JP2012149056A - New stabilized solid formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid formulation which contains an active ingredient candesartan cilexetil that is an antihypertensive drug, which suppresses increase of impurity and which is excellent in storage stability.SOLUTION: The solid formulation contains candesartan cilexetil and triethyl citrate. The content of the triethyl citrate is preferably 0.1-6.0 mass%. The solid formulation is preferably one obtained by compression-molding a composition containing the candesartan cilexetil and the triethyl citrate.

Description

  The present invention relates to a solid preparation containing candesartan cilexetil in which an increase in impurities over time when stored for a long period of time is suppressed.

Angiotensin II receptor antagonist is a clinically useful antihypertensive drug. Among them, candesartan cilexetil is a useful drug having an excellent therapeutic effect with a small dose.
However, candesartan cilexetil is stable in a single solid state, but the content deterioration with time is accelerated by formulation. As a method for improving the content reduction, a method of blending a low melting point oily substance selected from a higher alcohol, a fatty acid ester of a polyhydric alcohol and a polymer or copolymer of an alkylene oxide is effective. Among them, polyethylene glycol 6000 is used. A method of stabilizing by blending is disclosed (Patent Document 1).

  On the other hand, it has been reported that various impurities increase with a decrease in the content of candesartan cilexetil preparation, and impurities are isolated and identified from the viewpoint of safety as pharmaceuticals (Non-patent Document 1). , 2).

Japanese Patent No. 2682353

Chromatographia 2009, 69, 1211-1220 Collect. Czech. Chem. Commun. 2009, 74, 347-362

  The subject of this invention is providing the formulation which suppressed the increase in the impurity with time in the case of long-term storage in the solid formulation containing a candesartan cilexetil especially the solid formulation formed by compression molding.

  As a result of diligent studies to solve the above problems, the present inventor formulated triethyl citrate which is not incorporated in a solid preparation as a normal use in a solid preparation containing candesartan cilexetil as an active ingredient. Thus, it has been found that the increase in impurities over time of candesartan cilexetil can be remarkably suppressed.

  That is, the present invention is characterized in that (1) a solid preparation containing candesartan cilexetil and triethyl citrate, and (2) 0.1 to 6.0% by mass of triethyl citrate. The solid preparation according to (1) or (2), which is obtained by compression-molding a composition containing the solid preparation of (1), (3) candesartan cilexetil and triethyl citrate.

  The present invention also includes a method for inhibiting decomposition of candesartan cilexetil in a solid preparation (compression-molded solid preparation) obtained by compression molding with triethyl citrate, and a method for producing the above-mentioned compression-molded solid preparation.

  According to the present invention, after formulation of candesartan cilexetil, the increase in impurities over time when stored for a long time is suppressed, and it is excellent in the safety of patients requiring treatment and stable supply to treatment sites. It became possible to provide a solid formulation.

FIG. 1 is a graph showing the amount of increase in impurities after the tablets obtained in Example 1 and the tablets obtained in Comparative Examples 1 and 2 were stored at 60 ° C. for 1 week. FIG. 2 is a graph showing the amount of increase in impurities after the tablets obtained in Examples 2 and 3 and the tablet obtained in Comparative Example 3 were stored at 60 ° C. for 2 weeks. FIG. 3 is a graph showing the amount of increase in impurities after the tablets obtained in Example 4 and the tablets obtained in Comparative Example 4 were stored at 60 ° C. for 2 weeks. FIG. 4 is a graph showing the amount of increase in impurities after storing the tablets obtained in Examples 5 and 6, the tablet obtained in Comparative Example 5, and the commercial preparation of candesartan cilexetil tablet at 60 ° C. for 2 weeks. It is.

  This embodiment is a solid preparation characterized by containing candesartan cilexetil and triethyl citrate. Candesartan cilexetil preferably has a crystal form, and in particular, a crystal having a melting point of 163 ° C. is preferable.

  Moreover, in this embodiment, content in the solid formulation of candesartan cilexetil is not specifically limited, Those skilled in the art can set suitably.

  The form of the solid preparation in this embodiment can be, for example, a capsule, powder, granule, tablet, orally disintegrating agent. Among them, particularly in solid preparations obtained by compression molding (compression molding solid preparations), it is possible to suppress an increase in impurities, and examples of the compression molding solid preparations include tablets and orally disintegrating tablets. .

