Development of cannabinoid-opioid combination with opioid sparing and synergistic analgesic effects to prevent opioid use disorder and overdose.

项目摘要/摘要 在美国，超过160万人符合阿片类药物使用障碍的标准，其中数百万人 在过去的一个月里，有更多的报告使用或误用阿片类止痛药。同时还增加了 在阿片类药物使用障碍方面，与阿片类药物有关的过量死亡在过去十年中有所上升。 慢性疼痛和阿片类药物滥用比构成公共健康危机之前更加普遍 并给患者、照顾者、医生和社会带来沉重的代价。有一股水流 管理阿片类药物使用、阿片类药物戒断症状、慢性疼痛和/或 相关的焦虑和抑郁。仍然迫切需要替代和安全的治疗方法 恰当地治疗这些疾病的养生法。我们建议开发一种大麻类阿片类药物 联合阿片类药物节制和协同止痛预防阿片类药物使用障碍 和过量，解决了目前全国范围内的阿片类药物流行问题。BDH Pharma，LLC完成了一项 一种固定剂量大麻素-阿片类药物组合的概念验证临床前研究 展示了阿片类药物的节制和协同止痛效果，联合提供了 在慢性疼痛的啮齿动物模型中，比标准剂量的阿片类药物单独使用有更好的止痛效果。 在这些数据的基础上，我们的SBIR第一阶段资助支持了临床前药代动力学药物-药物 相互作用和安全性研究，以确定联合给药是否改变了药代动力学和/或 与啮齿动物体内的任何一种化合物有关的呼吸抑制。研究结果表明PK 参数保持不变，除了阿片类药物的半衰期减少。当测量时 呼吸抑制，我们发现大麻素的存在能够减弱 阿片类药物引起的呼吸抑制。总而言之，研究结果表明，我们的 主要候选药物BDH-001显示出协同和非阿片类药物的止痛作用，而不是 显示出显著的药物相互作用，对呼吸道也没有任何有害影响 抑郁症。这表明Bdh-001可能在较低的阿片类药物剂量下改善了止痛效果。 从而降低依赖、戒断、转移注意力、滥用和过量服药的风险。这 建议书将继续开发BDH-001，完成预制和 配方研究，以支持我们的FDC的共同配方，以进行语下管理，并提供 提交IND所需的数据。简而言之，这些研究将支持原型的选择- GMP条件下临床制剂生产前的长期稳定性试验 术语稳定性测试。在完成拟议的第二阶段目标和随后的IND 提交，Bdh-001将准备好进入临床开发阶段，并有初步的适应症 慢性腰背痛。

Project Summary/Abstract More than 1.6 million individuals in the US meet criteria for an opioid use disorder, with millions more reporting use or misuse of opioid pain relievers in the past month. Along with an increase in opioid use disorders, a rise in opioid-related overdose deaths has occurred in the last decade. Chronic pain and opioid abuse are more prevalent than before constituting a public health crisis and exacting a heavy toll on patients, caregivers, physicians, and society. There is a current therapeutic challenge for managing opioid use, opioid withdrawal symptoms, chronic pain, and/or associated anxiety and depression. A severe need remains for alternative and safe therapeutic regimens that properly treat these conditions. We propose to develop a cannabinoid-opioid combination with opioid-sparing and synergistic analgesic effects to prevent opioid use disorder and overdose, addressing the current national opioid epidemic. BDH Pharma, LLC completed a proof-of-concept preclinical study of a fixed dose cannabinoid-opioid combination that demonstrated opioid-sparing and synergistic analgesic effects, with the combination providing greater analgesia in a rodent model of chronic pain than a standard dose of the opioid alone. Building on that data, our SBIR Phase I grant supported a preclinical pharmacokinetic drug-drug interaction and safety study to determine if co-administration altered the pharmacokinetics and/or respiratory depression related to either compound in rodents. Study results indicated PK parameters remained unaltered, except for a decrease in half-life for the opioid. When measuring respiratory depression, we found that the presence of the cannabinoid was able to attenuate respiratory depression induced by the opioid. Taken together, study results have shown that our lead candidate, BDH-001, exhibits synergistic and opioid-sparing analgesic effects and does not display significant drug-drug interactions nor has any deleterious effects on respiratory depression. This suggests that BDH-001 may have improved analgesia with lower opioid doses and thereby lower the risk of dependence, withdrawal, diversion, abuse, and overdose. This proposal will continue the development of BDH-001 by completing pre-formulation and formulation studies to support co-formulation of our FDC for sublingual administration and provide required data for IND submission. These studies will support the selection of prototypes for short- term stability testing before the clinical supply manufacturing under GMP conditions and long- term stability testing. Upon completion of the proposed Phase II aims and subsequent IND submission, BDH-001 will be ready for the clinical phase of development with an initial indication of chronic low back pain.