Kv7.2 / 7.3 potassium channel activator sustained-release formulation

Abstract

Solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulations are described herein. In certain embodiments, the formulation has a specific solubility profile and / or a specific peak-to-trough ratio. In one embodiment, the formulation comprises an intragranular portion comprising a Kv7.2 / 7.3 potassium channel activator, a hydrophilic matrix polymer, a filler, and a binder, and an extragranular portion comprising a sustained-release polymer, optionally a hydrophilic matrix polymer, and a lubricant. The Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. JPEG2026527631000010.jpg3468

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 518,859, filed on August 10, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to sustained - release formulations of Kv7.2 / 7.3 potassium channel activators, particularly formulations having specific in vitro dissolution profiles and providing specific pharmacokinetic parameters upon administration.

Background Art

[0003] Potassium (K + ) channels, which are present on the plasma membranes of most cell types, are the most diverse class of all ion channels and are associated with a wide range of physiological functions, including regulation of the electrical properties of excitable cells. The Kv7 gene (originally called KCNQ, a name assigned by the HUGO Gene Nomenclature Committee (HGNC)) was designated by the International Union of Pharmacology (IUPHAR) as a voltage - dependent K +The Kv7 channel was assigned to a subfamily. The Kv7 subfamily consists of five homologous pore-forming α subunits Kv7.1–7.5, which have a typical structure for voltage-dependent K+ channels, possessing a 6TM region (S1–S6) adjacent to the intracellular N-terminal and C-terminal domains, a typical voltage-sensing domain located at S4 composed of alternately positively charged residues, and a single P region between S5 and S6 of each subunit. The channel is formed as a tetramer of the primary α subunit, either as a homotetramer or a heterotetramer. Neurons are known to express Kv7 channels composed of α subunits Kv7.2–7.5. While some of these gene products may be exclusively neuronal, other gene products such as Kv7.4 and Kv7.5 can be found in other tissues such as smooth muscle and skeletal muscle. Notably, reducing or eliminating the influence of Kv7.2 and Kv7.3 channels can dramatically alter neuronal excitability.

[0004] As described in U.S. Patent No. 10,851,067, Kv7.2 / 7.3 potassium channel activators were predicted to be useful in treating various forms of epilepsy. What is needed is a novel formulation of Kv7.2 / 7.3 potassium channel activators, particularly suitable for the treatment of epilepsy and other conditions that respond to Kv7.2 / 7.3 potassium channel activators. [Overview of the project]

[0005] In one embodiment, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation comprises: i) an intragranular portion comprising a Kv7.2 / 7.3 potassium channel activator, a hydrophilic matrix polymer, a filler, and a binder; and ii) an extragranular portion comprising a sustained-release polymer, optionally a hydrophilic matrix polymer, and a lubricant, wherein the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. [ka]

[0006] In another embodiment, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation comprises a hydrophilic matrix polymer and a sustained-release polymer, wherein the formulation has a solubility such that less than 25%, preferably less than 20%, of the Kv7.2 / 7.3 potassium channel activator is released in 2 hours, the solubility being measured in 900 mL of pH 6.8 phosphate buffer containing 3% SLS in a USP Dissolution Apparatus 2 with a stationary basket at 50 rpm, and the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof.

[0007] In another embodiment, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation exhibits a ratio of approximately 1 to approximately 3 of the peak to the 24-hour trough of Kv7.2 / 7.3 potassium channel activator plasma levels when administered orally to human subjects, wherein the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing]

[0008] [Figure 1] This shows the dissolution profile of BHV-7000 10 mg sustained-release tablets. [Figure 2] This shows the mean plasma concentration (ng / mL) over time for BHV-7000 sustained-release tablets administered as a single dose to human subjects. [Figure 3] The dissolution profiles of BHV-7000 10mg, 25mg, 50mg, and 75mg sustained-release tablets are shown. [Modes for carrying out the invention]

[0009] The features described above and other features will be recognized and understood by those skilled in the art from the following detailed description, drawings, and attached claims.

[0010] Sustained-release formulations of Kv7.2 / 7.3 potassium channel activators, including oral sustained-release formulations for once-daily administration, are described herein. In the treatment of epilepsy, for example, sustained-release formulations are desirable to improve patient compliance, improve quality of life, maintain therapeutic systemic drug levels, and minimize side effects. In patients with poor adherence to antiseizure medications, breakthrough seizures may be observed, along with increased side effects such as dizziness, drowsiness, diplopia / blurred vision, dyscoordination, unsteadiness, headache, and gastrointestinal intolerance. During the development of sustained-release formulations of BHV-7000, it was found that certain formulations produced a spike in mean plasma concentration within 4–8 hours post-release. Unexpectedly, it was found that sustained-release formulations with a sustained-release profile could avoid this initial spike in mean plasma concentration and result in a more consistent release profile. Specifically, the sustained-release formulation preferably has a peak Kv7.2 / 7.3 potassium channel activator plasma level relative to the 24-hour trough of approximately 1 to 3.

[0011] In one embodiment, the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. [ka]

[0012] "Pharmacologically acceptable salts" refer to salts that, within the bounds of sound medical judgment, are suitable for use in contact with patient tissues without excessive toxicity, irritation, or allergic reactions, and that offer a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the relevant art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol. 6, 1-19 provides a detailed description of pharmaceutically acceptable salts. A pharmaceutically acceptable “salt” is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, and is not limited to halogen salts such as hydrobromide, hydrochloride, hydrofluoric acid, and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; for example, sulfonates (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate), acetate, malate, fumarate, succinate, citrate, benzoate, gluconate, lactate, man. Examples include organic acid salts such as delates, mucins, pamoates, pantothenates, oxalates, and maleates; as well as amino acid salts such as aspartates or glutamates. The acid addition salt may be a monovalent or divalent acid addition salt such as a hydrohalide, disulfate, diphosphate, or diorganic acid salt. In all cases, the acid addition salt is used as an achiral reagent that is not selected based on any expected or known preference for interaction with specific optical isomers of the products of this disclosure or for precipitation of specific optical isomers.

