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

描述：这项研究的总体目标是利用DETERx(注册商标)平台技术进一步开发一种有效的阿片类止痛药羟吗啡酮的滥用威慑配方。DETERx技术是一种获得专利的滥用威慑配方方法，它建立了物理和化学屏障，旨在避免在配方受到各种常见篡改技术时的“剂量倾销”。缓释(ER)DETERx胶囊包含由于其小尺寸和物理特性而难以粉碎的微球(微球为蜡状，在粉碎时容易熔化)，从而在尝试物理操作后保持ER特性。在微球内，活性阿片类药物以疏水络合物的形式分子分布在蜡质基质中，即使在物理操作之后，也可以防止在各种溶剂中快速提取。科莱姆制药公司已经将这种独特的微球制剂方法应用于一种目前处于晚期(第三阶段)临床开发的阿片类铅药物(羟考酮)。体内摄入或吸入粉碎的羟考酮DETERx微球的结果表明，物理操作实际上可以导致比原封不动的产品更低的最大血浆浓度(Cmax)。此外，由于微球的多颗粒性质，患者可以通过替代方法给药，如喷洒在软食物上或通过肠道喂养管。因此，DETERx方法满足了尚未得到满足的高度优先的公共卫生需求：对物理操作和化学提取具有强大的滥用威慑力，以及对吞咽困难(吞咽困难)疼痛患者和需要肠道管的患者易于管理。Colcium在DETERx技术平台上的经验，包括为羟考酮产品开发已扩大到接近商业规模的制造工艺，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。Oxymorphone DETERx的可行性配方已经开发和测试；然而，主导配方尚未确定，该计划尚未进入临床研究。根据Colcium对羟吗啡酮的初步研究，配方方法有望类似于羟考酮配方，并使用相同的基本制造工艺。然而，由于每个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、制剂组成比例和微球尺寸分布，以产生具有优化的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适当的分析测试方法和4种候选配方，以满足所需的释放情况、稳定性以及对物理操作和化学提取的抵抗力。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这些制剂，展示较长期的稳定性，并相对于 上市的参考产品。

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.