JP7212484B2 - METHOD FOR MANUFACTURING COMPRESSION-FORMED PREPARATION IN WHICH ACID RESISTANCE IS IMPROVED IN ENTERIC-COATED GRANULES - Google Patents

Description

The present invention relates to a solid formulation containing an acid-labile drug such as duloxetine hydrochloride.

Duloxetine hydrochloride (generic name) is a serotonin and norepinephrine reuptake chemical whose chemical name is (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride. It is an inhibitor and is useful for the treatment of depression/depressive state, pain associated with diabetic neuropathy, pain associated with fibromyalgia, and pain associated with chronic low back pain (see Non-Patent Document 1, etc.).

Currently, duloxetine hydrochloride is provided to medical practice in the form of capsules. Since duloxetine hydrochloride is acid-labile and may be deactivated by gastric acid, it is coated with an enteric polymer (see page 163 of Non-Patent Document 1). A formulation and manufacturing method for capsules in which an enteric polymer is coated around duloxetine hydrochloride is introduced in US Pat.

Tablets are the most common solid dosage form, and tablets are known to have many advantages such as ease of swallowing (especially orally disintegrating tablets) and ease of printing characters. . However, in the manufacture of tablets containing coated drug-containing granules, part of the coating film of the granules may be destroyed during compression molding, resulting in acid resistance (prevention of drug elution in acidic solutions). There is a problem that the suppressing effect (the same shall apply hereinafter) is impaired. The inventors of the present application have found that the drug-containing coated granules obtained by compression molding containing duloxetine hydrochloride are more excellent in acid resistance even in a simple manufacturing method using more general manufacturing conditions and additives than in the prior art literature. Aimed at developing tablets.

Japanese Patent No. 3707831

"Cymbalta (registered trademark) Capsules 20 mg Cymbalta (registered trademark) Capsules 30 mg" Pharmaceutical Interview Form Revised April 2016 (revised 9th edition)

The present invention provides a technical technique for producing a compressed tablet containing granules containing an acid-labile drug such as duloxetine hydrochloride coated with an enteric polymer and having significantly improved acid resistance. It is intended to provide a means.

As a result of intensive studies to solve the above problems, the present inventors found that tablets produced by compressing granules containing duloxetine hydrochloride coated with an enteric polymer that is a cellulose derivative have good acid resistance. I found something. Based on this knowledge, the present inventors have conducted further extensive studies, and have completed the present invention described below.

The present invention relates to a compression-molded tablet containing an enteric polymer that is a cellulose derivative and granules containing an acid-labile drug such as duloxetine. is described.
(1) A compressed tablet containing granules containing an acid-labile drug and an enteric polymer coating the granules, wherein the enteric polymer is a cellulose derivative. .
(2) The compressed tablet of (1) above, wherein the acid-labile drug is selected from duloxetine hydrochloride, esomeprazole magnesium hydrate, omeprazole, rabeprazole sodium and lansoprazole.
(3) The compressed tablet of (1), wherein the acid-labile drug is duloxetine hydrochloride.
(4) the enteric polymer is selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate and carboxymethylethylcellulose; ) to (3).
(5) The compressed tablet according to any one of (1) to (3) above, wherein the enteric polymer is hydroxypropylmethylcellulose acetate succinate or carboxymethylethylcellulose.
(6) The compressed tablet according to any one of (1) to (5) above, wherein a separating layer is present between the acid-labile drug and the coating layer containing the enteric polymer.
(7) The compressed tablet according to any one of (1) to (6), which is an orally disintegrating tablet.
(8) According to the 17th revision of the Japanese Pharmacopoeia Dissolution Test Method (paddle method), the dissolution rate of an acid-labile drug at 120 minutes after the start of the dissolution test under the following measurement conditions is 5.0% or less. The compression-molded tablet according to any one of (1) to (7), characterized in that
[Measurement condition]
Test solution: Dissolution test 1st solution (pH 1.2)
Test liquid volume: 900 mL
Paddle rotation speed: 75 rpm
Liquid temperature: 37°C
(9) A method of producing tablets by compressing granules containing an acid-labile drug and a powder containing an enteric polymer that is a cellulose derivative coating the granules.
(10) Step (C) to obtain coated granules by coating granules containing an acid-labile drug with an enteric polymer that is a cellulose derivative, and the granules and excipients obtained through the step (B) , a process for producing a compressed tablet, comprising the step (D) of mixing together a disintegrant and a lubricant before tableting.
(11) A step (A) and the step ( (10) above, comprising the step (B) of coating the core granules obtained through A) with a separating layer comprising a non-enteric additive to obtain granules containing the acid-labile drug. A method for making compressed tablets.
(12) The method for producing a compression-molded tablet according to (10) or (11) above, wherein the tableting pressure is 800 kgf or more.

