Formulation of radiprodil

Abstract

The disclosure provides, in part, pharmaceutical compositions comprising radiprodil and a pharma- ceutically acceptable excipient, and methods of use thereof in the treatment of disorders, such as epileptic disorders.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 230,331, filed August 6, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] N-methyl-D-aspartate (NMDA) receptors are ligand-gated cation channels embedded in the cell membrane of neurons. Overactivation of NMDA receptors by glutamate, their natural ligand, can cause cellular calcium overload. This triggers a cascade of intracellular events that can alter cell function and ultimately cause neuronal death. Modulators of NMDA receptors can be used to treat many disorders involving excessive release of glutamate, the major excitatory neurotransmitter in the central nervous system. For example, selective antagonists of the NR2B subtype of NMDA receptors are expected to have little or no undesirable side effects typically caused by nonselective antagonists of NMDA receptors, i.e., psychotomimetic effects such as dizziness, headache, hallucinations, dysphoria, and impaired cognitive and motor function. There is a need for NMDA receptor modulators useful in treating disorders. Summary of the Invention [Problem to be solved by the invention]

[0003] The present disclosure, in one embodiment, provides compositions comprising radiprodil and methods of use thereof. [Means for solving the problem]

[0004] In one embodiment, described herein is a compound of formula I: [ka] A pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising, based on the total weight of the composition, about 0.5% to about 15% by weight of a compound of formula I; at least one filler; a disintegrant; a binder; and a surfactant.

[0005] In some embodiments, the compositions described herein comprise Form A of the compound of Formula I. Form A may be characterized by an X-ray powder diffraction pattern having characteristic peaks at and including the following 2θ values ​​(in degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2 degrees 2θ.

[0006] In some embodiments, the compositions described herein comprise Form C of the compound of Formula I. Form C may be characterized by an X-ray powder diffraction pattern having characteristic peaks at and including the following 2θ values ​​(in degrees): 6.4, 13.7, and 25.8±0.2 degrees 2θ.

[0007] In one embodiment, provided herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ; about 50%-80% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0008] In one embodiment, described herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 1% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ; about 70%-89% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0009] In one embodiment, described herein is a compound of formula I: [ka] and about 0.5% to 15% by weight of an anhydrous crystalline form of the compound of formula I, the anhydrous crystalline form having an X-ray powder diffraction pattern having characteristic peaks at and including the following 2θ values ​​(degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ, based on the total weight of the composition; about 0.1% to 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) based on the amount of the compound, as measured by HPLC; and one or more pharmaceutically acceptable excipients.

[0010] In one embodiment, provided herein is a pharma- ceutically acceptable aqueous suspension comprising a pharma- ceutically acceptable composition described herein and an aqueous medium.

[0011] In one embodiment, described herein is a compound of formula I: [ka] and (ii) an aqueous medium; and (iii) a solid pharmacopoietin-containing composition for the oral delivery of about 0.1 mg / kg to 2 mg / kg of a compound of formula I, the aqueous suspension comprising: (i) a solid pharmacopoietin-containing composition comprising about 10% by weight of an anhydrous crystalline form of the compound of formula I, based on the total weight of the composition, the anhydrous crystalline form having an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(degrees) of 2θ: 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ; about 50% to 80% by weight of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; about 5% by weight of crospovidone, based on the total weight of the composition; about 4% povidone, based on the total weight of the composition; and about 1% polysorbate, based on the total weight of the composition; and (ii) an aqueous medium.

[0012] In one embodiment, provided herein is a compound of formula I: [ka] The present invention relates to a pharma- ceutically acceptable aqueous suspension for oral delivery of about 0.2 mg / kg to 2 mg / kg of a compound of formula I, the aqueous suspension comprising: (i) a solid pharma-ceutically acceptable composition comprising about 1 wt. % of anhydrous crystalline form of the compound of formula I, based on the total weight of the composition, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following 2θ values ​​(degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2° 2θ; about 70 wt. % to 89 wt. % of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; about 5 wt. % of crospovidone, based on the total weight of the composition; about 4 wt. % of povidone, based on the total weight of the composition; and about 1 wt. % of polysorbate, based on the total weight of the composition; and (ii) an aqueous medium. In some embodiments, the aqueous medium comprises a starch-based suspension (e.g., SYRSPEND® SF).

