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

项目总结/摘要 药物成瘾和过量是美国日益严重的问题，2021年有107，622人因过量死亡。 超过60%的药物过量死亡涉及滥用处方或非法阿片类药物。30%的阿片类药物处方 在口腔外科或牙科手术后书写，以控制术后急性疼痛。大约10 每年有100万颗智齿被拔除。持续性高血压的绝对风险增加6.8%， 阿片类药物的使用和5.4%的增加，在随后的诊断阿片类药物滥用后，一个疗程的阿片类药物 智齿拔除后因此，迫切需要开发非阿片类药物为基础的急性疼痛 门诊口腔外科手术的管理策略，最好是通过局部给药， 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 发生严重副作用。 RevBio开发了Tetranite®粘性牙科骨支架（ADBS），一种新型的粘合剂矿物有机 一种既能作为骨传导支架填充空间又能排除刺激物到达切割骨的生物材料 面这种以器械为主导的专利组合产品可作为药物输送载体， 控制可改变孔隙率，以提供任何目标适应症的药物释放曲线。一项I期 对TN-ADBS药物释放动力学的研究表明布比卡因（Bp）遵循可预测的 在感兴趣的时间窗口上的可调谐模式，并且体内试点研究已经证明了该方法的可行性。 提出的模型。初步安全性研究表明，TN-ADBS+Bp无细胞毒性， 牙龈组织愈合顺利后，材料的植入到拟议的模型提取部位， 犬齿该公司相信，有效的Bp剂量可以在5天的窗口期内释放， 最需要止痛来限制智齿拔除后的术后疼痛。 由NIH-HEAL Initiative授予的先前I期资金（1 R43 DE 029369 -01）已用于：（a）设计一个 评价了能够使布比卡因时间依赖性释放的多孔粘性和粘合剂制剂（B 不包含布比卡因的制剂的处理性质，（c）确定的软组织 使用犬齿缺损的制剂的相容性，和（d）进行制剂的初步功效， 没有药物的制剂，即，犬模型中的骨替代率。此外，拟议的 监管途径通过指定申请（RFD）流程提交给FDA。根据FDA的反馈， 该产品将作为器械主导的组合产品进行监管，其中OPLS和布比卡因被归类为 作为药物成分。以下建议的第二阶段拨款申请是为了解决以下两个问题 具体目的：（1）进行人为因素评估和（2）证明缓解疼痛和骨的能力 在犬模型中BP负载的TN-ADBS的再生特性，通过（i）开发用于 （ii）证明TN-ADBS和TN-ADBS+Bp在遥测数据收集中的疼痛缓解功效， 与对照相比（p<0.05），（iii）证实TN-ADBS和TN-ADBS+Bp在骨再生中的功效。 与对照组相比（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）。 本II期研究、外科医生确认的模拟使用试验和体内动物研究的结果将 转化为在试验用器械豁免（IDE）中对这种有前途的方法进行的评估-批准 问题研究这将关闭脆弱人群接触阿片类药物的主要途径之一， 帮助结束成瘾长期计划（HEAL）RevBio的使命是为外科医生提供 使用新型骨移植产品简化手术并改善术后患者结局 产生骨缺损。

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.