Enteric-coated granules and solid preparations containing them

Abstract

To provide a duloxetine-containing solid preparation that releases duloxetine hydrochloride quickly in the intestines and has high stability and a duloxetine-containing granular material for producing the same.SOLUTION: A duloxetine-containing granular material contains (a) a drug layer containing duloxetine hydrochloride, (b) an intermediate layer, and (c) an enteric film layer containing hydroxypropyl methylcellulose acetate succinate, which are laminated on one another, around which (d) a sugar alcohol layer is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an enteric coated granule containing duloxetine as an active ingredient and a solid preparation containing said granule. [Background technology]

[0002] Duloxetine is an antidepressant known as a serotonin-noradrenaline reuptake inhibitor (SNRI) (Non-Patent Document 1) that is indicated for the treatment of depression, depressive states, and pain associated with diabetic neuropathy, fibromyalgia, and chronic low back pain. In Japan, it is sold as enteric-coated capsules under the brand name Cymbalta (registered trademark).

[0003] Duloxetine is known to be unstable under acidic conditions such as in the stomach, decomposing to form related substances. Therefore, duloxetine formulations must be in the form of an enteric-coated formulation coated with an enteric polymer to control drug release in the stomach and protect it from gastric acid.

[0004] As mentioned above, although duloxetine capsules are commercially available, a tablet formulation is desired from the viewpoint of ease of swallowing, etc. When making a tablet containing duloxetine, it is necessary to make it an enteric-release tablet due to the above-mentioned properties of duloxetine. As an example of a solid formulation containing duloxetine, Patent Document 1 discloses an enteric-coated pellet in which a core containing duloxetine is coated with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Patent Document 2 discloses a method for stabilizing a duloxetine enteric-coated formulation, which comprises a drug core containing duloxetine or a pharmaceutically acceptable salt thereof, an intermediate layer, and an enteric layer containing hypromellose acetate succinate, and the intermediate layer does not contain sugars and / or sugar alcohols with a solubility of more than 50 mg / mL. Patent Documents 3 and 4 disclose technologies relating to oral pharmaceutical formulations containing duloxetine, etc., in which the formation of analogs derived from pharmaceutical ingredients such as duloxetine that deteriorate under acidic conditions is suppressed by the presence of an inorganic or organic alkalizing agent in the formulation.

[0005] The applicant has also filed a patent application for an enteric particulate composition with excellent drug release and stability for drugs such as duloxetine, which is acid-labile and interacts with methacrylic acid copolymers and the like (Patent Document 5), and which comprises (a) a drug core containing an acid-labile active ingredient, (b) an intermediate layer containing a disintegrant with an average particle size of 0.1 to 40 μm, (c) a sustained-release layer containing a poorly water-soluble polymer, and (d) an enteric layer containing an enteric polymer that can be granulated with water.

[0006] On the other hand, the manufacturing process of enteric-coated granules themselves can impair the stability of drugs. For example, enteric-coated granules may have their enteric coating broken during tableting due to the combination of pharmaceutical additives used in tableting. In this case, the breakage of the enteric coating may cause the active ingredient to be decomposed by acid in the stomach, resulting in the problem of the expected medicinal effect not being fully exerted. Furthermore, the mixing process in the manufacture of pharmaceutical solid dosage forms is an important process for uniformly dispersing each ingredient to be compounded into tablets, improving manufacturability in the tableting process, and ensuring uniformity of the active ingredient in the final formulation. The large particle size difference between enteric-coated granules and conventional pharmaceutical additives can lead to problems such as non-uniformity of the active ingredient or reduced dissolution. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 3707831 [Patent Document 2] Japanese Patent Publication No. 2020-189815 [Patent Document 3] Japanese Patent Application Publication No. 2017-203671 [Patent Document 4] Japanese Patent Application Laid-Open No. 2017-214341 [Patent Document 5] Japanese Patent Application Publication No. 2018-008917 [Non-patent literature]

[0008] [Non-Patent Document 1] "Cymbalta (registered trademark) Capsules 20 mg, 30 mg" Pharmaceutical Interview Form, Revised February 2020 (Revised 14th Edition) Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention relates to providing a highly stable duloxetine-containing solid preparation that rapidly releases duloxetine hydrochloride in the intestine, and duloxetine-containing granules for producing the same. [Means for solving the problem]

[0010] The present inventors have produced duloxetine-containing granules comprising a drug layer containing duloxetine hydrochloride, an intermediate layer, and an enteric membrane layer laminated together, with a sugar alcohol layer provided on the outer periphery, and have discovered that by mixing and granulating this with a specific excipient, damage to the enteric layer during tableting can be prevented, and a highly stable solid preparation can be obtained, thereby completing the present invention.

