Method for producing sustained-release granule containing venlafaxine hydrochloride

Abstract

To provide a method for producing sustained-release granules containing venlafaxine hydrochloride, with suppressed fluctuation in sustained release of venlafaxine hydrochloride depending on production scale.SOLUTION: A method for producing sustained-release granules containing venlafaxine hydrochloride comprises the step of forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating solution comprising a solvent containing ethanol and a binder, an ethanol concentration relative to a total solvent being 90 mass% or higher. The solvent of the coating solution may include water and ethanol, and the binder of the coating solution may include ethyl cellulose and hypromellose.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for producing sustained-release granules containing venlafaxine hydrochloride, and a coating liquid used in this method. [Background technology]

[0002] Venlafaxine hydrochloride (1-[(1RS)-2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol monohydrochloride) is an active ingredient in drugs for treating depression and depressive states, and is a compound represented by the following structural formula. [ka]

[0003] Effexor (registered trademark) SR Capsules 37.5 mg and 75 mg (Viatris Pharmaceutical Co., Ltd.) are clinically used preparations containing venlafaxine hydrochloride. Effexor SR Capsules are hard capsules with a gelatin base filled with granules containing venlafaxine hydrochloride, crystalline cellulose, hypromellose, and ethylcellulose (Non-Patent Document 1).

[0004] An example of a document that is believed to disclose Effexor SR Capsules is Patent Document 1. Patent Document 1 describes a sustained-release preparation of venlafaxine hydrochloride in which fine granules consisting of granules containing venlafaxine hydrochloride, microcrystalline cellulose, and hypromellose, and a layer coating the granules containing ethyl cellulose and hypromellose, are filled into a hard gelatin capsule (Claim 1). These granules are manufactured by coating core granules containing venlafaxine hydrochloride, microcrystalline cellulose, and hypromellose with a coating solution prepared by dissolving ethyl cellulose and hypromellose in a 1:1 (v / v) mixture of methylene chloride and absolute ethanol (paragraphs 0017-0018). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 4771565 [Non-patent literature]

[0006] [Non-Patent Document 1] Effexor SR Capsules Package Insert Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have found that venlafaxine hydrochloride-containing sustained-release granules, in which granules containing venlafaxine hydrochloride are coated with a sustained-release layer containing a binder, can achieve the desired sustained release of venlafaxine hydrochloride on a laboratory scale, but the sustained release varies when the production is scaled up. Therefore, an object of the present invention is to provide a method for producing sustained-release granules containing venlafaxine hydrochloride, in which fluctuations in the sustained release properties of venlafaxine hydrochloride due to production scale are suppressed. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems and have obtained the following findings. (1) The ethanol concentration in the coating solution used to form the sustained-release layer affects the dissolution behavior of venlafaxine hydrochloride. (2) When the ethanol concentration in the coating solution used to form the sustained-release layer is 90% by mass or more relative to the total amount of solvent in the coating solution, fluctuations in the dissolution behavior of venlafaxine hydrochloride due to production scale can be suppressed.

[0009] The present invention was completed based on the above findings, and provides the following [1] to

[11] . [1] A method for producing sustained-release granules containing venlafaxine hydrochloride, comprising a step of forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing an ethanol-containing solvent and a binder, the ethanol concentration relative to the total amount of the solvent being 90% by mass or more. [2] The method according to [1], wherein the venlafaxine hydrochloride-containing sustained-release granules have one or more intermediate layers between the venlafaxine hydrochloride-containing granules and the sustained-release layer, and the method comprises a step of forming the intermediate layer by coating the venlafaxine hydrochloride-containing granules with a coating liquid containing an ethanol-containing solvent and a binder, wherein the ethanol concentration relative to the total amount of the solvent is 90% by mass or more. [3] The method according to [1] or [2], wherein the solvent of the coating liquid contains water and ethanol. [4] The method according to any one of [1] to [3], wherein the binder of the coating liquid contains ethyl cellulose and hypromellose. [5] The method according to any one of [1] to [4], wherein the coating amount of the sustained-release layer is 0.001 to 1 part by mass per 1 part by mass of the venlafaxine hydrochloride-containing granules. [6] Sustained-release granules containing venlafaxine hydrochloride obtained by a method including a step of forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing an ethanol-containing solvent and a binder, the ethanol concentration relative to the total amount of the solvent being 90% by mass or more. [7] The sustained-release granules containing venlafaxine hydrochloride according to [6], wherein the coating amount of the sustained-release layer is 0.001 to 1 part by mass per 1 part by mass of the venlafaxine hydrochloride-containing granules. [8] A coating solution for venlafaxine hydrochloride-containing granules, comprising an ethanol-containing solvent and a binder, wherein the ethanol concentration relative to the total amount of the solvent is 90% by mass or more. [9] The coating liquid according to [8], wherein the solvent of the coating liquid contains water and ethanol.

