ABSTRACT
A transdermal drug delivery system (TDDS) is generally designed to deliver an active pharmaceutical ingredient (API) through the skin for systemic action. Permeation of an API through the skin is controlled by adjusting drug concentration, formulation composition, and patch design. A bilayer, drug-in-adhesive TDDS design may allow improved modulation of the drug release profile by facilitating varying layer thicknesses and drug spatial distribution across each layer. We hypothesized that the co-release of two fixed-dose APIs from a bilayer TDDS could be controlled by modifying spatial distribution and layer thickness while maintaining the same overall formulation composition. Franz cell diffusion studies demonstrated that three different bilayer patch designs, with different spatial distribution of drug and layer thicknesses, could modulate drug permeation and be compared with a reference single-layer monolith patch design. Compared with the monolith, decreased opioid antagonist permeation while maintaining fentanyl permeation could be achieved using a bilayer design. In addition, modulation of the drug spatial distribution and individual layer thicknesses, control of each drug's permeation could be independently achieved. Bilayer patch performance did not change over an 8-week period in accelerated stability storage conditions. In conclusion, modifying the patch design of a bilayer TDDS achieves an individualized permeation of each API while maintaining constant patch composition.
Subject(s)
Drug Delivery Systems , Transdermal Patch , Aged , Animals , Drug Compounding , Humans , Male , Skin/metabolismABSTRACT
OBJECTIVE: These in vitro studies compared abuse-deterrent properties of REMOXY ER (extended-release oxycodone), a novel, high-viscosity gel formulation, versus the two currently marketed ER oxycodone formulations. METHODS: Tampering methods were tailored to each product to maximize oxycodone release with the least complexity, time, and effort, based on the physical/chemical properties of each formulation. Oral abuse was simulated by extracting oxycodone from each manipulated formulation in Common Ingestible Liquids and in Advanced Solvents (not ingestible and requiring additional separation). To simulate injection abuse, oxycodone was extracted from each manipulated formulation in low volumes of injection vehicles, heated or unheated. Inhalation abuse potential was assessed by volatilization. RESULTS: In oral abuse simulations, manipulated REMOXY ER released 2-22 percent of its oxycodone in 20 minutes in five Common Ingestible Liquids, versus 77-85 percent oxycodone released from OxyContin® ER in 5 minutes in four of the five. In six Advanced Solvents, REMOXY ER released 3-37 percent at 20 minutes, versus 55-89 percent released from OxyContin ER at 5 minutes. Minimal oxycodone was extracted from REMOXY ER in five injection vehicles, heated or unheated. In contrast, OxyContin ER released 65-87 percent of its oxycodone within 10 minutes in all vehicles, regardless of heating. Xtampza® ER released 96 percent of its oxycodone in a heated injection vehicle and released 50-60 percent in two unheated injection vehicles. Showing minimal inhalation abuse potential, 9 percent of oxycodone was vaporized from manipulated REMOXY ER at 20 minutes compared to 8.8 percent at 5 minutes for OxyContin ER. CONCLUSIONS: In these studies, REMOXY ER demonstrated robust and meaningful abuse-deterrence relative to OxyContin ER and Xtampza ER. PERSPECTIVE: Abuse-deterrent drugs were intended to help fight opioid abuse. Yet, the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are sorely needed. A new, high-viscosity, ER oxycodone formulation showed much improved abuse-deterrent properties in simulations of oral, injection, and inhalation abuse, compared to earlier, first-generation formulations.