Method for administering an NMDA receptor antagonist to a subject
Inventors
Went, Gregory T. • Fultz, Timothy J. • Meyerson, Laurence R.
Assignees
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Publication Number
US-8598233-B2
Publication Date
2013-12-03
Expiration Date
Abstract
Compositions and methods for administering memantine to a subject are provided. In particular, a solid pharmaceutical composition in a unit dosage form for once daily oral administration is provided. The compositions comprises an extended release formulation of 22.5 mg to 33.75 mg memantine, or a pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a mean plasma memantine concentration profile characterized by a change in memantine concentration as a function of time (dC/dT) that is less than 50% of the dC/dT provided by the same quantity of an immediate release form of memantine, determined in a time period between 0 hours to 6 hours after administration of memantine, and wherein dC/dT is measured in a single-dose human PK study. Methods of treating dementia, in particular Alzheimer's diseases, using the compositions are provided.
Core Innovation
The invention relates to controlled/extended release dosing of N-methyl-D-Aspartate receptor antagonists, including memantine, in a solid pharmaceutical composition in a unit dosage form for once daily oral administration. The compositions include an extended release formulation of a specified amount of memantine or a pharmaceutically acceptable salt thereof and are characterized by plasma memantine concentration profiles after administration to a human subject.
A central problem addressed is that immediate release forms provide a dC/dT that is higher, and that an extended release formulation is needed such that the mean plasma memantine concentration profile provides a dC/dT that is less than about 50% of the dC/dT provided by the same quantity of an immediate release form. The described reduction is evaluated over a time period between 0 hours to 6 hours after administration, with further refinements over narrower windows.
The invention further ties the plasma profile constraints to extended release dosage forms and formulation concepts for unit dosage forms, including matrix tablets and coated tablets/beads, and pellets/capsules. The described solid pharmaceutical composition is provided in an extended release dosage form, with memantine amount ranges and associated dC/dT comparison criteria relative to immediate release.
Claims Coverage
The provided content includes two independent claims. Both independent claims define a solid pharmaceutical composition in a unit dosage form with extended release memantine and require a single-dose human PK study to assess a reduced early dC/dT relative to an immediate release form.
Once daily extended release memantine with reduced early dC/dT versus immediate release
A solid pharmaceutical composition in a unit dosage form for once daily oral administration comprising an extended release formulation of memantine or a pharmaceutically acceptable salt, wherein administration to a human provides a mean plasma memantine concentration profile characterized by dC/dT less than 50% of the dC/dT provided by the same quantity of an immediate release form, determined in a time period between 0 hours to 6 hours, with dC/dT measured in a single-dose human PK study.
Extended release dosage form with reduced early dC/dT for essentially 22.5 to 37.5 mg memantine
A solid pharmaceutical composition in a unit dosage form consisting essentially of 22.5 to 37.5 mg memantine or a pharmaceutically acceptable salt in an extended release dosage form, wherein administration provides a mean plasma memantine concentration profile characterized by dC/dT less than about 50% of the dC/dT provided by the same quantity of an immediate release form, determined in a time period between 0 hours to 6 hours, and wherein dC/dT is measured in a single-dose human PK study.
Across both independent claims, the claim coverage is centered on extended release unit dosage forms of memantine or salts for oral dosing, where the extended release composition is defined by a reduced early-time dC/dT relative to an immediate release form and is confirmed using a single-dose human PK study over a 0 to 6 hour window.
Stated Advantages
Extended release dosing provides a mean plasma memantine concentration profile with dC/dT less than 50% of the dC/dT provided by the same quantity of an immediate release form.
The specified reduced dC/dT characterization is evaluated over a defined early time period between 0 hours to 6 hours using a single-dose human PK study.
Documented Applications
Controlled/extended release formulations for therapeutic use of memantine in dementia (Alzheimer’s disease), major depression, and Parkinson’s disease dyskinesia, supported by the described PK/PD and clinical scoring contexts (UPDRS scoring, HAMD, MADRS, and NPI).
Clinical/therapeutic use case and trial designs are described across dementia, depression, and Parkinson-related indications, in connection with extended release versus immediate release comparisons and PK characterization.
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