Pharmaceutical composition comprising guanfacine or pharmaceutically acceptable salt thereof

Abstract

To provide a pharmaceutical composition that enables sustained release of guanfacine or a pharmaceutically acceptable salt thereof.SOLUTION: A pharmaceutical composition comprises guanfacine or a pharmaceutically acceptable salt thereof and a glycerin fatty acid ester in an amount of 18 mass% or more relative to the total amount of the pharmaceutical composition. The content of an organic acid, particularly fumaric acid, can be 20 mass% or less relative to the total amount of the pharmaceutical composition. The pharmaceutical composition can be provided in tablet form.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof.

Background Art

[0002] Guanfacine hydrochloride (N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride) is an active ingredient of a therapeutic agent for attention deficit / hyperactivity disorder and is a compound represented by the following structural formula.

Chemical Formula

[0003] As preparations containing guanfacine hydrochloride, Intuniv tablets 1 mg and Intuniv tablets 3 mg (manufactured by Shionogi & Co., Ltd.) are used. Intuniv tablets 1 mg are tablets containing guanfacine hydrochloride, hypromellose, copolymer LD of methacrylic acid, crystalline cellulose, light anhydrous silicic acid, lactose hydrate, povidone, crospovidone, glycerin fatty acid ester, and fumaric acid. Further, Intuniv tablets 3 mg are tablets containing lake blue No. 2 and yellow ferric oxide in addition to the same components as Intuniv tablets 1 mg (Non-Patent Document 1). Intuniv tablets 1 mg and Intuniv tablets 3 mg are sustained-release tablets to be taken once a day, respectively.

[0004] Here, Patent Document 1 discloses that a tablet that sustains the release of guanfacine or a salt thereof can be obtained by blending (a) a tablet containing guanfacine or a salt thereof, (b) a non-pH-dependent sustained-release agent, (c) a polymer that swells at a pH exceeding 5.5 or an enteric drug, and (d) an organic acid. Examples of (b) include hypromellose, examples of (c) include acrylate / methacrylate copolymer, and examples of (d) include fumaric acid.

[0005] Further, Patent Document 2 discloses that in a pharmaceutical composition containing guanfacine or a salt thereof, hydrolysis due to the storage of guanfacine or a salt thereof is more suppressed when succinic acid, maleic acid, benzoic acid, glutamic acid, or aspartic acid is contained rather than fumaric acid as an organic acid.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Non - Patent Documents

[0007]

Non - Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] An object of the present invention is to provide a pharmaceutical composition capable of obtaining good sustained release of guanfacine or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as "guanfacine or a salt thereof").

Means for Solving the Problems

[0009] The present inventor has conducted extensive research to solve the above problems and has found that by blending a glycerin fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition in a pharmaceutical composition containing guanfacine or a salt thereof, excellent sustained release of guanfacine or a salt thereof can be obtained.

[0010] The present invention has been completed based on the above findings and provides the following [1] to [6]. 〔1〕 A pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof and a glycerol fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition. 〔2〕 The pharmaceutical composition according to 〔1〕, wherein the content of the organic acid is 20% by mass or less based on the total amount of the pharmaceutical composition. 〔3〕 The pharmaceutical composition according to 〔2〕, wherein the organic acid is fumaric acid. 〔4〕 The pharmaceutical composition according to any one of 〔1〕 to 〔3〕, wherein the pharmaceutical composition is a tablet. 〔5〕 The pharmaceutical composition according to any one of 〔1〕 to 〔4〕, further comprising at least one selected from hypromellose, methacrylic acid copolymer, and hypromellose acetate succinate. 〔6〕 A method for improving the sustained release property of guanfacine or a salt thereof by adding a glycerol fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition to a pharmaceutical composition containing guanfacine or a salt thereof.

Advantages of the Invention

[0011] The pharmaceutical composition of the present invention contains 18% by mass or more of a glycerol fatty acid ester, so that the sustained release property of guanfacine or a salt thereof is sufficiently improved. Further, according to Patent Document 1, the sustained release property of guanfacine or a salt thereof is improved by blending an organic acid. On the other hand, according to Patent Document 2, it is known that the storage stability of guanfacine or a salt thereof decreases when a specific organic acid is contained. In this regard, since the pharmaceutical composition of the present invention contains 18% by mass or more of a glycerol fatty acid ester, the sustained release property of guanfacine or a salt thereof from the pharmaceutical composition is ensured, and good sustained release property can be obtained regardless of the presence or absence and type of the organic acid.

