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的一个主要问题，2017年有70，237人死亡。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。每年大约有1000万颗智齿被拔除。 持续使用阿片类药物的绝对风险增加6.8%， 随后的阿片类药物滥用诊断遵循智齿拔除后的阿片类药物的单一疗程。 因此，迫切需要开发一种前线，非阿片类药物为基础的急性疼痛管理策略 用于门诊口腔外科手术。 LaunchPad Medical开发了Tetranite®（TN），一种新型骨再生矿物有机自固化材料， 粘性生物材料TN已在犬颌骨模型中进行了广泛的体内研究，并显示出有效性 而且很宽容此外，初步的体外研究表明，药物可以被并入到 TN制剂和随时间释放，并且已经充分确定的是，靶药物的释放曲线可以是恒定的。 使用常规的时间释放技术如被动扩散来定制时间-剂量曲线。施用 局部作用的镇痛剂（例如，萘普生），局部麻醉剂（例如，布比卡因）和/或加巴喷丁类（例如， 普瑞巴林）被动释放超过5天的窗口时，疼痛缓解是最需要的，是一个强大的和创新的 限制智齿拔除后急性术后疼痛的策略，同时采用TN作为一种 填充剂/密封剂将允许同时封闭对骨伤口的环境刺激物，从而防止 骨炎和允许骨再生。 在这个I期项目中，我们将证明载药TN可以是一种新的途径， 通过测定各种疼痛的释放曲线， 不同浓度TN中的药物（目标I），验证TN处理和药物浓度的一致性 在复合制剂中（目的II），并使用 人成骨细胞（Aim III）。能够以受控的方式并直接在患者体内释放疼痛治疗剂， 损伤部位在口腔外科手术后提供改善的疼痛控制，而不会使患者暴露于 阿片类药物此外，这种新的疼痛管理方法可以扩展到更具侵入性的骨科手术。 例如关节置换、脊柱融合或重建创伤手术。在第二阶段，我们将 进行一项体内研究，以评估含药TN在解决术后疼痛方面的疗效， 牙齿切除术，优化TN制剂中药物的掺入和释放，开发cGMP 复合产品的生产工艺，并最终使用 药物TN

Project Summary/Abstract Drug addiction and overdose are a major problem in the US, accounting for 70,237 deaths in 2017. Over 60% of drug overdose deaths involved misuse of prescription or illicit opioids, and 30% of opioid prescriptions are written following oral surgical or dental procedures. 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 a front line, non-opioid-based acute pain management strategy for outpatient oral surgical procedures. LaunchPad Medical has developed Tetranite® (TN), a novel bone regenerative mineral-organic self-setting adhesive biomaterial. TN has been extensively studied in vivo in a canine jaw model and shown to be effective and well-tolerated. Additionally, preliminary in vitro studies have shown that medication can be incorporated into TN formulations and released over time, and it is well established that the release profile of a target drug can be tailored to time-dose curve using conventional time release technology such as passive diffusion. Administering locally-acting analgesics (e.g., naproxen), local anesthetics (e.g., bupivacaine) and/or gabapentinoids (e.g., pregabalin) passively released over the 5-day window when pain relief is most needed, is a strong and innovative strategy for limiting acute postoperative pain following wisdom tooth removal, while employing TN as a filler/sealant will allow for simultaneous occlusion of environmental irritants to the bone wound, thus preventing osteitis and allowing bone regeneration. In this Phase I project, we will demonstrate that drug-loaded TN can be a novel route to providing localized and time release pain medication following wisdom tooth extraction by determining the release profile of various pain medications from TN at different concentrations (Aim I), verifying the consistency of TN handling and exotherm in compounded formulations (Aim II), and verifying the biocompatibility of TN-drug formulation in vitro using human osteoblasts (Aim III). The ability to release pain therapeutics in a controlled fashion and directly at the site of injury offers improved pain control following oral surgical procedures without exposing the patient to opioids. In addition, this novel approach to pain management can be extended to more invasive orthopedic procedures such as joint replacement, spinal fusions or reconstructive trauma surgery. In Phase II we will conduct an in vivo study to assess efficacy of medicated TN to address post-operative pain following wisdom tooth odontectomy, optimize incorporation and release of medications in TN formulations, develop cGMP manufacturing process for the compounded product, and ultimately conduct clinical trials for bone void filler using medicated TN.