SBIR Phase II: A complete bioprocess for medicinal plant opioids

该小型企业创新研究（SBIR）第二阶段项目的更广泛影响/商业潜力是开发阿片类药物的制造平台。阿片类药物使医生能够为患有急性或慢性疾病和创伤的患者提供富有同情心的护理。对于外科医生来说，阿片类镇痛药的需求更加突出，因为他们预计患者的术后恢复并计划临终护理。然而，类阿片是高度成瘾的药物，这一特性被制药业的某些参与者利用来谋取商业利益。该项目的影响将是提供一种技术，通过消除将罂粟作为毒品作物种植的必要性，改变现有的类阿片供应链。这项新技术将允许在美国的一个安全工业设施中完成类阿片的生产，而不是从罂粟种植国采购罂粟材料，联邦机构可以在那里进行监督和监管。此外，对这项技术的投资将使更多的现有和实验性药物的开发成为可能，这些药物来自植物，包括大大改进的阿片类药物，其疗效和安全性得到提高，以及延长和提高人类生命的心血管和化疗疗法。 SBIR第二阶段项目将开发阿片类药物活性成分（API）的生物工艺。迄今为止，制造阿片类药物和相关生物碱的唯一具有商业竞争力的方法是从植物中提取这些分子。然而，面包酵母最近被改造成生物合成阿片类药物，这是一项技术进步，可以通过发酵生产阿片类药物。然而，在开发基于现有菌株的可靠且具有成本效益的商业上可行的生产系统方面仍然存在许多技术障碍。该第二阶段项目的目标是提供一个完整的示范和中试规模的操作的API生物工艺，准备工业规模。该研究采用了四种方法：1）进一步开发工程酵母菌株，2）将发酵从实验室规模扩大到中试规模，3）优化下游回收和纯化，以及4）评估所得产品，以确定其作为现有阿片类药物原料药的直接替代品的有效性。其结果将是一个在中试规模上得到验证的工艺，并准备将技术转让给一个安全的工业设施，该设施将制造和销售阿片类药物API市场。这项研究将用一种现代生物工艺取代罂粟，该工艺类似于抗生素和生物API的既定标准化制药工业方法。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to develop a manufacturing platform for opioid medicines. Opioids enable physicians to provide compassionate care to patients suffering from acute or chronic disease and trauma. The need for opioid analgesics is even more salient for surgeons anticipating the post-operative recovery of their patients and planning for end-of-life care. However, opioids are highly addictive medicines, a property that has been exploited for commercial gain by certain players in the pharmaceutical industry. The impact of this project will be to deliver a technology that transforms the existing supply chain for opioids by removing the need to grow opium poppy as a drug crop. Instead of sourcing poppy materials from poppy-growing countries, this new technology will allow for complete production of opioids in a secure industrial facility located in the United States where federal agencies can provide oversight and regulation. Additionally, investment in this technology will enable the development of many more existing and experimental medicines derived from plants, including greatly improved opioids with improved efficacy and safety, and cardiovascular and chemotherapeutic therapies that will extend and enhance human lives. This SBIR Phase II project will develop a bioprocess for opioid active pharmaceutical ingredients (APIs). To date, the only commercially-competitive method for manufacturing opioids and related alkaloids is to extract these molecules from plants. However, Baker's yeast was recently engineered to biosynthesize opioids, which is a technological advance that could enable opioid production by fermentation. However, many technical hurdles remain in developing a reliable and cost-effective, commercially-viable production system based on existing strains. The objective of this Phase II project is to provide a complete demonstration and pilot-scale operation of an API bioprocess that is ready for industrial scale up. The research employs four approaches: 1) Further development of the engineered yeast strains, 2) scale up of fermentation from laboratory scale to pilot scale, 3) optimization of downstream recovery and purification, and 4) evaluation of the resulting products to establish their validity as drop-in-replacements for existing opioid APIs. The outcome will be a process validated at pilot scale and ready for technology transfer to a secure industrial facility that will make and sell into the opioids API market. This research will replace opium poppies with a modern bioprocess that resembles established, standardized pharmaceutical industry methods for antibiotic and biologic APIs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.