[10] The coating liquid according to [8] or [9], wherein the binder of the coating liquid contains ethyl cellulose and hypromellose.

[11] A method for producing sustained-release granules containing venlafaxine hydrochloride by forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing a solvent and a binder, wherein the concentration of ethanol relative to the total amount of solvent in the coating liquid is 90 mass% or more, thereby suppressing fluctuations in the dissolution behavior of venlafaxine hydrochloride from the sustained-release granules containing venlafaxine hydrochloride due to production scale. [Effects of the Invention]

[0010] In conventional methods for producing sustained-release granules containing venlafaxine hydrochloride, the dissolution behavior of venlafaxine hydrochloride from the resulting sustained-release granules varies depending on the production scale. In contrast, the venlafaxine hydrochloride-containing sustained-release granules produced by the method of the present invention have reduced variation in the dissolution behavior of venlafaxine hydrochloride depending on the production scale, so there is less need to consider conditions when scaling up a production method determined on a laboratory scale. Surprisingly, even though ethanol normally does not remain in the resulting sustained-release granules containing venlafaxine hydrochloride, variation in the dissolution behavior of venlafaxine hydrochloride can be reduced by setting the ethanol concentration of the coating solution solvent to 90% by weight or more. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a graph comparing the time course of dissolution rates of granules produced on a lab scale and granules produced on a medium scale in Example 1 (granules with one sustained-release layer were produced using a coating liquid with an ethanol concentration of 90% by mass). [Figure 2] FIG. 1 is a graph comparing the time course of dissolution rates of granules produced on a lab scale and granules produced on a medium scale in Comparative Example 1 (granules with one sustained-release layer were produced using a coating liquid with an ethanol concentration of 70% by mass). [Figure 3] FIG. 1 is a graph comparing the time course of dissolution rates of granules produced on a lab scale and granules produced on a medium scale in Example 2 (two-layer sustained-release granules produced using a coating solution with an ethanol concentration of 90% by mass). DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention will be described in detail below. The method for producing sustained-release granules containing venlafaxine hydrochloride of the present invention is a method comprising a step of forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing an ethanol-containing solvent and a binder, the ethanol concentration being 90% by mass or more relative to the total amount of the solvent.

[0013] Venlafaxine hydrochloride-containing granules can have a variety of layer configurations. Examples include granules made by granulating venlafaxine hydrochloride and additives, and granules in which core particles are coated with one or more drug layers containing venlafaxine hydrochloride. Granules in which core particles are coated with a drug layer containing venlafaxine hydrochloride can have one or more intermediate layers (intermediate layer 1) between the core particle and the drug layer.

[0014] The content of venlafaxine hydrochloride can be 30% by mass or more, 40% by mass or more, or 50% by mass or more, and 85% by mass or less, 80% by mass or less, or 75% by mass or less, based on the total amount of the venlafaxine hydrochloride-containing granules. Within this range, fluctuations in the dissolution behavior of venlafaxine hydrochloride due to production scale are suppressed, and when the core granules are made into granules coated with a drug layer, wetting and aggregation of the granules during drug layer formation are suppressed.

[0015] The core particles in the granules coated with a drug layer containing venlafaxine hydrochloride can be produced by granulating excipients and the like using a conventional method. Alternatively, commercially available products can be used. Examples of commercially available products include Cellupher (registered trademark) (crystalline cellulose, Asahi Kasei Corporation), Nonpareil (registered trademark)-108 (D-mannitol, Freund Corporation), Nonpareil-105 (lactose and crystalline cellulose, Freund Corporation), Nonpareil-103 (refined sucrose, Freund Corporation), Nonpareil-101 (refined sucrose and corn starch, Freund Corporation), Fujicalin (Fuji Chemical Industry Co., Ltd.), PCS (registered trademark) (partially pregelatinized starch, Asahi Kasei Corporation), and Sucreine (registered trademark) (refined sucrose, Ensuiko Sugar Refining Co., Ltd.).

[0016] The drug layer of the granules, in which core particles are coated with a drug layer containing venlafaxine hydrochloride, can be formed, for example, by spraying a coating liquid containing venlafaxine hydrochloride, a binder, and other additives added as needed. The optional intermediate layer 1 can be formed, for example, by spraying a coating liquid containing a binder and other additives added as needed. The drug layer and intermediate layer 1 can typically be formed by fluidized bed granulation, but can also be formed by other methods such as centrifugal tumbling granulation.

