Orally available pharmaceutical formulation suitable for improved management of movement disorders
Inventors
Hansen, John Bondo • Thomsen, Mikael S. • Mikkelsen, Jens D. • Nielsen, Peter Gudmund • Kreilgaard, Mads
Assignees
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Publication Number
US-10561618-B2
Publication Date
2020-02-18
Expiration Date
Abstract
The present invention provides a pharmaceutical formulation for oral administration comprising an agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors, such as a triptan, e.g. zolmitriptan, in a matrix constituent with extended release characteristics, and further comprising a 5-HT1A-R agonist, such as buspirone, in a constituent with immediate-release characteristics. The special formulation is particularly well-suited for use in the treatment of movement disorders by combining the two active ingredients in a manner that achieves synergy from both the combination per se and the special release parameters of the pharmaceutical formulation, allowing for ease of administration and reducing the risk of adverse effects of each of the two active ingredients.
Core Innovation
The invention relates to an orally available fixed-dose pharmaceutical formulation for movement disorders that combines zolmitriptan with buspirone. The formulation includes a matrix constituent that provides extended release of zolmitriptan and a constituent that provides immediate release of buspirone.
The formulation is described as mimicking sequential dosing by coordinating the extended-release profile of zolmitriptan with the immediate-release profile of buspirone. This coordination is stated to improve the therapeutic index by aligning a zolmitriptan exposure during buspirone’s immediate-release peak.
Embodiments include solid dosage forms such as a bi-layered tablet and a capsule with separate granules or pellets, where the zolmitriptan and buspirone components are positioned to provide different release rates. The document describes zolmitriptan in an extended-release matrix constituent and buspirone in an immediate-release constituent, including structural architectures such as an inner core matrix and an outer coating.
The disclosure includes development and evaluation using dissolution profiles and pharmacokinetic results. In vivo pharmacokinetic results in cynomolgus monkeys are described as showing a delayed controlled zolmitriptan peak and a rapid buspirone immediate-release peak, sustained for about 12 hours.
Claims Coverage
The independent claims cover two main inventive elements: an extended-release matrix constituent containing zolmitriptan and a separate immediate-release constituent containing buspirone.
Extended release zolmitriptan matrix with immediate release buspirone constituent
A pharmaceutical formulation comprising a matrix constituent comprising zolmitriptan, and pharmaceutically acceptable derivatives thereof, said matrix constituent providing for extended release of said zolmitriptan, and a constituent comprising buspirone, and pharmaceutically acceptable derivatives thereof, said constituent providing for immediate release of said buspirone.
The core inventive coverage is the combination of an extended-release zolmitriptan matrix constituent with a separate immediate-release buspirone constituent in a single pharmaceutical formulation.
Stated Advantages
Improves therapeutic index by coordinating zolmitriptan extended release with buspirone immediate-release peak exposure.
Reduces adverse effects risk, including serotonin syndrome or serotonin toxicity.
Documented Applications
Treatment of movement disorders, including Parkinson’s disease-related movement disorders and dyskinesias, such as L-DOPA induced dyskinesia and tardive dyskinesia.
Treatment of movement disorders associated with use of drugs, including conditions involving altered synaptic dopamine levels and withdrawal of drugs.
Additional movement-disorder categories include ataxia, akathisia, dystonia, essential tremor, Huntington’s disease, myoclonus, Rett syndrome, Tourette syndrome, Wilson’s disease, chorea, Machado-Joseph disease, restless leg syndrome, spasmodic torticollis, and geniospasm.
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