[0011] That is, the present invention relates to the following [1] to [8]. [1] (a) a drug layer containing duloxetine hydrochloride; (b) middle class; (c) An enteric film layer containing hydroxypropyl methylcellulose acetate succinate is laminated on the outer periphery of the layer. (d) Sugar alcohol layer A duloxetine-containing granule comprising: [2] The granules according to [1], wherein the intermediate layer contains a sugar. [3] The granules according to [2] above, wherein the sugar is sucrose or refined sucrose. [4] A duloxetine-containing granule obtained by mixing and granulating the granule according to any one of [1] to [3] above with one or more excipients selected from sugars, sugar alcohols, crystalline cellulose, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate. [5] The granulated material according to [4] above, wherein the excipient is a granulating sugar alcohol. [6] A duloxetine-containing solid formulation containing the granules of [4] or [5] above. [7] A method for producing duloxetine-containing tablets, comprising mixing the granules of [4] or [5] with an excipient and tableting the mixture. [8] A method for producing a duloxetine-containing capsule, comprising mixing the granules of [4] or [5] above with an excipient as desired, and filling the mixture into a capsule. [Effects of the Invention]

[0012] According to the present invention, it is possible to provide a granular material that rapidly releases duloxetine hydrochloride in the intestines, and a solid preparation that contains the granular material, prevents damage to the enteric layer during tableting, and has improved content uniformity and stability of duloxetine hydrochloride. DETAILED DESCRIPTION OF THE INVENTION

[0013] The duloxetine-containing granules of the present invention are composed of (a) a drug layer containing duloxetine hydrochloride, (b) an intermediate layer, and (c) an enteric membrane layer containing hydroxypropyl methylcellulose acetate succinate, and (d) a sugar alcohol layer provided around the outer periphery.

[0014] <(a) Drug layer containing duloxetine hydrochloride> Duloxetine hydrochloride used in the present invention can be produced by the production methods described in, for example, JP-A No. 04-226948, JP-A No. 2002-541235, and Japanese Patent No. 2549681. Duloxetine hydrochloride is preferably crystalline, and one having a volume average particle size (D90) of 1 μm to 100 μm, preferably 1 μm to 50 μm, more preferably 2 μm to 30 μm, and even more preferably 2 μm to 20 μm can be used. The volume average particle size (D90) can be measured by a laser diffraction particle size distribution measurement method using a laser diffraction scattering particle size distribution analyzer (SALD-2300, manufactured by Shimadzu Corporation) or the like.

[0015] The drug layer containing duloxetine hydrochloride means the portion that becomes the core (drug core) in the duloxetine-containing granules of the present invention. The form of the drug layer is not particularly limited, and examples thereof include a granule in which a layer containing duloxetine hydrochloride, the active ingredient, is provided on the periphery of a core particle, or a core granule formed from duloxetine hydrochloride and usable additives. Among these, a granule in which a layer containing duloxetine, the active ingredient, is provided on the periphery of a core particle is preferred. The average particle size of these drug layers is 100 to 1000 μm, preferably 200 to 800 μm, and more preferably 200 to 600 μm. The amount of duloxetine hydrochloride in the drug layer is 20 to 90% by mass, preferably 30 to 80% by mass, more preferably 35 to 75% by mass, and even more preferably 50 to 70% by mass, relative to the total mass of the drug core.

[0016] The core particles used in the drug layer are not particularly limited as long as they do not interact with duloxetine hydrochloride and other additives, and examples include inert carriers such as sucrose / starch spherical granules (Nonpareil (registered trademark): manufactured by Freund Corporation) and crystalline cellulose (Celphere (registered trademark): manufactured by Asahi Kasei Corporation). The average particle size of the core particles can be selected within the range of 100 to 1000 μm, preferably 200 to 800 μm, and more preferably 300 to 600 μm.

