KR20130020740A

KR20130020740A - Delayed release formulation comprising duloxetine or pharmaceutically acceptable salt thereof and method for manufacturing the same

Info

Publication number: KR20130020740A
Application number: KR1020110081765A
Authority: KR
Inventors: 이상준; 장관영; 안재순; 조재민; 강경언; 남대식; 이현주
Original assignee: 주식회사 바이오파마티스
Priority date: 2011-08-17
Filing date: 2011-08-17
Publication date: 2013-02-27

Abstract

The present invention relates to a delayed release formulation comprising duloxetine or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a sustained release tablet comprising a duloxetine or a pharmaceutically acceptable salt thereof and a specific binder and an enteric coating layer and a method for preparing the same.

Description

Delayed-release formulation comprising duloxetine or a pharmaceutically acceptable salt thereof and a method for preparing the same

The present invention relates to a delayed release formulation comprising duloxetine or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a delayed-release tablet comprising a drug layer containing duloxetine or a pharmaceutically acceptable salt thereof and a specific binder and an enteric coating layer formed directly on the drug layer and a method for preparing the same.

Duloxetine is a compound having the compound name N-methyl-3- (1-naphthyloxy) -2-thiophenpropylamine and having selective serotonin and norepinephrine reuptake inhibitory activity. It has therapeutic utility for diabetic peripheral neuropathic pain. Duloxetine is commonly used as a hydrochloride thereof, which is disclosed in European Patent Publication No. 273658, which is manufactured by Eli Lilly under the trade name Cymbalta? It is currently commercially available as a delayed release capsule containing enteric coated duloxetine pellets under.

Since duloxetine is unstable in acidic solutions, it is preferable to prepare it as an enteric preparation. In general, enteric pharmaceutical preparations are prepared in such a way that the drug does not change, passes through the stomach of the patient, dissolves as it leaves the stomach and enters the small intestine, thereby rapidly releasing the active ingredient. Such formulations are typically in the form of tablets or pellets, wherein the active ingredient is enclosed in a film or film called an "enteric coating" which is packed into tablets or pellets and which does not dissolve in an acidic environment such as the stomach but dissolves in an almost neutral environment such as the small intestine. have. In the case of duloxetine-containing enteric preparations, pellet formulations have been considered preferred over tablets, according to the initial formulation studies, which resulted in a more uniform plasma profile when pellets were administered. It is reported that this is caused.

In particular, it has been pointed out that duloxetine reacts with many enteric coating bases to form a slowly dissolving or insoluble coating, which results in a low elution of the drug and consequently a decrease in bioavailability. In addition, it has been pointed out that it is difficult to prepare an enteric preparation capable of filling a large amount of drug without releasing duloxetine in an acidic environment, and thus a problem has been pointed out that the drug may be released in the stomach.

Thus, in order to overcome the side reaction problem between duloxetine and the enteric coating base, a formulation in which a separation layer exists between the drug layer and the enteric coating layer has been devised.

For example, US Patent US5508276 and Korean Patent No. 0356240 include (a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; (b) any separation layer; (c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate and a pharmaceutically acceptable excipient; And (d) an enteric duloxetine pellet comprising any finish layer. In addition, U. S. Patent Application Publication No. US2011 / 0008439 discloses (a) a pellet core; (b) a core consisting of duloxetine and a pharmaceutically acceptable excipient; (c) any separation layer comprising an inorganic component; And (d) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate and / or hydroxypropylmethylcellulose phthalate and a pharmaceutically acceptable excipient.

However, in the case where the separation layer is present between the drug layer and the enteric coating layer, there is a problem that a large amount of coating is made for complete separation between the drug and the enteric coating layer. In addition, in the case of pellets, special equipment (Pelletizer, Spheronizer, Fluidized bed, etc.) is required, and the yield problem may occur during the screening process for selecting the same size during pellet production, which is a problem in yield and economic aspects in the actual process. In particular, in the case of enteric pellets, there is a problem that loss of the enteric coating layer may occur during filling. In addition, although the use is contraindicated in patients with rare genetic pathological disorders such as fructose intolerance, glucose-galactose malabsorption, and sucrose isomaltase deficiency, sugar, which is a key ingredient used in pellets, is unnecessary sugar. There is a problem that causes ingestion.

