JP2016124861A - Orally disintegrating tablet containing olmesartan medoxomil - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally disintegrating tablet containing olmesartan medoxomil that inhibits bitter taste by a simple manufacturing process.SOLUTION: According to one embodiment of the present invention, an olmesartan medoxomil-containing orally disintegrating tablet containing olmesartan medoxomil and more than 10 mg to equal or less than 35 mg of carmellose is provided. According to one embodiment of the invention, by adding carmellose, the acid bitter taste of olmesartan medoxomil can be inhibited.SELECTED DRAWING: Figure 1

Description

The present invention relates to an orally disintegrating tablet containing olmesartan medoxomil. In particular, the present invention relates to an orally disintegrating orally disintegrating tablet that suppresses bitterness.

Olmesartan medoxomil ((5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1-{[2 '-(1H-tetrazol -5-yl) -1,1'-biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate) is converted to olmesartan, an active metabolite, after oral administration. Olmesartan selectively acts on the AT ₁ (A II type 1) receptor involved in the increase of blood pressure and competitively inhibits the binding of angiotensin II (A II), so that it is an effective drug for the treatment of hypertension. It is. Olmetec (registered trademark) tablets, which are olmesartan medoxomil-containing tablets, contain 5 mg, 10 mg, 20 mg, or 40 mg of olmesartan medoxomil as an active ingredient (Patent Document 1).

On the other hand, there is an increasing expectation for orally disintegrating tablets of olmesartan medoxomil that can be taken without water. Orally disintegrating tablets disintegrate rapidly in about 30 seconds or less with only saliva in the oral cavity or a small amount of water. Therefore, olmesartan medoxomil has a bitter taste, although it is easy for patients to take. Therefore, it is necessary to devise so as not to feel uncomfortable when taking the medicine.

Patent Document 2 discloses a powdery form having an unpleasant taste in the presence of a fluidizing agent capable of masking an unpleasant taste (such as a bitter taste) of a drug and rapidly disintegrating, thereby suppressing aggregation of the powdery drug. The first granule in which the unpleasant taste of the drug is suppressed by granulating or coating the drug (main drug) with a water-insoluble carrier using a fluidized bed granulator, a saccharide as a base component, water An orally disintegrating tablet is described in which a disintegrant having a small swelling degree is mixed with a second granule granulated with a small amount of a water-soluble binder having a small aqueous solution viscosity and tableted. Moreover, the same description is described also in patent document 3 and patent document 4, for example.

International Publication No. 2008/078726 JP 2012-36140 A JP2013-127209A International Publication No. 2012/005359

In Patent Document 2, it is necessary to granulate or coat the main agent with a water-insoluble carrier and granulate two kinds of granules, which makes the production process complicated. It is also possible that the solubility of the active ingredient is affected by granulation or coating with a water-insoluble carrier. There is concern that the solubility of the active ingredient may affect the absorption in vivo.

This invention solves the above-mentioned subject, Comprising: It aims at providing the olmesartan medoxomil containing orally disintegrating tablet which suppresses a bitter taste by a simple manufacturing process.

According to one embodiment of the present invention, there is provided an ormesartan medoxomil-containing orally disintegrating tablet, comprising olmesartan medoxomil and more than 10 mg and 35 mg or less of carmellose.

According to the present invention, there is provided an ormesartan medoxomil-containing orally disintegrating tablet in which bitterness is suppressed by a simple production method.

In the olmesartan medoxomil containing orally disintegrating tablet which concerns on the Example of this invention, it is a figure which shows the result by which the bitter taste suppression effect was recognized by adding carmellose. It is a figure which shows the result by which the further bitterness suppression effect was recognized by post-adding carmellose in the olmesartan medoxomil containing orally disintegrating tablet which concerns on the Example of this invention. It is a figure which shows the result by which the bitterness suppression effect was recognized depending on the carmellose compounding quantity in the olmesartan medoxomil containing orally disintegrating tablet which concerns on the Example of this invention. It is a graph which shows the relationship between the amount of carmellose addition of the olmesartan medoxomil containing orally disintegrating tablet which concerns on the Example of invention, and the bitterness suppression effect.

