SBIR Phase II: A complete bioprocess for medicinal plant opioids

这项小企业创新研究（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，对阿片类镇痛药的需求甚至更加突出，因为他们预计病人的术后恢复和计划临终关怀。然而，阿片类药物是极易上瘾的药物，制药行业的某些参与者利用这一特性谋取商业利益。该项目的影响将是提供一种技术，通过消除种植罂粟作为药物作物的需要来改变现有的阿片类药物供应链。这项新技术将允许在位于美国的安全工业设施中完全生产阿片类药物，而不是从种植罂粟的国家采购罂粟材料，联邦机构可以提供监督和管理。此外，对这项技术的投资将有助于开发更多现有的和实验性的植物药物，包括大大改善的阿片类药物，提高其疗效和安全性，以及延长和改善人类生命的心血管和化疗疗法。该SBIR二期项目将开发阿片类药物活性药物成分（api）的生物工艺。迄今为止，唯一具有商业竞争力的制造阿片类药物和相关生物碱的方法是从植物中提取这些分子。然而，贝克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，在开发一种基于现有菌株的可靠的、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。第二阶段项目的目标是提供API生物工艺的完整示范和中试操作，为工业规模做好准备。该研究采用了四种方法：1)进一步开发工程酵母菌株；2)将发酵规模从实验室规模扩大到中试规模；3)优化下游回收和纯化；4)评估所得产品，以确定其作为现有阿片类原料药的替代产品的有效性。结果将是一个在试点规模上得到验证的过程，并准备将技术转移到一个安全的工业设施，该设施将生产和销售阿片类原料药市场。这项研究将用一种现代生物工艺取代罂粟，这种工艺类似于抗生素和生物原料药的既定标准化制药业方法。该奖项反映了美国国家科学基金会的法定使命，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.