Despite the above problems, due to the inherent physical properties of duloxetine, tablets having stable release characteristics have not been developed.

Accordingly, the present inventors have developed a tablet that can inhibit the interaction between the main component and the enteric coating base by associating duloxetine with a binder such as hydroxypropyl cellulose in advance. Tablets according to the present invention can suppress the interaction between the drug layer and the enteric coating layer by the use of a specific binder, it is possible to omit a separate intermediate layer between the drug layer and the enteric coating layer, furthermore, approximately 10 times the content ratio of the enteric coating base Since the degree is reduced, the dissolution characteristics over time in the intestine is excellent.

It is an object of the present invention to provide a duloxetine-containing delayed-release tablet composition with improved stability without the presence of an intermediate layer between the drug layer and the enteric coating layer.

Accordingly, one object of the present invention comprises duloxetine or a pharmaceutically acceptable salt thereof, and at least one binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Drug layer; And it provides a delayed-release tablet composition comprising an enteric coating layer formed directly on the drug layer.

It is another object of the present invention to provide a method for preparing the duloxetine-containing delayed release tablet composition.

As one aspect for solving the above problems, the present invention relates to a delayed-release tablet composition comprising a drug layer comprising duloxetine and a binder, and an enteric coating layer formed directly on the drug layer.

The drug layer refers to an active ingredient-containing site present in the coating layer, and specifically refers to a duloxetine-containing layer present in the enteric coating layer. Preferably, since the formulation of the present invention is a tablet, the drug layer consists of uncoated tablets. The drug layer may comprise about 15 to 60% by weight, preferably about 25 to 50% by weight of the total formulation composition.

As used herein, the term "Duloxetine" refers to a compound having the compound name N-methyl-3- (1-naphthyloxy) -2-thiophenpropylamine and acting as a selective serotonin and norepinephrine reuptake inhibitor. Say. Duloxetine has particular therapeutic utility against depression and diabetic peripheral neuropathic pain.

In addition, the term duloxetine is used herein to include all of duloxetine or a pharmaceutically acceptable salt thereof. Duloxetine may be in the form of racemates, enantiomers, isomers, hydrates, anhydrides and solvates, preferably (+) duloxetine.

Pharmaceutically acceptable salts of duloxetine are preferably acid addition salts. Suitable acid addition salts are formed with pharmaceutically acceptable organic or inorganic acids and include those well known to those skilled in the art. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Particularly preferred acid addition salts are duloxetine hydrochloride.

Duloxetine and a method for preparing the same can be referred to as conventionally reported. See, for example, US Pat. No. 5023269, 4956388, Tetrahedron Letters, 31, (49), 7101-04, 1990, and Drugs of the Future 2000, 25 (9) 907-916. In addition, duloxetine may be prepared by various organic synthesis methods known in the art.

The present invention is characterized in that duloxetine is previously associated with a specific binder in the drug layer containing duloxetine in order to suppress side reactions between duloxetine and the enteric coating base. As such, by inhibiting the interaction between duloxetine and the enteric coating base using a specific binder, it is not necessary to have a separate separation layer between the drug layer and the enteric coating layer, and furthermore, because the content of the enteric coating base is reduced, the elution characteristics over time This has the effect of becoming excellent.

Preferably, the binder is one or more selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and polyvinylpyrrolidone. More preferably, it is hydroxypropyl cellulose.

The binder may be contained in 2 to 10% by weight based on the total composition, preferably 2 to 4% by weight. If it is contained within the above range, there is a possibility that the reaction with the drug and the enteric coating base may occur, and if it exceeds the above range, the desired dissolution pattern may not be realized and complete drug release may not occur before the prescribed time. The drug layer may further comprise pharmaceutically acceptable excipients or additives in addition to duloxetine and binders, which may be appropriately selected by one of ordinary skill in the art. Preferably, pharmaceutically acceptable excipients, disintegration aids, glidants and the like, and may include, but are not limited to, croscarmellose sodium, lactose monohydrate, hydrated silicon dioxide, magnesium stearic acid, and the like. .