Hereinafter, the olmesartan medoxomil-containing orally disintegrating tablet according to the present invention will be described. However, the olmesartan medoxomil-containing orally disintegrating tablet of the present invention is not construed as being limited to the description of the embodiments and examples shown below. In the present invention, “post-addition” refers to addition and mixing after granulating, drying and sizing particles containing an active ingredient.

The present inventors examined an oral disintegrating tablet containing olmesartan medoxomil that can effectively suppress the acid bitterness of olmesartan medoxomil. By adding carmellose (carboxymethylcellulose), the acid bitterness of olmesartan medoxomil was suppressed. I found out that it was possible.

The olmesartan medoxomil-containing orally disintegrating tablet according to the present invention contains olmesartan medoxomil and carmellose. In this embodiment, the olmesartan medoxomil-containing orally disintegrating tablet contains a predetermined amount of olmesartan medoxomil, and the content of olmesartan medoxomil is, for example, 5 mg, 10 mg, 20 mg, or 40 mg / tablet.

In one embodiment, the carmellose added to the olmesartan medoxomil-containing orally disintegrating tablet is preferably in the range of more than 10 mg to 35 mg or less, more preferably more than 10 mg and not more than 20 mg per olmesartan medoxomil-containing orally disintegrating tablet. . The content of carmellose can be appropriately adjusted within this range depending on the content of olmesartan medoxomil and other additives. In addition, when the content of carmellose is 10 mg or less per olmesartan medoxomil-containing orally disintegrating tablet, acidic bitterness cannot be sufficiently suppressed. Moreover, when the content of carmellose increases, the orally disintegrating orally disintegrating tablet easily absorbs moisture and the hardness decreases, so it is not preferable to add more than 35 mg.

In addition, as shown in the examples described later, in place of carmellose, carmelose salt such as carmellose calcium, calcium sodium, or a carmellose cross-linked polymer such as croscarmellose sodium may be used in the oral cavity containing olmesartan medoxomil. The acid bitterness of disintegrating tablets cannot be sufficiently suppressed.

The olmesartan medoxomil-containing orally disintegrating tablet of this embodiment can further contain additives such as excipients, binders, emulsifiers, stabilizers, flavoring agents, diluents, lubricants and the like.

The excipient can be selected from, for example, sugar derivatives, starch derivatives, cellulose derivatives, gum arabic, dextran, pullulan, silicate derivatives, phosphates, carbonates and sulfates. Examples of sugar derivatives include lactose, sucrose, sucrose, mannitol and sorbitol. Examples of starch derivatives include corn starch, potato starch, α-starch, and dextrin. As the cellulose derivative, crystalline cellulose and the like can be exemplified. Examples of the silicate derivative include light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate, and the like. Examples of the phosphate include calcium hydrogen phosphate. Examples of the carbonate include calcium carbonate. Examples of sulfates include calcium sulfate.

The binder can be selected from, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the compounds shown above as excipients.

The emulsifier can be selected from, for example, colloidal clay, metal hydroxide, anionic surfactant, cationic surfactant and nonionic surfactant. Examples of colloidal clay include bentonite and bee gum. Examples of the metal hydroxide include magnesium hydroxide and aluminum hydroxide. Examples of the anionic surfactant include sodium lauryl sulfate and calcium stearate. Examples of the cationic surfactant include benzalkonium chloride. Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester.

Stabilizers can be selected from, for example, parahydroxybenzoates, alcohols, phenols, thimerosal, dehydroacetic acid, sorbic acid, and the like. Examples of parahydroxybenzoic acid esters include methyl paraben and propyl paraben. Examples of alcohols include chlorobutanol, benzyl alcohol, and phenylethyl alcohol.

The flavoring agent can be selected from, for example, sweeteners, acidulants, and fragrances. Examples of sweeteners include saccharin sodium and aspartame. Examples of the sour agent include citric acid, malic acid, tartaric acid and the like. Examples of the fragrances include menthol, lemon extract, orange extract and the like.