[0013] Where stereochemistry is not indicated, the name or structural expression may include any stereoisomer or any mixture of stereoisomers, and the applicant reserves the right to specifically identify and assert the compound as a single stereoisomer or any particular mixture of stereoisomers.

[0014] The compounds described herein may contain chiral centers and therefore may exist as enantiomers. If the compounds according to the embodiments herein have two or more chiral centers, they may further exist as diastereomers. The embodiments herein include all such possible stereoisomers as substantially pure divided enantiomers, racemic mixtures thereof, and mixtures of diastereomers. In some embodiments, the formula is shown without definitive stereochemistry at a particular position. The embodiments herein include all stereoisomers of such formulas and their pharmaceutically acceptable salts. Diastereomer pairs of enantiomers may be separated, for example, by fractional crystallization from a suitable solvent, and the enantiomer pairs thus obtained may be separated into individual stereoisomers by conventional means, for example, by using an optically active acid or base as a resolving agent, or on a chiral HPLC column. Furthermore, any enantiomer or diastereomer of a compound of the general formula may be obtained by optically pure starting material or enantiomer-enriched starting material, or by stereospecific or stereoselective synthesis using reagents of known configurations. The scope of the embodiments described and claimed herein encompasses racemic forms of the compound, as well as individual enantiomers, diastereomers, and stereoisomer-enriched mixtures, and the applicant reserves the right to specifically identify and claim any such form of the compound.

[0015] The compounds disclosed herein may exist not only in isotopic forms such as deuterated compounds, but also in all proportions of all stereoisomers, structural isomers, and mixtures thereof, and thus may include these, and the applicant reserves the right to specifically identify and claim any such form of compound.

[0016] In one aspect, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation comprises i) an intra-granular portion and ii) an extra-granular portion. In one aspect, i) the intra-granular portion comprises, consists essentially of, or consists of a Kv7.2 / 7.3 potassium channel activator, a hydrophilic matrix polymer, a filler, and a binder. ii) The extra-granular portion comprises, consists essentially of, or consists of a sustained-release polymer, a lubricant, and optionally a hydrophilic matrix polymer. The Kv7.2 / 7.3 potassium channel activator is of Formula I or a pharmaceutically acceptable salt thereof.

[0017] In one aspect, the Kv7.2 / 7.3 potassium channel activator is embedded or dispersed in the hydrophilic matrix polymer and filler of the intra-granular portion. In another aspect, the Kv7.2 / 7.3 potassium channel activator is contained at 5 to 60% by weight, specifically 10 to 45% by weight, more specifically 15 to 45% by weight of the total weight of the intra-granular portion excluding water. In certain aspects, the Kv7.2 / 7.3 potassium channel activator is contained at about 15% by weight, about 30% by weight, or about 45% by weight of the total weight of the intra-granular portion excluding water.

[0018] In one aspect, the Kv7.2 / 7.3 potassium channel activator is contained at 5 to 60% by weight, specifically 10 to 40% by weight, more specifically 10 to 30% by weight of the total weight of the intra-granular and extra-granular portions. In certain aspects, the Kv7.2 / 7.3 potassium channel activator is contained at about 10% by weight, about 20% by weight, or about 30% by weight of the total weight of the intra-granular and extra-granular portions.

[0019] Exemplary hydrophilic matrix polymers include hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), poly(ethylene oxide), poly(vinyl alcohol), xanthan gum, carbomer, carrageenan, and mixtures thereof. Other similar hydrophilic polymers may also be used. The hydrophilic matrix polymer swells and eventually dissolves in water. Without being bound by theory, the Kv7.2 / 7.3 potassium channel activator is thought to be released by both diffusion from the matrix polymer and erosion of the matrix polymer. The release of the Kv7.2 / 7.3 potassium channel activator may be controlled by the amount and viscosity / molecular weight of the hydrophilic matrix polymer. Generally, using a greater amount of hydrophilic matrix polymer results in a decreased dissolution rate, similar to using a polymer of higher molecular weight. Using a hydrophilic matrix polymer of lower molecular weight increases the dissolution rate. Thus, in one aspect, the hydrophilic matrix polymer in the granule interior is a release control polymer in the formulation.

[0020] In one aspect, the hydrophilic matrix polymer is a low-viscosity HPMC (50 - 200 cPs at 2% in water at 20°C) having a medium degree of hydroxypropyl substitution (5.0 - 12.0%). The viscosity of HMPC is determined by testing under standard conditions including the concentration of HMPC in solution and the temperature of the solution. As used herein, such conditions are 2% polymer in water at 20°C. The degree of substitution may be expressed as the weight percent of the substituent or as the molar ratio of the substituent to glucose units. In the case of cellulose derivatives having two different substituents such as HPMC, the polymer form may be described by the degree of substitution of each substituent.

[0021] Exemplary low-viscosity HPMCs (80–120 cPs at 2% in water at 20°C) with a moderate degree of hydroxypropyl substitution (7.0–12.0%) for inclusion in the granular portion are commercially available as METHOCEL® K100LV, more specifically METHOCEL® K100LVCR. METHOCEL® K100LV has a methoxyl content of 22–24%.

[0022] In one embodiment, the hydrophilic matrix polymer is present in an amount of 4-10% by weight, specifically 5-9% by weight, and more specifically 5.5-8% by weight, of the total weight of the granular portion excluding water. In another embodiment, the hydrophilic matrix polymer is present in an amount of approximately 6% by weight of the granular portion excluding water.