[0013] In one embodiment, provided herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 6.4, 13.7, and 25.8±0.2°2θ; about 50%-80% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0014] In one embodiment, described herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 1% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 6.4, 13.7, and 25.8±0.2°2θ; about 70% to 89% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0015] In one embodiment, described herein is a compound of formula I: [ka] a pharmaceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising, based on the total weight of the composition, about 0.5% to 15% by weight of an anhydrous crystalline form of the compound of formula I (wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following 2θ values ​​(degrees): 6.4, 13.7, and 25.8±0.2° 2θ; about 0.1% to 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) based on the amount of the compound as measured by HPLC; and one or more pharmaceutically acceptable excipients.

[0016] In one embodiment, provided herein is a pharma- ceutically acceptable aqueous suspension comprising a pharma- ceutically acceptable composition described herein and an aqueous medium.

[0017] In one embodiment, described herein is a compound of formula I: [ka] and (ii) an aqueous medium; and (iii) a solid pharmacopoietin-containing composition for the oral delivery of about 0.1 mg / kg to 2 mg / kg of a compound of formula I, the aqueous medium comprising: (i) a solid pharmacopoietin-containing composition comprising about 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(degrees) of 2θ: 6.4, 13.7, and 25.8±0.2°2θ; (ii) an aqueous medium comprising about 50% to 80% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; (iii) an aqueous medium comprising about 5% by weight, based on the total weight of the composition, of crospovidone; (iv) an aqueous medium comprising about 4% by weight, based on the total weight of the composition, of povidone; and (v) an aqueous medium comprising about 1% by weight of a polysorbate;

[0018] In one embodiment, provided herein is a compound of formula I: [ka] The present invention relates to a pharma- ceutically acceptable aqueous suspension for oral delivery of about 0.2 mg / kg to 2 mg / kg of a compound of formula I, the aqueous suspension comprising: (i) a solid pharma-ceutically acceptable composition comprising about 1% by weight of anhydrous crystalline form of the compound of formula I, based on the total weight of the composition, the anhydrous crystalline form having an X-ray powder diffraction pattern having characteristic peaks between and including the following 2θ values ​​(degrees): 6.4, 13.7, and 25.8±0.2° 2θ; about 70% to 89% by weight of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; about 5% by weight of crospovidone, based on the total weight of the composition; about 4% of povidone, based on the total weight of the composition; and about 1% of polysorbate, based on the total weight of the composition; and (ii) an aqueous medium. In some embodiments, the aqueous medium comprises a starch-based suspension (e.g., SYRSPEND® SF). [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows an exemplary manufacturing process for 1% and 10% by weight radiprodil granules. [Diagram 2] FIG. 1 shows the dissolution profile of an exemplary radiprodil sample that was not reconstituted prior to dissolution testing. [Diagram 3] FIG. 1 shows the dissolution profile of an exemplary radiprodil sample that was reconstituted prior to dissolution testing. [Figure 4] FIG. 1 shows the dissolution profile of an exemplary radiprodil sample that underwent immediate reconstitution prior to dissolution testing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The features and other details of the present disclosure will now be described more specifically. Certain terms used in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0021] compound In one embodiment, provided herein is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0022] Pharmaceutical Compositions In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0023] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0024] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable for use as dosage units for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, and pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound is usually a minor component, with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0025] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, orange flavoring, or compounds of a similar nature.

[0026] Injectable compositions are typically based on injectable sterile saline, phosphate buffered saline, or other injectable excipients known in the art. As mentioned above, the active compound in such compositions is typically a minor component, with the remainder being the injectable excipient, etc.

[0027] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as ointments, active ingredients are typically combined with either a paraffinic or water-miscible ointment base. Alternatively, active ingredients can be formulated in creams, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance skin penetration of active ingredients or the stability of the formulation. All such known transdermal formulations and ingredients are included within the disclosure provided herein.