  In producing the solid preparation in the present embodiment, commonly used excipients, disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, acidulants, flavors, fluids Additives such as an agent can be optionally used.

  In the present specification, as the “excipient”, lactose, sucrose, fructose, powdered reduced maltose starch syrup, glucose, trehalose, D-mannitol, xylitol, erythritol, D-sorbitol, xylitol, maltose, crystalline cellulose, dextrin, corn Starch, potato starch, wheat starch, hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, calcium hydrogen phosphate, calcium dihydrogen phosphate, precipitated calcium carbonate, light anhydrous silicic acid, etc., especially lactose, corn starch Mannitol or crystalline cellulose is preferred.

  In the present specification, examples of the “disintegrant” include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, partially pregelatinized starch, sodium starch glycolate, etc. Hydroxypropyl cellulose and carmellose calcium are preferred.

  As used herein, “binder” includes hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, potato starch, corn starch, partially saponified polyvinyl alcohol, completely saponified polyvinyl alcohol, polyvinylpyrrolidone, partially pregelatinized starch, starch glycolic acid Sodium, etc. are mentioned, and hydroxypropyl cellulose is particularly preferable.

  In this specification, examples of the “lubricant” include stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sodium stearyl fumarate, sucrose fatty acid ester and the like, and magnesium stearate is particularly preferable.

  Examples of the “coloring agent” in the present specification include edible lake pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, ferric sesquioxide, and yellow ferrodioxide.

  Examples of the “pH adjusting agent” in the present specification include hydrochloric acid, citric acid, sodium citrate, acetic acid, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, lactic acid and the like.

  Examples of the “surfactant” in the present specification include sodium lauryl sulfate, polyoxyethylene, polyoxypropylene, polysorbates and the like.

  Examples of the “stabilizer” in the present specification include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins. Examples of acidulants in the present specification include citric acid, tartaric acid, malic acid, ascorbic acid and the like.

  Examples of “fragrance” in the present specification include menthol, mint oil, orange oil, lemon oil and the like.

  Examples of the “fluidizing agent” in the present specification include light anhydrous silicic acid, hydrous silicon dioxide and the like.

  Two or more of the above-mentioned additives may be mixed and used in an arbitrary ratio.

  When manufacturing the solid formulation in this embodiment, it can manufacture by the arbitrary methods which manufacture solid formulations, such as a dry process and a wet method.

  In this specification, the dry method means a method that does not include a drying step in the production process.

  An example is a method in which an active ingredient and other additives are uniformly mixed and then compression-molded with a tableting machine to produce a tablet. Alternatively, the mixture containing the active ingredient can be made into a compressed body, which can be granulated with an appropriate granulator, and then compressed to produce a tablet. If necessary, additives can be further added to the obtained granulated product.

  In this specification, the wet method means a method including a drying step in the production process. As an example, it is a method of granulating using an appropriate solvent while mixing an active ingredient and an additive, drying the granulated product, and compression-molding to produce a tablet. If necessary, an additive can be further added to the obtained granulated product.

(Triethyl citrate)
Triethyl citrate is a substance having a melting point of −55 ° C. and a liquid form at room temperature (15 to 25 ° C.), and is generally used as a plasticizer or a coating agent (Pharmaceutical Additives Dictionary 2007).

  From the viewpoint of suppressing decomposition of candesartan cilexetil in the solid preparation, triethyl citrate is 0.1 to 6.0 mass%, preferably 0.2 to 5.0 mass% in the solid preparation of the present embodiment. %, More preferably 0.2 to 4.0% by mass.

  As a method of blending triethyl citrate with other components, any method such as a method of adding directly or a method of adding by mixing or turbidity with a solvent is used.

  Examples of the solvent that can be used when the triethyl citrate-containing solution is mixed or turbid include water, methanol, ethanol, acetone, 2-propanol, and diethyl ether, and preferably water or ethanol.

  The concentration of triethyl citrate when mixed or turbid in the solvent can be arbitrarily set, but is preferably 0.5 to 10 w / w%, more preferably 2 to 8 w / w%.