INDUSTRIAL APPLICABILITY The present invention makes it possible to produce compressed tablets containing granules containing an acid-labile drug such as duloxetine hydrochloride coated with an enteric polymer having significantly improved acid resistance and the like. do.

Compressed tablets containing granules containing an acid-labile drug such as duloxetine coated with an enteric polymer that is a cellulose derivative of the present invention (hereinafter referred to as "coated granules according to the present invention"). Or the manufacturing method thereof will be explained in detail. However, the following description is an example for explaining the present invention, and is not intended to limit the technical scope of the present invention only to the scope of this description.

<Acid-labile drugs>
The acid-labile drug used in the production of the tablet of the present invention is a compound that is chemically unstable in the acidic range or is inactive by acid, specifically duloxetine or a salt thereof (especially duloxetine duloxetine hydrochloride; hereinafter the same), esomeprazole or its salts (especially esomeprazole magnesium hydrate; hereinafter the same), omeprazole, rabeprazole or its salts (especially rabeprazole sodium; hereinafter) and lansoprazole, preferably duloxetine or its salts or esomeprazole or its salts, most preferably duloxetine or its salts.
The median diameter (d ₅₀ ) of an acid-labile drug (especially duloxetine or a salt thereof; hereinafter the same) is preferably 1.0 to 50.0 μm, more preferably 1.0 to 10.0 μm. . Duloxetine hydrochloride can be optionally dry- or wet-pulverized to have an arbitrary particle size. The particle diameter such as the median diameter can be measured (by volume) by a laser diffraction/scattering method. The acid-labile drug is contained in the uncoated tablet (refers to a tablet not covered with a coating layer; the same shall apply hereinafter), and is contained in an amount of 1.0 to 50.0% by weight, preferably It is contained in the uncoated tablet (in the coated granules according to the present invention) in the range of 2.0 to 15.0% by weight, more preferably 5.0 to 10.0% by weight. It is desirable that 22.4 mg (20 mg as duloxetine) or 33.7 mg (30 mg as duloxetine) of duloxetine hydrochloride is contained per tablet.

<Form of tablet>
The tablet of the present invention is a tablet compressed by tableting or the like (compressed tablet), and the dosage form is a normal tablet or an orally disintegrating tablet, preferably an orally disintegrating tablet. Orally disintegrating tablet is a tablet that can be disintegrated and swallowed only by saliva present in the oral cavity (= can be taken without water) and is provided to the patient and taken. A disintegration time of less than 60 seconds (more preferably less than 40 seconds, and even more preferably less than 30 seconds) is desirable. The disintegration time in the oral cavity is obtained, for example, by measuring the time required for disintegration when the tablet is placed on the tongue and infiltrated with saliva, or by an orally disintegrating tablet tester (eg, OD-mate / Higuchi Shokai) using a test liquid: water (37 ° C.) It may be obtained by measuring the time for the tablet to disintegrate, and other people skilled in the field to which the present invention belongs can determine the disintegration in the oral cavity. It may be determined by a method generally available for measuring time.
The tablets of the present invention (especially orally disintegrating tablets) are preferably uncoated tablets, but can be coated with a coating agent to form film-coated tablets, if necessary. The shape of the tablet obtained in the present invention may be any shape such as a circular tablet, a circular R tablet, a circular square tablet, a circular two-stage R tablet, and an irregularly shaped tablet, but the circular tablet is preferable. The weight of the tablets of the invention is preferably in the range of 200-500 mg.