[0017] To obtain a drug layer by coating duloxetine hydrochloride onto core particles, for example, the drug may be dissolved or dispersed in a solution of water, methanol, ethanol, propanol, butanol, acetone, hexane, or a mixture thereof containing a binder, as described below, and the solution may be sprayed onto the inert carrier cores, followed by drying to coat. The manufacturing equipment is not particularly limited, but examples include a fluidized bed granulator, centrifugal tumbling granulator, and tumbling granulator. The thickness of the formed drug coating layer is 20 to 200 μm, preferably 50 to 140 μm, and more preferably 70 to 120 μm.

[0018] When core particles are not used, granules prepared by granulating duloxetine hydrochloride and the excipients and binders described below using an agitator granulator, wet extrusion granulator, fluidized bed granulator, centrifugal tumbling granulator, tumbling granulator, spray dryer, or the like are used as the drug layer. The resulting granules can be sieved to select particles of the desired size. Granules may also be prepared by dry granulation using a roller compactor, for example.

[0019] <(b) Middle layer> In the duloxetine-containing granules of the present invention, the intermediate layer can contain an appropriate combination of pharmaceutical additives, such as excipients, binders, disintegrants, plasticizers, lubricants, flow agents, and colorants, as described below. However, it is generally preferred to use excipients and binders. Preferred excipients used in the intermediate layer include sugars. Examples of sugars include sugars or sugar alcohols, such as lactose, sucrose, refined sucrose, powdered sugar, and trehalose, and examples of sugar alcohols include D-mannitol, sorbitol, erythritol, and xylitol. Preferred sugars include sucrose or refined sucrose. The intermediate layer can be formed in an amount of 1 to 30 parts by mass, preferably 5 to 20 parts by mass, relative to the drug layer (a). The amount of excipient used in the intermediate layer can be in the range of 30 to 70 parts by mass relative to the total amount of the intermediate layer, and the amount of binder used in the intermediate layer can be in the range of 30 to 70 parts by mass relative to the total amount of the intermediate layer. Other additives may be appropriately adjusted and used within a range that does not impair the effects of the present invention. The intermediate layer may be formed in the same manner as in the formation of the drug coating layer in the drug layer (a). Specifically, the pharmaceutical additives for the intermediate layer may be dissolved or dispersed in an appropriate solvent such as water or a lower alcohol, and the resulting solution or dispersion may be sprayed onto the drug layer and dried to form the desired intermediate layer. There are no particular restrictions on the thickness of the intermediate layer, but if it is too thin, the expected effect cannot be fully exerted, and if it is thicker than necessary, the particle size of the granules will become larger, raising concerns about a decrease in tablet hardness, etc. Therefore, the thickness is 2 to 30 μm, preferably 5 to 15 μm, and more preferably 7 to 13 μm.

[0020] <(c) Enteric film layer> In the duloxetine-containing granules of the present invention, hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as HPMCAS) is used as the enteric polymer for the enteric membrane layer. Commercially available HPMCAS can be used, for example, AQOAT (registered trademark, manufactured by Shin-Etsu Chemical Co., Ltd.). As described in Patent Document 1, HPMCAS has free carboxyl groups, and these free carboxyl groups can be neutralized before use. Neutralization can be performed using a neutralizing agent (e.g., ammonia or sodium hydroxide), with neutralization using ammonia being preferred. The degree of neutralization is 2 to 70%, preferably 5 to 50%, more preferably 7 to 40%, and even more preferably 10 to 30%. The degree of neutralization is the ratio of the neutralized salt to the total amount of free carboxylic acids contained in hydroxypropyl methylcellulose acetate succinate. Since the number of succinoyl groups substituted varies depending on the grade of hydroxypropyl methylcellulose acetate succinate, the amount of neutralizing agent added is adjusted depending on the degree of neutralization. The enteric film layer may contain pharmaceutical additives, such as plasticizers, lubricants, fluidizing agents, surfactants, colorants, light-shielding agents, excipients, and pH adjusters, which will be described later. The enteric film layer can be formed in the same manner as in the formation of the drug coating layer for the drug layer. Specifically, HPMCAS can be dissolved or dispersed in an appropriate solvent such as water or a lower alcohol together with pharmaceutical additives such as the plasticizers described above, and the resulting solution or dispersion can be sprayed onto the granules with the intermediate layer and dried to form the desired enteric film layer. The thickness of the formed enteric film layer is 20 to 150 μm, preferably 50 to 120 μm, and more preferably 70 to 100 μm.