[0028] The compounds provided herein can also be administered by a transdermal device.Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0029] The above components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials, as well as processing techniques, etc., are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0030] The pharma- ceutically acceptable compositions described herein may contain one or more impurities, for example, as described herein. Exemplary impurities include the compounds listed in Table 7 provided herein.

[0031] In one embodiment, described herein is a compound of formula I: [ka] A pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising, based on the total weight of the composition, about 0.5% to about 15% by weight of a compound of formula I; at least one filler; a disintegrant; a binder; and a surfactant.

[0032] In some embodiments, the composition comprises about 1% by weight of the compound based on the total weight of the pharma- ceutically acceptable composition. In some embodiments, the composition comprises about 10% by weight of the compound based on the total weight of the pharma- ceutically acceptable composition. In some embodiments, the composition comprises an anhydrous crystalline form of the compound of formula I. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern with characteristic peaks at and including the following 2θ values ​​(degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ. In some embodiments, the pharmaceutical composition comprises about 10% to about 80% by weight of at least one filler based on the total weight of the pharmaceutical composition. In some embodiments, the at least one filler is selected from the group consisting of confectionery sugar, compressible sugar, dextrates, dextrin, glucose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, talc, and combinations thereof. In some embodiments, the composition comprises two fillers. In some embodiments, the pharmaceutical composition comprises about 1% to about 10% by weight of a disintegrant, based on the total weight of the pharmaceutical composition. In some embodiments, the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and combinations thereof. In some embodiments, the pharmaceutical composition comprises about 1% to about 10% by weight of a binder, based on the total weight of the pharmaceutical composition.

[0033] In some embodiments, the binder is selected from the group consisting of povidone, starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol skin, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and combinations thereof. In some embodiments, the pharmaceutical composition comprises from about 0.01% to about 5% by weight of a surfactant, based on the total weight of the pharmaceutical composition. In some embodiments, the surfactant is selected from the group consisting of polyoxyethylene stearates, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, poloxamers, polyoxyethylene castor oil derivatives, phospholipids, sodium lauryl sulfate, polysorbates (polyoxyethylene sorbitan fatty acid esters), and combinations thereof. In some embodiments, the composition is a granule of oral solution.

[0034] In one embodiment, provided herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ; about 50%-80% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0035] In one embodiment, described herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 1% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ; about 70%-89% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0036] In some embodiments, the composition contains about 0.1%-0.5% or less (e.g., 0.05% or less) of impurities relative to the amount of the compound as measured by HPLC. In some embodiments, the composition contains about 0.1%-0.5% or less 6-amino-2-benzoxazolone relative to the amount of the compound as measured by HPLC.

[0037] In one embodiment, described herein is a compound of formula I: [ka] and about 0.5% to 15% by weight of an anhydrous crystalline form of the compound of formula I, the anhydrous crystalline form having an X-ray powder diffraction pattern having characteristic peaks at and including the following 2θ values ​​(degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2° 2θ, based on the total weight of the composition; about 0.1% to 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) based on the amount of the compound, as measured by HPLC; and one or more pharmaceutically acceptable excipients.

[0038] In one embodiment, provided herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 6.4, 13.7, and 25.8±0.2°2θ; about 50%-80% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0039] In one embodiment, described herein is a compound of formula I: [ka] a solid pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising: about 1% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(in degrees) of 2θ: 6.4, 13.7, and 25.8±0.2°2θ; about 70% to 89% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; about 5% by weight, based on the total weight of the composition, of crospovidone; about 4% by weight, based on the total weight of the composition, of povidone; and about 1% by weight, based on the total weight of the composition, of polysorbate.

