Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation
Inventors
BETANCOURT, Aimesther • Rehlaender, Bruce • Thibert, Roch
Assignees
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Publication Number
US-10925832-B2
Publication Date
2021-02-23
Expiration Date
Abstract
Provided herein is an oral pharmaceutical composition, comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof; and a plurality of trospium beads having a core comprising a salt of trospium.
Core Innovation
The invention provides an oral pharmaceutical composition comprising a plurality of xanomeline beads and a plurality of trospium beads. Each bead population has a specified size range and a core composition that includes xanomeline tartrate with microcrystalline cellulose and talc, and trospium chloride with microcrystalline cellulose, lactose monohydrate, and talc. The xanomeline beads and the trospium beads are each defined to have a dissolution rate of more than about 95% within about the first 45 minutes, or about the first 20 minutes, following entry into an aqueous solution.
In the capsule form, the invention specifies a capsule containing the plurality of xanomeline beads and the plurality of trospium beads with tighter ranges for bead size and core weight percentages. Both bead types are required to dissolve rapidly, more than about 95% within about the first 20 minutes, after the dosage form enters an aqueous solution. The composition is characterized by dosage performance when administered to a patient for at least 7 days at 20 mg trospium twice daily.
When administered under the specified dosing conditions, the composition provides mean trospium pharmacokinetic parameters. The mean Cmax of trospium is 7850±3360 pg/mL and the mean AUC0-12 is 41900±15500 hr·pg/mL.
Claims Coverage
Two independent claims are provided: one directed to an oral pharmaceutical composition and a second directed to an oral capsule dosage form. Across the independent claims, the inventive features center on paired bead populations of xanomeline beads and trospium beads with specified bead size and core composition, rapid dissolution, and specified trospium pharmacokinetic outcomes after at least 7 days at 20 mg trospium twice daily.
Dual bead populations with specified size and core composition
An oral pharmaceutical composition comprising a plurality of xanomeline beads and a plurality of trospium beads, each having a specified bead size range and a core comprising xanomeline tartrate, microcrystalline cellulose, and talc for the xanomeline beads, and trospium chloride, microcrystalline cellulose, lactose monohydrate, and talc for the trospium beads.
Rapid dissolution of both bead populations in aqueous solution
The plurality of xanomeline beads and the plurality of trospium beads each having a dissolution rate of more than about 95% within about the first 45 minutes or within about the first 20 minutes following entry of the dosage form into an aqueous solution.
Trospium pharmacokinetic outcome after at least 7 days at 20 mg twice daily
When administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean Cmax of trospium at 7850±3360 pg/mL and a mean AUC0-12 of 41900±15500 hr·pg/mL.
Capsule containing xanomeline and trospium beads with tighter bead specifications
A capsule containing a plurality of xanomeline beads and a plurality of trospium beads, with the xanomeline beads and trospium beads each having bead sizes between 0.6 mm and 0.85 mm and specified core weight percentages.
Overall, the independent claims cover an oral composition that combines xanomeline beads and trospium beads with defined bead size and core compositions, requires each bead population to dissolve rapidly in aqueous solution, and ties the dosage form to specified trospium pharmacokinetic outcomes after at least 7 days at 20 mg trospium twice daily. The capsule independent further constrains bead sizes and core weight percentages while maintaining the rapid dissolution and trospium PK outcome requirements.
Stated Advantages
Rapid dissolution of both xanomeline beads and trospium beads, each having a dissolution rate of more than about 95% within about the first 45 minutes, or about the first 20 minutes in an embodiment, following entry into an aqueous solution.
Achieving specified mean trospium pharmacokinetic values (Cmax and AUC0-12) after at least 7 days dosing at 20 mg trospium twice daily.
Reduction of cholinergic peripheral adverse events associated with xanomeline when co-administered with trospium chloride.
Predictable shifting of Tmax in pharmacokinetic comparisons.
Documented Applications
Oral pharmaceutical compositions for administration to a patient for at least 7 days at 20 mg trospium twice daily, where the composition includes xanomeline beads and trospium beads meeting rapid dissolution and specified trospium pharmacokinetic outcomes.
Capsule dosage forms containing a plurality of xanomeline beads and a plurality of trospium beads with rapid dissolution performance and specified trospium pharmacokinetic outcomes.
Use context includes tolerability rationale for reducing cholinergic peripheral adverse events associated with xanomeline by co-administration of trospium chloride in Phase I studies.
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