[0021] <(d) Sugar alcohol layer> The duloxetine-containing granules of the present invention have a sugar alcohol layer on the outer periphery of the enteric membrane layer (c). Examples of sugar alcohols used in the sugar alcohol layer include D-mannitol, sorbitol, erythritol, xylitol, etc., and preferably D-mannitol. The amount of sugar alcohol used to form the sugar alcohol layer is 1 to 20 parts by mass, preferably 2 to 15 parts by mass, and more preferably 4 to 10 parts by mass, per 100 parts by mass of the particles to be coated. The sugar alcohol layer can be formed in the same manner as in the formation of the drug coating layer in the drug layer (a). Specifically, the sugar alcohol can be dissolved or dispersed in an appropriate solvent such as water or a lower alcohol, together with optional pharmaceutical additives, to form a solution or dispersion, which can be sprayed onto the granules provided with the enteric membrane layer (c), to form the desired sugar alcohol layer.

[0022] From the viewpoint of the stability of duloxetine hydrochloride, the duloxetine-containing granules of the present invention preferably contain a light-shielding agent. The light-shielding agent is usually contained in the enteric film layer as described above. However, in some cases, a light-shielding layer may be provided to cover at least the drug layer in a layered manner, preferably disposed between the drug layer and the sugar alcohol layer.

[0023] The light-shielding layer contains a light-shielding agent, which will be described later, and the amount of the light-shielding agent used is in the range of 40 to 85 parts by mass, preferably 50 to 75 parts by mass, per 100 parts by mass of the light-shielding layer. In addition to the light-shielding agent, the light-shielding layer may contain an appropriate combination of pharmaceutical additives, such as excipients, binders, disintegrants, plasticizers, lubricants, fluidizing agents, and colorants, which will be described later. However, if the purpose is light-shielding, it is sufficient to use only a binder.

[0024] There are no particular restrictions on the thickness of the light-shielding layer, but if it is too thin, the expected effect will not be fully exerted, and if it is thicker than necessary, the particle size of the granules will become larger, raising concerns about a decrease in tablet hardness, etc. Therefore, the thickness is 2 to 30 μm, preferably 5 to 15 μm, and more preferably 7 to 13 μm.

[0025] The duloxetine-containing granules of the present invention can be produced by known methods as described above, specifically by fluidized bed granulation methods such as tumbling fluidized bed granulation and fluidized bed granulation, tumbling granulation methods such as centrifugal tumbling granulation, and agitation granulation methods, with fluidized bed granulation being preferred.

[0026] The duloxetine-containing solid formulation of the present invention is produced by mixing and granulating the above-mentioned duloxetine-containing granules with one or more excipients selected from sugars, sugar alcohols, crystalline cellulose, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate to form a granule, and then appropriately formulating the granules, for example, by compressing the granules into tablets or capsules.

[0027] The excipient used for granulation is a solid excipient with good tabletability, such as sugars (e.g., sucrose, lactose, glucose, etc.), sugar alcohols (e.g., D-mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, etc.), crystalline cellulose, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, etc., preferably sugar alcohols, lactose, or crystalline cellulose, more preferably sugar alcohols, and even more preferably D-mannitol. The average particle size of the excipient used for granulation is, for example, 20 to 300 μm, preferably 100 to 300 μm, and more preferably 150 to 250 μm. The solid excipient used here is preferably a granulated product, such as granulated lactose, granulated D-mannitol, or granulated crystalline cellulose. When a sugar alcohol is used as the excipient, it is preferable to use the same type of sugar alcohol as that used in the sugar alcohol layer (d) of the duloxetine-containing granules. The mass ratio of the duloxetine-containing granules of the present invention to the excipient is in the range of 1:0.2 to 1:5, preferably 1:0.3 to 1:3, and more preferably 1:0.5 to 1:2, since if the amount of excipient is too small, the effect of preventing breakage of the enteric layer during tableting will be insufficient, and if the amount is too large, the formulation size will be too large and difficult to ingest. The mixed granulation is carried out by placing the duloxetine-containing granules and the above-mentioned excipients in a granulator such as a fluidized bed granulator, and then spraying a spray liquid containing, as needed, a binder, a neutralizing agent, a pH adjuster, a colorant, etc. onto the mixture to granulate. The mixture is then dried and classified through a sieve to obtain granules. The granules obtained here are granules in which the surface is molded with an excipient layer, with the excipient attached to the periphery of duloxetine-containing granules (also referred to as "molded layer granules"). The average particle size of the granules is, for example, 0.5 to 2.0 mm, preferably 0.85 to 2.0 mm, and more preferably 1.0 to 1.7 mm.