[0017] The solvents for the coating liquid used to form the drug layer and intermediate layer include water, ethanol, acetic acid, acetone, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, and dichloromethane. , ethylene glycol, hexane, toluene, acetonitrile, methylene chloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, and the like. One or more solvents can be used.

[0018] The coating amount of the drug layer can be 0.2 parts by mass or more, 0.5 parts by mass or more, or 1 part by mass or more per part by mass of the core particle, and can be 10 parts by mass or less, 5 parts by mass or less, or 3 parts by mass or less. Within this range, fluctuations in the dissolution behavior of venlafaxine hydrochloride due to production scale can be suppressed.

[0019] The sustained-release layer is formed by, for example, spraying a coating liquid containing a binder and an ethanol-containing solvent onto the venlafaxine hydrochloride-containing granules. The sustained-release layer can be formed typically by fluidized bed granulation, but can also be formed by other methods such as centrifugal tumbling granulation.

[0020] The solvent of the coating liquid used to form the sustained-release layer only needs to contain ethanol, and may also contain one or more of the solvents exemplified above as solvents used to form the drug layer and intermediate layer 1. Among these, it is preferable that the solvent contains ethanol and water, and it is more preferable that the solvent consists of ethanol and water. The ethanol content is 90% by mass or more relative to the total amount of the solvent. It can also be 91% by mass or more, 92% by mass or more, 93% by mass or more, or 94% by mass or more. Within this range, the dissolution behavior of venlafaxine hydrochloride is less likely to vary depending on the production scale. The ethanol content can also be 99% by mass or less, 98% by mass or less, 97% by mass or less, 96% by mass or less, or 95% by mass or less relative to the total amount of the solvent. Within this range, the coating solution contains a binder dissolved to an extent that a sustained-release layer can be formed.

[0021] The coating liquid may contain a binder. Binders include cellulose binders (ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hypromellose, carboxymethylethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylethyl cellulose, calcium carboxymethylethyl cellulose, hydroxyethyl cellulose, hypromellose acetate succinate, hypromellose phthalate, low-substituted hydroxypropyl cellulose), gum arabic, powdered gum arabic, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, corn starch, potato starch), hydroxypropyl starch, sodium alginate, gelatin, dextrin, sodium starch glycolate (sodium carboxymethyl starch), pullulan, macrogol (macrogo Macrogol 400, Macrogol 4000, Macrogol 6000), ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer E, etc.), ammonioalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer RS), carboxyvinyl polymer, agar powder, guar gum, copolyvidone, cetanol, 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 (dried methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S). One or more binders may be used. Among these, cellulose-based binders are preferred, and examples thereof include ethyl cellulose, hypromellose, and a combination of ethyl cellulose and hypromellose. When ethyl cellulose and hypromellose are contained, the amount of hypromellose may be 0.1 part by mass or more, 0.13 part by mass or more, or 0.15 part by mass or more, or 5 parts by mass or less, 3 parts by mass or less, or 1 part by mass or less, per part by mass of ethyl cellulose. Within these ranges, fluctuations in the dissolution behavior of venlafaxine hydrochloride due to production scale can be suppressed. Also preferred is a combination of a water-soluble binder and a water-insoluble or poorly soluble binder, such as a combination of ethyl cellulose and povidone, or a combination of ethyl cellulose and polyvinyl alcohol.

[0022] The binder concentration can be 1% by mass or more, 2% by mass or more, 3% by mass or more, or 4% by mass or more, or 10% by mass or less, 8% by mass or less, or 5% by mass or less, based on the total amount of the coating solution. This range can minimize variations in the dissolution behavior of venlafaxine hydrochloride due to production scale. Furthermore, the coating solution is less likely to clog the device nozzle, and the coating time is not too long.

[0023] The sustained-release layer can be formed as one layer or two or more layers. When forming two or more layers, coating solutions with different compositions can be used as long as the concentration of ethanol in the solvent is 90% by mass or more. The coating amount of the sustained-release layer can be 0.001 part by weight or more, 0.01 part by weight or more, 0.05 part by weight or more, or 0.1 part by weight or more per part by weight of the venlafaxine hydrochloride-containing granules, and can be 1 part by weight or less, 0.5 parts by weight or less, 0.3 parts by weight or less, 0.27 parts by weight or less, or 0.25 parts by weight or less. Within this range, the release rate of venlafaxine hydrochloride is appropriate. When the sustained-release layer has two or more layers, this coating amount is the total amount of the layers. This ratio of the coating amount is the ratio of the coating amount in the obtained sustained-release granules containing venlafaxine hydrochloride, and therefore is the ratio of the solid content.

