Composition and method for treating neurological disease
Inventors
Meyer, Glenn A. • Faour, Joaquina • Pastini, Ana Cristina • Befumo, Marcelo Fernando
Assignees
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Publication Number
US-10213394-B1
Publication Date
2019-02-26
Expiration Date
Abstract
The present disclosure is directed to methods of treating neurological disorders in a patient such as Parkinson's disease, drug-induced extrapyramidal reactions, and/or levodopa-induced dyskinesia comprising administering to the patient once daily in the morning a pharmaceutical composition comprising about 50 mg to about 400 mg of extended-release amantadine or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to extended release amantadine HCl compositions and methods for treating a drug-induced extrapyramidal reaction in an adult patient. The disclosed approach administers amantadine once daily in the morning using a pharmaceutical composition that includes an extended release component and an immediate release component. Each composition is characterized as an osmotic device comprising an osmotic agent and an osmotic coating.
In the disclosed dosing regimens, the method starts with about 129 mg of amantadine free base equivalent once daily in the morning, for one week, and then increases the dose in morning administrations. Dose escalation includes increasing to about 193 mg and, in some regimens, to about 258 mg, with a maximum daily dose limited to about 322 mg of amantadine free base equivalent. The compositions are structured to provide a pharmacokinetic profile defined by a mean change in amantadine plasma concentration as a function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine in an immediate release form.
The osmotic device is disclosed as providing an osmotic gradient-controlled extended release, including a semipermeable membrane and an osmotic core plus an immediate-release layer. Formulation performance is characterized using USP Type II paddle dissolution profiles, including dissolution in water and in 0.1 N HCl, and includes fed versus fasting relative bioavailability comparisons. Clinical and pharmacokinetic results are used to support improvements for levodopa-induced dyskinesia, including reductions on Unified Dyskinesia Rating Scale (UdysRS) and increased awake ON hours without dyskinesia, as well as quantified exposure and related assessments.
Claims Coverage
The independent claims cover three related methods that share the same core treatment framework: once-daily morning administration of an osmotic extended release/immediate release amantadine composition with a defined initial dose and weekly dose increase to a maximum daily dose, and pharmacokinetic performance constrained by a mean dC/dT measured in a single-dose human pharmacokinetic study between 0 and 4 hours after administration. Across these independent claims, the pharmacokinetic and composition features are consistent, while the dosing sequence differs in the number of escalation steps and the initial dose regimen details.
Once-daily morning osmotic ER/IR dosing for drug-induced extrapyramidal reactions
A method of treating a drug-induced extrapyramidal reaction in an adult patient by administering once daily in the morning an osmotic device comprising an osmotic agent and an osmotic coating, where each pharmaceutical composition includes an extended release component and an immediate release component.
Stepwise escalation from about 129 mg to higher morning doses up to a maximum daily dose of about 322 mg
Administer about 129 mg of amantadine free base equivalent once daily in the morning for one week, increase the dose by administering once daily in the morning about 193 mg of amantadine free base equivalent (and in some formulations to about 258 mg), and limit the maximum daily dose to about 322 mg of amantadine free base equivalent administered once daily in the morning using weekly intervals.
ER and IR component definition with immediate release about 48 mg free base equivalent
Define each pharmaceutical composition as an osmotic device having an extended release component comprising amantadine free base equivalent and an immediate release component comprising about 48 mg of amantadine free base equivalent, or where the components consist essentially of amantadine free base equivalent for ER and consisting essentially of about 48 mg of amantadine free base equivalent for IR.
Pharmacokinetic dC/dT constraint relative to immediate release measured 0 to 4 hours
Require that each pharmaceutical composition provides a mean change in amantadine plasma concentration as a function of time (dC/dT) between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, with dC/dT values measured in a single dose human pharmacokinetic study over the time period between 0 and 4 hours after administration.
Across the independent claims, the inventive subject matter is an osmotic ER/IR amantadine regimen for drug-induced extrapyramidal reactions in adults, using once-daily morning dosing with defined ER and immediate-release components (including an immediate release component of about 48 mg amantadine free base equivalent), weekly escalation from about 129 mg to a maximum daily dose of about 322 mg, and a defined exposure/kinetic target using mean dC/dT between about 40% and about 70% of immediate release, assessed in a single-dose human pharmacokinetic study over 0–4 hours after administration.
Stated Advantages
Provides a mean dC/dT between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine in an immediate release form.
Reduces levodopa-induced dyskinesia as reflected by Unified Dyskinesia Rating Scale (UdysRS) reductions.
Increases awake ON hours without dyskinesia.
Claims reduced dose-dumping and food effects based on fed versus fasting bioequivalence comparisons.
Documented Applications
Treating a drug-induced extrapyramidal reaction in an adult patient using once daily morning amantadine osmotic extended release/immediate release pharmaceutical compositions.
Treatment of levodopa-induced dyskinesia, including improvements indicated by UdysRS reductions and increased awake ON hours without dyskinesia.
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