[0028] The duloxetine-containing granules are then molded into solid preparations such as tablets, orally disintegrating tablets, granules, fine granules, chewable tablets, and capsules, preferably tablets. These solid preparations can be produced by known methods.

[0029] When the solid preparation of the present invention is a tablet or an orally disintegrating tablet, it can be produced by mixing a molded layer granulation product of duloxetine-containing granules with pharmaceutical additives such as excipients, lubricants, plasticizers, binders, disintegrants, fluidizing agents, surfactants, light-blocking agents, pH adjusters, colorants, and antistatic agents described below, and compressing the mixture using a tablet press.

[0030] Here, mixing can be performed by a commonly used mixing method, such as mixing, kneading, granulation, etc. Mixing can be performed using, for example, a high-speed stirring mixer, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double cone mixer, a ribbon mixer, a rotary screw mixer, manual mixing in a bag, etc.

[0031] The compression molding can be performed using a rotary tablet press or the like commonly used for pharmaceuticals, and the molding pressure during tableting varies depending on the size of the tablet, but for example, for a φ10 mm tablet it is 2 to 10 kN, preferably 3 to 9 kN, and for a φ8.5 mm tablet it is 2 to 6 kN, preferably 3 to 5 kN. In this case, the set hardness is 30 to 100 N, preferably 40 to 100 N, more preferably 50 to 90 N.

[0032] When the solid preparation of the present invention is a capsule, the duloxetine-containing granules are formed by molding and granulating them into gelatin or hypromellose capsules. If desired, the granules may be blended with conventional pharmaceutical additives and filled. Specific examples of pharmaceutical additives include excipients, lubricants, antistatic agents, stabilizers, and the like. One or more of these may be blended and filled into capsules together with the granules. The blending ratio of each of the other pharmaceutical additives may be 0.01 to 30% by mass of one or more components of the other pharmaceutical additives relative to the total weight of the capsule.

[0033] Specific examples of pharmaceutical additives (e.g., excipients, lubricants, plasticizers, binders, disintegrants, fluidizing agents, surfactants, light-blocking agents, pH adjusters, colorants, and antistatic agents) used to produce the solid preparation of the present invention are as follows. Lubricants: for example, talc, glycerin monostearate, macrogol, magnesium stearate, calcium stearate, or sodium stearyl fumarate, preferably talc, glycerin monostearate, magnesium stearate, calcium stearate, or sodium stearyl fumarate, and most preferably magnesium stearate.

[0034] Plasticizers: Examples include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, poloxyethylene hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, etc., and preferably triethyl citrate.

[0035] Binders: Examples of binders include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, macrogol, Pluronic F68, gum arabic, gelatin, starch, etc., and preferably include hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose, and more preferably include hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0036] Disintegrants: Examples include starches such as corn starch and potato starch, partially pregelatinized starch, carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, etc.

[0037] Glidants: For example, talc, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, and the like.

[0038] Surfactants: for example, sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, poloxamer, and the like.

[0039] Light-shielding agents include, for example, titanium oxide, zinc oxide, talc, iron oxides such as yellow ferric oxide, ferric oxide, and black ferric oxide, Food Yellow No. 5, Food Red No. 102, and the like, and preferably titanium oxide.

[0040] pH adjusters: Examples include acids such as succinic acid, maleic acid, tartaric acid, citric acid, and aspartic acid, and alkalis such as sodium hydroxide, ammonia, magnesium oxide, silicon dioxide, and sodium hydrogen carbonate.

