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 项目摘要/摘要 Ser-227是一种丁丙诺啡的长效聚合物前体药物，正在开发中，用于治疗后遗症。 大手术后的手术疼痛，如球囊切除术、腹部成形术、开胸手术和 膝盖和臀部手术。Ser-227本身没有生物活性，但在体内给药时 通过皮下注射，它进入血管间，在那里血浆酯酶 (丁酰胆碱酯酶，BChE)酶促释放活性药物成分， 丁丙诺啡。该聚合物可延长循环半衰期，使丁丙诺啡 持续释放超过3-4天。丁丙诺啡是MU的混合激动剂和拮抗剂。 阿片受体(MOR)和kappa阿片受体的拮抗剂。单一的政府 已证明SER-227在布伦南具有即时和持久的镇痛作用。 模特。迅速止痛，随后持续约3-4天，应消除启动 在医院接受可能使人上瘾的阿片类药物治疗，并允许患者在 非添加剂药物，如扑热息痛或非甾体抗炎药。 术后立即皮下注射Ser-227 (例如，恢复室)。本产品为一次性注射剂(由 外科医生/麻醉师)，这将提供即时和3天的止痛。Ser-227是 预计将显示非常低的滥用责任(实际上，丁丙诺啡的长效植入物 用于治疗阿片类药物使用障碍)，很可能在外科中心大量使用；它不是 用于自我管理的。 提出了以早期开发和临床前研究为重点的研究策略 该计划的目标，其中的最终目标是证明SER-227可以 制造和临床前测试表明，在I期临床研究中使用它是安全的。 1.Ser-227化学和工艺优化，以生成一揽子技术方案，以及 2.根据当前良好制造规范制造的Ser-227，以及 3.在啮齿动物和非啮齿动物的正式毒理学研究中进行评估，以便证明 可以用来支持“第一人”研究， 4.提交研究用新药申请(IND)和第一阶段临床申请 在正常志愿者中测量其安全性、耐受性和药代动力学的方案 丁丙诺啡是从SER-227释放的。 这份直接提交给第二阶段的文件是在《Hear Initiative，感兴趣的通知》下提交的 小型企业创新研究(SBIR)和小型企业技术转让(STTR) 针对加强疼痛管理和改善阿片类药物滥用治疗的应用 和上瘾。根据之前类似设计研究的经验，我们预计这一阶段 该计划将需要18至24个月的时间才能完成。