[0024] In addition to the binder, the coating layer may contain additives such as excipients, disintegrants, lubricants, fluidizing agents, glossing agents, stabilizers, antioxidants, emulsifiers, surfactants, solubilizers, suspending agents, dispersing agents, buffers, pH adjusters, thickening agents, adsorbents, colorants, flavoring agents, sweeteners, fragrances, preservatives or antiseptics, foaming agents, antifoaming agents, etc. In other words, the coating liquid may contain these additives in addition to the binder. In addition, venlafaxine hydrochloride-containing granules (granules made by granulating venlafaxine hydrochloride and additives; core particles of granules in which a core particle is coated with a drug layer containing venlafaxine hydrochloride, drug layer, intermediate layer 1; intermediate layer 2 described below) can also contain similar additives. One or more additives can be used.

[0025] Excipients include erythritol, lactose and crystalline cellulose spherical granules, candy powder, gum arabic, powdered gum arabic, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, potato starch, corn starch), isomalt hydrate, 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 sucrose, refined sucrose 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, white sugar, white sugar-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 aluminometasilicate, glycerin monostearate, calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, etc.

[0026] Examples of the binder include those exemplified as binders that can be added to the coating liquid.

[0027] Disintegrants include starch (wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, hydroxypropyl cellulose, partially pregelatinized starch, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminum metasilicate, carmellose, carmellose calcium, calcium silicate, sodium lauryl sulfate, etc.

[0028] Lubricants include talc, glyceryl monostearate, dimethylpolysiloxane (for oral use), sucrose fatty acid esters, stearic acid, stearates (calcium stearate, magnesium stearate, sodium stearyl fumarate), and dl-leucine.

[0029] Examples of the fluidizing agent include calcium silicate, talc, light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0030] Examples of glossing agents include carnauba wax, refined paraffin-carnauba wax mixed wax, white beeswax, and refined shellac.

[0031] 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 aluminum metasilicate, glycerin monostearate, sucrose fatty acid ester, stearic acid, sodium lauryl sulfate, macrogol (Macrogol 400, Macrogol 4000, etc.), carboxyvinyl polymer, polyvinyl alcohol, etc. Ingredients include methylparaben, methylparaben, methylparaben, methylparaben (vitamin B1), methylparaben (vitamin B2), ...2), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B3), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vitamin B3), methylparaben (vitamin B1), methylparaben (vitamin B2), methylparaben (vitamin B2), methylparaben (vit

[0032] Antioxidants include anhydrous citric acid, citric acid hydrate, soybean lecithin, dibutylhydroxytoluene, tocopherol, and propyl gallate.

[0033] Examples of emulsifiers include glycerin monostearate, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, medium-chain fatty acid triglyceride, soybean lecithin, and lauromacrogol.

[0034] Examples of surfactants include glycerin monostearate, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, macrogol (such as macrogol 400), polyoxyethylene (N) polyoxypropylene (N) glycol, and the like.

[0035] Solubilizers include sodium lauryl sulfate, 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 (Macrogol 4000, Macrogol 6000, etc.), polyvinyl alcohol (partially saponified), L-aspartic acid, L-arginine, sodium hydroxide, sodium bicarbonate, lactic acid, concentrated glycerin, hydroxypropyl cellulose, β-cyclodextrin, glycerin, soybean oil, and triacetin.

[0036] Suspending agents include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, soybean lecithin, sucrose fatty acid esters, macrogol (such as macrogol 4000 and macrogol 6000), sodium hydroxide, hydroxypropyl cellulose, glycerin, D-sorbitol, magnesium aluminum metasilicate, carboxyvinyl polymer, dried aluminum hydroxide gel, xanthan gum, butylated hydroxyanisole, propylene glycol, crystalline cellulose, gum arabic, powdered gum arabic, hypromellose, powdered agar, povidone, methylcellulose, kaolin, carrageenan, carmellose sodium, glycerin fatty acid esters, and magnesium aluminum silicate.

[0037] Dispersing agents include propylene glycol alginate, ethanol, carmellose sodium, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid esters, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, titanium oxide, sucrose fatty acid esters, stearic acid, magnesium stearate, oleic acid, sorbitan fatty acid esters, low-substituted hydroxypropyl cellulose, dextrin, sodium starch glycolate, corn starch, concentrated glycerin, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, propylene glycol, povidone, polysorbate 80, macrogol (Macrogol 300, Macrogol 4000, etc.), anhydrous sodium citrate, magnesium aluminometasilicate, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sodium lauryl sulfate, lauromacrogol, and calcium hydrogen phosphate hydrate.

