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

项目概要/摘要 美国有超过160万人符合阿片类药物使用障碍的标准，其中数百万人 在过去一个月里，更多的报告使用或滥用阿片类止痛药。沿着 关于类阿片使用障碍，过去十年中与类阿片有关的过量死亡有所增加。 慢性疼痛和阿片类药物滥用比以前更加普遍，构成公共卫生危机 并对患者、护理人员、医生和社会造成沉重的负担。存在电流 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 正确治疗这些疾病的方案。我们建议开发一种大麻类阿片 与阿片样物质节省和协同镇痛作用的组合以预防阿片样物质使用障碍 和过量，解决目前的国家阿片类药物流行病。BDH Pharma，LLC完成了 固定剂量大麻素-阿片类药物组合的概念验证临床前研究， 证明了阿片样物质节省和协同镇痛作用， 在慢性疼痛的啮齿动物模型中比单独的标准剂量的阿片样物质具有更大的镇痛作用。 基于这些数据，我们的SBIR I期资助支持了一种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药代动力学和/或 呼吸抑制与啮齿类动物中的任一化合物有关。研究结果表明PK 参数保持不变，但阿片类药物的半衰期缩短。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综合来看，研究结果表明， 主要候选药物BDH-001显示出协同和阿片样物质节省的镇痛作用， 显示出显著的药物相互作用，对呼吸系统也没有任何有害影响。 萧条这表明BDH-001可能在较低阿片类药物剂量下改善了镇痛作用 从而降低依赖、戒断、转移、滥用和过量的风险。这 该提案将通过完成预制定和 制剂研究，以支持我们的FDC舌下给药联合制剂，并提供 IND提交所需的数据。这些研究将支持选择原型，简称- GMP条件下临床供应品生产前的长期稳定性试验和 长期稳定性测试。在完成拟议的第二阶段目标和随后的IND后 提交，BDH-001将准备用于临床开发阶段，具有初始适应症 慢性腰痛的症状

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.