Transdermal Dextromethorphan Patch Bypasses CYP2D6 Inhibitors
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Solution Overview
Problem
Current oral formulations of dextromethorphan, such as NUEDEXTA, require co-administration of a CYP2D6 inhibitor like quinidine, which can cause side effects and limit administration to individuals sensitive or intolerant to these inhibitors, and do not account for varying metabolizer statuses, leading to suboptimal dosing and bioavailability.
Innovation Solution
Transdermal delivery devices comprising dextromethorphan, specifically drug-in-adhesive patches with a skin permeation enhancer like isopropyl myristate and a crystallization inhibitor like vinylpyrrolidone polymer, allowing for consistent high flux and effective plasma concentrations without the need for CYP2D6 inhibitors, suitable for diverse metabolizer types and reducing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If oral formulations of dextromethorphan are used with CYP2D6 inhibitors like quinidine, then systemic bioavailability of dextromethorphan is increased, but side effects increase and administration is limited to individuals sensitive or intolerant to these inhibitors
Solution Approach 1:
The patent extracts and removes the CYP2D6 inhibitor (quinidine) from the formulation, delivering dextromethorphan alone via transdermal route. This eliminates the harmful interaction with CYP2D6 metabolism while maintaining therapeutic efficacy through sustained transdermal delivery and high flux formulation design.
Solution Approach 2:
The patent introduces a transdermal delivery system as an intermediary between the drug and systemic circulation. This mediator bypasses first-pass hepatic metabolism and avoids CYP2D6 enzyme interaction, allowing dextromethorphan to reach systemic circulation without requiring CYP2D6 inhibition.
2Object-affected harmful factors
If oral formulations without CYP2D6 inhibitors are used, then fewer side effects occur, but bioavailability and dosing accuracy become suboptimal
Solution Approach 1:
The patent changes the delivery parameters by using transdermal route instead of oral administration, and formulates with high flux materials and optimized drug-adhesive ratios. These parameter changes enable controlled, sustained delivery that achieves optimal bioavailability without CYP2D6 inhibitors, eliminating the need for dose adjustments based on metabolizer status.
3Device complexity
If dextromethorphan is delivered transdermally without crystallization inhibitor, then formulation is simpler, but flux is insufficient to achieve therapeutically effective plasma concentrations
Solution Approach 1:
The patent incorporates a crystallization inhibitor (vinylpyrrolidone polymer) that replicates and enhances the flux-promoting effects observed with other inhibitors. This polymer copy provides sustained high flux by preventing drug crystallization in the adhesive matrix, maintaining drug in soluble state for continuous transdermal delivery without adding significant formulation complexity.
4Productivity
If transdermal delivery uses high drug loading in adhesive, then flux increases, but drug distribution uniformity decreases
Solution Approach 1:
The patent creates a composite adhesive formulation combining dextromethorphan with vinylpyrrolidone polymer at optimized ratios. This composite material prevents drug-aggregate formation and ensures homogeneous distribution throughout the adhesive matrix, enabling high drug loading while maintaining uniform drug dispersion and consistent flux over the wear period.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The transdermal delivery achieves therapeutically effective plasma concentrations of dextromethorphan with reduced side effects, improved dosing accuracy, and increased bioavailability, enabling treatment of neurological disorders like pseudobulbar affect without the limitations of oral formulations.
Implementation Method 1
The transdermal delivery devices (patches) herein can be administered to achieve a therapeutically effective plasma concentration without regard to whether a CYP2D6 inhibitor such as quinidine is co-administered
Implementation Method 2
the inclusion of a crystallization inhibitor, a vinylpyrrolidone polymer (Plasdone K29/32), in dextromethorphan transdermal patches significantly enhanced the permeation of dextromethorphan from the patches
Implementation Method 3
The transdermal delivery of dextromethorphan herein achieves therapeutically effective plasma concentrations of dextromethorphan
Data Source
AI summary
Provided herein are novel transdermal delivery devices (or patches) comprising dextromethorphan, pharmaceutical compositions comprising dextromethorphan, methods of preparation thereof, and methods of administering dextromethorphan transdermally. Also provided herein are methods of treating various diseases and disorders such as neurological diseases or disorders (e.g., PBA) using the transdermal delivery devices and/or pharmaceutical compositions herein.