<Enteric polymer that is a cellulose derivative>
Specific examples of enteric polymers that are cellulose derivatives include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate, and carboxymethylethylcellulose. is preferably selected from hydroxypropylmethylcellulose acetate succinate and carboxymethylethylcellulose, more preferably hydroxypropylmethylcellulose acetate succinate. It is desirable that the tablet of the present invention contains one enteric polymer. The enteric polymer according to the present invention is substantially insoluble in an aqueous solution solvent having an acidic pH value assuming a gastric environment, and an aqueous solution having a neutral to alkaline pH value assuming an intestinal environment. An aqueous solution solvent (e.g., pH 10.2 (0.05 mol/L sodium carbonate buffer) It is preferable that the polymer has a solubility of 1.0 g or more at 25° C. and a molecular weight of 10,000 or more. The enteric polymer is contained in the uncoated tablet (in the coated granules according to the present invention) in a range of 5.0 to 70.0% by weight, preferably 10.0 to 50.0% by weight, based on the total weight of the uncoated tablet. contained in

<Additive>
In order to produce the tablet of the present invention, in addition to the above excipients, commonly used excipients, binders, disintegrants, lubricants, plasticizers, flavoring agents, coating agents, etc. Additives can be used. In this specification, the interpretation of the terms of various additives (binders, plasticizers, coating agents, etc.) is used with the expectation that they will play their role as additives in formulation. It is preferable to understand that it is the one that is used as the additive, and as a result, the role of the additive is exhibited. It should also be understood that drug substances are not included in the interpretation of the term excipient herein.

<Excipient>
Examples of excipients include sugar {lactose (including anhydrous lactose, lactose hydrate), sucrose, sucrose, glucose, etc.} or sugar alcohol (mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, etc.). , crystalline cellulose, starch (corn starch, potato starch, rice starch, wheat starch, etc.), hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl starch, dextrin, etc., preferably sugar or Sugar alcohol (especially mannitol) or crystalline cellulose, more preferably crystalline cellulose or crystalline cellulose and sugar or sugar alcohol (especially mannitol), still more preferably crystalline cellulose and sugar alcohol (especially mannitol). The excipient is contained in the uncoated tablet in the range of 10.0 to 95.0% by weight, preferably 35.0 to 85.0% by weight, based on the total weight of the uncoated tablet.

<Binder>
Specific binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), methyl cellulose, povidone, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyethylene glycol, methacrylic acid copolymer, and acrylic acid. Ethyl-methyl methacrylate copolymer dispersions and the like can be mentioned, and hypromellose is preferred. The binder is contained in the uncoated tablet (preferably in the coated granules according to the present invention) in a range of preferably 0.1 to 8.0% by weight based on the total weight of the uncoated tablet. The above binder can be used as a coating agent to coat an object (preferably together with talc).

<Disintegrant>
Specific examples of disintegrants include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, croscarmellose sodium, carboxymethyl starch sodium, crospovidone and the like, preferably It is selected from croscarmellose sodium, carboxymethyl starch sodium and crospovidone, more preferably crospovidone. Incorporation of a super disintegrant (croscarmellose sodium, carboxymethyl starch sodium, or crospovidone) in the orally disintegrating tablet of the present invention is extremely desirable from the viewpoint of achieving rapid disintegration in the oral cavity. The disintegrant is contained in the uncoated tablet in an amount of preferably 2.0 to 15.0% by weight, more preferably 3.0 to 8.0% by weight, based on the total weight of the uncoated tablet.