Brief Description of the Drawings

[0012]

Figure 1

Embodiments for Carrying Out the Invention

[0013] The present invention will be described in detail below. The pharmaceutical composition of the present invention is a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof and a glycerin fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition.

[0014] The content of guanfacine or its salt can be 0.1% by mass or more, 0.3% by mass or more, or 0.5% by mass or more, and 10% by mass or less, 5% by mass or less, or 2% by mass or less based on the total amount of the pharmaceutical composition. Examples of the salt of guanfacine include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; organic acid salts such as acetate, oxalate, maleate, fumarate, malonate, lactate, tartrate, citrate, benzoate, methanesulfonate, succinate, malate, ascorbate, adipate, and benzoate. Among them, inorganic acid salts are preferred, and hydrochloride is more preferred.

[0015] The pharmaceutical composition of the present invention contains a glycerin fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition. The content of the glycerin fatty acid ester can also be 20% by mass or more, 25% by mass or more, or 30% by mass or more based on the total amount of the pharmaceutical composition. Within this range, good sustained release of guanfacine or its salt can be obtained. In addition, the content of the glycerin fatty acid ester can be 50% by mass or less, 45% by mass or less, 40% by mass or less, or 35% by mass or less based on the total amount of the pharmaceutical composition. Within this range, the elution of guanfacine or its salt will not be too slow, and good sustained release can be obtained.

[0016] The pharmaceutical composition of the present invention may or may not contain an organic acid. Examples of the organic acid include acetic acid, oxalic acid, maleic acid, fumaric acid, malonic acid, lactic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, succinic acid, malic acid, ascorbic acid, adipic acid, benzoic acid, amino acids (such as glutamic acid and aspartic acid), and hydrates thereof. When the pharmaceutical composition of the present invention contains an organic acid, its content is preferably 20% by mass or less, 15% by mass or less, 10% by mass or less, or 5% by mass or less based on the total amount of the pharmaceutical composition. When it contains an organic acid, its content only needs to be more than 0% by mass, but can be 0.1% by mass or more, 0.5% by mass or more, or 1% by mass or more. When it contains a hydrate of an organic acid, the content in terms of the anhydrous organic acid only needs to be within this range. Even when the pharmaceutical composition of the present invention does not contain an organic acid, sufficient sustained release of guanfacine or its salt can be obtained. When it does not contain an organic acid, particularly fumaric acid, a sustained release property biologically equivalent to that of the pioneer formulation, Intuniv tablets, can be obtained. In the present invention, "not containing an organic acid" includes the case where inevitable impurities are mixed in.

[0017] Examples of the dosage form of the pharmaceutical composition include solid preparations such as powders, granules, fine granules, capsules (hard capsules, soft capsules), dry syrups, tablets, films, lozenges, chewing gum agents, etc. Among them, tablets are preferred. Special tablets also include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc.

[0018] The pharmaceutical composition of the present invention can contain various additives added to the pharmaceutical composition. Such additives include excipients, binders, disintegrants, lubricants, fluidizing agents, brightening agents, stabilizers, antioxidants, emulsifiers, surfactants, solubilizers, suspending agents, dispersants, buffers, pH adjusters, thickeners, adsorbing agents, coloring agents, flavoring agents, sweetening agents, fragrances, preservatives or antiseptics, foaming agents, defoaming agents, coating agents, plasticizers, etc. One or more additives can be used. As shown below, glycerin fatty acid esters can be added as suspending agents, dispersants, coating agents, plasticizers, etc. In the present invention, regardless of the purpose of addition, the total amount thereof is 18% by mass or more based on the total amount of the pharmaceutical composition.

[0019] Excipients include erythritol, lactose - crystalline cellulose spherical granules, starch syrup, gum arabic, powdered gum arabic, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, potato starch, corn starch), isomalt hydrate (ISOMALT), kaolin, reduced palatinose, xylitol, L - glutamine, croscarmellose sodium, crospovidone, silicic acid - treated crystalline cellulose, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, β - cyclodextrin, aluminum hydroxide gel, refined sugar, refined sugar spherical granules, gelatin, D - sorbitol, talc, medium - chain fatty acid triglycerides, precipitated calcium carbonate, low - substituted hydroxypropyl cellulose, sodium starch glycolate (sodium carboxymethyl starch), trehalose hydrate, lactose hydrate, sucrose, sucrose - starch spherical granules, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, glucose, pullulan, polyoxyethylene hydrogenated castor oil (N), polyoxyethylene (N) polyoxypropylene (N) glycol, macrogol (macrogol 4000, macrogol 6000), maltitol, D - mannitol, anhydrous lactose, anhydrous calcium hydrogen phosphate, magnesium aluminum metasilicate, glycerol monostearate, calcium dihydrogen phosphate, calcium hydrogen phosphate hydrate, etc.

