Formulations of a somatostatin modulator
Inventors
Burke, Gerald • Yates, Ian • Bulovsky, Hannah • Kyburz, Kyle • Tyler, Clayton
Assignees
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Publication Number
US-11957674-B2
Publication Date
2024-04-16
Expiration Date
Abstract
Described herein are formulations of a somatostatin modulator, methods of making such formulations, and methods of using such formulations in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.
Core Innovation
The disclosed invention relates to pharmaceutical compositions for orally administering a selective nonpeptide SST2 biased agonist, comprising 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A) or a pharmaceutically acceptable salt or solvate thereof, including Compound A-HCl and Compound A monohydrochloride. The compositions use spray-dried solid dispersions to form substantially amorphous drug in a polymer matrix.
The polymer matrix is formed with high glass transition temperature pharmaceutically acceptable polymers, including HPMCAS and PVP/VA, to support an amorphous drug state. The solid dispersions are described with specific drug-to-polymer weight ratios, minimum drug loading, and characterization of amorphous and crystallinity behavior using PXRD and DSC.
The invention also encompasses tablet dosage forms that include the solid dispersion together with pharmaceutical acceptable ingredients such as diluents, disintegrants, lubricants, and glidants, and optional film coatings and enteric coatings. Treatment concepts are provided for modulation of somatostatin activity by suppressing growth hormone and related hormones in a human, including use in acromegaly and neuroendocrine tumors.
Claims Coverage
The independent claim covers oral suppression of specified peptide or protein hormones in a human using Compound A or a pharmaceutically acceptable salt or solvate, with an empty-stomach regimen. The claim set includes multiple inventive features tied to administration timing, patient condition, dosage form, and spray-dried dispersion formulation ranges.
Empty-stomach oral suppression of selected hormones using Compound A
Suppressing growth hormone, insulin, glucagon, insulin-like growth factor 1, prolactin, or combinations thereof in a human by orally administering, on an empty stomach at least 30 minutes before a meal, a therapeutically effective amount of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutical acceptable ingredients.
Acromegaly patient treatment
A method in which the human patient has acromegaly.
Once-daily administration with an empty-stomach timing
Administering the pharmaceutical composition once daily to a human with a glass of water on an empty stomach at least 30 minutes before a meal.
Active amount defined by monohydrochloride-equivalent dosing
Including a pharmaceutical composition containing an amount equivalent to about 20 mg to about 60 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride.
Spray-dried dispersion formulation with defined HPMCAS ratio
Including about 20% by weight to about 40% of a spray-dried dispersion made from 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate to hydroxypropyl methyl cellulose acetate succinate, with about 15/85 to about 35/65 ratios.
Tablet composition with excipient ranges and optional limited film coating agents
Including about 60% by weight to about 80% by weight of selected acceptable pharmaceutical ingredients and optionally less than about 5% by weight of film coating agents, with example excipients including microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, silicon dioxide, and magnesium stearate.
The claims primarily cover an oral, empty-stomach suppression method for specified hormones using Compound A or a salt or solvate, with dependent claims narrowing to acromegaly and adding administration regimen constraints. Additional dependent claims further restrict formulation and dosage by defining the active amount as monohydrochloride-equivalent, specifying spray-dried dispersion composition ranges and HPMCAS ratio ranges, and constraining excipient content and optional film coating agent levels.
Stated Advantages
Improved performance of certain SDD tablets under higher gastric pH.
Relatively small impact from PPI coadministration.
Dose proportionality.
Systemic exposure supported by fasting-time optimization.
Documented Applications
Modulation of somatostatin activity by suppressing growth hormone and related hormones in a human, including use for acromegaly.
Modulation of somatostatin activity by suppressing growth hormone and related hormones in a human, including use for neuroendocrine tumors.
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