<Lubricant>
Specific examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated oil, etc. Magnesium stearate is preferred. The lubricant is preferably contained in the uncoated tablet in a range of 0.1 to 5.0% by weight based on the total weight of the uncoated tablet.

<Plasticizer>
Specific examples of plasticizers include tributyl citrate, triethyl citrate, glycerin, glycerin monostearate, sesame oil, castor oil, cottonseed oil/soybean oil mixture, dimethylpolysiloxane/silicon dioxide mixture, medium-chain fatty acid triglyceride, triacetin, and phthalate. Diethyl acid, dioctyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, propylene glycol, macrogol, polysorbate 80, stearic acid, etc., preferably tributyl citrate, triethyl citrate, glycerin, glycerin mono It is selected from stearate, macrogol, polysorbate 80, stearic acid and the like, more preferably triethyl citrate. The plasticizer is contained in the uncoated tablet (preferably in the coated granules according to the present invention) in a range of preferably 0.5 to 5.0% by weight based on the total weight of the uncoated tablet.

<Flavoring agent>
Specific examples of flavoring agents include ascorbic acid, L-aspartic acid, aspartame, sucralose, acesulfame potassium, and thaumatin. The flavoring agent is preferably contained in the uncoated tablet in a range of 0.5 to 2.0% by weight with respect to the total weight of the uncoated tablet.

<Enteric coated granules>
The tablet of the present invention contains granules containing an acid-labile drug coated with an enteric polymer that is a cellulose derivative (coated granules of the present invention). The coated granules according to the present invention comprise a layer (elution control layer) containing an enteric polymer around the granules containing the acid-labile drug (relative to 100.0 parts by weight of the granules containing the acid-labile drug). 20.0 parts by weight or more, desirably 30.0 to 100.0 parts by weight of the elution control layer), but the part containing the acid-labile drug (core granules) and It is particularly preferable that a coating layer (separation layer) made of non-enteric additives is present between the enteric polymer-containing layer (dissolution control layer) (needlessly, the separation layer does not contain a drug). . In the preferred configuration, the separation layer (the separation layer is 20.0 parts by weight or more, preferably 30.0 to 100.0 parts by weight with respect to 100.0 parts by weight of the core granules) is added to the core granules. It can be obtained by coating the elution control layer after coating. Preferably, the separating layer contains a coating agent such as hydroxypropylcellulose, hypromellose or methylcellulose (preferably hypromellose), more preferably with talc. The granules containing an acid-labile drug are excipients (particularly mannitol, crystalline cellulose, etc., preferably crystalline cellulose), which are core particles (the particle diameter of which is 500.0 μm or less, preferably 300 μm). .0 μm or less, more preferably 50.0 to 250.0 μm) is provided with a coating layer (drug-containing layer) containing an acid-labile drug (and is further coated with the separation layer above). Including those that exist.) is preferable. The drug-containing layer preferably contains a coating agent such as hydroxypropylcellulose, hypromellose or methylcellulose (preferably hypromellose) together with the drug. The drug-containing layer is 50.0 parts by weight or more, preferably 120.0 parts by weight or more, more preferably 150.0 parts by weight or more, still more preferably 200.0 parts by weight with respect to 100.0 parts by weight of the core particles. There are more than one. The coated granules according to the present invention contain 20.0 to 80.0% by weight, preferably 30.0 to 70.0% by weight, more preferably 30.0 to 45.0% by weight of the total weight of the uncoated tablet. It is contained in the uncoated tablet within the range.
The compression-molded tablet containing the coated granules according to the present invention had a drug dissolution rate of 5.0 at 120 minutes after the start of a dissolution test conducted using an aqueous solution of pH 1.2 (eg, dissolution test liquid 1). It is preferably 0% or less (preferably 3.0% or less), and the dissolution of the drug at 120 minutes after the start of the dissolution test using an aqueous solution of pH 6.8 (e.g., dissolution test liquid 2) The ratio is preferably 50.0% or more (desirably 70.0% or more). Detailed conditions of the dissolution test can be referred to Test Example 1 or 2.