[0038] Examples of buffering agents include sodium citrate hydrate, anhydrous citric acid, sodium bicarbonate, lactic acid, citric acid hydrate, sodium benzoate, tartaric acid, DL-malic acid, sodium chloride, acetic acid, sodium acetate hydrate, anhydrous sodium monohydrogen phosphate, L-glutamic acid, and dilute hydrochloric acid.

[0039] Examples of pH adjusters include L-glutamine, sodium citrate hydrate, anhydrous citric acid, sodium bicarbonate, lactic acid, citric acid hydrate, tartaric acid, DL-malic acid, acetic acid, sodium acetate hydrate, anhydrous sodium monohydrogen phosphate, dilute hydrochloric acid, sodium hydroxide, meglumine, succinic acid, and aqueous ammonia.

[0040] Examples of thickening agents include guar gum, hydroxypropyl cellulose, carboxyvinyl polymer, xanthan gum, propylene glycol, hypromellose, carrageenan, carmellose sodium, concentrated glycerin, gelatin, hydroxyethyl cellulose, carob bean gum, α-cyclodextrin, and locust bean gum.

[0041] Examples of the adsorbent include magnesium aluminometasilicate, kaolin, light anhydrous silicic acid, synthetic aluminum silicate, magnesium silicate, precipitated calcium carbonate, and the like.

[0042] Coloring agents include titanium oxide, indigo carmine, yellow ferric oxide, carmine, black iron oxide, ferric oxide, synthetic food colors (food blue No. 1, food blue No. 2 aluminum lake, food yellow No. 4, food yellow No. 4 aluminum lake, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, etc.), and natural food colors.

[0043] Examples of flavoring agents include erythritol, xylitol, refined sucrose, D-sorbitol, lactose hydrate, sucrose, 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, saccharin sodium hydrate, tartaric acid, sucralose, purified stevia extract, peppermint oil, anhydrous citric acid, l-menthol, and DL-malic acid.

[0044] Sweeteners include xylitol, refined white sugar, D-sorbitol, lactose hydrate, white sugar, glucose, D-mannitol, aspartame, reduced maltose syrup, licorice, licorice extract, saccharin, saccharin sodium hydrate, sucralose, purified stevia extract, maltitol, acesulfame potassium, and thaumatin.

[0045] Flavoring agents include peppermint oil, l-menthol, vanillin, etc.

[0046] Examples of preservatives or antiseptics include citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, parahydroxybenzoic acid esters (isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, etc.).

[0047] Examples of the foaming agent include hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), and carbonates (magnesium carbonate, calcium carbonate, etc.).

[0048] Antifoaming agents include dimethylpolysiloxane (for internal use).

[0049] One or more intermediate layers (intermediate layer 2) may be provided between the venlafaxine hydrochloride-containing granules and the sustained-release layer. The intermediate layer 2 may be formed, for example, by spraying a coating liquid containing a binder. When two or more intermediate layers 2 are formed, coating liquids with different compositions may be used. The intermediate layer 2 may contain one or more of the additives exemplified as additives for the sustained-release layer. As the solvent for the coating liquid used to form intermediate layer 2, one or more of the solvents exemplified as those used to form the drug layer and intermediate layer 1 can be used, and among them, a solvent containing ethanol and water is preferred, and a solvent consisting of ethanol and water is more preferred. When the solvent contains ethanol, the content of ethanol in the solvent can be 90% by mass or more, 91% by mass or more, 92% by mass or more, 93% by mass or more, or 94% by mass or more, relative to the total amount of the solvent, and can be 99% by mass or less, 98% by mass or less, 97% by mass or less, 96% by mass or less, or 95% by mass or less. The coating amount of the intermediate layer 2 can be 0.00001 part by mass or more, 0.0001 part by mass or more, 0.0001 part by mass or more, 0.001 part by mass or more, 0.01 part by mass or more, 0.05 part by mass or more, or 0.1 part by mass or more, and can be 0.5 part by mass or less, 0.3 part by mass or less, 0.27 part by mass or less, or 0.25 part by mass or less, relative to 1 part by mass of the venlafaxine hydrochloride-containing granules. When the intermediate layer 2 is two or more layers, this coating amount is the total amount of the layers.

[0050] When the venlafaxine hydrochloride-containing granules consist of a core particle and a drug layer, and when the venlafaxine hydrochloride-containing granules consist of a core particle, an intermediate layer 1, and a drug layer, the solvent used to form the drug layer and the intermediate layer 1 preferably contains ethanol and water, and preferably consists of ethanol and water. When the solvent contains ethanol, the content of ethanol in the solvent can be 90% by mass or more, 91% by mass or more, 92% by mass or more, 93% by mass or more, or 94% by mass or more, relative to the total amount of the solvent, and can be 99% by mass or less, 98% by mass or less, 97% by mass or less, 96% by mass or less, or 95% by mass or less.