[0020] Examples of the binder include cellulose binders (ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hypromellose, carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl ethyl cellulose, calcium carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hypromellose acetate succinate, hypromellose phthalate), gum arabic, powdered gum arabic, α - starch, partially α - starch, starch (wheat starch, rice starch, corn starch, potato starch), hydroxypropyl starch, sodium alginate, gelatin, low - degree - of - substitution hydroxypropyl cellulose, dextrin, sodium starch glycolate (sodium carboxymethyl starch), pullulan, macrogol (macrogol 400, macrogol 4000, macrogol 6000), ethyl acrylate - methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer (such as aminoalkyl methacrylate copolymer E), ammonioalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer RS), carboxyvinyl polymer, agar powder, guar gum, copovidone, cetyl alcohol, shellac, dextrin, pectin, povidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, polyvinyl alcohol (partially saponified), polyvinyl alcohol - polyethylene glycol graft copolymer, methacrylic acid copolymer (dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S), and the like.

[0021] When the pharmaceutical composition of the present invention contains a binder, its total content can be 1% by mass or more, 5% by mass or more, or 7% by mass or more, and 30% by mass or less, 20% by mass or less, or 15% by mass or less based on the total amount of the pharmaceutical composition. Among them, when the pharmaceutical composition of the present invention contains hypromellose, its content can be 1% by mass or more, 5% by mass or more, or 7% by mass or more, and 30% by mass or less, 20% by mass or less, or 15% by mass or less based on the total amount of the pharmaceutical composition. In addition, when the pharmaceutical composition of the present invention contains a methacrylic acid / acrylic acid copolymer (especially dry methacrylic acid copolymer LD or methacrylic acid copolymer LD), its content can be 5% by mass or more, 10% by mass or more, 15% by mass or more, or 20% by mass or more, and 45% by mass or less, 35% by mass or less, or 25% by mass or less based on the total amount of the pharmaceutical composition. When containing methacrylic acid copolymer LD, the above content is the content converted to dry methacrylic acid copolymer LD. In addition, when the pharmaceutical composition of the present invention contains hypromellose acetate succinate, its content can be 1% by mass or more, 5% by mass or more, 10% by mass or more, and 40% by mass or less, 30% by mass or less, or 20% by mass or less based on the total amount of the pharmaceutical composition. Within the above range, good sustained release of guanfacine or its salt can be obtained.

[0022] Examples of the disintegrant include starch (wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, hydroxypropyl cellulose, partially gelatinized starch, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminometasilicate, carmellose, carmellose calcium, calcium silicate, sodium lauryl sulfate, and the like.

[0023] Examples of the lubricant include talc, glycerin monostearate, dimethylpolysiloxane (for oral use), sucrose fatty acid ester, stearic acid, stearates (calcium stearate, magnesium stearate, sodium stearyl fumarate), dl-leucine, and the like.

[0024] Examples of fluidizing agents include calcium silicate, talc, light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, magnesium aluminometasilicate, etc.

[0025] Examples of brightening agents include carnauba wax, refined paraffin-carnauba wax blend, bleached beeswax, refined shellac, etc.

[0026] Examples of stabilizers include meglumine, citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, xylitol, D-sorbitol, lactose hydrate, D-mannitol, sodium citrate hydrate, tartaric acid, anhydrous citric acid, DL-malic acid, talc, light anhydrous silicic acid, magnesium aluminometasilicate, glyceryl monostearate, sucrose fatty acid ester, stearic acid, sodium lauryl sulfate, macrogol (such as macrogol 400, macrogol 4000, etc.), carboxyvinyl polymer, polyvinyl alcohol (partially saponified), polyoxyethylene hydrogenated castor oil (N), L-aspartic acid, sodium L-aspartate hydrate, DL-alanine, L-alanine, L-arginine, sodium chloride, dried aluminum hydroxide gel, xanthan gum, glycine, acetic acid, sodium acetate hydrate, sodium hydroxide, sodium hydrogen carbonate, tocopherol, lactic acid, concentrated glycerin, butylhydroxyanisole, fumaric acid, propylene glycol, propyl gallate, polysorbate 80, sodium monohydrogen phosphate anhydrous, etc.

