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(由申请人提供)：药品短缺通过导致治疗延误、用药差错以及由于需要特别的患者管理策略来应对短缺而增加医疗成本，从而对公共健康产生负面影响。连续流动结晶是一种在动态流动条件下产生结晶物质的过程，需要非常高的活性药物成分(API)浓度(过饱和)，这可能会降低产品质量和制造工艺。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。这种SBIR的产品将是包含成核面的连续流动结晶模块，允许快速扩大制造广泛范围的原料药，以应对治疗药物短缺。公众健康受益于连续流动结晶的扩大使用，以及QC效率和经济节省，可以抵消因质量问题造成的短缺和业务停产短缺。将成本效益高、可调的增强成核面与连续流动结晶相结合的总体创新代表了一个颠覆性、可扩展的平台，在应对原料药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型连续流动结晶模块，这些模块在管理药物短缺和生产孤儿、专科(例如，儿科/老年)和商业相关原料药方面有效。第一阶段的假设是，增强的成核面可以结合到连续流动结晶中，以提高结晶速度，而不会对API晶体的尺寸和粒度分布产生不利影响。具体目标是：(1)在给定的一组条件下，成核增强结晶的平均晶体尺寸、粒度分布或产量比传统流动结晶提高10%，以及(2)开发和演示成核增强连续流动结晶模块，能够制造千克数量的结晶EGCG，以克服该原料药目前的短缺。如果预算和时间允许，也将对酮康唑进行研究。计划 第二阶段强调扩大原料药目标;，例如，酮康唑;目前短缺的两种药物：地塞米松和柠檬酸舒芬太尼;，以及与美国国立卫生研究院协商定义的其他药物。DeNovX在4.25M600亿美元的潜在市场中以高价值的产品和服务模式运营，进入市场战略将利用与CRO、CMO和原料药设备制造商的适当战略合作伙伴关系。