[0023] Fillers, also known as diluents, increase the bulk or volume of the final product, ensure consistent dosage form size, result in uniform mixing, and / or assist in the manufacture of the dosage form. Examples of fillers include lactose (e.g., spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose®, Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Solka-Floc®), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrin, dextran, maltodextrin, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugars, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, and mixtures thereof. In some embodiments, the filler is microcrystalline cellulose, for example, Avicel® PH-101.

[0024] In one embodiment, the filler comprises 40-90% by weight, specifically 45-85% by weight, and more specifically 45-80% by weight, of the total weight of the granular portion excluding water.

[0025] Binders help improve the processability of tablets and granules and ensure the integrity of the dosage form during processing. Exemplary binders include polyvinylpyrrolidone (povidone), cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, silicified microcrystalline cellulose, polyvinyl alcohol, starch, acacia, alginic acid, sodium alginate, and mixtures thereof. In one embodiment, the binder is hydroxypropyl cellulose having 53.4-80.5% hydroxypropoxy groups. In another embodiment, the binder is KLUCEL® EXF, an ultrafine hydroxypropyl cellulose binder.

[0026] In one embodiment, the binder is present in an amount of 0.5 to 4% by weight, specifically 1.5 to 3% by weight, of the total weight of the granular portion excluding water.

[0027] In one embodiment, the hydrophilic matrix polymer contains hydroxypropyl methylcellulose having a viscosity of 50-200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0-12%, the filler is microcrystalline cellulose, and the binder is hydroxypropyl cellulose.

[0028] In one embodiment, the granular portion comprises 5-60% by weight, preferably 10-45% by weight, more preferably 15-45% by weight of Kv7.2 / 7.3 potassium channel activator of formula I or a pharmaceutically acceptable salt thereof; 4-10% by weight, specifically 5-9% by weight, more specifically 5.5-8% by weight of hydroxypropyl methylcellulose having a viscosity of 50-200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0-12%; 40-90% by weight, specifically 40-85% by weight, more specifically 45-80% by weight of microcrystalline cellulose; and 0.5-4% by weight, specifically 1.5-3% by weight of hydroxypropyl cellulose, all based on the total weight of the granular portion excluding water.

[0029] The granular portion can be prepared, for example, by wet granulation. In an exemplary wet granulation process, a Kv7.2 / 7.3 potassium channel activator, a hydrophilic matrix polymer, and a filler are mixed in a mixer to form a blend. The blend is then added to a binder solution (binder dissolved in water) that forms a wet blend. The wet blend is then granulated to produce wet granules. Examples of wet granulation processes include fluidized bed granulation, top spray granulation, high shear granulation, and low shear granulation. The wet granules can be screened to provide granules of a specific size, which can be optionally dried to produce, for example, dried granules. If desired, the dried granules can be crushed and / or sized.

[0030] Next, the internal portion of the granules (for example, granules produced by wet granulation and drying) is mixed with a sustained-release polymer and optionally a hydrophilic matrix polymer from the external portion of the granules, and then lubricated with a lubricant.

[0031] The sustained-release polymers in the granular outer portion provide the release of the active agent over a controlled or extended period. Exemplary sustained-release polymers include: homopolymers or copolymers, e.g., random copolymers, block copolymers, and graft copolymers, e.g., cellulosic polymers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, microcrystalline cellulose, and polysaccharides and their derivatives; polyalkylene oxides, particularly poly(ethylene oxide), polyethylene glycol, and poly(ethylene oxide)-polypropylene oxide copolymers; polymers of acrylic acid and methacrylic acid, their copolymers and esters, preferably acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl methacrylate, and their copolymers, and those formed from each other or from additional acrylate species, e.g., aminoethyl acrylate; maleic anhydride copolymers; polymaleic acid; Poly(acrylamides) such as poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide); polyalkylene oxides; poly(olefin alcohols) such as poly(vinyl alcohol); poly(N-vinyl lactams) such as poly(vinylpyrrolidone), poly(N-vinylcaprolactam), and copolymers thereof; polyols, e.g., glycerol, polyglycerol (especially highly branched polyglycerol), propylene glycol, and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono, di and tripolyoxyethylated glycerol, mono and dipolyoxyethylated propylene glycol, and mono and dipolyoxyethylated trimethylene glycol; polyoxyethylated sorbitol and polyoxyethylated glucose; polyoxazolines including poly(methyloxazoline) and poly(ethyloxazoline); polyvinylamines;Examples include polyvinyl acetate itself, as well as polyimines such as ethylene-vinyl acetate copolymer, polyvinyl acetate phthalate, and polyethyleneimine; starch and starch-based polymers; polyurethane hydrogels; chitosan; polysaccharide gums; xanthan gum; zein; and shellac, ammonia-modified shellac, shellac-acetyl alcohol, shellac n-butyl stearate, and mixtures thereof.

[0032] In one embodiment, the sustained-release polymer comprises a cellulosic polymer, such as an alkyl-substituted cellulose derivative, specifically HPMC. In one embodiment, the sustained-release polymer comprises high-viscosity HPMC (50,000 to 200,000 cPs at 2% in water at 20°C) having a moderate degree of hydroxypropyl substitution (5.0 to 12.0%).

[0033] An exemplary high-viscosity HPMC (75,000–140,000 cPs at 2% in water at 20°C) with a moderate degree of hydroxypropyl substitution (7.0–12.0%) is marketed as METHOCEL® K100M Premium. METHOCEL® K100M has a methoxyl content of 22–24%.

[0034] In one embodiment, the sustained-release polymer is present in an amount of 20-40% by weight, specifically 25-35% by weight, and more specifically 25-28% by weight, of the total weight of the intragranular and extragranular portions.

[0035] Lubricants reduce friction during the mixing of the internal and external components of granules, as well as during tablet formation. Examples of lubricants include talc, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, calcium stearate, magnesium trisilicate, polyethylene glycol, and mixtures thereof. An example lubricant is PRUV® sodium stearyl fumarate.