[0027] Examples of antioxidants include anhydrous citric acid, citric acid hydrate, soy lecithin, dibutylhydroxytoluene, tocopherol, propyl gallate, etc.

[0028] Examples of emulsifiers include glyceryl monostearate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, medium-chain fatty acid triglyceride, soy lecithin, lauromacrogol, etc.

[0029] Examples of surfactants include glycerin monostearate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, macrogol (such as macrogol 400), polyoxyethylene (N) polyoxypropylene (N) glycol, etc.

[0030] Examples of solubilizers include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, polyoxyethylene (N) polyoxypropylene (N) glycol, medium-chain fatty acid triglyceride, soybean lecithin, meglumine, D-mannitol, sodium citrate hydrate, anhydrous citric acid, sucrose fatty acid ester, macrogol (such as macrogol 4000, macrogol 6000), polyvinyl alcohol (partially saponified), L-aspartic acid, L-arginine, sodium hydroxide, sodium hydrogen carbonate, lactic acid, concentrated glycerin, hydroxypropyl cellulose, β-cyclodextrin, glycerin, soybean oil, triacetin, etc.

[0031] Examples of suspending agents include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, soybean lecithin, sucrose fatty acid ester, macrogol (such as macrogol 4000, macrogol 6000), sodium hydroxide, hydroxypropyl cellulose, glycerin, D-sorbitol, magnesium aluminum metasilicate, carboxyvinyl polymer, dried aluminum hydroxide gel, xanthan gum, butylhydroxyanisole, propylene glycol, crystalline cellulose, gum arabic, powdered gum arabic, hypromellose, agar powder, povidone, methylcellulose, kaolin, carrageenan, sodium carboxymethylcellulose, glycerin fatty acid ester, magnesium aluminum silicate, etc.

[0032] Examples of the dispersant include propylene glycol alginate, ethanol, sodium carboxymethyl cellulose, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose - sodium carboxymethyl cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, oleic acid, sorbitan fatty acid ester, low - degree - substituted hydroxypropyl cellulose, dextrin, sodium starch glycolate, corn starch, concentrated glycerin, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, propylene glycol, povidone, polysorbate 80, macrogol (such as macrogol 300, macrogol 4000, etc.), sodium anhydrous citrate, magnesium aluminum metasilicate, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sodium lauryl sulfate, lauromacrogol, calcium hydrogen phosphate hydrate, etc.

[0033] Examples of the buffer include sodium citrate hydrate, anhydrous citric acid, sodium hydrogen carbonate, lactic acid, citric acid hydrate, sodium benzoate, tartaric acid, DL - malic acid, sodium chloride, acetic acid, sodium acetate hydrate, anhydrous monosodium hydrogen phosphate, L - glutamic acid, dilute hydrochloric acid, etc.

[0034] Examples of the pH adjuster include L - glutamine, sodium citrate hydrate, anhydrous citric acid, sodium hydrogen carbonate, lactic acid, citric acid hydrate, tartaric acid, DL - malic acid, acetic acid, sodium acetate hydrate, anhydrous monosodium hydrogen phosphate, dilute hydrochloric acid, sodium hydroxide, meglumine, succinic acid, aqueous ammonia, etc.

[0035] Examples of thickeners include guar gum, hydroxypropyl cellulose, carboxyvinyl polymer, xanthan gum, propylene glycol, hypromellose, carrageenan, sodium carboxymethyl cellulose, concentrated glycerin, gelatin, hydroxyethyl cellulose, carob bean gum, α-cyclodextrin, locust bean gum, and the like.

[0036] Examples of adsorbents include magnesium aluminometasilicate, kaolin, light anhydrous silicic acid, synthetic aluminum silicate, magnesium silicate, precipitated calcium carbonate, and the like.

[0037] Examples of colorants include titanium oxide, indigocarmin, yellow ferric oxide, carmine, black iron oxide, ferric oxide, synthetic food colors (such as Food Blue No. 1, Aluminum Lake of Food Blue No. 2, Food Yellow No. 4, Aluminum Lake of Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), natural food colors, and the like.

[0038] Examples of flavor correctives include erythritol, xylitol, refined sugar, D-sorbitol, lactose hydrate, granulated sugar, glucose, D-mannitol, aspartame, cocoa powder, reduced maltose syrup, reduced syrup, licorice, licorice extract, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, succinic acid, saccharin, sodium saccharin hydrate, tartaric acid, sucralose, stevia extract purified product, peppermint oil, anhydrous citric acid, l-menthol, DL-malic acid, and the like.