[0041] Coloring agents: For example, food blue No. 1, food blue No. 2, food yellow No. 4, food red No. 2, food red No. 3, food blue No. 1 aluminum lake, food blue No. 2 aluminum lake, food red No. 2 aluminum lake, ferric oxide (red), titanium oxide, yellow ferric oxide, caramel, talc, etc.

[0042] Antistatic agents: For example, silicon dioxide (including hydrous silicon dioxide), silicon dioxide anhydride, talc, titanium oxide, stearic acid, magnesium stearate, and calcium stearate.

[0043] An example of the steps for producing the duloxetine-containing granules of the present invention and the steps for producing a duloxetine-containing solid formulation from the granules is shown below. In each step, drying can be carried out as necessary, and can be carried out by any method commonly used for drying formulations, such as vacuum drying or fluidized bed drying. (Step 1: Drug Layer) Core particles such as sucrose and starch spherical granules are placed in a granulator such as a fluidized bed granulator, and a solution of duloxetine hydrochloride (duloxetine hydrochloride, purified water, binder such as hypromellose, etc.) is sprayed onto the core particles, layered, and dried to obtain drug cores. If desired, additional drying is carried out, and the core particles are then sieved to classify them. (Process 2: Middle layer) The drug layer produced in the first step is placed in a granulator such as a fluidized bed granulator, and an intermediate layer coating solution (purified water, a binder such as hypromellose, an excipient such as sucrose, etc.) is sprayed onto the layer, which is then dried to form an intermediate layer. If desired, the layer is further dried, and then sieved to classify it. (Step 3: Light shielding layer) The granules produced in the second step are placed in a granulator such as a fluidized bed granulator, and a coating liquid (purified water, a light-shielding agent such as titanium oxide, a binder such as hypromellose, etc.) is sprayed onto the granules, which are then dried to form a light-shielding layer. Subsequently, the granules are further dried if desired, and then classified through a sieve. (Step 4: Enteric membrane layer) The granules produced in the third step are placed in a granulator such as a fluidized bed granulator, and a coating solution (HPMCAS, purified water, surfactants such as lauryl sulfate, pH adjusters, plasticizers, colorants, etc.) that has been neutralized as needed is sprayed onto the granules, which are then dried to form an enteric coating layer. Subsequently, the granules are further dried as desired, and then classified through a sieve. (Step 5: Sugar alcohol layer) The granules produced in step 4 are placed in a granulator such as a fluidized bed granulator, sprayed with a sugar alcohol solution such as D-mannitol, and dried to form a sugar alcohol layer. Subsequently, after additional drying if desired, the granules are passed through a sieve to obtain enteric-coated granules (duloxetine-containing granules). (Step 6: Molded layer granules) The granules produced in the fifth step and solid excipients such as granulated D-mannitol are placed in a granulator such as a fluidized bed granulator, and a spray liquid (containing excipients, purified water, binders, neutralizing agents, pH adjusters, colorants, etc.) is sprayed onto the mixture to granulate. The mixture is then dried and classified through a sieve to obtain a molded bed granule. (Step 7: Tableting) The molded granules produced in the sixth step, a disintegrant, a lubricant, etc. are mixed in a V-type mixer and compressed into tablets using a tablet press such as a rotary tablet press. [Example]

[0044] The present invention will be described in more detail below with reference to examples, comparative examples and test examples, but the present invention is not limited to these.

[0045] Example 1 [Drug core formation] A drug dispersion was prepared by dissolving / dispersing 7.5 parts by mass of hypromellose (Shin-Etsu Chemical Co., Ltd., degree of substitution type 2910, nominal viscosity 3 mPa·s) and 50 parts by mass of duloxetine hydrochloride in 175 parts by mass of purified water. 100 parts by mass of Nonpareil 101 (Freund Corporation, sucrose / starch spherical granules, particle size 355-500 μm) were placed in a tumbling fluidized bed coating machine (Powrex Corporation, MP-01 model), and the drug dispersion was sprayed at an exhaust temperature of approximately 45°C. The core particles were then dried to form a drug-containing layer, yielding drug cores.