[0040] In one embodiment, described herein is a compound of formula I: [ka]

[0041] A pharma- ceutically acceptable composition formulated for oral administration of a compound of formula I, the composition comprising, based on the total weight of the composition, about 0.5% to 15% by weight of an anhydrous crystalline form of the compound of formula I (wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following 2θ values ​​(degrees): 6.4, 13.7, and 25.8±0.2° 2θ); about 0.1% to 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) relative to the amount of the compound as measured by HPLC; and one or more pharma- ceutically acceptable excipients. In some embodiments, the composition comprises about 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) relative to the amount of the compound as measured by HPLC. In some embodiments, the composition comprises about 0.05% or less of an impurity (e.g., 6-amino-2-benzoxazolone) relative to the amount of the compound as measured by HPLC. In some embodiments, the composition contains about 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) when compared to when exposed to 60% relative humidity at 25° C. for about 6 months. In some embodiments, the composition contains about 0.05% or less of an impurity (e.g., 6-amino-2-benzoxazolone) when compared to when exposed to 60% relative humidity at 25° C. for about 6 months. In some embodiments, the composition contains about 0.5% or less of an impurity (e.g., 6-amino-2-benzoxazolone) when compared to when exposed to 60% relative humidity at 25° C. for about 36 months. In some embodiments, the composition contains about 0.05% or less of an impurity (e.g., 6-amino-2-benzoxazolone) when compared to when exposed to 60% relative humidity at 25° C. for about 36 months. In some embodiments, the composition contains about 10% of the anhydrous crystalline form based on the total weight of the composition. In some embodiments, the composition contains about 1% of the anhydrous crystalline form based on the total weight of the composition. In some embodiments, the composition releases at least 80% of the compound after 30 minutes when the composition is tested in 900 mL of aqueous sodium lauryl sulfate using a USPII paddle apparatus at 37° C. and a paddle speed of 75 rpm.In some embodiments, when the composition is stirred in an aqueous medium at least 1 minute to about 24 hours after reconstitution, the composition releases at least 80% (e.g., at least 90% or at least 95%) of the compound. In some embodiments, the aqueous medium comprises a starch-based suspension. In one embodiment, provided herein is a pharma- ceutically acceptable aqueous suspension comprising a pharma- ceutically acceptable composition described herein and an aqueous medium. In some embodiments, the aqueous medium comprises a starch-based suspension (e.g., SYRSPEND® SF).

[0042] In one embodiment, described herein is a compound of formula I: [ka] and (ii) an aqueous medium; and (iii) a solid pharmacopoietin-containing composition for the oral delivery of about 0.1 mg / kg to 2 mg / kg of a compound of formula I, the aqueous suspension comprising: (i) a solid pharmacopoietin-containing composition comprising about 10% by weight of an anhydrous crystalline form of the compound of formula I, based on the total weight of the composition, the anhydrous crystalline form having an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(degrees) of 2θ: 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ; about 50% to 80% by weight of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; about 5% by weight of crospovidone, based on the total weight of the composition; about 4% povidone, based on the total weight of the composition; and about 1% polysorbate, based on the total weight of the composition; and (ii) an aqueous medium.

[0043] In one embodiment, provided herein is a compound of formula I: [ka] The present invention relates to a pharma- ceutically acceptable aqueous suspension for oral delivery of about 0.2 mg / kg to 2 mg / kg of a compound of formula I, the aqueous suspension comprising: (i) a solid pharma-ceutically acceptable composition comprising about 1 wt. % of anhydrous crystalline form of the compound of formula I, based on the total weight of the composition, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following 2θ values ​​(degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2° 2θ; about 70 wt. % to 89 wt. % of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; about 5 wt. % of crospovidone, based on the total weight of the composition; about 4 wt. % of povidone, based on the total weight of the composition; and about 1 wt. % of polysorbate, based on the total weight of the composition; and (ii) an aqueous medium. In some embodiments, the aqueous medium comprises a starch-based suspension (e.g., SYRSPEND® SF).