[0039] Examples of sweeteners include xylitol, refined sugar, D-sorbitol, lactose hydrate, granulated sugar, glucose, D-mannitol, aspartame, reduced maltose syrup, licorice, licorice extract, saccharin, sodium saccharin hydrate, sucralose, stevia extract purified product, maltitol, acesulfame potassium, thaumatin (sau matin), and the like.

[0040] Examples of fragrances include peppermint oil, l-menthol, vanillin, and the like.

[0041] Examples of preservatives or antiseptics include citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, paraoxybenzoic acid esters (such as isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, etc.).

[0042] Examples of foaming agents include hydrogen carbonates (such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), carbonates (such as magnesium carbonate, calcium carbonate, etc.).

[0043] Examples of coating agents include polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, polyvinyl alcohol·polyethylene glycol·graft copolymer, dimethyl polysiloxane (for oral use), magnesium aluminometasilicate, kaolin, light anhydrous silicic acid, anhydrous citric acid, hydroxypropyl cellulose, carboxyvinyl polymer, propylene glycol, hypromellose, thick glycerin, gelatin, DL - malic acid, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, sucrose fatty acid ester, macrogol (macrogol 400, macrogol 4000, macrogol 6000, etc.), glycerin, D - sorbitol, crystalline cellulose, povidone, methyl cellulose, glycerin fatty acid ester, lauromacrogol, polyoxyethylene (N) polyoxypropylene (N) glycol, D - mannitol, polyvinyl alcohol (partially saponified), triacetin, glycerin monostearate, lactose hydrate, talc, stearic acid, refined sugar, granulated sugar, titanium oxide, white beeswax, starch (corn starch, potato starch, etc.), pullulan, ethyl acrylate·methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer RS), ethyl cellulose, carboxymethyl ethyl cellulose, cetanol, shellac, hypromellose acetate succinate, hypromellose phthalate, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer (dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, etc.), aluminum hydroxide gel, calcium hydrogen phosphate anhydride, calcium hydrogen phosphate monohydrate, calcium hydrogen phosphate hydrate, ammonioalkyl methacrylate copolymer dispersion, ethyl cellulose aqueous dispersion, triethyl citrate, cellulose acetate, ceracefate, etc.

[0044] When the pharmaceutical composition of the present invention is a tablet, it may be a tablet without a coating layer, or a tablet with a coating layer coated on the core tablet, but it is preferably without a coating layer. Even a tablet without a coating layer can generally contain components used as coating agents in the tablet.

[0045] Examples of plasticizers include polyethylene glycol, propylene glycol, glycerin, glycerin fatty acid esters such as triacetin (glycerol triacetate), liquid paraffin, sorbitan monolaurate, monostearin, triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, poloxamer, polyoxyethylene hydrogenated castor oil, and the like.

[0046] When the pharmaceutical composition of the present invention is a tablet, the diameter can be 5 mm or more, 6 mm or more, or 7 mm or more, and 10 mm or less, 9 mm or less, or 8 mm or less. Also, the thickness can be 1 mm or more, 2 mm or more, or 3 mm or more, and 7 mm or less, 6 mm or less, or 5 mm or less. The tablet (core tablet in the case of having a coating layer) may be manufactured by a direct compression method in which all components are mixed and tabletted, or by a method in which some components are granulated and then mixed with other components and tabletted.

[0047] The present invention provides a method for improving the sustained release of guanfacine or a salt thereof by adding a glycerin fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition to a pharmaceutical composition containing guanfacine or a salt thereof. The present invention also provides a method for optimizing the sustained release of guanfacine or a salt thereof by including a glycerol fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition, and setting the content of an organic acid (particularly fumaric acid) to 20% by mass or less based on the total amount of the pharmaceutical composition. This method includes setting the content of the organic acid (particularly fumaric acid) to 0% by mass based on the total amount of the pharmaceutical composition. Optimization means having a sustained release equivalent to that of Intuniv tablets 1 mg or 3 mg, which are reference products. In each method of the present invention, the composition, dosage form, properties, manufacturing method, etc. of the pharmaceutical composition are as described for the pharmaceutical composition of the present invention.

