A Novel Opioid-Free Targeted Pain Control Method for Acute Post-Operative Localized Pain Related to Oral Surgical Procedures

一种新型无阿片类药物靶向疼痛控制方法，用于治疗与口腔手术相关的急性术后局部疼痛

基本信息

批准号：
10761260
负责人：
Rahul Jadia
金额：
$ 205.04万
依托单位：
REVBIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2025-09-18
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10761260
关键词：
Absence of pain sensation Accounting Acute Acute pain management Address Adhesives Alveolar periostitis Analgesics Animals Applications Grants Award Behavioral Biocompatible Materials Blood coagulation Bone Regeneration Bone Substitutes Bone Surface Bone Transplantation Bupivacaine Cadaver Canis familiaris Characteristics Classification Coupled Data Collection Defect Dental Care Devices Diagnosis Dose Drug Addiction Drug Controls Drug Delivery Systems Engineering Excision Exclusion Exposure to Feedback Formulation Funding Future Gingiva Health Personnel Helping to End Addiction Long-term Histocompatibility Human Implant Incidence Injury Investigation Irritants Legal patent Mandible Marketing Measurement Medical Device Methods Minerals Mission Modeling Operative Surgical Procedures Opioid Oral Surgical Procedures Orthopedic Procedures Outcome Outpatients Output Overdose Pain Pain Measurement Pain management Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phase Physiological Pilot Projects Porosity Postoperative Pain Postoperative Period Procedures Process Property Regulatory Pathway Replacement Arthroplasty Risk Safety Site Spinal Fusion Surgeon System Techniques Teenagers Telemetry Time Tissues Tooth Extraction Translating United States National Institutes of Health Validation Vulnerable Populations Writing bone bone scaffold canine model clinically relevant comparison control delivery vehicle dental adhesive dental surgery design dosage drug release kinetics drug release profile healing histopathological examination illicit opioid implantation improved in vivo interest method development non-opioid analgesic novel opioid abuse opioid exposure opioid use overdose death phase 2 study prescription opioid prescription opioid misuse regeneration potential regenerative response safety study scaffold side effect soft tissue trauma surgery usability wisdom tooth young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Drug addiction and overdose are a growing problem in the US, accounting for 107,622 overdose deaths in 2021. Over 60% of drug overdose deaths involved misuse of prescription or illicit opioids. 30% of opioid prescriptions are written following oral surgical or dental procedures to control acute post-operative pain. Approximately 10 million wisdom teeth are removed annually. A statistically significant 6.8% absolute risk increase in persistent opioid use and a 5.4% increase in the subsequent diagnosis of opioid abuse follows a single course of opiates following wisdom tooth extraction. Therefore, there is a compelling need to develop non-opioid-based acute pain management strategies for outpatient oral surgical procedures, preferably via local delivery of medication to the target tissue because the medication can provide the desired pain control with lower total dosage and lower incidence of serious side effects. RevBio has developed Tetranite® Adhesive Dental Bone Scaffold (ADBS), a novel adhesive mineral-organic biomaterial that can both fill space as an osteoconductive scaffold and exclude irritants from reaching cut bone surface. This device-led patented combination product can serve as a drug delivery vehicle with designing controls available to vary porosity to provide drug release profiles for any targeted indication. A Phase I investigation into the TN-ADBS drug release kinetics has shown that bupivacaine (Bp) follows predictable and tunable patterns over the time window of interest, and an in vivo pilot study has demonstrated feasibility of the proposed model. Preliminary safety studies have shown that TN-ADBS+Bp was not cytotoxic and that overlying gingival tissues healed uneventfully following the material’s implantation into proposed model extraction sites in canines. The company is confident that an effective Bp dose can be released over the 5-day window when analgesia is most needed to limit post-operative pain following wisdom tooth removal. Prior Phase I funding (1R43DE029369-01) awarded by NIH-HEAL Initiative has been used to: (a) designed a porous cohesive and adhesive formulation that enables time-dependent release of bupivacaine, (b) evaluated the handling properties of the formulation without the inclusion of bupivacaine, (c) determined soft tissue compatibility of the formulation using a canine molar defect, and (d) conducted preliminary efficacy of the formulation without the drug, i.e., rate of bone substitution in a canine model. Additionally, the proposed regulatory pathway was presented to FDA via request for designation (RFD) process. Based on FDA’s feedback, this product will be regulated as a device-led combination product in which OPLS, and bupivacaine are classified as the drug constituents. The following proposed Phase II grant application is to address the following two Specific Aims: (1) conduct human factor assessment and (2) to demonstrate the ability to mitigate pain and bone regenerative properties of BP loaded TN-ADBS in canine model by (i) developing a validation model for the use of Telemetric data collection, (ii) demonstrate pain mitigation efficacy of TN-ADBS and TN-ADBS+Bp in comparison to controls (p<0.05), (iii) demonstrate bone regenerative efficacy of TN-ADBS and TN-ADBS+Bp in comparison to controls (p<0.05), and (iv) demonstrate safety of TN-ADBS and TN-ADBS+Bp on local soft and hard tissue as per ISO 10993-6:2016 (Annex E). The results from this Phase II study, surgeon validated simulated use trails and in vivo animal studies, will translate to assessment of this promising method to humans in Investigational Device Exemption (IDE)-approved studies. This would close one of the major gateways into opioid exposure to vulnerable populations as supported by the NIH Helping to End Addiction Long-term® (HEAL) Initiative. RevBio’s mission is to provide surgeons with a novel bone grafting product to simplify surgery and improve patient outcomes following procedures generating bony defects.