  Triethyl citrate can be added at any step during the preparation manufacturing process, but from the viewpoint of suppressing the decomposition of candesartan cilexetil in the solid preparation, candesartan cilexetil is in contact with triethyl citrate The addition at is preferred. For example, (1) a method of mixing candesartan cilexetil drug substance with triethyl citrate, (2) a method of adding triethyl citrate after mixing candesartan cilexetil and excipient, (3) candesartan cilexe Examples thereof include a method of adding cetyl alone or after mixing candesartan cilexetil and an excipient to a triethyl citrate-containing solution.

  Moreover, when a compression molding process is included in the manufacturing process, it is preferable to add triethyl citrate before the compression molding process in order to suppress decomposition of candesartan cilexetil by the compression molding process. In other words, in the preferred embodiment, the solid preparation is obtained by compression molding a composition comprising candesartan cilexetil and triethyl citrate. Moreover, the composition containing candesartan cilexetil and triethyl citrate can be a solid composition. Here, in the present specification, the solid composition refers to a composition having a form that is solid at room temperature composed of a plurality of components, such as a powder obtained by mixing or a granule obtained by granulation. Can be mentioned.

An example of the preferable manufacturing method in the case of a tablet is as follows.
(Step 1) After mixing candesartan cilexetil and an excipient, a solid composition is formed by granulation while adding a mixed solution or turbid liquid (for example, triethyl citrate-containing aqueous solution) of triethyl citrate to the obtained mixture. To obtain a granule.
(Step 2) The remaining components (for example, any component selected from one or more of excipients, binders, disintegrants, lubricants and fluidizing agents) are mixed with the granules obtained in Step 1, and tableted. .

  As another example, in Step 1, granules may be prepared by granulation while adding a mixed liquid or turbid liquid of candesartan cilexetil and triethyl citrate to the excipient.

  Orally disintegrating tablets can be produced in the same manner as tablets.

  Hereinafter, although the solid formulation of this embodiment is demonstrated more concretely by an Example, this invention is not limited by a following example.

Example 1
3.8 g of candesartan cilexetil, 366.3 g of lactose hydrate and 76.0 g of corn starch were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by mixing 9.9 g of triethyl citrate (Citroflex 2, Morimura Corporation) in a solution obtained by dissolving 15.2 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) in 491.0 g of purified water is sprayed. , Granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S).

  Carmellose calcium (ECG-505, manufactured by Nichirin Chemical Industry Co., Ltd.) 21.3 g and magnesium stearate 1.5 g were mixed into the obtained sized product, and a rotary tableting machine (manufactured by Hata Kogakusho: HT-EX18 type) and compression-molded with a diameter of 7 mm to obtain one tablet of 130 mg.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 1.0
Lactose hydrate 96.4
Corn starch 20.0
Hydroxypropylcellulose 4.0
Triethyl citrate 2.6
Carmellose calcium 5.6
Magnesium stearate 0.4

(Comparative Example 1) (Patent Document 1 Example 1 Control)
3.8 g of candesartan cilexetil, 376.2 g of lactose hydrate and 76.0 g of corn starch were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by dissolving 15.2 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 491.0 g of purified water was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S).

  Carmellose calcium (ECG-505, manufactured by Nichirin Chemical Industry Co., Ltd.) 21.3 g and magnesium stearate 1.5 g were mixed into the obtained sized product, and a rotary tableting machine (manufactured by Hata Kogakusho: HT-EX18 type) and compression-molded with a diameter of 7 mm to obtain one tablet of 130 mg.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 1.0
Lactose hydrate 99.0
Corn starch 20.0
Hydroxypropylcellulose 4.0
Carmellose calcium 5.6
Magnesium stearate 0.4

(Comparative Example 2) (Patent Document 1 Example 1)
3.8 g of candesartan cilexetil, 353.4 g of lactose hydrate, 76.0 g of corn starch and 22.8 g of Macrogol 6000 were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by dissolving 15.2 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 491.0 g of purified water was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S).