The enteric coating layer is substantially insoluble in an acidic environment as above, but is preferably soluble in a near neutral environment such as the small intestine. Thus, the formulations of the present invention are intact while passing through the acidic environment of the stomach, but are preferably dissolved to release duloxetine when passed through an environment close to the neutral of the small intestine. The enteric coating layer may be included in about 2 to 15% by weight, preferably about 2 to 10% by weight of the total formulation composition.

In the present invention, the enteric coating layer is characterized in that formed directly on the drug layer. Thus, in the composition of the formulation of the present invention, there is no separate separation layer between the drug layer and the enteric coating layer, the enteric coating is formed directly on the surface of the drug layer.

The enteric coating layer includes an enteric coating base, and the enteric coating base is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP) and methacrylic acid copolymer. The above is preferable. More preferably, hydroxypropylmethylcellulose acetate succinate or methacrylic acid copolymer can be used, in particular methacrylic acid copolymers are commercially available EUDRAGIT® L30 D-55 (Degussa, Germany) and Acryl-EZE® ( Colorcon, USA).

The enteric coating base may be included in about 2-7% by weight, preferably about 2-5% by weight of the total formulation composition. If it is contained below the above ranges, the coating layer in the gastric juice may be decomposed to inactivate duloxetine due to the release of duloxetine, and when exceeding the above range, the release of duloxetine is excessively suppressed to reach a desired pharmacological effect. There is a problem that cannot be done.

The enteric coating layer may further include a pharmaceutically acceptable additive in addition to the enteric coating base, and the additive may be appropriately selected by those skilled in the art. For example, pharmaceutically acceptable plasticizers, lubricants, dissolution aids, coloring agents, and the like, and may include, but are not limited to, triethyl citrate, sodium lauryl sulfate, titanium dioxide, and the like.

The particular form and dosage of administration of the formulations of the invention may be selected by the attending physician depending on the characteristics of the patient, in particular age, weight, lifestyle, level of symptoms and case. The formulation of the present invention is preferably a tablet. The shape of the tablet is not particularly limited, and it may be an uncoated tablet having a shape such as a circle, an ellipse, a rectangle, and a coated tablet of the above-mentioned shape. In addition, the solid preparation of the present invention may be a multi-layer tablet, a press-coated tablet or a press-coated tablet such as a group tablet, a two-layer tablet and a three-layer tablet prepared by mixing two or more kinds of granules.

As another aspect, the present invention relates to a method for preparing a delayed-release tablet composition comprising a drug layer comprising duloxetine and a binder, and an enteric coating layer comprising an enteric coating base.

The preparation method comprises the steps of: (a) providing a drug layer comprising duloxetine and a binder; And (b) applying an enteric coating layer comprising an enteric coating base and a pharmaceutically acceptable additive. Each layer of the formulation may be formed by any method known to those skilled in the art.

Preferably, step (a) may be accomplished by mixing duloxetine and excipients and then preparing and tableting the granules using a binder. In an embodiment, the granules may be prepared after mixing the duloxetine and excipients and then combined with a solution comprising a binder, and the dried granules obtained after granulation are mixed with other pharmaceutical additives as necessary and then in a tablet press. It can be compressed. Granulation can preferably be carried out in a fluidized bed granulator under suitable conditions. Step (b) is preferably applied in the form of a suspension or solution comprising an enteric coating base. The suspension or solution may be sprayed onto the drug layer at an inlet air temperature of about 30 ° C to 60 ° C and an outlet air temperature of about 25 ° C to about 50 ° C to form a coating layer.

The tablet of the present invention is prepared by coating the main ingredient duloxetine in advance with a specific binder to prevent interaction between duloxetine and enteric coating membranes, which is excellent in stability, and does not change the dissolution rate with time, and the intestinal environment (pH 6.8 Duloxetine has an effective and stable elution.