[0051] The venlafaxine hydrochloride-containing sustained-release granules produced by the method of the present invention can be prepared into dosage forms such as granules, fine granules, dry syrup, etc., either alone or mixed with additives such as lubricants and fluidizers. They can also be filled into hard capsules containing a base such as gelatin or hypromellose, either alone or together with additives such as lubricants and fluidizers, to form capsules (hard capsules). Furthermore, they can be compressed into tablets, either alone or together with additives such as lubricants and fluidizers. In these dosage forms, additives that may be mixed with the granules of the present invention can be in powder or granular form.

[0052] The present invention provides sustained-release granules containing venlafaxine hydrochloride, which are produced by the above-described method for producing sustained-release granules containing venlafaxine hydrochloride of the present invention. The sustained-release granules containing venlafaxine hydrochloride are obtained by a method comprising the step of forming a sustained-release layer by coating the venlafaxine hydrochloride-containing granules with a coating liquid containing an ethanol-containing solvent and a binder, the ethanol concentration relative to the total amount of the solvent being 90% by mass or more. In these granules, the composition, layer structure, and production method of the venlafaxine hydrochloride-containing sustained-release granules and sustained-release layer are as explained above for the method of the present invention. Referring again to the coating amount of the sustained-release layer, the coating amount of the sustained-release layer can be 0.001 parts by weight or more, 0.01 parts by weight or more, 0.05 parts by weight or more, or 0.1 parts by weight or more per part by weight of the venlafaxine hydrochloride-containing granules, and can be 1 part by weight or less, 0.5 parts by weight or less, 0.3 parts by weight or less, 0.27 parts by weight or less, or 0.25 parts by weight or less. Within this range, the release rate of venlafaxine hydrochloride is appropriate. When the sustained-release layer has two or more layers, this coating amount is the total amount of the layers.

[0053] The present invention provides a method for producing sustained-release granules containing venlafaxine hydrochloride by forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing a solvent and a binder, wherein the concentration of ethanol relative to the total amount of solvent in the coating liquid is 90 mass% or more, thereby suppressing fluctuations in the dissolution behavior of venlafaxine hydrochloride from the sustained-release granules containing venlafaxine hydrochloride due to production scale. In this method, the composition, layer structure, production method, etc. of the venlafaxine hydrochloride-containing sustained-release granules and sustained-release layer are as explained above for the method of the present invention. [Example]

[0054] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0055] (1) Elution test method Dissolution tests were performed according to Japanese Pharmacopoeia Method 2 (rotating paddle method) using 900 mL of diluted McIlavine buffer solution (pH 7.2) at a test solution temperature of 37°C and a paddle rotation speed of 50 rpm (NTR-6400AC, Toyama Sangyo Co., Ltd.). Samples of the dissolution solution were taken 1, 2, 3, 4, 6, 9, 12, 18, and 24 hours after the start of the test, and the amount of venlafaxine dissolved was quantified by high-performance liquid chromatography to evaluate the dissolution behavior.

[0056] Column: Symmetry C18 (a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm packed with 5 μm octadecylsilanized silica gel for liquid chromatography) Column temperature: constant temperature around 30°C Developing solvent: 17 g of ammonium dihydrogen phosphate was dissolved in 1500 mL of water, and phosphoric acid was added to adjust the pH to 2.5. 500 mL of acetonitrile was added to 1500 mL of this solution. Flow rate of developing solvent: adjusted so that the retention time of venlafaxine was approximately 4 minutes. Detector: UV-visible absorbance detector

[0057] (2) Venlafaxine hydrochloride-containing sustained-release granules (one sustained-release layer) Preparation of Example 1 (Lab scale) Hypromellose was dispersed in absolute ethanol. Ethyl cellulose and purified water were added to this to prepare a coating solution for forming a sustained-release layer (ethanol concentration 90% by mass). Venlafaxine hydrochloride-containing granules (136.97 mg / Cap, charge amount: 534.2 g) were placed in a fluidized bed granulator dryer, and the coating solution for forming a sustained-release layer was sprayed. After coating, all samples except those sampled during spraying were dried in the same machine. The granules were then sieved using 1.4 mm and 0.355 mm sieves, and those with 1.4 mm Pass to 0.355 mm On were mixed with light anhydrous silicic acid and talc and filled into hypromellose capsules. This gave venlafaxine hydrochloride-containing sustained-release granules (single sustained-release layer).

[0058] (medium scale) Venlafaxine hydrochloride-containing sustained-release granules with one sustained-release layer were produced using a coating solution with an ethanol concentration of 90% by mass in the solvent, in the same manner as in the lab-scale production, except that the amount of venlafaxine hydrochloride-containing granules was scaled up to 136.97 mg / Cap (charge amount: 3150.3 g).