<Manufacturing method>
Specific examples of the method for producing coated granules according to the present invention include a fluidized bed granulation method and a fine particle coating method, with the fine particle coating method being preferred. There is no difficulty in operating the above production method, and the desired coated granules can be easily produced according to a conventional method. For example, in the fine particle coating method, a drug-containing coating liquid is sprayed and dried onto excipients (nuclear particles) fluidized in a fluidized bed granulator to coat the drug with the drug (i.e., form the drug-containing layer). In addition, a coating solution containing a non-enteric additive is sprayed and dried to coat with only the non-enteric additive (that is, to form the separation layer), and the acid-labile drug is contained. The coated granules according to the present invention are obtained by obtaining granules and further coating them with an enteric polymer by spraying and drying a coating liquid containing an enteric polymer (that is, forming the elution control layer). can be manufactured. The coated granules of the present invention (including granules coated one or more times) can be mixed with excipients, disintegrants and lubricants and tableted to produce tablets of the present invention. is. The pressure for tableting is 300 kgf or more, preferably 700 kgf or more (especially 1500 kgf or less), more preferably 800 kgf or more (especially 1500 kgf or less), and still more preferably any value within the range of 800 to 1300 kgf. be.

<Packaging>
It is also possible to obtain a PTP sheet product containing the tablet of the present invention by sandwiching and covering the tablet with a packaging sheet and aluminum foil or the like and heat-sealing. Specific materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, and the like. In addition, in order to improve the stability of the tablet of the present invention against humidity, it is necessary to manufacture a PTP sheet product using a material with a drying function, package the PTP sheet product in an aluminum pillow, or add a desiccant together with the tablet. A well-known method such as sealing in a bottle can be performed.

EXAMPLES The present invention will be described below with reference to Examples and the like, but the present invention is not limited to these Examples and the like. The duloxetine hydrochloride used in the tablet production of Examples 1 and 2 and Comparative Example 1 had a particle size distribution of d ₁₀ =2.0, d ₅₀ =7.0, d ₉₀ =18.0 {laser diffraction・It was confirmed that it was measured by a scattering method (volume basis)}.

(A: core granules) Microcrystalline cellulose {Cellphia CP-102 (particle size range: 106 to 212 μm/manufactured by Asahi Kasei Corp.) 500.0 g was put into a spout fluidized bed granulator (MP-01-SPC type/manufactured by Powrex Corporation). , 250.0 g of hydroxypropyl methylcellulose dissolved in 6250 g of purified water, and 1120.0 g of duloxetine hydrochloride dispersed/suspended was sprayed and dried to obtain granule A.
(B: Barrier layer) 748.0 g of the granulated material A obtained above was charged into a spout fluidized bed granulator, and 75.0 g of hydroxypropylmethylcellulose was dissolved in 1875 g of purified water. A granule B was obtained by spraying and drying a liquid in which 150.0 g of titanium was dispersed and suspended.
(C: Dissolution control layer) 561.5 g of the granulated material B obtained above was put into a spout fluidized bed granulator, 376.0 g of carboxymethylethyl cellulose and 37.6 g of triethyl citrate were dissolved, and light anhydrous silicic acid was added. A mixed liquid of 5760 g of ethanol in which 37.6 g was dispersed and suspended and 1440 g of purified water was sprayed and dried to obtain enteric coated granules.
(D: Compressed tablet) To 101.27 g of the enteric coated granules obtained above, 128.23 g of mannitol, 60.0 g of crystalline cellulose, 9.0 g of crospovidone and 1.5 g of magnesium stearate were added and mixed with a mixer. Mixed. The mixed powder was tableted with a tableting machine at a pressure of 1000 kgf to obtain orally disintegrating tablets (round tablets, diameter 9.5 mm, thickness 3.4 mm) weighing 300.0 mg per tablet.