[0044] In one embodiment, described herein is a compound of formula I: [ka] and (ii) an aqueous medium; and (iii) a solid pharmacopoietin-containing composition for the oral delivery of about 0.1 mg / kg to 2 mg / kg of a compound of formula I, the aqueous medium comprising: (i) a solid pharmacopoietin-containing composition comprising about 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern having characteristic peaks between and including the following values ​​(degrees) of 2θ: 6.4, 13.7, and 25.8±0.2°2θ; (ii) an aqueous medium comprising about 50% to 80% by weight, based on the total weight of the composition, of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof; (iii) an aqueous medium comprising about 5% by weight, based on the total weight of the composition, of crospovidone; (iv) an aqueous medium comprising about 4% by weight, based on the total weight of the composition, of povidone; and (v) an aqueous medium comprising about 1% by weight of a polysorbate;

[0045] In one embodiment, provided herein is a compound of formula I: [ka] The present invention relates to a pharma- ceutically acceptable aqueous suspension for oral delivery of about 0.2 mg / kg to 2 mg / kg of a compound of formula I, the aqueous suspension comprising: (i) a solid pharma-ceutically acceptable composition comprising about 1% by weight of anhydrous crystalline form of the compound of formula I, based on the total weight of the composition, the anhydrous crystalline form having an X-ray powder diffraction pattern having characteristic peaks between and including the following 2θ values ​​(degrees): 6.4, 13.7, and 25.8±0.2° 2θ; about 70% to 89% by weight of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; about 5% by weight of crospovidone, based on the total weight of the composition; about 4% of povidone, based on the total weight of the composition; and about 1% of polysorbate, based on the total weight of the composition; and (ii) an aqueous medium. In some embodiments, the aqueous medium comprises a starch-based suspension (e.g., SYRSPEND® SF).

[0046] How to use The present disclosure provides, in one embodiment, a method of treating a disorder in a subject, comprising administering to the subject radiprodil or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is a pediatric subject.

[0047] In some embodiments, the disorder is epileptic disorder.In some embodiments, the disorder is infantile spasm syndrome.In some embodiments, the disorder is a brain disorder characterized by hyperactive glutamatergic transmission, a trait or state, including genetic disorder characterized by mutations in NMDA glutamate receptor subunits such as GRIN2B, GRIN2A, GRIN1 and GRIN2D, or other epileptic disorders determined by impaired cortical development characterized by overexpression of NDMA receptor subunit NR2B (e.g., focal cortical dysplasia and tuberous sclerosis complex).

[0048] In one embodiment, provided herein is a method for treating a convulsive disorder in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition described herein or a pharma- ceutically acceptable suspension described herein. In some embodiments, the convulsive disorder is epilepsy. In some embodiments, the subject is a pediatric subject. In some embodiments, the convulsive disorder is infantile spasm syndrome.

[0049] definition The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and sub-animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lauryl sulfate, glycerol ... Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-butyl esters. + (C 1-4 Alkyl) 4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0050] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0051] Disease, disorder, and condition are used interchangeably herein.

[0052] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition, or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment").

[0053] In general, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0054] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids the symptoms or pathogenesis of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0055] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and the oxygen may be, for example, 18 O, where the nitrogen can be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element occupying a particular site on a compound.

[0056] "Radiprodil" refers to a compound of formula I, as described herein, having the structure: [ka] has.

[0057] Radiprodil is a negative allosteric modulator of the NMDA (N-methyl D-aspartate) receptor. As used herein, "radiprodil drug substance" refers to the dihydrate of radiprodil. EXAMPLES

[0058] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization.

[0059] Abbreviations: ACN: acetonitrile; LOQ: limit of quantification; NMT: below;

[0060] Example 1. Synthesis of radiprodil. An exemplary synthesis of radiprodil is provided in International Publication WO2003 / 010159, which is incorporated herein by reference.

[0061] Example 2. Preparation of radiprodil form A. Exemplary preparation and characterization of radiprodil Form A is provided in U.S. Patent Application Publication No. 2012 / 0059034, which is incorporated herein by reference.

[0062] Example 3. Radiprodil Drug Granules. The pediatric formulation was developed as a multiple unit oral dosage form. The approach was to develop a highly dispersible granule that could be reconstituted by a wet granulation process in a fluid bed granulator prior to administration.

[0063] The manufacturing process of radiprodil granules for oral suspension consists of granulation in a fluid bed granulator followed by filling of the final granules in bottles. Radiprodil granules are manufactured according to current Good Manufacturing Practice (cGMP). The equipment described may be replaced by any equipment with similar performance. The flow diagram of the manufacturing process of radiprodil granules for oral suspension is shown in Figure 1.