Figure 1 shows the dissolution test results in pH 6.8 conditions for the formulation of Comparative Example 1.
Figure 2 shows the dissolution test results at pH 6.8 conditions for the formulation of Example 9.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Purpose of Mixing Ingredients Content (unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 chief ingredient Duloxetine hydrochloride 67.3 67.3 67.3 67.3 67.3 67.3 67.3 67.3 67.3 Disintegration Aids Croscarmellose sodium 23.8 23.8 23.8 23.8 23.8 23.8 23.8 11.8 17.8 Excipient Lactose monohydrate 123.2 123.2 123.2 123.2 123.2 123.2 116 128 122 Binder Crosslinked polyvinylpyrrolidone 5 5 5 - - - - - - Binder Hydroxypropyl cellulose - - - 5 5 5 9.5 9.5 9.5 Lubricant Hydrated Silicon Dioxide 3 3 3 3 3 3 3 3 3 Lubricant Magnesium Stearate 6 6 6 6 6 6 5.4 5.4 5.4 Enteric coating base HPMCAS-LF - - 7 - - 7 7 7 7 Enteric coating base HPMCP-55 - 7 - - 7 - - - - Enteric coating base EUDRAGIT L30D55 7 - - 7 - - - - - Coating base
(Plasticizer) Triethyl citrate 1.5 1.5 1.48 1.5 1.5 1.4 1.4 1.4 1.4 Coating base
(Dissolution aid) Sodium Lauryl Sulfate 0.21 - 0.21 0.21 - 0.21 0.21 0.21 0.21 Coating base
(coloring agent) Titanium dioxide 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 total 241 241 241 241 241 241 238 238 238

Example One. Methacrylic acid Copolymer Endurance Coating layer and Crosslinking Polyvinylpyrrolidone With binder Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

1-1. Preparation of Drug Layer

Duloxetine hydrochloride, lactose and croscarmellose sodium were sieved using a 35 mesh pharmacist and then mixed and combined with a crosslinked polyvinylpyrrolidone binder solution using water as a solvent. The association was dried at 50 ° C. and then sieved to a 20 mesh pharmacist, followed by tableting after addition of hydrated silicon dioxide and magnesium stearic acid.

1-2. Preparation of Enteric Coating Layer

EUDRAGIT® L30 D-55 methacrylic acid copolymer and triethyl citrate, sodium lauryl sulfate and titanium dioxide were mixed for 30 minutes in a mixer to form a 20-30% solution. The resulting suspension was coated at an inlet air temperature of 40 ° C. and an outlet air temperature of 30 ° C.

Example 2. Hydroxypropylmethylcellulose Phthalate Endurance Coating layer and Crosslinking Polyvinylpyrrolidone With binder Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

2-1. Preparation of Drug Layer

Duloxetine containing tablets were prepared according to Example 1-1.

2-2. Preparation of Enteric Coating Layer

HPMCP-55 was dissolved in a solvent of ethanol / purified water (80/20 wt /% by weight) to prepare a 5 ~ 7% solution of HPMCP, followed by addition of triethyl citrate and titanium dioxide and stirring for 30 minutes. The inlet air temperature was 55 ° C and the outlet air temperature was 35 ° C.

Example 3. Hydroxypropylmethylcellulose acetate Succinate Endurance Coating layer and Crosslinking Polyvinylpyrrolidone With binder Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

3-1. Preparation of Drug Layer

Duloxetine containing tablets were prepared according to Example 1-1.

3-2. Preparation of Enteric Coating Layer

HPMCAS-LF was added to purified water in which triethyl citrate and sodium lauryl sulfate were dissolved, followed by stirring until complete dissolution by adding titanium dioxide. The inlet air temperature was 70 ° C and the outlet air temperature was 40 ° C.

Example 4. Methacrylic acid Copolymer Endurance Coating layer and Hydroxypropyl cellulose With binder Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

4-1. Preparation of Drug Layer

Duloxetine hydrochloride, lactose and croscarmellose sodium were sieved using a 35 mesh pharmacopeia and then mixed and combined with a hydroxypropyl cellulose binder solution using water as a solvent. The association was dried at 50 ° C., and then sieved to 20 meshes, followed by addition of silicon dioxide and magnesium stearic acid, followed by compression.