[0036] In one embodiment, the lubricant is present in an amount of 0.05 to 2% by weight, specifically 0.05 to 0.15% by weight, of the total weight of the internal and external portions of the granules.

[0037] In one embodiment, the outer portion of the granules optionally comprises a hydrophilic matrix polymer, for example, METHOCEL® K100LV.

[0038] In one embodiment, the lubricant comprises sodium stearyl fumarate, a hydrophilic matrix polymer, and hydroxypropyl methylcellulose having a viscosity of 50-200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0-12%.

[0039] In one embodiment, the hydrophilic matrix polymer is present in an amount of 0-8% by weight, specifically 1-5% by weight, of the total weight of the intragranular and extragranular portions.

[0040] In one embodiment, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator preparation is i) A granular portion comprising a Kv7.2 / 7.3 potassium channel activator, hydroxypropyl methylcellulose having a viscosity of 80-120 cPs at 2% in water at 20°C, and a degree of hydroxypropyl substitution of 7.0-12.0%, microcrystalline cellulose, and hydroxypropylcellulose, ii) A granular external component comprising hydroxypropyl methylcellulose having a viscosity of 50,000 to 200,000 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12.0%, sodium stearyl fumarate, and optionally a hydrophilic matrix polymer, comprising, essentially consisting of, or consisting of, The Kv7.2 / 7.3 potassium channel activator is either that of formula I or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator preparation is i) Based on the weight of the granular internal portion, the granular internal portion comprises 5-60 wt% Kv7.2 / 7.3 potassium channel activator, 4-10 wt% hydroxypropyl methylcellulose with a viscosity of 80-120 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 7.0-12.0%, 50-90 wt% microcrystalline cellulose, and 0.5-4 wt% hydroxypropyl cellulose, ii) A granular external component comprising 20-40% by weight of hydroxypropyl methylcellulose having a viscosity of 50,000-200,000 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0-12.0%, 0.05-2% by weight of sodium stearyl fumarate, and optionally a hydrophilic matrix polymer, or comprising, essentially consisting of, or consisting of, The Kv7.2 / 7.3 potassium channel activator is either that of formula I or a pharmaceutically acceptable salt thereof.

[0042] In addition to the components described above, the intragranular and extragranular portions may include additional components, insofar as these additional components result in the desired solubility profile and / or pharmacokinetic parameters. Exemplary additional components include diluents, binders, surfactants, solubilizers, cosolvents, absorbents, colorants, dyes, permeation enhancers, stabilizers, penetrants, disintegrants, wetting agents, plasticizers, tableting aids, flow enhancers, lubricants, antistatic agents, dispersants, and mixtures thereof.

[0043] The internal and external portions of the granules are mixed, and the mixture can be filled into capsules (e.g., hard, soft, or gel capsules) or compressed into tablets, for example, by direct compression. Exemplary compressive forces are 5kN–100kN, 5kN–75kN, and most commonly 10kN–30kN.

[0044] The tablets or capsules may further comprise, for example, a protective topcoat layer comprising a coating polymer and optionally one or more excipients, such as plasticizers, anti-adhesion agents or flow promoters, one or more pigments / opacifiers, and mixtures thereof.

[0045] In one embodiment, the coating may be a water-soluble film coating that does not affect the release of the Kv7.2 / 7.3 potassium channel activator. The thickness of the soluble film coating may be, for example, about 20 μm to about 100 μm.

[0046] Examples of film coating materials include, for example, cellulose derivatives, such as cellulose ethers, such as methylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose; polyvinylpyrrolidone, or mixtures of polyvinylpyrrolidone and polyvinyl acetate copolymers with hydroxypropylmethylcellulose; shellac and mixtures of hydroxypropylmethylcellulose, polyvinyl acetate, or copolymers thereof with polyvinylpyrrolidone; or water-soluble cellulose derivatives, such as mixtures of hydroxypropylmethylcellulose and water-insoluble ethylcellulose, and mixtures thereof. These coating agents may be used in combination with other auxiliary agents, if desired, such as talc, wetting agents, such as polysorbate (e.g., to facilitate application), or pigments (e.g., for marking purposes). Depending on the solubility of the components, these coatings can be applied to aqueous solutions or organic solutions (e.g., solutions of shellac or ethylcellulose in organic solvents). Mixtures of water-insoluble acrylates themselves may also be used. For example, a copolymer of ethyl acrylate and methyl methacrylate may be used in an aqueous dispersion with one or more water-soluble additives such as lactose, polyvinylpyrrolidine, polyethylene glycol, or hydroxypropyl methylcellulose.

[0047] Examples of plasticizers for protective topcoats include, for example, triacetin, diethyl phthalate, dibutyl sebacate, tributyl polyethylene glycol sebacate, and mixtures thereof.

[0048] Examples of anti-adhesion agents or flow promoters for protective topcoats include, for example, talc, fumed silica, magnesium stearate, and mixtures thereof.

[0049] In one embodiment, a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation comprises a hydrophilic matrix polymer and a sustained-release polymer, wherein the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the hydrophilic matrix polymer is located in the intragranular portion, and the sustained-release polymer is located in the extragranular portion.

[0050] In one embodiment, the oral sustained-release dosage form releases the active drug over a period of approximately 24 hours. In another embodiment, the oral sustained-release dosage form releases the active drug over a period of approximately 12 hours. In yet another embodiment, the oral sustained-release dosage form releases the active drug over a period of approximately 8 hours. In yet another embodiment, the oral sustained-release dosage form releases the active drug over a period of approximately 6 hours.