[0046] [Formation of intermediate layer] A solution of 24 parts by weight of sucrose (JP) and 8 parts by weight of hypromellose dissolved in 270 parts by weight of purified water was sprayed onto the drug core under the same conditions as when the drug-containing layer was formed, followed by drying to form an intermediate layer, thereby obtaining granules (1).

[0047] [Enteric membrane layer formation] An enteric coating solution was prepared by dissolving / dispersing 87.5 parts by mass of hydroxypropyl methylcellulose acetate succinate (hereinafter abbreviated as HPMCAS) (AQOAT HPMCAS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.), 8.75 parts by mass of triethyl citrate (manufactured by Morimura Shoji Co., Ltd.), 26.25 parts by mass of talc (manufactured by Nippon Talc Co., Ltd.), and 2.5 parts by mass of sodium lauryl sulfate (manufactured by Nikko Chemicals Co., Ltd.) in 1,125 parts by mass of purified water. The granules (1) were placed in a tumbling fluidized bed coating machine (MP-01, manufactured by Powrex Corporation), and the enteric coating solution was sprayed onto the granules at an exhaust temperature of approximately 42°C. The granules were then dried to form an enteric film layer, thereby obtaining granules (2).

[0048] [Formation of sugar alcohol layer] A solution of 15.73 parts by mass of D-mannitol (Mannit-P, manufactured by Mitsubishi Corporation Life Sciences) dissolved in 141.57 parts by mass of purified water was sprayed onto the granules (2) under the same conditions as when the drug-containing layer was formed, and the mixture was dried to form a sugar alcohol layer, thereby obtaining granules (3).

[0049] [Molded layer granules] 160 parts by mass of the granular material (3) and 138.5 parts by mass of D-mannitol (Pearlitol 200SD, manufactured by Roquette, average particle size 170 μm) were placed in a tumbling fluidized bed coating machine (MP-01 model, manufactured by Powrex Corporation), and 186 parts by mass of purified water was sprayed at an exhaust temperature of approximately 45°C to form a molded layer on the core particles, thereby obtaining a molded layer granulation product.

[0050] [tablet] 298.5 parts by mass of the molded layer granules and 1.5 parts by mass of magnesium stearate were mixed and compressed into tablets using a rotary tablet press (manufactured by Kikusui Seisakusho, VIRGO type) at a rotation speed of 30 rpm and a tablet diameter of 9 mm with a flat corner (flat corner) punch at a tableting pressure of 7 kN / punch, to obtain tablets weighing 300 mg each.

[0051] (Comparative Example 1) Granules, their granules, and tablets were obtained in the same manner as in Example 1, except that the sugar alcohol layer formation step was not carried out.

[0052] (Test Example 1) [Measurement of dissolution rate] According to the method of the dissolution test for one fluid in the Japanese Pharmacopoeia, the drug dissolution rates after 2 hours were measured at a rotation speed of 100 rpm for the tablets of Example 1 and Comparative Example 1. The measurement results are shown in Table 1.

[0053] [Table 1]

[0054] The tablets of Example 1 showed a lower dissolution rate than the tablets of Comparative Example 1, indicating that they had excellent acid resistance and that the enteric coating layer of the granules was maintained.

[0055] (Example 2) to (Example 4) Granules, their granules, and tablets were obtained in the same manner as in Example 1, except that aqueous ammonia was added to neutralize HPMCAS during the process of forming the enteric coating layer, as shown in the composition in Table 2 below. The composition of the granules (parts by mass) is shown in Table 2, the composition of the tablets (parts by mass) is shown in Table 3, and the results of measuring the dissolution rate as Test Example 2 are shown in Table 4.

[0056] [Table 2]

[0057] [Table 3]

[0058] [Table 4]

[0059] The tablets of Examples 2 to 4 showed low dissolution rates, and in particular the tablets of Examples 3 and 4, which were neutralized, showed an even lower drug dissolution rate than the tablet of Example 2, which was not neutralized, demonstrating a dramatic improvement in acid resistance.

[0060] Example 5 [Drug core formation] A drug dispersion was prepared by dissolving / dispersing 7.5 parts by mass of hypromellose and 100 parts by mass of duloxetine hydrochloride in 350 parts by mass of purified water. 100 parts by mass of Nonpareil 101 was placed in a tumbling fluidized bed coating machine, and the drug dispersion was sprayed onto the core particles at an exhaust temperature of approximately 45°C to form a drug-containing layer, yielding drug cores.

