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（由适用提供）：医用大麻现在在20个州和哥伦比亚特区获得了多种医疗状况，例如卡赫西亚，癌症，慢性疼痛，癫痫和其他以癫痫发作，青光眼，艾滋病毒，艾滋病，艾滋病，多发性硬化症，肌肉痉挛和恶性为特征的疾病。在多个方面取得了进展，用于使用大麻素进行医学用途，例如夏洛特的网络（CW）通过患者倡导组织的临时开发用于儿童癫痫。 Sativex¿（英格兰GW Pharmaceuticals）是一种含有相同比例的Δ-THC和CBD的药物，最近被批准为在加拿大，新西兰和8个欧洲国家的多重巩固（MS）相关痉挛的二线治疗（MS）。根据CGMP指南制造的药品级CBD的现成可用性和标准CW产品将促进NIH研究人员和其他研究人员的癫痫，MS和其他CNS疾病的临床评估。开发的过程还将用于制造Δ9-THC，已经用于癌症疼痛，恶心和与艾滋病相关的卡希克西亚以及其他大麻素的开发中。该研究计划的主要目的是在美国FDA的当前良好制造实践（CGMP）中开发制造药品级CBD的过程，以用于NIH和其他研究人员的儿童癫痫和其他CNS指示的临床试验。我们的次要目标是开发标准化的，丰富的CBD分数，类似于夏洛特的网络（CW）用于儿童癫痫。我们假设CBD和CW可以是通过使用超临界流体技术的高CBD含量大麻（HEMP）成本效益生产的，并且这种过程还可以生产其他生物活性大麻素混合物，以供未来的研究和治疗使用。我们建议遵循CGMP指南，生产药物级CBD（> 98.5％和<0.3％δ9-THC）和标准的CW分数（30％CBD和<0.3％Δ9-THC），均遵循CGMP指南。这些烟道是诸如二氧化碳之类的气体，在压缩时，暴露的增强的热力学特性可以“微调”，以快速和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的种植者和/或NIDA中获得足够数量的高CBD含量大麻sativa，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场法案，大麻的农业和州内运输（<0.3％δ9-THC）现在不受毒品执法机构的附表1要求。自2002年以来，Aphios一直是批准的附表1研究机构，具有DEA许可证编号RC0288058，以研究和开发DEA附表1产品。我们的许可每年更新。我们的I阶段特定目的如下：（1）确定选择性超流体的最佳条件。大麻sativa分馏以隔离CBD，绝对纯度> 30％> 30％和<0.3％δ9-THC； （2）定义超流体„色谱纯化条件，以进一步纯化CBD的绝对纯度> 80％且<0.3％€9-THC； （3）建立下游色谱条件，以最终纯化CBD，其绝对纯度的CBD> 98.5％，<0.3％Δ9-THC。我们的II期特定目的如下：（4）超级流体的CGM​​P工艺CXP和大麻sativa的分割色谱法生产标准化的CW和药品级CBD； （5）修改额外的超级流体�CXP单元，构造分割色谱系统和升级设施，以生产CGMP后制造标准化的CW和药品级CBD； （6）在CGMP指南和批处理记录和产品发布中，制造至少3个背对背的大规模CW和CBD大规模CW和CBD； （7）在CMC（化学，制造和控制措施）中为FDA申请中的制造过程，并与FDA建立药物主文件（DMF）。在第三阶段，我们将制造NIH和其他制药公司的药品级CBD，用于临床评估，并标准化CW，用于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，我们将出售小型CXP制造单元，过程条件和支持文件，以通过医用大麻分配法律向其他州制造标准化的CW产品。大麻在几种医学迹象中的合法使用已经超过了对大麻和特定大麻素的医学和临床评估，用于不同的医疗用途。 1997年，美国国立卫生研究院召集了一个临时专家小组，讨论了有关大麻医学用途的当前知识。该报告讨论了其他大麻素及其对THC的潜在相互作用的重要性，并指出：“其他大麻素（主要是大麻二酚）（CBD）和大麻醇（CBN）的不同比例也存在于大麻中，有时也会在数量上，可能会改变其自身的静态药理学，而不是静态的。药物活动可能与THC相互作用。”医学研究所（IOM，1999年）得出结论，科学数据表明，应进行症状管理大麻素药物，原发性Δ9-THC的潜在治疗价值，用于缓解疼痛，对恶心和呕吐的控制以及食欲模拟以及大麻素药物的临床试验。我们建议制造NIH和其他制药公司的临床评估制药级CBD，以用于多发性硬化症和其他中枢神经系统疾病，以及标准化的夏洛特网络（CW）产品，可用于马萨诸塞州和其他州的医用大麻药房，用于儿童癫痫发作。