[0051] In one embodiment, the oral sustained-release dosage form is for once-daily administration, i.e., approximately once every 24 hours. In another embodiment, the oral sustained-release dosage form is for twice-daily administration, i.e., approximately once every 12 hours. In yet another embodiment, the oral sustained-release dosage form is for three-times-daily administration, approximately once every 8 hours. In yet another embodiment, the oral sustained-release dosage form is for four-times-daily administration, approximately once every 6 hours.

[0052] In any of the embodiments described above, the solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation has a specific in vitro solubility profile. In one embodiment, solubility is measured in a suitable dissolving medium that maintains sink conditions within a USP Dissolution Apparatus. In one embodiment, solubility is measured in vitro in 900 mL of pH 6.8 phosphate buffer containing 3% (w / v) sodium lauryl sulfate (SLS) in a USP Dissolution Apparatus 2 with a stationary basket at 50 rpm.

[0053] In one embodiment, the Kv7.2 / 7.3 potassium channel activator formulation of the present disclosure has a solubility such that less than 25%, preferably less than 20%, of the Kv7.2 / 7.3 potassium channel activator is released in 2 hours, and the solubility is measured in a suitable dissolving medium that maintains sink conditions in a USP Dissolution Apparatus, or in 900 mL of pH 6.8 phosphate buffer containing 3% SLS in a USP Dissolution Apparatus 2 with a stationary basket at 50 rpm. In another embodiment, 35-65%, preferably about 50%, of the Kv7.2 / 7.3 potassium channel activator is released in 4 hours. In yet another embodiment, more than 80%, preferably more than 85%, of the Kv7.2 / 7.3 potassium channel activator is released in 8 hours. In another embodiment, the Kv7.2 / 7.3 potassium channel activator formulation of this disclosure releases more than 95% of the Kv7.2 / 7.3 potassium channel activator after 14 to 24 hours.

[0054] In one embodiment, the Kv7.2 / 7.3 potassium channel activator formulation of the present disclosure releases less than 25%, preferably less than 20%, of the Kv7.2 / 7.3 potassium channel activator after 2 hours, and less than 50%, preferably less than 40%, of the Kv7.2 / 7.3 potassium channel activator after 4 hours.

[0055] In another embodiment, the Kv7.2 / 7.3 potassium channel activator formulation of the present disclosure releases less than 25%, preferably less than 20%, of the Kv7.2 / 7.3 potassium channel activator after 2 hours, 35-65%, preferably about 50%, of the Kv7.2 / 7.3 potassium channel activator after 4 hours, and more than 80%, preferably more than 85%, of the Kv7.2 / 7.3 potassium channel activator after 8 hours.

[0056] In one embodiment, the formulations described herein have favorable pharmacokinetics, particularly when administered to human subjects in single and multiple doses. The pharmacokinetic profile is the time course of absorption, distribution, metabolism, and excretion of the active drug. The pharmacokinetic profile can be determined after a single dose or after multiple doses.

[0057] As used herein, the terms “subject” and “patient” are interchangeable. As used herein, the term “patient” refers to mammals, preferably animals, including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, etc.) and primates (e.g., monkeys and humans), most preferably humans. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, pig, or cattle) or a pet (e.g., a dog or cat). In specific embodiments, the subject is a human.

[0058] The term "peak-to-trough ratio" refers to a comparison of the peak (high points in a line graph) plasma level of an active drug with the trough (e.g., low points in a line graph) level over a set time period. For example, a line graph with plasma concentration values ​​ranging from 400 ng / ml (peak) to 200 ng / ml (trough) over a 24-hour period gives a peak-to-trough ratio of 2 for that time period.

[0059] "C max " represents the maximum plasma concentration observed. Oral drug administration is one C maxThis can result in more than one "peak plasma concentration" or "plasma concentration peak" (for example, after administration of pulsed dose formulations).

[0060] “Mean maximum plasma concentration” (mean C max The term refers to the maximum mean plasma drug concentration found in multiple plasma samples.

[0061] "Mean plasma concentration" is the geometric mean plasma concentration found in multiple plasma samples.

[0062] "T max The term "peak (maximum) plasma drug concentration" refers to the time when the peak (maximum) plasma drug concentration was observed for each individual participating in the bioavailability study.

[0063] AUC is a measure of the area under the plasma concentration-time curve and represents the amount of drug absorbed after a single dose of the drug is administered.

[0064] AUC 0-∞ " or "AUC inf The term "area under the plasma concentration-time curve" refers to the average area under the plasma concentration-time curve extrapolated to infinity. It is calculated as the arithmetic mean of the area under the plasma concentration-time curve extrapolated from time 0 to infinity, and is calculated for each individual participating in the bioavailability study.

[0065] In one embodiment, a sustained-release Kv7.2 / 7.3 potassium channel activator formulation (e.g., of formula I or a pharmaceutically acceptable salt thereof) is described herein, wherein when a single dose of the Kv7.2 / 7.3 potassium channel activator formulation is orally administered to a human subject, the ratio of the peak to the 24-hour trough of the Kv7.2 / 7.3 potassium channel activator plasma level is about 1 to about 3. In one embodiment, the human subject is an adult human subject. In another embodiment, the ratio of the peak to the 24-hour trough of the Kv7.2 / 7.3 potassium channel activator plasma level is about 1 to about 2.

[0066] As used herein, the terms “therapeutic dose” or “therapeutic dosage” are interchangeable and may refer to the amount of an active agent, pharmaceutical compound, or composition that elicits a clinical response, biological response, or pharmacokinetic response in a tissue, system, animal, individual, or human, as sought by researchers, veterinarians, physicians, or other clinical professionals. A clinical response, biological response, or pharmacokinetic response may include, for example, one or more of the following: (1) preventing a disease, condition, or disorder in an individual that is susceptible to the disease, condition, or disorder but has not yet experienced or exhibited any lesions or symptoms of the disease, condition, or disorder; (2) inhibiting the disease, condition, or disorder in an individual that has experienced or exhibited any lesions or symptoms of the disease, condition, or disorder, or halting the further development of the lesions and / or symptoms of the disease, condition, or disorder; and (3) improving the disease, condition, or disorder in an individual that has experienced or exhibited any lesions or symptoms of the disease, condition, or disorder, or reversing the individual's experience of the lesions and / or symptoms or the lesions and / or symptoms exhibited by that individual.