  Carmellose calcium (ECG-505, manufactured by Nichirin Chemical Industry Co., Ltd.) 21.3 g and magnesium stearate 1.5 g were mixed into the obtained sized product, and a rotary tableting machine (manufactured by Hata Kogakusho: HT-EX18 type) and compression-molded with a diameter of 7 mm to obtain one tablet of 130 mg.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 1.0
Lactose hydrate 93.0
Corn starch 20.0
Macrogol 6000 6.0
Hydroxypropylcellulose 4.0
Carmellose calcium 5.6
Magnesium stearate 0.4

(Test Example 1)
(Test example: Comparison of storage stability of preparations by severe test)
The amount of increase in impurities was compared for the tablets obtained in Example 1 and the tablets obtained in Comparative Examples 1 and 2 under the same conditions after storage at 60 ° C. for 1 week.

Impurities are measured by the high performance liquid chromatograph method. The total area values of all impurity peaks confirmed on the chromatogram are summed, divided by the sum of the peak area values confirmed on the chromatogram, and multiplied by 100. (Area percentage).
(Measurement condition)
Detector: UV absorption photometer (wavelength: 254 nm)
Column: A stainless tube having an inner diameter of 3.9 mm and a length of 15 cm packed with 5 μm octadesilylated silica gel.
Column temperature: constant temperature mobile phase around 25 ° C .: mobile phase A: acetonitrile / water / glacial acetic acid mixture (57: 43: 1)
Mobile phase B: acetonitrile / water / glacial acetic acid mixture (90: 10: 1)
Transfer of mobile phase: Concentration control is performed by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.
Flow rate: 0.8 mL / min

(result)
FIG. 1 shows the measurement results of the amount of increase in impurities after storage at 60 ° C. for 1 week. The tablets obtained in Example 1 showed less increase in impurities than the tablets obtained in Comparative Examples 1 and 2, indicating that the increase in impurities over time during storage was suppressed.

(Example 2)
Candesartan cilexetil 24.0 g, lactose hydrate 268.2 g and corn starch 60.0 g were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by mixing 7.8 g of triethyl citrate (Citroflex 2, Morimura Corporation) in a solution of 12.0 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 388.0 g of purified water is sprayed. , Granulated. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve.

  16.8 g of carmellose calcium (ECG-505, manufactured by Nichirin Kagaku Kogyo) and 1.2 g of magnesium stearate were mixed with the obtained sized product, and a rotary tableting machine (manufactured by Hata Plant): HT-EX18 type) and compression-molded with a diameter of 7 mm to obtain one tablet of 130 mg.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 8.0
Lactose hydrate 89.4
Corn starch 20.0
Hydroxypropylcellulose 4.0
Triethyl citrate 2.6
Carmellose calcium 5.6
Magnesium stearate 0.4

(Example 3)
Candesartan cilexetil 24.0 g, lactose hydrate 260.4 g and corn starch 60.0 g were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by mixing 15.6 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) in 388.0 g of purified water and 15.6 g of triethyl citrate (Citroflex 2, Morimura Corporation) is sprayed. , Granulated. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve.

  16.8 g of carmellose calcium (ECG-505, manufactured by Nichirin Kagaku Kogyo) and 1.2 g of magnesium stearate were mixed with the obtained sized product, and a rotary tableting machine (manufactured by Hata Plant): HT-EX18 type) and compression-molded with a diameter of 7 mm to obtain one tablet of 130 mg.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 8.0
Lactose hydrate 86.8
Corn starch 20.0
Hydroxypropylcellulose 4.0
Triethyl citrate 5.2
Carmellose calcium 5.6
Magnesium stearate 0.4

(Comparative Example 3)
Candesartan cilexetil 24.0 g, lactose hydrate 276.0 g and corn starch 60.0 g were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by dissolving 12.0 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 388.0 g of purified water was sprayed and granulated. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. 16.8 g of carmellose calcium (ECG-505, manufactured by Nichirin Kagaku Kogyo) and 1.2 g of magnesium stearate were mixed with the obtained sized product, and a rotary tableting machine (manufactured by Hata Plant): HT-EX18 type) and compression-molded with a diameter of 7 mm to obtain one tablet of 130 mg.

[Components] [Weight (mg) per 130 mg tablet]
Candesartan cilexetil 8.0
Lactose hydrate 92.0
Corn starch 20.0
Hydroxypropylcellulose 4.0
Carmellose calcium 5.6
Magnesium stearate 0.4

(Test Example 2)
(Test example: Comparison of storage stability of preparations by severe test)
The amount of increase in impurities was compared for each tablet obtained in Examples 2 and 3 and the tablet obtained in Comparative Example 3 under the same conditions after storage at 60 ° C. for 2 weeks.