(C: Dissolution control layer) 673.8 g of the granulated material B obtained in Example 1 was put into a spout fluidized bed granulator, 511.2 g of hydroxypropylmethylcellulose acetate succinate was dissolved, and 163.2 g of talc was dispersed. A mixture of 8750 g of suspended purified water and 126.8 g of 10% aqueous ammonia was sprayed and dried to obtain enteric coated granules.
(D: Compressed tablet) To 112.35 g of the enteric coated granules obtained above, 117.15 g of mannitol, 60.0 g of crystalline cellulose, 9.0 g of crospovidone and 1.5 g of magnesium stearate were added and mixed with a mixer. Mixed. The mixed powder was tableted with a tableting machine at a pressure of 1000 kgf to obtain orally disintegrating tablets (round tablets, diameter 9.5 mm, thickness 3.4 mm) weighing 300.0 mg per tablet.

[Comparative Example 1]
(A: core granules) Microcrystalline cellulose {Cellphia CP-102 (particle size range: 106 to 212 μm/manufactured by Asahi Kasei Corp.) 500.0 g was put into a spout fluidized bed granulator (MP-01-SPC type/manufactured by Powrex Corporation). , 250.0 g of hydroxypropyl methylcellulose dissolved in 6250 g of purified water, and 1120.0 g of duloxetine hydrochloride dispersed/suspended was sprayed and dried to obtain granule A.
(B: Barrier layer) 748.0 g of the obtained granule A was put into a spouted fluidized bed granulator, and 176.0 g of talc was dispersed/suspended in a liquid obtained by dissolving 44.0 g of hydroxypropylmethylcellulose in 1320 g of purified water. The resulting liquid was sprayed and dried to obtain granules B (secondary coated granules).
(C: Dissolution control layer) 484.0 g of the granule B obtained above was put into a spout fluidized bed granulator, and 24.0 g of glycerin monostearate, 75.0 g of triethyl citrate, 8.0 g of polysorbate 80 and In a liquid obtained by dissolving 0.5 g of citric acid in 1662.5 g of purified water, 1128.3 g of methacrylic acid copolymer LD (L30D-55) (solid content: 338.5 g), and ethyl acrylate/methyl methacrylate copolymer dispersion ( NE30D) (126.7 g (solid content: 38.0 g)) was added, and the mixture was gently mixed and stirred, and the liquid was sprayed and dried to obtain enteric-coated granules.
(D: Compressed tablets) To 96.8 g of the enteric-coated granules obtained above, 132.7 g of mannitol, 60.0 g of crystalline cellulose, 9.0 g of crospovidone and 1.5 g of magnesium stearate were added and mixed with a mixer. Mixed. The mixed powder was tableted with a tableting machine at a pressure of 1000 kgf to obtain orally disintegrating tablets (round tablets, diameter 9.5 mm, thickness 3.4 mm) weighing 300.0 mg per tablet.

The formulation of each tablet obtained in Examples 1 and 2 and Comparative Example 1 is listed in Table 1 below. The unit of numerical values is mg.

[Test Example 1] Drug dissolution test in an acidic environment For the enteric-coated granules and tablets produced in Examples 1 and 2 and Comparative Example 1, the dissolution test method ( The dissolution rate of duloxetine hydrochloride was determined 120 minutes after the start of the test by the paddle method), and the results (n=3) are shown in Table 2 below.
Apparatus used: Dissolution tester / NTR-6100 type (manufactured by Toyama Sangyo)
Ultraviolet absorption photometer / UV-1600 type (manufactured by Shimadzu Corporation)
Measurement conditions: Test liquid: Japanese Pharmacopoeia 1st liquid (dissolution test 1st liquid, pH 1.2)
(Manufactured by Nacalai Tesque)
Test liquid volume: 900 mL
Paddle rotation speed: 75 rpm
Liquid temperature: 37°C
Measurement wavelength (duloxetine): 288 nm