[0067] In any of the embodiments described above, the solid oral sustained-release Kv7.2 / 7.3 potassium channel activator preparation is in the form of a tablet containing 10 to 100 mg, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of Kv7.2 / 7.3 potassium channel activator.

[0068] The terms “to treat,” “to be treated,” or “to treat” may be interpreted as meaning the prevention of a particular disorder, disease, or condition, the improvement of symptoms associated with a particular disorder, disease, or condition, and / or the prevention of symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term means slowing the progression of a disorder, disease, or condition, or improving symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term means improving symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term means improving symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term means restoring function that has been impaired or lost as a result of a particular disorder, disease, or condition.

[0069] In one embodiment, a method for treating a Kv7-related disorder is included, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Kv7-related disorders include epilepsy, neonatal seizures, pain, migraines, neurotransmitter release disorders, smooth muscle contraction disorders, dyskinesia, dystonia, manic episodes, hearing impairment, neuropathic pain, inflammatory pain, chronic pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, bladder dysfunction, vascular disorders, tinnitus, benign familial neonatal seizures, epilepsy, neurological disorders mediated by decreased basal M current (and subsequent neuronal excitability), sensory hearing impairment, intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neurological disorders, infantile spasms with hypsalhythmia, myoclonic tonic seizures, myoclonic seizures, tonic seizures, absence seizures and focal-origin seizures with impaired consciousness, and congenital conditions with intellectual disability or epileptic encephalopathy. The following may be selected from the group consisting of sexual neurological disorders, benign familial neonatal seizures, severe epileptic encephalopathy, congenital neurodevelopmental disorders with a non-symptomatic intellectual disability or epileptic encephalopathy phenotype, neonatal seizures, neonatal convulsions, epileptic encephalopathy, benign familial neonatal seizures type 1, benign familial neonatal seizures 1, neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infant epileptic encephalopathy 7, early infant epileptic encephalopathy with psychomotor developmental delay, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial flushing, hypotonia, febrile seizures, corpus callosum hypoplasia, hypsalhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, gynecological disorders, and combinations thereof. In some embodiments, Kv7-related disorders are selected from epilepsy, neonatal seizures, pain, migraine, neurotransmitter release disorders, smooth muscle contraction disorders, dyskinesia, dystonia, manic episodes, hearing impairment, neuropathic pain, inflammatory pain, chronic pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, tinnitus, frontotemporal dementia (FTD), familial FTD, or amyotrophic lateral sclerosis. In some embodiments, such compounds may be administered in the pharmaceutical compositions described herein.

[0070] In some embodiments, gynecological disorders are selected from the group consisting of premature birth, postpartum hemorrhage, uterine atony, uterine perforation, uterine hyperstimulation, menorrhagia, irregular uterine bleeding, functional uterine bleeding, dysmenorrhea, and endometriosis.

[0071] The KCNQ gene encodes five Kv7 potassium channel subunits (1-5). Functional Kv7 potassium channels can be assembled using combinations of these five subunits arranged as homotetramers or heterotetramers. KCNQ2, KCNQ3, KCNQ4, and KCNQ5 are expressed in the nervous system and are associated with a range of neuronal excitability disorders.

[0072] Embodiments of this specification relate to methods for treating disorders associated with the KCNQ subunit, comprising administering a therapeutically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0073] The compounds described herein have been shown to activate the Kv7 potassium channel. Mutations in KCNQ2, the gene encoding the Kv7 potassium channel, cause widespread impairment. Embodiments herein relate to methods for treating impairments associated with KCNQ2 mutations, comprising administering a therapeutically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Disorders associated with KCNQ2 mutations are selected from the group consisting of neonatal seizures, neonatal convulsions, epilepsy, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal convulsions type 1 (BFNS1), neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with psychomotor developmental delay, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial flushing, hypotonia, febrile seizures, corpus callosum hypoplasia, hypsalhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, and combinations thereof. In some embodiments, such compounds may be administered in the pharmaceutical compositions described herein.

[0074] The sustained-release formulations described herein are particularly useful for treating epilepsy. The main symptom of epilepsy is recurrent seizures. An investigation of the types of seizures the patient is experiencing is conducted to determine the type of epilepsy or epileptic syndrome the patient has. Focal (partial) seizures, which occur within a network limited to only one hemisphere, are also classified as a subcategory. Here, seizures are characterized according to one or more features of the seizure, including aura, motor, autonomic, and conscious / responsive. When a seizure begins as a focal seizure and rapidly progresses to distribute within the bilateral network, this seizure is known as a bilateral convulsive seizure, a term proposed to replace secondary generalized seizures (generalized seizures that progress from a focal seizure and no longer remain localized).

[0075] Focal seizures in which the subject's consciousness / responsiveness changes are called focal seizures with impaired consciousness, while focal seizures in which the subject's consciousness or responsiveness is not impaired are called focal seizures without impaired consciousness.

[0076] Focal seizures may occur in epileptic syndromes including: Lennox-Gastaut syndrome; tuberous sclerosis; Dravet syndrome; CDKL5; neuronal ceroid lipofuscinosis (NCL); febrile infection-associated epilepsy syndrome (FIRES); Aicardi syndrome; and brain abnormalities.

