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

项目摘要/摘要 在美国，吸毒和吸毒过量是一个日益严重的问题，2021年吸毒过量死亡人数为107,622人。 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 是在口腔外科或牙科手术后书写的，以控制手术后的急性疼痛。大约10 每年有数百万颗智齿被拔掉。持续存在6.8%的统计上显著的绝对风险增加 阿片类药物的使用和随后诊断的阿片类药物滥用增加了5.4% 在拔掉智齿之后。因此，迫切需要发展非阿片类药物引起的急性疼痛。 门诊口腔外科手术的管理策略，最好是通过局部给药 靶向组织，因为药物能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公司开发了Tetranite®粘附性牙科骨支架(ADBS)，这是一种新型粘结性矿物-有机 一种生物材料，既可以作为骨传导支架填充空间，又可以阻止刺激物到达切割的骨 浮出水面。这种以装置为主导的专利组合产品可以作为药物输送载体，其设计 可提供不同孔隙率的控制，以提供任何靶向适应症的药物释放概况。A阶段I 对TN-ADBS药物释放动力学的研究表明，布比卡因(BP)遵循可预测的和 在感兴趣的时间窗口上的可调模式，体内试点研究已经证明了 建议的模型。初步安全性研究表明，TN-ADBS+BP无细胞毒性，覆盖 将该材料植入建议的模型拔牙部位后，牙龈组织顺利愈合。 犬科动物。该公司相信，在以下情况下，有效的BP剂量可以在5天的窗口内释放 最需要的是止痛，以限制智齿拔除术后的疼痛。 由NIH-Hear倡议授予的先前第一阶段资金(1R43DE029369-01)已用于：(A)设计 能够实现布比卡因时间依赖释放的多孔粘性和粘合剂配方，(B)评价 不含布比卡因的制剂的处理性能，(C)测定软组织 使用犬磨牙缺陷的制剂的配伍性，以及(D)进行了 不含该药物的配方，即犬模型中的骨骼替代率。此外，建议的 调控途径通过申请指定(RFD)程序提交给FDA。根据FDA的反馈， 本产品将被规定为设备主导的组合产品，其中OPLS和布比卡因被归类 作为药物成分。以下拟议的第二阶段赠款申请将解决以下两个问题 具体目标：(1)进行人的因素评估和(2)展示缓解疼痛和骨骼的能力 BP负载TN-ADBS在犬模型中的再生特性(I)验证模型的建立 (Ii)显示TN-ADBS和TN-ADBS+BP的止痛效果 与对照组的比较(p&lt；0.05)，(Iii)TN-ADBS和TN-ADBS+BP的骨再生效果 与对照组的比较(p&lt；0.05)，以及(Iv)证明TN-ADBS和TN-ADBS+BP在局部软组织和 硬组织符合国际标准化组织10993-6：2016(附件E)。 来自外科医生验证的模拟使用试验和活体动物研究的第二阶段研究的结果将 翻译为在研究设备豁免(IDE)批准的情况下对这一有前景的方法进行评估 学习。这将关闭获得支持的弱势人群接触阿片类药物的主要途径之一 由美国国立卫生研究院帮助结束成瘾长期®(Hear)倡议。RevBio的使命是为外科医生提供 使用一种新的骨移植产品来简化手术并改善手术后患者的预后 产生骨质缺陷。

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.