[0064] Different granule prototypes were manufactured with different qualitative compositions in terms of fillers, surfactants, binders and disintegrants, always with excipients suitable for pediatric formulations. During formulation development, it was observed that all granule prototypes manufactured via fluid bed granulation contained radiprodil form A. Therefore, the manufacturing process was optimized to allow complete conversion of the dihydrate form to form A through a drying step at the end of the granulation process.

[0065] The manufacturing recipe given below corresponds to a theoretical batch size of 1 kg of granules. For other batch sizes, the amounts of all ingredients are adjusted proportionately.

[0066] The 1 kg batch formulations for 1% radiprodil and 10% radiprodil drug granules are provided below in Tables 1 and 3, respectively. The bottle filling steps for 1% radiprodil and 10% radiprodil drug granules are provided in Tables 2 and 4, respectively.

[0067] [Table 1]

[0068] [Table 2]

[0069] [Table 3]

[0070] [Table 4]

[0071] Scale-up of the granulation process in a fluid bed granulator was carried out to produce granules at 1 kg scale. The process conditions were set with the aim to obtain complete conversion of the dihydrate form (radiprodil drug substance) to Form A by checking the XRPD pattern of the final granules. The study demonstrated the feasibility of such a procedure to obtain a final product containing only Form A.

[0072] Finally, one GMP batch was successfully manufactured at 1 kg scale with 10% drug loading for ICH stability study by applying the process conditions from the scale-up study.

[0073] Example 3.1% Radiprodil Granules. The radiprodil drug product is supplied as granules in bottles for oral suspension from the process described in Example 3. Granules with 1% radiprodil drug load are filled into 60 mL round amber Type III glass bottles with polypropylene child resistant caps.

[0074] The quantitative composition of the ingredients used in the radiprodil 1% drug product granules is provided in Table 5. All excipients used are standard compendial excipients commonly used in granulation processes.

[0075] [Table 5]

[0076] Example 4. 10% Radiprodil Granules. Radiprodil drug product is supplied as granules in bottles for oral suspension from the process described in Example 3. Granules at 10% drug loading are filled into 60 mL round amber Type III glass bottles with polypropylene child resistant caps.

[0077] The quantitative composition of the ingredients used in the radiprodil 10% drug product is provided in Table 6. All excipients used are standard compendial excipients commonly used in granulation processes.

[0078] [Table 6]

[0079] Example 5. Suspension of 1% and 10% radiprodil granules. The 1% and 10% radiprodil drug loaded granules (Examples 2 and 3, respectively) are reconstituted as extemporaneously prepared suspensions by adding 40 mL of diluent (4 mL drinking water and 36 mL SYRSPEND® SF).

[0080] Example 6. Impurity and stability analysis of radiprodil drug granules. The impurities in the radiprodil drug substance and granules were analyzed.

[0081] The HPLC-DAD method is used for the identification of radiprodil. The retention time and DAD spectrum should have the same characteristics as those obtained with the reference standard of radiprodil.

[0082] An HPLC method is used for the assay of radiprodil and the determination of degradation products in radiprodil granules for oral suspension. Quantitation of the drug substance is performed by comparing the peak area of ​​the sample with the corresponding peak of the reference solution (external standard method). Quantitation of degradation products is performed as the area percentage of the sum of all peaks not included in the chromatogram of the blank solution or derived from excipients that is ≥ 0.05%.

[0083] An HPLC method is used to determine the level of the impurity 6-amino-2-benzoxazolone in radiprodil granules for oral suspension. Quantitation is performed by comparing the peak area of ​​the sample with that of a reference solution (external standard method).

[0084] The potential and observed organic impurities in the radiprodil drug substance batches are shown in Table 7.