[0077] The present invention is further illustrated by the following non-limiting examples. [Examples]

[0078] Development of BHV-7000 dosage form The initial formulation for BHV-7000 used in the early Phase 1 clinical trials was a spray-dried dispersion suspension requiring twice-daily dosing to achieve the expected therapeutic concentration for safety evaluation before the start of Phase 2 / 3 trials. To reduce the peak-to-trough ratio observed in the suspension and enable once-daily dosing of BHV-7000, sustained-release tablets were developed. Compared to the original spray-dried dispersion suspension formulation, in healthy adults receiving a single 10 mg dose, the sustained-release tablets reduced the Cmax of BHV-7000 by approximately one-quarter while minimizing the impact on overall absorption, as measured by AUC. During the development of BHV-7000, a Kv7.2 / 7.3 potassium channel activator formulation, it was observed that the BHV-7000 spray-dried dispersion suspension resulted in a high peak-to-trough ratio requiring twice-daily dosing to achieve the expected therapeutic concentration. Sustained-release tablet formulations were developed to provide a once-daily dosing option with a reduced peak-to-trough ratio without affecting overall absorption. It was found that the sustained-release formulations have different release profiles depending on the composition, referred to as ER (fast) and ER (slow). ER (Rapid): When used herein, ER (Rapid) formulations release at least 85% or more of the active ingredient within 8 hours, as determined by the in vitro dissolution test described herein. ER (Slow): When used herein, ER (Slow) formulations release at least 85% or more of the active ingredient within 12–14 hours, as determined by the in vitro dissolution test described herein.

[0079] Table 1 provides the composition of an example ER (slow formulation). [Table 1]

[0080] ER (slow) tablets were prepared as follows: The granular portion of the formulation was prepared by mixing BHV-7000, MCC, and low-viscosity HPMC with a granulating fluid (HPC binder in water). The resulting granules were dried, mixed with high-viscosity HPMC, lubricated with sodium stearyl fumarate, and compressed into tablets.

[0081] The ER (fast) tablets have the same composition as the ER (slow) tablets, but with METHOCEL® K100M PREMIUM DC2 replaced by METHOCEL® K 100 PREMIUM LVCR from the granule outer component.

[0082] Figure 1 shows the dissolution profiles of exemplary ER (slow) and ER (fast) formulations. Dissolution was performed in a USP Dissolution Apparatus 2 with a stationary basket at 50 rpm in 3% SLS pH 6.8 phosphate buffer.

[0083] Pharmacokinetic studies of single doses in humans were also conducted, and the results are shown in Figure 2. A single 10 mg dose of exemplary ER (slow) and ER (fast) tablets was administered to (number, explanation) human subjects, and plasma concentrations against time were determined. As shown in Figure 2, the ER (fast) formulation showed a spike in mean plasma concentration at approximately 8 hours in this study, while the ER (slow) formulation had a smaller peak-to-trough ratio.

[0084] Based on release characteristics, nonparametric simulations, and preliminary pharmacokinetic studies, we selected the ER (slow) formulation for further development.

[0085] Dosage forms containing BHV-7000 in 25 mg, 50 mg, and 75 mg doses were prepared as shown in Table 2. [Table 2]

[0086] As shown in Figure 3, the three tablet formulations in Tables 1 and 2 exhibit similar dissolution characteristics. Dissolution was performed in a USP Dissolution Apparatus 2 with a stationary basket at 50 rpm, in 3% SLS pH 6.8 phosphate buffer. [Table 3]

[0087] The f1 coefficient is the percentage difference between the two dissolution profiles at each time point, and is a measure of the relative error between the two profiles. The f2 coefficient is a measure of the similarity in the percentage of dissolution between the two profiles.

[0088] When determining the similarity of dosage forms, f1 values ​​(difference coefficients) up to 15 (0-15) and f2 values ​​(similarity coefficients) above 50 (50-100) ensure the "identity" or "equivalence" of two profiles. 25, 50, and 75 mg tablets have high equivalence to 10 mg tablets, which indicates high similarity.

[0089] The terms “a,” “an,” “the,” and similar references (particularly in the context of the following claims) should be interpreted as encompassing both singular and plural forms unless otherwise indicated herein or unless clearly inconsistent with the context. The terms “first,” “second,” etc., as used herein, are not intended to indicate any particular order, but are merely for convenience to indicate multiple, e.g., layers. Unless otherwise indicated herein, terms such as “comprising,” “having,” “including,” and “containing” should be interpreted as open-ended terms (i.e., “including but not limited to.” Enumerations of value ranges are intended, unless otherwise indicated herein, simply as a concise way of referring individually to each distinct value within that range, and each distinct value is incorporated into the specification as if it were individually described herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein may be carried out in a preferred order, unless otherwise indicated herein or unless the context clearly contradicts it. Any and all examples, or the use of exemplary language (e.g., "etc.") are intended solely to better illustrate the invention and, unless otherwise claimed, do not limit the scope of the invention. No language herein should be construed as indicating that any unclaimed element is essential to the practice of the invention as used herein.

[0090] While the present invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various modifications can be made and elements can be replaced with equivalents without departing from the scope of the invention. In addition, many modifications can be made to adapt the teachings of the invention to specific situations or materials without departing from the essential scope of the invention. Accordingly, the invention is not limited to the specific embodiments disclosed as the best mode intended to carry out the invention, and the invention is intended to include all embodiments that fall within the scope of the appended claims. Any combination of the elements described above in all possible variations is encompassed by the invention unless otherwise indicated herein or unless there is a clear difference in context.

Claims

1. A solid oral sustained-release Kv7.2 / 7.3 potassium channel activator preparation, iii) A granular portion comprising a Kv7.2 / 7.3 potassium channel activator, a hydrophilic matrix polymer, a filler, and a binder, iv) A granular outer component comprising a sustained-release polymer, optionally a hydrophilic matrix polymer, and a lubricant, A solid, orally sustained-release Kv7.2 / 7.3 potassium channel activator formulation, wherein the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. 【Chemistry 1】

2. i) The hydrophilic matrix polymer of claim 1 comprises hydroxypropyl methylcellulose having a viscosity of 50 to 200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12.0%.