Examples

[0048] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[0049] (1) Tablet manufacturing Examples 1 to 5, Comparative Example 1 Guanfacine hydrochloride, hypromellose, dry methacrylic acid copolymer LD, crystalline cellulose, lactose hydrate, glycerol fatty acid ester, and magnesium stearate were placed in a high-speed stirring granulator (High Speed Mixer FS-2, Earth Technica) and mixed. Using a rotary tablet press (VIRGO24, Kikusui Seisakusho), the mixture was tableted so that the tablet thickness was 4 mm to produce tablets. The composition of the obtained tablets is shown in Table 1.

[0050] Examples 6 and 7 Guanfacine hydrochloride, hypromellose, dry methacrylic acid copolymer LD, crystalline cellulose, lactose hydrate, glycerol fatty acid ester, and fumaric acid were placed in a high-speed stirring granulator (High Speed Mixer FS-2, Earth Technica) and mixed. Using a rotary tablet press (VIRGO24, Kikusui Seisakusho), the mixture was tableted so that the tablet thickness was 4 mm to produce tablets. The composition of the obtained tablets is shown in Table 1.

[0051] Examples 8 to 13 Guanfacine hydrochloride, hypromellose, dry methacrylic acid copolymer LD, hypromellose acetate succinate, crystalline cellulose, lactose hydrate, glycerin fatty acid ester, fumaric acid, magnesium stearate, light anhydrous silicic acid and a pigment were put into a high-speed stirring granulator (High-Speed Mixer FS-2, Earth Technica) and mixed. Using a rotary tableting machine (VIRGO24, Kikusui Seisakusho), tablets were produced such that the tablet thickness was 4 mm for the mixture. The composition of the obtained tablets is shown in Table 1.

[0052] (2) Dissolution test For each of the tablets of Examples 1 to 13, Comparative Example 1, and Initinib tablets 3 mg, a dissolution test of guanfacine hydrochloride was performed. The dissolution test was carried out in accordance with the second method (rotating paddle method) of the dissolution test of the 18th revised Japanese Pharmacopoeia. The test solution used was 900 mL of the second dissolution test solution (pH 6.8). The operating conditions were a test solution temperature of 37°C and a paddle rotation speed of 50 rpm (NTR-6100A, Toyama Sangyo Co., Ltd.). Samples were taken from the eluate at 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 240 minutes, 360 minutes, 540 minutes, 720 minutes, 1080 minutes, and 1440 minutes after the start of the test. The elution amount of guanfacine hydrochloride was quantified by high-performance liquid chromatography, and the dissolution rate (the ratio of the elution amount to the total amount in the tablet before the start of the dissolution test) (%) was calculated. Also, in accordance with the guidelines for the bioequivalence of generic drugs, the equivalence with Initinib tablets 3 mg was determined from the dissolution rate 1080 minutes after the start of the test for each tablet. (HPLC conditions) Column: CERI L-colum3 (trade name) Column temperature: 40°C Mobile phase: Sodium hydrogen carbonate buffer / acetonitrile mixed solution (3:1) Flow rate of the mobile phase: Adjusted so that the retention time of guanfacine is about 8 minutes (about 0.85 mL per minute) Detector: Ultraviolet absorptiometer (measurement wavelength: 226 nm)

[0053]

Table 1

[0054] Figure 1 shows the change in the dissolution rate of Example 2 and Example 6. It can be seen that the dissolution rate decreases and the sustained release property improves by containing fumaric acid. According to Table 1, since the dissolution rate of Example 6 was 15% or more lower than that of Intuniv tablets 3 mg, equivalence was not applicable. However, the dissolution property was lower than that of Intuniv tablets 3 mg, that is, the sustained release property was more excellent.

Industrial Applicability

[0055] The pharmaceutical composition of the present invention ensures the sustained release of guanfacine or a salt thereof by adjusting the content of glycerol fatty acid ester. The pharmaceutical composition of the present invention has high commercial value in that good sustained release property can be obtained regardless of the presence or type of organic acid that affects the stability of guanfacine or a salt thereof.

Claims

1. A pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof and a glycerol fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the content of the organic acid is 20% by mass or less based on the total amount of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 2, wherein the organic acid is fumaric acid.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is a tablet.

5. The pharmaceutical composition according to any one of claims 1 to 3, further comprising at least one selected from hypromellose, methacrylic acid copolymer, and hypromellose acetate succinate.

6. A method for improving the sustained release of guanfacine or a salt thereof by adding a glycerol fatty acid ester in an amount of 18% by mass or more based on the total amount of the pharmaceutical composition to a pharmaceutical composition containing guanfacine or a salt thereof.

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