[0085] [Table 7]

[0086] Stability and impurity analysis of 1% and 10% granules, as described in Examples 3 and 4, respectively, and reconstituted formulations were studied. Table 8 shows the stability data and impurity profile of 1% radiprodil granules stored at 25° C. / 60% relative humidity (RH) at various time points. Table 9 shows the stability data and impurity profile of 1% radiprodil granules stored at 40° C. / 75% relative humidity at various time points.

[0087] [Table 8]

[0088] [Table 9]

[0089] Table 10 shows the stability data and impurity profile of 10% radiprodil granules stored at 40° C. / 75% relative humidity at various time points.

[0090] [Table 10]

[0091] Example 7. Dissolution profiles of radiprodil compositions. This study summarizes the dissolution experiments performed on radiprodil drug substance and drug product, including two drug loads with and without reconstitution in SYRSPEND® and water prior to dissolution testing.

[0092] Every dissolution experiment was performed in six vessels and their average was used to plot the comparative curves.

[0093] Prior to dissolution, some dissolution experiments were performed using Syrpend® and reconstitution in water, where the reconstitution was prepared and stirred overnight prior to dissolution testing. Additional tests were performed with extemporaneous suspensions (stirred for 15 minutes prior to dissolution) to mimic the Clinical Pharmacy Manual.

[0094] The dissolution and high performance liquid chromatography (HPLC) parameters used in the experiments are shown below in Tables 11 and 12, respectively.

[0095] [Table 11]

[0096] [Table 12]

[0097] Dissolution experiments without reconstitution of SYRSPEND® SF and water prior to dissolution testing Radiprodil was subjected to dissolution testing in sodium lauryl sulfate (0.5% in water) as the dihydrate and Form A, as well as Form A-containing granules (1% and 10% as above) and blends of the dihydrate with Form A (1% and 10% blends of the dihydrate form with Form A).

[0098] An exemplary dissolution profile is shown in Figure 2. The dissolution profile of the dihydrate form appears more rapidly in aqueous media than the one of anhydrous form A. This observation supports the results of stability studies showing that anhydrous form A is more stable than the dihydrate even in the presence of water.

[0099] Dissolution experiments with SYRSPEND® SF and water reconstitution prior to dissolution testing Radiprodil as the dihydrate and Form A, as well as Form A-containing granules (1% and 10% as above) and blends of the dihydrate and Form A (1% and 10% blends of the dihydrate form and Form A), were first reconstituted in a mixture of SYRSPEND® and water and stirred for 24 hours. The suspensions were subsequently subjected to dissolution testing.

[0100] An exemplary dissolution profile is shown in Figure 3. For formulations reconstituted in a mixture of SYRSPEND® and water prior to dissolution testing (stirring overnight), no differences are observed between the 10% formulations with the dihydrate form or the anhydrous Form A. This observation reveals that reconstitution in SYRSPEND® and water can smooth out the differences with the solid form of radiprodil drug substance (possibly due to better wetting and uniformity).

[0101] Dissolution experiments with immediate reconstitution in SYRSPEND® SF and water prior to dissolution testing To evaluate the effect of time of reconstituted solution, an extemporaneous solution of 1% radiprodil Form A granules in SYRSPEND® and water was prepared 15 minutes prior to dissolution testing and compared to 1% radiprodil Form A granules reconstituted in SYRSPEND® and water for 24 hours. Exemplary profiles are shown in Figure 4. No differences in dissolution profiles were observed between the extemporaneous reconstituted granules and the granules reconstituted 24 hours prior to dissolution testing.

[0102] Example 8. Preparation of radiprodil form C. Exemplary preparation and characterization of radiprodil form C is provided in U.S. Patent Application Publication No. 2012 / 0010044, which is incorporated herein by reference.

[0103] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. Formula I: 【Chemical 1】 1. A pharmaceutically acceptable composition formulated for oral administration of a compound of formula (I), about 0.5% to about 15% by weight of the compound of formula I, based on the total weight of the composition; at least one filler; Disintegrants; a binder; and A composition comprising a surfactant. (a) 1% by weight of said compound, based on the total weight of said pharmaceutically acceptable composition; or 2. The pharmaceutically acceptable composition of claim 1, comprising: (b) 10% by weight of said compound, based on the total weight of said pharmaceutically acceptable composition.

