Nucleation Enhanced Crystallization of Pharmaceuticals in Continuous Flow Manufacturing to Mitigate Therapeutic Drug Shortages

在连续流程制造中成核增强药物结晶以缓解治疗药物短缺

• 批准号: 9137884
• 负责人: Andrew H. Bond
• 金额: $ 22.49万
• 依托单位: DENOVX, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137884
• 关键词: Affect; Alzheimer' s Disease; Antiviral Agents; Birth; Budgets; Businesses; Capital; Chemistry; Childhood; Citrates; Clinical Trials; Collection; Consult; Crystallization; Dexamethasone; Economics; Elderly; Ensure; Epigallocatechin Gallate; Equipment; FDA approved; Failure; Generic Drugs; Goals; Health Benefit; Health Care Costs; Ketoconazole; Kilogram; Kinetics; Manufacturer Name; Marketing; Medication Errors; Modeling; Modification; Monitor; Orphan; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Productivity; Public Health; Reaction Time; Savings; Services; Small Business Innovation Research Grant; Sufentanil; Surface; Techniques; Technology; Therapeutic; Thermodynamics; Time; United States National Institutes of Health; Work; age-related muscle loss; base; commercial application; coping; cost; cost effective; improved; innovation; interest; manufacturing process; manufacturing scale-up; medical specialties; prevent; public health relevance; residence; response; scale up; technological innovation

 DESCRIPTION (provided by applicant): Drug shortages negatively affect Public Health by causing treatment delays, medication errors, and by increasing healthcare costs from the need for ad hoc patient management strategies to cope with the shortage. Continuous flow crystallization, a process in which crystalline material is generated under dynamic flow conditions, requires very high concentrations (supersaturation) of the Active Pharmaceutical Ingredient (API), which can degrade the quality of the product and manufacturing process. These issues can be resolved by inducing crystallization at lower supersaturations using surface chemistry modifications. The product of this SBIR will be continuous flow crystallization modules that contain nucleation surfaces allowing for rapid scale up manufacturing of a broad spectrum of APIs in response to therapeutic drug shortages. Public Health benefits accrue from the expanded use of continuous flow crystallization and the QC efficiencies and economic savings that can offset shortages attributable to quality issues and business discontinuation shortages. The overarching innovation of combining cost effective, tunable enhanced nucleation surfaces with continuous flow crystallization represents a disruptive, scalable platform of broad relevance in responding to API and drug shortages. The long term objective is to develop nucleation enhanced continuous flow crystallization modules that are effective in managing drug shortages and in the manufacture of orphan, specialty (e.g., pediatric/geriatric), and commercially relevant APIs. The Phase I hypothesis is that enhanced nucleation surfaces can be incorporated into continuous flow crystallization to improve crystallization rates without adversely affecting the API crystal size and size distribution. The Specific Aims are: (1) For a given set of conditions, demonstrate a 10% improvement in average crystal size, size distribution, or throughput for nucleation enhanced vs. conventional flow crystallization, and (2) Develop and demonstrate a nucleation enhanced continuous flow crystallization module capable of manufacturing kilogram quantities of crystalline EGCg to overcome a current shortage of this API. Ketoconazole will also be studied if the budget and timing allow. Plans for Phase II emphasize an expansion of API targets; For example, ketoconazole; Two drugs with current shortages: dexamethasone and sufentanil citrate; And others defined in consult with NIH. DeNovX operates with a high value products and services model in a $425M600M addressable market, and the Go to Market strategy will leverage appropriate strategic partnerships with CROs, CMOs, and API equipment manufacturers.

 描述（适用提供）：药物短缺通过导致治疗延迟，用药错误以及增加医疗保健费用而从需要应对短缺的患者管理策略中增加医疗费用来对公共卫生产生负面影响。连续流结晶（在动态流动条件下生成结晶材料）需要高浓度（过饱和）活性药物成分（API），这可以降低产品和制造过程的质量。这些问题可以通过使用表面化学修饰在较低的过饱和度下诱导结晶来解决。该SBIR的乘积将是包含成核表面的连续流结晶模块，可以快速扩大对治疗药物短缺的响应的广泛API的生产。公共卫生的福利是由于持续流动结晶的扩大使用以及QC的效率和经济节省所带来的，这些效率和经济节省可能会抵消可归因于优质问题和业务终止短缺的短缺。结合成本效益，可调的增强成核表面与连续流结晶的总体创新是一个破坏性的，可扩展的平台，在响应API和药物短缺方面具有广泛的相关性。长期目标是开发成核增强连续的流量结晶模块，这些模块可有效地管理药物短缺和制造孤儿，专业（例如儿科/老年医生）和商业上相关的API。第一阶段的假设是，增强的成核表面可以纳入连续的流结晶中，以提高结晶速率，而不会不利地影响API晶体尺寸和尺寸分布。具体目的是：（1）对于给定的一组条件，证明了核能增强与传统流量结晶的平均晶体尺寸，尺寸分布或吞吐量的提高10％，并且（2）开发并证明了能够生产核能千克千克结晶模块，能够生产晶体千克量的晶体量，以克服该API的当前短期。如果预算和时间允许，酮康唑也将研究。计划 第二阶段强调API靶标的扩展；例如，酮康唑；目前短缺的两种药物：地塞米松和柠檬酸苏芬太尼；以及其他与NIH协商的定义。 Denovx在4.25亿美元的可寻址市场中采用高价值产品和服务模式运营，而Go Market Strategy将利用CRO，CMOS和API设备制造商的合适战略合作伙伴关系。