项目概要/摘要吸毒成瘾和吸毒过量是美国日益严重的问题，2021 年有 107,622 人因吸毒过量死亡。超过 60% 的药物过量死亡涉及滥用处方药或非法阿片类药物（30% 的阿片类药物处方）。大约 10 是在口腔外科或牙科手术后撰写的，用于控制急性术后疼痛。每年拔除 100 万颗智齿，持续性的绝对风险增加了 6.8%，具有统计学意义。单一疗程阿片类药物使用后，阿片类药物的使用和随后阿片类药物滥用的诊断增加了 5.4% 因此，迫切需要开发非阿片类药物的急性疼痛。门诊口腔外科手术的管理策略，最好是通过局部给药的方式靶向组织，因为药物可以以较低的总剂量和较低的剂量提供所需的疼痛控制严重副作用的发生率。 RevBio 开发了 Tetranite® 粘合剂牙科骨支架 (ADBS)，这是一种新型矿物有机粘合剂生物材料既可以作为骨传导支架填充空间，又可以排除刺激物到达切骨这种以设备为主导的专利组合产品可以作为药物输送载体。可通过控制来改变孔隙率，从而为任何目标 A 期适应症提供药物释放曲线。对 TN-ADBS 药物释放动力学的研究表明，布比卡因 (Bp) 遵循可预测和在感兴趣的时间窗口内可调模式，并且体内试点研究证明了该方法的可行性初步安全性研究表明 TN-ADBS+Bp 没有细胞毒性并且覆盖。将材料植入建议的模型拔牙部位后，牙龈组织愈合不均匀该公司有信心在 5 天的时间内释放有效的 Bp 剂量。最需要镇痛来限制智齿拔除术后的疼痛。 NIH-HEAL Initiative 授予的先前第一阶段资金 (1R43DE029369-01) 已用于：(a) 设计多孔内聚剂和粘合剂制剂，可实现布比卡因的时间依赖性释放，(b) 评估不含布比卡因的制剂的处理特性，(c) 确定的软组织使用犬牙磨牙缺陷来确定制剂的相容性，并且（d）进行了初步功效研究不含药物的配方，即犬模型中的骨替代率。根据 FDA 的反馈，通过指定请求 (RFD) 流程向 FDA 提交了监管途径。该产品将作为器械主导的组合产品进行监管，其中 OPLS 和布比卡因被分类作为药物成分，以下拟议的第二阶段资助申请是为了解决以下两个问题。具体目标：(1) 进行人为因素评估，(2) 证明减轻疼痛和骨骼的能力通过 (i) 开发使用验证模型，在犬模型中加载 BP 的 TN-ADBS 的再生特性遥测数据收集，(ii) 证明 TN-ADBS 和 TN-ADBS+Bp 的疼痛缓解功效与对照相比 (p<0.05)，(iii) 证明 TN-ADBS 和 TN-ADBS+Bp 的骨再生功效与对照相比（p<0.05），以及（iv）证明 TN-ADBS 和 TN-ADBS+Bp 对局部软组织和硬组织符合 ISO 10993-6:2016（附录 E）。这项二期研究的结果、外科医生验证的模拟使用试验和体内动物研究将转化为在研究设备豁免 (IDE) 批准中对这种有前景的人类方法进行评估研究表明，这将关闭弱势群体接触阿片类药物的主要途径之一。由 NIH Helping to End Addiction Long-term® (HEAL) Initiative 发起，RevBio 的使命是为外科医生提供帮助。使用新型骨移植产品来简化手术并改善术后患者的预后产生骨缺损。