(result)
FIG. 2 shows the measurement results of the increase in impurities after storage at 60 ° C. for 2 weeks. Each tablet obtained in Examples 2 and 3 showed less increase in impurities than the tablet obtained in Comparative Example 3, indicating that the increase in impurities over time during storage was suppressed.

Example 4
Candesartan cilexetil 24.0 g, lactose hydrate 190.2 g, and corn starch 60.0 g were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by mixing 7.8 g of triethyl citrate (Citroflex 2, Morimura Corporation) in a solution of 12.0 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 388.0 g of purified water is sprayed. , Granulated. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve.

  In the obtained sized product, 78.0 g of crystalline cellulose (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), carmellose calcium (ECCG-505, manufactured by Nichirin Chemical Industries) and 1 g of magnesium stearate Were mixed and compression-molded with a diameter of 7 mm using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain one tablet of 130 mg.

[Components] [Weight (mg) per 130 mg tablet]
Candesartan cilexetil 8.0
Lactose hydrate 63.4
Corn starch 20.0
Hydroxypropylcellulose 4.0
Triethyl citrate 2.6
Crystalline cellulose (UF-711) 26.0
Carmellose calcium 5.6
Magnesium stearate 0.4

(Comparative Example 4)
Candesartan cilexetil 24.0 g, lactose hydrate 198.0 g and corn starch 60.0 g were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by dissolving 12.0 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 388.0 g of purified water was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S). In the obtained sized product, 45.0 g of crystalline cellulose (Theolas UF-711, manufactured by Asahi Kasei Chemicals), 16.8 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Industries) and 1.2 g of magnesium stearate Were mixed and compression-molded with a diameter of 7 mm using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain one tablet of 130 mg.

[Components] [Weight (mg) per 130 mg tablet]
Candesartan cilexetil 8.0
Lactose hydrate 66.0
Corn starch 20.0
Hydroxypropylcellulose 4.0
Crystalline cellulose (UF-711) 26.0
Carmellose calcium 5.6
Magnesium stearate 0.4

(Test Example 3)
(Test example: Comparison of storage stability of preparations by severe test)
The increase in impurities was compared for the tablets obtained in Example 4 and the tablets obtained in Comparative Example 4 under the same conditions after storage at 60 ° C. for 2 weeks.

(result)
FIG. 3 shows the measurement results of the amount of increase in impurities after storage at 60 ° C. for 2 weeks. The tablets obtained in Example 4 showed less increase in impurities than the tablets obtained in Comparative Example 4, indicating that the increase in impurities over time during storage was suppressed.

(Example 5)
30.4 g of candesartan cilexetil, 121.6 g of lactose hydrate and 74.1 g of corn starch were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution in which 9.9 g of triethyl citrate (Citroflex 2, Morimura Corporation) is mixed with 11.0 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 355.7 g of purified water is sprayed. , Granulated.
The resulting granulated product is dried with 148.2 g of lactose hydrate, 40.3 g of corn starch and 37.2 g of low-substituted hydroxypropylcellulose (LH-11, manufactured by Shin-Etsu Chemical) in a fluidized bed granulator. (Made by Paulec: MP-01 type). Next, a solution obtained by dissolving 19.8 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) in 375.4 g of purified water was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S).

  The obtained sized product is mixed with 1.5 g of magnesium stearate, and compression-molded with a diameter of 7 mm using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type). Obtained.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 8.0
Lactose hydrate 70.9
Corn starch 30.1
Hydroxypropyl cellulose 8.2
Triethyl citrate 2.6
Low substituted hydroxypropylcellulose 9.8
Magnesium stearate 0.4

(Example 6)
Candesartan cilexetil 50.0 g, lactose hydrate 199.4 g and corn starch 121.8 g were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution in which 18.7 g of hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) is dissolved in 604.0 g of purified water is mixed with 16.3 g of triethyl citrate (Citroflex 2, Morimura Corporation). , Granulated.
169.0 g of the granules obtained by drying the granulated product were mixed with 112.2 g of lactose hydrate and 42.3 g of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) in a fluidized bed granulator (manufactured by Paulec) : MP-01 type). Next, a solution obtained by dissolving 13.5 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 257.0 g of purified water was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S).