4-2. Preparation of Enteric Coating Layer

EUDRAGIT L30 D-55 methacrylic acid copolymer and triethyl citrate, sodium lauryl sulfate were mixed in a mixer for 30 minutes to form a 20-30% solution. The resulting suspension was coated at an inlet air temperature of 40 ° C. and an outlet air temperature of 30 ° C.

Example 5. Hydroxypropylmethylcellulose Phthalate Endurance Coating layer and Hydroxypropyl cellulose With binder Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

5-1. Preparation of Drug Layer

A duloxetine-containing tablet was prepared according to Example 4-1.

5-2. Preparation of Enteric Coating Layer

HPMCP-55 was dissolved in a solvent of ethanol / purified water (80/20 wt / wt%) to prepare a HPMCP 5-7% solution, followed by addition of triethyl citrate and stirring for 30 minutes. The inlet air temperature was 55 ° C and the outlet air temperature was 35 ° C.

Example 6. Hydroxypropylmethylcellulose acetate Succinate Endurance Coating layer and Hydroxypropyl cellulose Containing Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

6-1. Preparation of Drug Layer

A duloxetine-containing tablet was prepared according to Example 4-1.

6-2. Preparation of Enteric Coating Layer

Example 7 to 9. Separation layer unused Hydroxypropylmethylcellulose acetate Succinate Endurance Coating layer and Hydroxypropyl cellulose Containing Duloxetine Preparation of Hydrochloride Delayed-Release Tablets

As the drug layer, duloxetine-containing tablets were prepared according to Example 4-1. As an enteric coating layer, HPMCAS-LF was added to purified water in which triethyl citrate and sodium lauryl sulfate were dissolved, followed by stirring until complete dissolution by addition of titanium dioxide, followed by inlet air temperature of 70 ° C., and outlet air. The temperature was set at 40 ° C.

Comparative example One . Patent 10- Of 0356240 Example Pellet preparation according to 1

As a comparative formulation, a formulation according to Korean Patent No. 0562240 was prepared. Namely, according to the ingredients and contents of Table 2, a delayed-release preparation containing duloxetine was prepared by the method described in Example 1 of the patent (unit: mg).

Bead Microcrystalline Cellulose 32-42 Mesh 30
Duloxetine layer Duloxetine 11.23 Beta-lactose 48.77 Crosslinked polyvinylpyrrolidone 6 Hydroxypropyl cellulose 0.72 talc 8
Separation layer Hydroxypropylmethylcellulose 1.2 Polyethylene Glycol 6000 4.6 talc 13.9 Titanium dioxide 1.2 Enteric layer HPMCAS-LF 44.7 Triethyl citrate 10.7 talc 13.4 Finishing layer trifle 1.9 Hydrated Silicon Dioxide 0.4 196.72

Experimental Example 1. Dissolution test

The dissolution test of the formulations of Examples 1 to 9 and Comparative Example 1 was performed by Method I (Basket) method in USP Dissolution test in pH 6.0 and pH 6.8 eluates, respectively. Table 3 shows the dissolution test results in the pH 6.8 eluent, and Table 4 shows the dissolution test results in the pH 6.0 eluate (unit: wt%).

Elution
time Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 15 minutes 15.8 29.7 33.5 19.1 23.8 25.7 18.4 64.0 18.2 17.9 30 minutes 45.5 65.0 62.3 52.2 57.5 56.1 52.2 80.6 54.0 49.9 60 minutes 67.3 88.2 86.2 75.1 79.4 78.4 71.2 92.8 75.2 70.6 90 minutes 80.5 94.6 102.6 88.5 89.5 93.5 87.6 94.5 87.6 84.4 120 minutes 88.1 101.6 103.2 96.3 96.4 97.2 93.4 95.0 93.5 91.2