[0059] Preparation of Comparative Example 1 (Lab scale) Venlafaxine hydrochloride-containing sustained-release granules having one sustained-release layer were produced in the same manner as in the laboratory-scale production of Example 1, except that the ethanol concentration of the coating liquid for forming the sustained-release layer was set to 70% by mass. (medium scale) Venlafaxine hydrochloride-containing sustained-release granules having one sustained-release layer were produced in the same manner as the medium-scale production in Example 1, except that the ethanol concentration in the coating liquid for forming the sustained-release layer was 70% by mass.

[0060] During the coating process for each example, samples were taken twice, and small and medium granules were selected based on the amount of ethyl cellulose used. Granules that had completed the coating process were designated large granules. The small, medium, and large granules differed in the amount of coating.

[0061] The ingredients used and the amount of each ingredient (mg) per capsule are shown in Table 1. In Table 1, the percentage by mass of absolute ethanol relative to the total amount of purified water and absolute ethanol is shown in parentheses. The amount of each ingredient per capsule obtained is the same in lab-scale production and medium-scale production. [Table 1]

[0062] Dissolution tests were conducted on a total of 12 samples: small, medium, and large granules obtained by laboratory-scale and medium-scale production in Example 1, and small, medium, and large granules obtained by laboratory-scale and medium-scale production in Comparative Example 1. Figure 1 shows the change in dissolution rate over time for the small granules of Example 1 up to 24 hours after the start of the test, and Figure 2 shows the change in dissolution rate over time for the small granules of Comparative Example 1 up to 24 hours after the start of the test. When the ethanol concentration in the solvent of the coating liquid was 90% by mass (Figure 1: Example 1), there was almost no difference in dissolution rate due to the difference in scale, unlike when it was 70% by mass (Figure 2: Comparative Example 1). Similar results were obtained for the medium and large granules.

[0063] Furthermore, the similarity and equivalence of dissolution rates between laboratory-scale and medium-scale tests were evaluated using the f2 function (Similarity Factor) for the dissolution test results of the granules of Example 1 and Comparative Example 1. The results are shown in Table 2. The f2 function is used as one of the indices for determining the similarity of dissolution behavior between formulations in pharmaceutical dissolution tests, and is an index expressed by the following formula. [ka] According to the guidelines for bioequivalence testing of generic drugs, when the average dissolution rate reaches 80% or more within a specified time, if f2 = 42 or more, the dissolution between the formulations is considered to be similar, and if f2 = 50 or more, the dissolution of the two compared formulations is considered to be equivalent. [Table 2] As shown in Table 2, when the ethanol concentration of the coating solution was 90% by mass, unlike when it was 70% by mass, the dissolution behavior was similar between the lab scale and medium scale for all granule sizes.

[0064] (3) Venlafaxine hydrochloride-containing sustained-release granules (two sustained-release layers) Preparation of Example 2 (Lab scale) Hypromellose was dispersed in absolute ethanol in the same manner as in the laboratory-scale production of Example 1. Ethyl cellulose and purified water were added to this to prepare a coating solution for forming a sustained-release layer (ethanol concentration 90% by mass). Venlafaxine hydrochloride-containing granules (136.97 mg / Cap, charge amount: 534.2 g) were placed in a fluidized bed granulation dryer, and the coating solution for forming a sustained-release layer was sprayed. After coating, all samples except those sampled during spraying were dried in the same machine. The granules were then sized using sieves with openings of 1.4 mm and 0.355 mm, and those with openings of 1.4 mm Pass to 0.355 mm On were used as sustained-release granules containing venlafaxine hydrochloride (single sustained-release layer). Mixing with light anhydrous silicic acid and talc was performed only after coating the second sustained-release layer. The coating solution for forming the sustained-release layer was prepared again using the same method as above. 149.21 mg / Cap of venlafaxine hydrochloride-containing sustained-release granules (charge amount: 522.2 g) was placed in a fluidized bed granulator and sprayed with the coating solution for forming the sustained-release layer. The granules were then sieved with 1.4 mm and 0.355 mm sieves, and the granules with a mesh size of 1.4 mm Pass to 0.355 mm On were mixed with light anhydrous silicic acid and talc and filled into hypromellose capsules. This resulted in venlafaxine hydrochloride-containing sustained-release granules (two-layer sustained-release layer).

[0065] Sampling was performed during the coating process of the two sustained-release layers, and the sample with an ethyl cellulose content of 9.18 mg / Cap in the second sustained-release layer was sampled as small granules. After coating was completed, the sample with an ethyl cellulose content of 12.24 mg / Cap in the second sustained-release layer was sampled as large granules.