  1.0 g of magnesium stearate is mixed with the obtained sized product, and compression-molded with a diameter of 7 mm using a rotary type tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type). Obtained.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 8.0
Lactose hydrate 75.0
Corn starch 19.5
Hydroxypropyl cellulose 8.2
Triethyl citrate 2.6
Low substituted hydroxypropylcellulose 16.3
Magnesium stearate 0.4

(Comparative Example 5)
Candesartan cilexetil (30.4 g), lactose hydrate (131.0 g) and corn starch (74.0 g) were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type). Next, a solution obtained by dissolving 11.4 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 367.8 g of purified water was sprayed and granulated.
The resulting granulated product is granulated with 148.3 g of lactose hydrate, 40.4 g of corn starch and 37.2 g of low-substituted hydroxypropylcellulose (LH-11, manufactured by Shin-Etsu Chemical) in a fluidized bed granulator. (Made by Paulec: MP-01 type). Next, a solution obtained by dissolving 19.8 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) in 375.9 g of purified water was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (manufactured by Paulek: QC-197S).

  The obtained sized product is mixed with 1.5 g of magnesium stearate, and compression-molded with a diameter of 7 mm using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type). Obtained.

[Components] [Weight per mg of 130 mg (mg)]
Candesartan cilexetil 8.0
Lactose hydrate 73.5
Corn starch 30.1
Hydroxypropyl cellulose 8.2
Low substituted hydroxypropylcellulose 9.8
Magnesium stearate 0.4

(Test Example 4)
(Test example: Comparison of storage stability of preparations by severe test)
The amount of increase in impurities was compared for the tablets obtained in Examples 5 and 6, the tablet obtained in Comparative Example 5 under the same conditions and the commercial preparation of candesartan cilexetil tablet after storage at 60 ° C. for 2 weeks.

(result)
FIG. 4 shows the results of measuring the amount of increase in impurities after storage at 60 ° C. for 2 weeks. Each tablet obtained in Examples 5 and 6 has less increase in impurities than the tablet obtained in Comparative Example 5 and the commercial preparation of candesartan cilexetil tablet, and the increase in impurities over time during storage is suppressed. It has been shown.

  The present invention provides a solid preparation containing candesartan cilexetil which is useful as a medicine and which suppresses an increase in impurities, and is industrially applicable.

Claims (11)

  A solid preparation comprising candesartan cilexetil and triethyl citrate.   The solid preparation according to claim 1, wherein the content of triethyl citrate is 0.1 to 6.0% by mass.   The solid preparation according to claim 1 or 2, wherein the solid preparation is obtained by compression molding a composition containing the candesartan cilexetil and the triethyl citrate.   A method for inhibiting decomposition of candesartan cilexetil in a compression-molded solid preparation by containing triethyl citrate in the solid preparation.   The method for inhibiting decomposition according to claim 4, wherein the amount of triethyl citrate is 0.1 to 6.0% by mass. A first step of obtaining a solid composition using candesartan cilexetil and triethyl citrate;
And a second step of compressing the solid composition containing candesartan cilexetil and triethyl citrate obtained in the first step, and a method for producing a compression-molded solid preparation containing candesartan cilexetil . The compression molded solid preparation further contains an excipient,
In the first step, the composition is granulated while adding a mixed solution or turbid solution of triethyl citrate to a mixture obtained by mixing the candesartan cilexetil and the excipient. The manufacturing method of Claim 6 which obtains a solid composition. The compression molded solid preparation further contains an excipient,
The manufacturing method according to claim 6, wherein in the first step, the solid composition is obtained by granulation while adding a mixed solution or turbid solution of candesartan cilexetil and triethyl citrate to the excipient. .   The manufacturing method according to any one of claims 6 to 8, wherein another component is further added to the solid composition obtained in the first step before the second step.   The manufacturing method according to claim 9, wherein the other component is an arbitrary component selected from an excipient, a binder, a disintegrant, a lubricant, and a fluidizing agent.   The production method according to any one of claims 6 to 10, wherein a content of the triethyl citrate is 0.1 to 6.0 mass%.