A Single Dose Long-Acting Non-Addictive Polymer Conjugate Formulation of Buprenorphine that Provides Immediate and Prolonged Analgesia for Post-Operative Pain

单剂量长效非成瘾性丁丙诺啡聚合物复合制剂，可为术后疼痛提供即时和长期镇痛

• 批准号: 9905086
• 负责人: RANDALL W MOREADITH
• 金额: $ 165.86万
• 依托单位: SERINA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905086
• 关键词: Absence of pain sensation; Acetaminophen; Address; Adverse event; Affinity; Agonist; Analgesics; Anesthesia and Analgesia; Animals; Binding; Biological; Blood Vessels; Buprenorphine; Businesses; Butyrylcholinesterase; Bypass; Cessation of life; Chemistry; Chronic; Clinical; Clinical Protocols; Clinical Research; Cohort Studies; Communities; Control Animal; Dependence; Development; Dose; Drug Delivery Systems; Drug Kinetics; Ethics; Event; Exhibits; Exposure to; Family; Formularies; Formulation; Goals; Half-Life; Hospitals; Hour; Ibuprofen; Implant; Individual; Injections; Investigational New Drug Application; Kinetics; Knee; Length of Stay; Link; Measures; Medical; Meta-Analysis; Minor; Modeling; Morphine; Morphine Receptors; Nausea; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Antagonist; Oral; Pain; Pain management; Pamphlets; Patient-Controlled Analgesia; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacy facility; Phase; Physicians; Physicians' Offices; Plasma; Polymers; Population; Postoperative Pain; Postoperative Period; Preclinical Testing; Preparation; Prevention; Preventive Intervention; Procedures; Prodrugs; Production; Protocols documentation; Pruritus; Pump; Randomized Controlled Clinical Trials; Recovery Room; Reporting; Research; Research Personnel; Risk; Rodent; Safety; Sedation procedure; Self Administration; Small Business Innovation Research Grant; Subcutaneous Injections; Supervision; Surgeon; Technology; Technology Transfer; Therapeutic; Thoracotomy; Time; Toxicology; Ventilatory Depression; Writing; addiction; analytical method; animal care; base; chemical release; clinical toxicology; combat; design; direct application; drug testing; esterase; experience; fight against; first-in-human; hip surgery; improved; in vivo; interest; intravenous administration; kappa opioid receptors; morphine administration; mu opioid receptors; mu receptors; novel; novel strategies; novel therapeutics; opioid abuse; opioid misuse; opioid overdose; opioid use disorder; pain relief; pre-clinical; prescription opioid; process optimization; programs; scale up; side effect; social; stability testing; standard care; trial comparing; volunteer

PA-18-574 Project Summary/Abstract SER-227 is a long-acting polymer pro-drug of buprenorphine that is being developed to treat post- operative pain following major surgeries such as bunionectomy, abdominoplasty, thoracotomy and knee and hip surgery. SER-227 has no biological activity by itself, but when administered in vivo by subcutaneous injection it enters the vascular compartment where a plasma esterase (butyrylcholinesterase, BChE) enzymatically releases the active pharmaceutical ingredient, buprenorphine. The polymer confers prolonged circulatory half-life, allowing buprenorphine to be released continuously over ~ 3-4 days. Buprenorphine is a mixed mu-agonist/antagonist at the mu opioid receptor (MOR), and an antagonist at the kappa opioid receptor. A single administration of SER-227 has been shown to provide both immediate and prolonged analgesia in the Brennan model. Prompt analgesia, which subsequently lasts ~ 3-4 days, should obviate the need to initiate therapy by a potentially addictive opioid in the hospital and allow patients to be discharged on non-additive drugs such as acetaminophen or NSAIDs. SER-227 is to be administered as a subcutaneous injection in the immediate post-operative period (e.g. recovery room). This product is intended to be a one-time injection (by a surgeon/anesthesiologist) that will provide both immediate and > 3 days of analgesia. SER-227 is predicted to demonstrate very low abuse liability (indeed, long-acting implants of buprenorphine are used to treat opioid use disorder) and is likely to be used largely in surgical centers; it is not intended for self-administration. A Research Strategy is presented that will focus on the early development and preclinical objectives of this program, where the ultimate goal is to demonstrate that SER-227 can be manufactured and tested preclinically to show that it is safe for use in a Phase I clinical study. 1. SER-227 chemistry and process optimization to generate a technical package, and 2. SER-227 manufactured under current Good Manufacturing Practices, and 3. Evaluated in formal toxicology studies in rodent and non-rodent animals so that justifications can be made to support a ‘first-in-man’ study, 4. Submission of an Investigational New Drug application (IND) along with a Phase I clinical protocol in normal volunteers to measure the safety, tolerability and pharmacokinetics of buprenorphine that is released from SER-227. This ‘Direct to Phase II’ submission is made under the ‘HEAL Initiative, Notice of Interest in Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Applications Directed at Enhanced Pain Management and Improved Treatments for Opioid Misuse and Addiction’. Based upon prior experience in studies of similar design, we anticipate this Phase of the program would take 18 to 24 months to complete.

PA-18 - 574 项目总结/摘要 SER-227是丁丙诺啡的长效聚合物前药，正在开发用于治疗后 大手术后的手术疼痛，如拇囊炎切除术、腹部成形术、胸廓切开术和 膝盖和臀部手术SER-227本身没有生物活性，但当体内给药时， 通过皮下注射，它进入血管室， （丁酰胆碱酯酶，BChE）酶促释放活性药物成分， 丁丙诺啡该聚合物赋予延长的循环半衰期，使丁丙诺啡能够被 持续释放约3 - 4天。丁丙诺啡是一种混合的μ激动剂/拮抗剂， 阿片受体（莫尔）和κ阿片受体拮抗剂。单次施用 SER-227已被证明可以在Brennan中提供立即和延长的镇痛作用。 模型迅速镇痛，随后持续约3 - 4天，应避免需要启动 在医院接受潜在成瘾性阿片类药物治疗，并允许患者出院。 非添加剂药物，如对乙酰氨基酚或NSAID。 SER-227将在术后即刻皮下注射给药 (e.g.恢复室）。本产品预期为一次性注射剂（通过 外科医生/麻醉师），其将提供立即和> 3天的镇痛。SER-227是 预计将表现出非常低的滥用倾向（事实上，丁丙诺啡的长效植入物 用于治疗阿片类药物使用障碍），并且可能主要用于外科中心;它不是 用于自我管理。 提出了一项研究战略，将重点放在早期开发和临床前 该计划的最终目标是证明SER-227可以 生产和临床前测试，以表明其在I期临床研究中使用是安全的。 1. SER-227化学和工艺优化，以生成技术包，以及 2.根据现行药品生产质量管理规范生产的SER-227，以及 3.在啮齿类动物和非啮齿类动物的正式毒理学研究中进行评价， 可以用来支持"首次人体"研究， 4.沿着提交研究性新药申请（IND）和I期临床试验 在正常志愿者中测量安全性、耐受性和药代动力学的方案 SER-227释放的丁丙诺啡。 本“直接进入第二阶段”的提交是根据“HEAL倡议， 小企业创新研究（SBIR）和小企业技术转移（STTR） 针对增强疼痛管理和改善阿片类药物滥用治疗的应用 上瘾”。根据类似设计研究的既往经验，我们预计本阶段 该计划将需要18至24个月才能完成。