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.
Oxymorphone is a potent opioid analgesic available as an immediate-release formulation and as an abuse- deterrent, extended-release (ER) formulation (OPANA ER, Endo Pharmaceuticals Inc., Malvern, PA). The Food and Drug Administration (FDA) has determined that OPANA ER can be compromised when subjected to cutting, grinding, or chewing followed by swallowing, and can be readily prepared for injection or snorting [1]. This research aims at developing an oxymorphone ER formulation utilizing the DETERx(R) technology platform that exhibits considerably greater resistance to these forms of abuse and, thereby, will help mitigate the drug abuse, misuse, and diversion public health epidemic.
