呕吐，刺激食欲以及用于症状管理的大麻素药物的临床试验我们建议生产药物级 CBD 供 NIH 和其他制药公司进行临床评估。硬化症和其他中枢神经系统疾病，以及供马萨诸塞州和其他州的医用大麻药房用于治疗儿童癫痫的标准化夏洛特网 (CW) 产品。