3. including anhydrous crystalline forms of said compound of formula I, 3. The pharmaceutically acceptable composition of claim 1 or 2, wherein the anhydrous crystalline form preferably has an X-ray powder diffraction pattern with characteristic peaks between and including the following 2θ values (degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2°2θ. (a) the pharmaceutical composition comprises 10% to 80% by weight of at least one filler, based on the total weight of the pharmaceutical composition; (b) the at least one filler is selected from the group consisting of confectionery sugar, compressible sugar, dextrates, dextrin, glucose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, talc, and combinations thereof; (c) the composition comprises two fillers; (d) the pharmaceutical composition comprises 1% to 10% by weight of the disintegrant, based on the total weight of the pharmaceutical composition. (e) the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and combinations thereof; (f) the pharmaceutical composition comprises 1% to 10% by weight of the binder, based on the total weight of the pharmaceutical composition. (g) the binder is selected from the group consisting of povidone, starch, gelatin, sugars, natural and synthetic gums, alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and combinations thereof; (h) the pharmaceutical composition comprises 0.01% to 5% by weight of the surfactant, based on the total weight of the pharmaceutical composition. (i) the surfactant is selected from the group consisting of polyoxyethylene stearate, polyoxyethylene alkyl ether, sorbitan fatty acid ester, poloxamer, polyoxyethylene castor oil derivative, phospholipid, sodium lauryl sulfate, polysorbate (polyoxyethylene sorbitan fatty acid ester), and combinations thereof; or (j) The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition is a granule for oral solution.

5. Formula I: 【Chemistry 2】 1. A pharmaceutically acceptable composition formulated for oral administration of a compound of formula (I), 0.5% to 15% by weight of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern with characteristic peaks between and including the following 2-theta values (degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2 degrees 2-theta, based on the total weight of the composition; and The composition further comprises one or more pharmaceutically acceptable excipients.

6. The pharmaceutically acceptable composition, (a) 10% of the anhydrous crystalline form based on the total weight of the composition; or 6. The pharmaceutically acceptable composition of claim 5, comprising (b) 1% of said anhydrous crystalline form based on the total weight of said composition.

7. when the composition is stirred in an aqueous medium at least 1 minute to 24 hours after reconstitution, the composition releases at least 80% of the compound; A composition according to any one of claims 1 to 6, wherein the aqueous medium preferably comprises a starch-based suspension.

8. A pharmaceutically acceptable aqueous suspension comprising the pharmaceutically acceptable composition according to any one of claims 1 to 7 and an aqueous medium.

9. 9. The pharmaceutically acceptable suspension of claim 8, wherein the aqueous medium comprises a starch-based suspension.

10. Formula I: 【Chemistry 3】 1. A pharmaceutically acceptable aqueous suspension for oral delivery of 0.1 mg / kg to 2 mg / kg of a compound of formula (I), (i) A solid pharmaceutically acceptable composition comprising: 10% by weight, based on the total weight of the composition, of an anhydrous crystalline form of the compound of formula I, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern with characteristic peaks at and including the following 2-theta values (degrees): 7.8, 22.0, 23.7, 27.0, and 27.6±0.2 degrees 2-theta; 50% to 80% by weight of a filler selected from the group consisting of mannitol, microcrystalline cellulose, and combinations thereof, based on the total weight of the composition; 5% by weight of crospovidone based on the total weight of the composition; 4% povidone based on the total weight of the composition; and the composition comprising 1% polysorbate based on the total weight of the composition; and (ii) The aqueous suspension, comprising an aqueous medium.

11. 11. The pharmaceutically acceptable suspension of claim 10, wherein the aqueous medium comprises a starch-based suspension.

12. 12. A method for treating a convulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 8, or a suspension according to any one of claims 9 to 11.

13. 13. The method of claim 12, wherein the convulsive disorder is epilepsy.

14. 14. The method of claim 12 or 13, wherein the subject is a pediatric subject.

15. The method of any one of claims 12 to 14, wherein the convulsive disorder is infantile spasm syndrome.

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