Development of Oxymorphone DETERx, an abuse-deterrent, extended-release opioid fo

描述：该研究的总体目标是利用DETERx(R)平台技术进一步开发强效阿片类镇痛药羟吗啡酮的滥用威慑配方。DETERx技术是一种用于防止滥用的专利配方方法，它建立了物理和化学屏障，旨在避免配方受到各种常见篡改技术时的“剂量倾倒”。缓释（ER） detx胶囊含有微球，由于其小尺寸和物理性质（微球呈蜡状，粉碎后容易融合）而难以粉碎，因此在物理操作尝试后保留了ER特性。在微球内，活性阿片以疏水复合物的形式分布在蜡质基质中，即使经过物理处理，也能防止在各种溶剂中快速提取。这种独特的微球制剂方法已被Collegium制药公司应用于一种主要的阿片类药物候选药物（羟考酮），该药物目前处于后期（3期）临床开发阶段。摄入或吸入粉碎的羟考酮微球的体内结果表明，物理操作实际上可以导致最大血浆浓度（Cmax）低于预期的完整服用产品。此外，由于它们的多颗粒性质，微球可以通过其他方法给病人施用，例如洒在软食物上或通过肠内喂食管。因此，DETERx方法解决了未满足的高度优先的公共卫生需求：对物理操作和化学提取的强大滥用威慑，以及对患有吞咽困难（吞咽困难）的疼痛患者和需要肠内插管的患者的易于给药。Collegium在DETERx技术平台上的经验，包括对羟考酮产品的生产工艺的开发，该工艺已扩大到接近商业规模，为成功开发商业上可行的Oxymorphone DETERx产品建立了必要的机构知识基础。研制并测试了Oxymorphone DETERx的可行性配方；然而，一个先导配方尚未确定，该计划尚未进入临床研究。基于Collegium对oxymorphone的初步研究，该配方方法有望与羟考酮配方相似，并利用相同的基本制造工艺。然而，由于每种分子的性质都是独一无二的，因此需要进行研究，以选择最合适的赋形剂、配方成分的比例和微球大小分布，从而获得具有优化药代动力学和滥用威慑特征的稳定产品。第一阶段的主要目标是确定合适的分析测试方法和4种候选制剂，它们具有所需的释放特性、稳定性和抗物理操作和化学提取能力。第二阶段的主要目标是使用具有代表性的中试规模工艺生产配方，证明长期稳定性，并评估相对于a的操纵和完整产品的体内生物利用度

DESCRIPTION: The overall objective of the research is to further the development of an abuse-deterrent formulation of the potent opioid analgesic oxymorphone utilizing the DETERx(R) platform technology. The DETERx technology is a patented formulation approach to abuse-deterrence that establishes physical and chemical barriers designed to avoid "dose dumping" when the formulation is subjected to a variety of common tampering techniques. The extended-release (ER) DETERx capsules contain microspheres that are difficult to crush due to their small size and physical properties (microspheres are waxy and tend to fuse upon crushing), thereby preserving the ER characteristics following attempts at physical manipulation. Within the microspheres, the active opioid is molecularly distributed as a hydrophobic complex in a waxy matrix, providing protection from rapid extraction in a variety of solvents even after physical manipulation. The unique microsphere formulation approach has been applied by Collegium Pharmaceutical, Inc. to a lead opioid candidate (oxycodone) that is currently in late-stage (Phase 3) clinical development. The in vivo results from ingesting or snorting crushed oxycodone DETERx microspheres indicate that physical manipulation can actually result in lower maximum plasma concentration (Cmax) than taking the product intact, as intended. Additionally, because of their multiparticulate nature, the microspheres can be administered to patients via alternative methods such as sprinkling on soft foods or via enteral feeding tubes. The DETERx approach therefore addresses unmet, high priority public health needs: strong abuse deterrence to physical manipulation and chemical extraction coupled with ease of administration in patients with pain with difficulty swallowing (dysphasia) and patients who require enteral tubes. Collegium's experience with the DETERx technology platform, including the development of a manufacturing process that has been scaled up to near commercial size for the oxycodone product, establishes the institutional knowledge base necessary for successful development of a commercially viable Oxymorphone DETERx product. Feasibility formulations of Oxymorphone DETERx have been developed and tested; however, a lead formulation has yet to be identified and the program has not advanced into clinical study. Based on Collegium's preliminary studies with oxymorphone, the formulation approach is expected to be analogous to the oxycodone formulation and to utilize the same basic manufacturing process. As each molecule is unique in its properties, however, studies will need to be conducted to select the most appropriate excipients, ratio of formulation components and microsphere size distribution that result in a stable product with optimized pharmacokinetic and abuse-deterrent profiles. The main objectives of Phase 1 are to identify appropriate analytical testing methods and 4 formulation candidates at the desired release profile, stability and resistance to physical manipulation and chemical extraction. The main objectives of Phase 2 are to manufacture the formulations using a representative pilot scale process, demonstrate longer term stability and evaluate in vivo bioavailability of manipulated and intact product relative to a marketed reference product.