[0066] (medium scale) Small and large venlafaxine hydrochloride-containing sustained-release granules with two sustained-release layers were produced using a coating solution with an ethanol concentration of 90% by mass in the same manner as in laboratory-scale production, except that the amount of venlafaxine hydrochloride-containing granules was scaled up to 136.2233 mg / Cap (charge amount: 11,579.0 g) and the amount of venlafaxine hydrochloride-containing sustained-release granules (one sustained-release layer) was scaled up to 148.4633 mg / Cap (charge amount: 12,396.7 g).

[0067] The ingredients used and the amount of each ingredient (mg) per capsule are shown in Table 3. In Table 3, the percentage by mass of absolute ethanol relative to the total amount of purified water and absolute ethanol is shown in parentheses. The amount of each ingredient per capsule obtained is the same in lab-scale production and medium-scale production. [Table 3]

[0068] Dissolution tests were conducted on a total of four samples of small and large granules obtained by laboratory-scale and medium-scale production in Example 2. Figure 3 shows the change in dissolution rate of large granules up to 24 hours after the start of the test. When the ethanol concentration in the solvent of the coating liquid was 90% by mass, there was almost no difference in dissolution rate due to differences in scale. Similar results were obtained with small granules. Even when two sustained-release layers were provided, it was found that when the ethanol concentration in the solvent of the coating liquid was 90% by mass, there was only a very small difference in dissolution rate due to differences in scale. Furthermore, the similarity and equivalence of the dissolution behavior between the lab-scale and medium-scale tests were evaluated using the f2 function for the dissolution test results of Example 2. The results are shown in Table 4. [Table 4] The value of f2 also shows that if the ethanol concentration of the coating solution is 90% by mass, fluctuations in dissolution behavior due to changes in manufacturing scale can be suppressed even when the sustained-release layer has two layers. [Industrial Applicability]

[0069] The venlafaxine hydrochloride-containing sustained-release granules produced by the method of the present invention are easy to change in production scale because the dissolution behavior of venlafaxine hydrochloride is unlikely to vary depending on the production scale. In this respect, it is superior to existing sustained-release granules containing venlafaxine hydrochloride and is suitable as a generic drug.

Claims

1. A method for producing sustained-release granules containing venlafaxine hydrochloride, comprising a step of forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing an ethanol-containing solvent and a binder, the ethanol concentration relative to the total amount of the solvent being 90% by mass or more.

2. 2. The method according to claim 1, wherein the venlafaxine hydrochloride-containing sustained-release granules have one or more intermediate layers between the venlafaxine hydrochloride-containing granules and the sustained-release layer, and the method comprises forming the intermediate layer by coating the venlafaxine hydrochloride-containing granules with a coating liquid containing an ethanol-containing solvent and a binder, the ethanol concentration relative to the total amount of the solvent being 90% by mass or more.

3. 3. The method according to claim 1, wherein the solvent of the coating liquid contains water and ethanol.

4. 3. The method according to claim 1 or 2, wherein the binder of the coating solution comprises ethyl cellulose and hypromellose.

5. 3. The method according to claim 1, wherein the coating amount of the sustained-release layer is 0.001 to 1 part by mass per 1 part by mass of the venlafaxine hydrochloride-containing granules.

6. Sustained-release granules containing venlafaxine hydrochloride obtained by a method including a step of forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing a solvent containing ethanol and a binder, the ethanol concentration being 90% by mass or more relative to the total amount of the solvent.

7. 7. The sustained-release granules containing venlafaxine hydrochloride according to claim 6, wherein the coating amount of the sustained-release layer is 0.001 to 1 part by mass per part by mass of the venlafaxine hydrochloride-containing granules.

8. A coating solution for venlafaxine hydrochloride-containing granules, comprising an ethanol-containing solvent and a binder, wherein the ethanol concentration relative to the total amount of the solvent is 90 mass% or more.

9. 9. The coating liquid according to claim 8, wherein the solvent of the coating liquid contains water and ethanol.

10. 10. The coating liquid according to claim 8 or 9, wherein the binder of the coating liquid comprises ethyl cellulose and hypromellose.

11. A method for producing sustained-release granules containing venlafaxine hydrochloride by forming a sustained-release layer by coating granules containing venlafaxine hydrochloride with a coating liquid containing a solvent and a binder, wherein the concentration of ethanol relative to the total amount of solvent in the coating liquid is 90 mass% or more, thereby suppressing fluctuations in the dissolution behavior of venlafaxine hydrochloride from the sustained-release granules containing venlafaxine hydrochloride due to production scale.

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