3. i) A solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to any one of the prior claims, wherein the hydrophilic matrix polymer in i) comprises hydroxypropyl methylcellulose having a viscosity of 80 to 120 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 7.0 to 12.0%.

4. i) The filler is microcrystalline cellulose, and i) The binder is hydroxypropyl cellulose, the solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to any one of the prior claims.

5. i) A solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to any one of the prior claims, wherein the Kv7.2 / 7.3 potassium channel activator is present in 5 to 60% by weight, the hydrophilic matrix polymer is present in 4 to 10% by weight, the filler is present in 40 to 90% by weight, and the binder is present in 0.5 to 4% by weight, all based on the total weight of the granular portion excluding water.

6. ii) The oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation in solid form according to any one of the prior claims, wherein the sustained-release polymer comprises hydroxypropyl methylcellulose having a viscosity of 50,000 to 200,000 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12.0%.

7. ii) The oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation in solid form according to any one of the prior claims, wherein the sustained-release polymer comprises hydroxypropyl methylcellulose having a viscosity of 75,000 to 140,000 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 7.0 to 12.0%.

8. ii) The oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation in solid form according to any one of the prior claims, wherein the sustained-release polymer is contained in 20 to 40% by weight, more specifically 25 to 28% by weight, of the total weight of the granular portion and the granular portion.

9. ii) The oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation in solid form according to any one of the prior claims, wherein the lubricant comprises sodium stearyl fumarate, the hydrophilic matrix polymer is present, and hydroxypropyl methylcellulose having a viscosity of 50 to 200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12%.

10. ii) The oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation in solid form according to any one of the prior claims, wherein the sustained-release polymer is present in an amount of 20 to 40% by weight, the lubricant is present in an amount of 0.05 to 2% by weight, and the hydrophilic matrix polymer is present in an amount of 1 to 5% by weight, all based on the total weight of the portion inside the granules and the portion outside the granules.

11. The formulation has a solubility such that less than 25%, preferably less than 20%, of the Kv7.2 / 7.3 potassium channel activator is released in 2 hours, and the solubility is measured in 900 mL of pH 6.8 phosphate buffer containing 3% sodium lauryl sulfate (SLS) in USP Dissolution Apparatus 2 having a stationary basket at 50 rpm, as a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to any one of the prior claims.

12. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to claim 11, wherein 35 to 65%, preferably about 50%, of the Kv7.2 / 7.3 potassium channel activator is released in 4 hours.

13. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to claim 12, wherein more than 80%, preferably more than 85%, of the Kv7.2 / 7.3 potassium channel activator is released in 8 hours.

14. A solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation comprising a hydrophilic matrix polymer and a sustained-release polymer, wherein the formulation has a solubility such that less than 25%, preferably less than 20%, of the Kv7.2 / 7.3 potassium channel activator is released in 2 hours, and the solubility was measured in 900 mL of pH 6.8 phosphate buffer containing 3% SLS in USP Dissolution Apparatus 2 having a stationary basket at 50 rpm. A solid, orally sustained-release Kv7.2 / 7.3 potassium channel activator formulation, wherein the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. 【Chemistry 2】

15. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to claim 14, wherein 35 to 65%, preferably about 50%, of the Kv7.2 / 7.3 potassium channel activator is released in 4 hours.

16. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to claim 15, wherein more than 80%, preferably more than 85%, of the Kv7.2 / 7.3 potassium channel activator is released in 8 hours.

17. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to any one of claims 14 to 16, wherein the hydrophilic matrix polymer is located in the granular portion and the sustained-release polymer is located in the granular portion.

18. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to claim 17, wherein the hydrophilic matrix polymer comprises hydroxypropyl methylcellulose having a viscosity of 50 to 200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12%, and the sustained-release polymer comprises hydroxypropyl methylcellulose having a viscosity of 50,000 to 200,000 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12%.

19. A solid, orally sustained-release Kv7.2 / 7.3 potassium channel activator preparation, wherein when a single dose of the Kv7.2 / 7.3 potassium channel activator preparation is orally administered to a human subject, the ratio of the peak to the 24-hour trough of the Kv7.2 / 7.3 potassium channel activator plasma level is approximately 1 to approximately 3. A solid, orally sustained-release Kv7.2 / 7.3 potassium channel activator formulation, wherein the Kv7.2 / 7.3 potassium channel activator is of formula I or a pharmaceutically acceptable salt thereof. 【Transformation 3】

20. The oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation in solid form according to claim 19, wherein the sustained-release Kv7.2 / 7.3 potassium channel activator formulation comprises a hydrophilic matrix polymer and a sustained-release polymer.

21. The solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to claim 20, wherein the hydrophilic matrix polymer comprises hydroxypropyl methylcellulose having a viscosity of 50 to 200 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12%, and the sustained-release polymer comprises hydroxypropyl methylcellulose having a viscosity of 75,000 to 140,000 cPs at 2% in water at 20°C and a degree of hydroxypropyl substitution of 5.0 to 12%.

22. A solid oral sustained-release Kv7.2 / 7.3 potassium channel activator formulation according to any one of the prior claims, in the form of a tablet containing 10 to 100 mg of Kv7.2 / 7.3 potassium channel activator.

23. A method for treating a Kv7-related disorder in a subject requiring treatment for the disorder, comprising administering to the subject a solid oral sustained-release Kv7.2 / 7.3 potassium channel activator preparation described in any one of the prior claims.

24. The method according to claim 23, wherein the Kv7-related disorder is epilepsy.

25. The method according to claim 23, wherein the subject suffers from a focal seizure.

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