Elution
time Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 30 minutes 23.3 9.0 5.6 27.9 6.5 3.1 20.5 34.7 11.8 21.4 45 minutes 35.9 27.5 21.9 42.8 24.5 18.9 31.7 51.0 16.9 33.8 60 minutes 48.5 39.4 32.7 54.0 36.5 29.8 42.5 63.7 21.0 45.0 90 minutes 58.9 53.8 48.5 67.2 48.9 43.6 53.8 74.7 28.1 56.5 120 minutes 68.7 62.7 62.8 78.7 55.8 55.9 60.9 82.1 35.4 63.2 180 minutes 77.5 79.0 76.5 91.8 68.5 66.0 72.2 90.5 47.8 75.8

Experimental Example 2. Leading substance evaluation

For the formulations of Example 9 and Comparative Example 1, the total cast material was evaluated in a lidless HDPE bottle under Open accelerated test conditions (40 ° C., 75% relative humidity). In each period, the analogues are expressed as% total analogues relative to duloxetine. It can be seen that the composition of Example 9 has improved stability than the pellet composition.

term Comparative Example 1 Example 9 Early 0.15% 0.08% 15th 0.17% 0.09% 30 days 0.16% 0.07% 45 days 0.22% 0.10% 60 days 0.28% 0.09%

Experimental Example 3. Accelerated Condition Dissolution Test

For the formulations of Example 9 and Comparative Example 1, the comparative dissolution test was evaluated in an HDPE bottle as a primary packaging material under Open accelerated test conditions (40 ° C., 75% relative humidity). Table 6 shows the dissolution test results at pH 6.8 conditions for the formulation of Comparative Example 1 (Fig. 1), Table 7 shows the dissolution test results at pH 6.8 conditions for the formulation of Example 9 (Fig. 2). As a result of confirming that the dissolution pattern changes with the passage of time, it can be confirmed that the dissolution pattern of the tablet composition is stable compared to the pellet composition (unit: wt%).

Dissolution time (minutes) Early 15th 30 days 45 days 60 days 15 15.8 15.2 16.5 10.5 6.2 30 45.5 45.2 46.7 37.3 31.6 45 67.3 65.4 68.5 57.8 50.5 90 80.5 79.5 80.1 73.2 68.8 120 88.1 87.7 84.9 82.5 78.4

Dissolution time (minutes) Early 15th 30 days 45 days 60 days 15 17.9 20.5 22.4 21.21 20.5 30 49.9 51.1 52.8 51.5 49.5 45 70.6 73.4 75.6 74.8 72.6 90 84.4 86.7 84.3 87.5 87.1 120 91.2 94.2 95.5 93.8 92.1

Claims

1) a drug layer comprising duloxetine or a pharmaceutically acceptable salt thereof and at least one binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone; And
2) comprising an enteric coating layer formed directly on the drug layer
Delayed release tablet compositions.

The delayed-release tablet composition according to claim 1, wherein the binder is contained in an amount of 2 to 10 wt% based on the total composition.

The delayed release tablet composition according to claim 1, wherein the binder is contained in an amount of 2 to 4 wt% based on the total composition.

The delayed-release tablet composition according to claim 1, wherein the binder is hydroxypropyl cellulose.

The delayed release of claim 1 wherein said enteric coating layer comprises at least one enteric coating base selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate and methacrylic acid copolymer. Type tablet composition.

6. The delayed release tablet composition according to claim 5, wherein the enteric coating base is contained in an amount of 2 to 7 wt% based on the total composition.

The delayed-release tablet composition according to claim 5, wherein the enteric coating base is contained in an amount of 2 to 5 wt% based on the total composition.

6. A delayed release tablet composition according to claim 5, wherein said enteric coating base is hydroxypropylmethylcellulose acetate succinate.

6. A delayed release tablet composition according to claim 5 wherein said enteric coating base is a methacrylic acid copolymer.

(a) providing a drug layer comprising duloxetine or a pharmaceutically acceptable salt thereof and at least one binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone ; And
(b) applying an enteric coating layer comprising an enteric coating base and a pharmaceutically acceptable additive.