[Test Example 2] Drug dissolution test from tablets in a neutral environment For the tablets manufactured in Examples 1 and 2 and Comparative Example 1, the dissolution test method (paddle 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes after the start of the test, the dissolution rate of duloxetine hydrochloride was determined according to the method), and the results (n = 3) are shown in Table 3 below. Indicated.
Apparatus used: Dissolution tester / NTR-6100 type (manufactured by Toyama Sangyo)
Ultraviolet absorption photometer / UV-1600 type (manufactured by Shimadzu Corporation)
Measurement conditions: Test liquid: Japanese Pharmacopoeia 2nd liquid (dissolution test 2nd liquid, pH 6.8)
(Manufactured by Nacalai Tesque)
Test liquid volume: 900 mL
Paddle rotation speed: 75 rpm
Liquid temperature: 37°C
Measurement wavelength (duloxetine): 288 nm

In Table 2, the dissolution rate of duloxetine hydrochloride in an acidic environment (assuming an intragastric environment) was suppressed to the same extent in Examples 1 and 2 for granules and compressed tablets. On the other hand, in Comparative Example 1, it was significantly higher in the case of compressed tablets than in the case of granules. Therefore, it was shown that the compressed tablet containing coated granules containing duloxetine hydrochloride of the present invention has excellent acid resistance (that is, suppressed dissolution in the stomach).

Further, in Table 3, the dissolution rate of duloxetine hydrochloride under a neutral environment (assuming an intestinal environment) was significantly higher in the tablets of Examples 1 and 2 than in the tablet of Comparative Example 1. rice field. Therefore, it was confirmed that duloxetine hydrochloride rapidly elutes in the intestine from the tablet of the present invention.

According to the present invention, a compressed tablet containing granules containing an acid-labile drug such as duloxetine hydrochloride, coated with an enteric polymer, having significantly improved acid resistance, etc. can be conveniently produced. It is possible to manufacture by a method. Therefore, it is also possible to provide the high-quality tablets to medical sites.

Claims (7)

A compressed tablet containing granules containing crystalline cellulose, hydroxypropyl methylcellulose and duloxetine hydrochloride and an enteric polymer coating the granules, wherein the granules containing duloxetine hydrochloride and a coating layer containing the enteric polymer There is a separating layer in between, the enteric polymer is a cellulose derivative selected from hydroxypropylmethylcellulose acetate succinate and carboxymethylethylcellulose, the coating layer comprises light silicic anhydride and/or talc, and the Compressed tablets, characterized in that the separating layer comprises hydroxypropylmethylcellulose, talc and titanium oxide. 2. The compressed tablet of claim 1, wherein said enteric polymer is hydroxypropylmethylcellulose acetate succinate and said coating layer comprises talc. 2. The compressed tablet of claim 1, wherein said enteric polymer is carboxymethylethylcellulose and said coating layer comprises light silicic anhydride. The compressed tablet according to any one of claims 1 to 3, which is an orally disintegrating tablet. The dissolution rate of duloxetine hydrochloride was 5.0 at 120 minutes after the start of the dissolution test conducted using the dissolution test solution 1 (pH 1.2) according to the dissolution test method (paddle method) of the 17th revision of the Japanese Pharmacopoeia. % or less, the compressed tablet according to any one of claims 1 to 4. A step of coating granules containing duloxetine hydrochloride with an enteric polymer to obtain coated granules, and a step of mixing the granules obtained through this step with an excipient, a disintegrant and a lubricant, followed by tableting. A method for producing a compressed tablet according to any one of claims 1 to 5, comprising A step of coating duloxetine hydrochloride around core particles having a particle size in the range of 50.0 to 250.0 μm to obtain granules; 7. A process for the preparation of compressed tablets according to claim 6, comprising the step of coating a separating layer consisting of a non-enteric excipient containing a to obtain granules containing duloxetine hydrochloride.