Dextromethorphan transdermal delivery device
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Publication Number
US-11382869-B2
Publication Date
2022-07-12
Expiration Date
Abstract
Provided herein are transdermal delivery devices comprising dextromethorphan. The transdermal delivery device can be characterized by the novel design, for example, with an adhesive layer and a reservoir layer, with an adhesive layer comprising a mixture of two adhesives, and/or with a skin permeation enhancer, e.g., in an amount that can significantly enhance the flux of dextromethorphan. The transdermal delivery device can also be characterized by its in vitro and/or in vivo release profile, for example, that can provide a desired pharmacokinetic profile described herein. Also provided herein are methods of administering dextromethorphan, and methods of treating a disease or disorder described herein, using the transdermal delivery device herein.
Core Innovation
The invention relates to a dextromethorphan transdermal delivery patch system for treating pseudobulbar affect in a human subject. The method includes transdermally administering a therapeutically effective amount of dextromethorphan by applying a transdermal delivery device to the skin, while the subject is not co-administered a CYP2D6 inhibitor. The delivery device is described in architectural terms including adhesive layer, reservoir layer, backing layer, and release liner, with patch formats including multilayer patch and two-zone patch designs.
The invention centers on a single layer drug-in-adhesive patch in which dextromethorphan is dispersed in the adhesive and is present in a free base form. Dextromethorphan is the only drug in the transdermal delivery device. The adhesive layer is defined by weight percentage ranges including an adhesive amount of about 65% to about 85%, dextromethorphan in an amount of about 2% to about 12%, and a permeation enhancer in an amount of about 6% to about 12%, with optional other ingredients in an amount of about 0% to about 20%.
The disclosure addresses the need to treat pseudobulbar affect in a way that achieves a therapeutically relevant pharmacokinetic profile without co-administration of a CYP2D6 inhibitor and without the subject requiring an antitussive effect. The invention specifies mean dextromethorphan exposure and mean dextrorphan exposure constraints, including Cmax and AUC0-24 values, as well as exposure ratios of dextromethorphan to dextrorphan based on both Cmax and AUC0-24. Human cadaver skin and in vivo pharmacokinetic evaluation are described, including comparisons to Neudexta® dosing involving quinidine.
Claims Coverage
The provided material contains one independent claim directed to a transdermal treatment method for pseudobulbar affect, with multiple inventive features related to patient eligibility, device structure, formulation composition, drug chemical form, and specified day-1 pharmacokinetic profile constraints.
Transdermal pseudobulbar affect treatment without CYP2D6 inhibitor co-administration
A method of treating pseudobulbar affect in a human subject by transdermally administering a therapeutically effective amount of dextromethorphan, wherein the subject is not co-administered a CYP2D6 inhibitor and the applying comprises applying a transdermal delivery device to the skin.
Single layer drug-in-adhesive patch with free base dextromethorphan as only drug
The transdermal delivery device is a single layer drug-in-adhesive patch in which dextromethorphan is dispersed in the adhesive, the dextromethorphan is in its free base form, and the transdermal delivery device comprises dextromethorphan as the only drug.
Adhesive layer composition with adhesive, dextromethorphan, and permeation enhancer ranges
The transdermal delivery device comprises an adhesive layer comprising by weight percentage of the adhesive layer an adhesive amount of about 65% to about 85%, dextromethorphan in an amount of about 2% to about 12%, a permeation enhancer in an amount of about 6% to about 12%, and optional other ingredients in an amount of about 0% to about 20%.
Specified day-1 pk profile for dextromethorphan and dextrorphan exposure and ratios
The applying results in one or more specified pharmacokinetic profile features at day 1 post application, including mean dextromethorphan Cmax and AUC0-24 ranges, mean ratio constraints of C24h/C12h, C24h/C6h, and C24h/C18h, mean dextrorphan Cmax and AUC0-24 constraints, and mean exposure ratios of dextromethorphan to dextrorphan of at least about 5 for both Cmax and AUC0-24.
Across the independent claim, coverage is directed to treating pseudobulbar affect in a human subject using a transdermal single layer drug-in-adhesive patch delivering free base dextromethorphan as the only drug, without CYP2D6 inhibitor co-administration, while achieving specified day-1 dextromethorphan and dextrorphan pharmacokinetic exposure levels and ratio constraints.
Stated Advantages
Achieves therapeutically relevant dextromethorphan pharmacokinetic exposure in humans as characterized by specified mean Cmax and AUC0-24 values at day 1 post application.
Provides defined dextrorphan exposure constraints, including mean dextrorphan Cmax and AUC0-24 not more than specified limits.
Provides specified dextromethorphan-to-dextrorphan exposure ratios of at least about 5 based on both Cmax and AUC0-24 at day 1 post application.
Allows treatment without co-administration of a CYP2D6 inhibitor and without the subject suffering from a cough or needing an antitussive effect.
Documented Applications
Treating pseudobulbar affect in a human subject using transdermal administration of dextromethorphan via a patch.
Comparative pharmacokinetic evaluation versus Neudexta® (dextromethorphan hydrobromide plus quinidine sulfate) as part of the documented human pharmacokinetics.
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