[0061] [Formation of intermediate layer] A solution of 20 parts by weight of sucrose (JP) and 20 parts by weight of hypromellose dissolved in 320 parts by weight of purified water was sprayed onto the drug core under the same conditions as when the drug-containing layer was formed, to form an intermediate layer, thereby obtaining granules (4).

[0062] [Formation of light-shielding layer] A solution in which 25 parts by mass of titanium oxide (Titanium Oxide A-HR manufactured by Freund Corporation) was dispersed in a solution in which 15 parts by mass of hypromellose was dissolved in 360 parts by mass of purified water was sprayed onto the granules (4) under the same conditions as when the drug-containing layer was formed, to form a light-shielding layer, thereby obtaining granules (5).

[0063] [Enteric membrane layer formation] An enteric coating solution was prepared by dissolving / dispersing 144.9 parts by mass of HPMCAS, 14.49 parts by mass of triethyl citrate, 43.47 parts by mass of talc, 4.14 parts by mass of sodium lauryl sulfate, and 1.14 parts by mass of aqueous ammonia (10%) in 1,900 parts by mass of purified water. The granules (5) were placed in a tumbling fluidized bed coater, and the enteric coating solution was sprayed onto the granules at an exhaust temperature of approximately 42°C to form an enteric film layer, thereby obtaining granules (6).

[0064] [Sugar alcohol layer] A solution of 25.11 parts by mass of D-mannitol dissolved in 225.99 parts by mass of purified water was sprayed onto the granules (6) under the same conditions as when the drug-containing layer was formed to form a sugar alcohol layer, thereby obtaining granules (7).

[0065] [Molded layer granules] 160 parts by mass of the granules (7) and 138.5 parts by mass of D-mannitol were placed in a tumbling fluidized bed coating machine, and 186 parts by mass of purified water was sprayed onto the core particles at an exhaust temperature of approximately 45°C to form a molded layer, thereby obtaining a molded layer granulation product.

[0066] [tablet] 298.5 parts by mass of the molded layer granules and 1.5 parts by mass of magnesium stearate were mixed and compressed into tablets using a rotary tablet press (manufactured by Kikusui Seisakusho, VIRGO type) at a rotation speed of 30 rpm and a tablet diameter of 9 mm with a flat corner (flat corner) punch at a tableting pressure of 7.0 kN / punch, to obtain tablets weighing 300 mg each.

[0067] (Examples 6 to 7) Tablets were obtained in the same manner as in Example 5, except that the amount of D-mannitol added during formation of the granulated material in the molding layer and the amount of magnesium stearate during tableting were changed as shown in the compositions in the table below. Table 5 shows the composition of the tablets (parts by mass), and Table 6 shows the results of measuring the dissolution rate as Test Example 3.

[0068] [Table 5]

[0069] [Table 6]

[0070] The tablets of Examples 5 to 7 had excellent acid resistance with dissolution rates of 10% or less, and it was demonstrated that decomposition of the drug in the stomach due to contact with gastric acid in the body could be sufficiently suppressed.

Claims

1. (a) a drug layer containing duloxetine hydrochloride; (b) a middle layer containing white sugar or refined white sugar; (c) an enteric membrane layer containing hydroxypropyl methylcellulose acetate succinate are laminated and then (d) Sugar alcohol layer A duloxetine-containing granule obtained by mixing and granulating a duloxetine-containing granule having the above structure with an excipient containing the same type of sugar alcohol as the sugar alcohol of (d).

2. The granulated product according to claim 1, wherein the excipient is a granulating sugar alcohol.

3. (d) A granulated product as described in claim 1, wherein the sugar alcohol in the sugar alcohol layer is D-mannitol.

4. A duloxetine-containing solid preparation comprising the granules according to any one of claims 1 to 3.

5. A method for producing duloxetine-containing tablets, comprising mixing the granules according to any one of claims 1 to 3 with an excipient and tableting the mixture.

6. A method for producing a duloxetine-containing capsule, comprising mixing the granule according to any one of claims 1 to 3 with an excipient, if desired, and filling the mixture into a capsule.

Images