Diluents include, for example, lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate And mixtures thereof.

Lubricants include, for example, stearic acid, metal stearates (calcium stearate, magnesium stearate, etc.), talc, colloidal silica, waxes (bead wax, gay wax, etc.), boric acid, adipic acid, sulfate (sodium sulfate) Etc.), glycol, fumaric acid, sodium benzoate, D, L-leucine, lauryl sulfate (sodium lauryl sulfate, magnesium lauryl sulfate, etc.), silicic acids (anhydrous silicic acid, silicic acid hydrate etc.) and the above excipients It can select from the compound etc. which were shown as.

(Production method)
The olmesartan medoxomil-containing orally disintegrating tablet according to the present invention can be produced according to a known production method in the pharmaceutical field. For example, fluidized bed granulation is carried out while spraying a solvent containing a binder onto a mixture containing olmesartan medoxomil, carmellose and, if necessary, the above-mentioned various additives.

In the production method of the present invention, commercially available machines such as “MP-1” (manufactured by POWREC) and “FLO-5” (manufactured by Freund) can be used as the fluidized bed granulator. Commercially available machines such as “LFS-GS-2J” (Fukae Kogyo) can be used for the agitation granulation.

The granulated product obtained in the wet granulation step is dried and sized, and then added with a disintegrant, a lubricant, and, if necessary, the above-mentioned various additives and mixed. The mixed composition can be pressed to obtain an orally disintegrating orally disintegrating tablet according to one embodiment.

In one embodiment, the carmellose may not be added in the wet granulation step, and the granulated product may be mixed and molded later (post-addition).

(Evaluation of bitterness)
In this specification, acidic bitterness can be evaluated using a taste sensor. As a taste sensor, Insent TS-5000Z or the like can be used, but is not limited thereto.

Specific examples and test results of the above-described olmesartan medoxomil-containing orally disintegrating tablet according to the present invention will be described in more detail.

Example 1
In a fluidized bed granulator (Freund Corporation, model: MP-01), 40.0 g of olmesartan medoxomil, 213.0 g of D-mannitol (P, Mitsubishi Corporation Foodtech), 35.0 g of carmellose (Nichirin Chemical), crystals After mixing 10.0 g of cellulose (KG1000, Asahi Kasei Chemicals), an aqueous solution in which 1.0 g of hydroxypropylcellulose (L, Nippon Soda) and 3.0 g of sucralose (Saneigen FFI) were dissolved was sprayed and fluidized Layer granulation was performed. The granulated product obtained in the fluidized bed granulation step was dried at 60 ° C.

After the dried granulated product is sized with sieve No. 22, 5.0 g of crospovidone (CL-F, BASF), 7.0 g of neucillin (UFL2, Fuji Chemical) and calcium stearate (Nippon Yushi) 6.0 g was added and mixed with a plastic bag to obtain a pre-tablet powder containing olmesartan medoxomil. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted so as to have a weight of 320 mg, and the oral disintegrating tablet containing olmesartan medoxomil of Example 1 was obtained.

(Comparative Example 1)
In a fluidized bed granulator (Freund Corporation, model: MP-01), olmesartan medoxomil () 40.0 g, lactose (DMV) 200.0 g, low-substituted hydroxypropylcellulose (L-HPC (21), Shin-Etsu Chemical Industry) After mixing 40.0 g of crystalline cellulose (PH-101, Asahi Kasei Chemicals) 20.0 g, sprayed with an aqueous solution in which 6.0 g of hydroxypropylcellulose (L, Nippon Soda) was dissolved, and fluidized bed granulation was performed. It was. The granulated product obtained in the fluidized bed granulation step was dried at 60 ° C. After the dried granulated product was sized with sieve No. 22, 4.0 g of calcium stearate (Japanese fat and oil) was added to the sized product and mixed with a plastic bag to obtain a pre-tablet powder containing olmesartan medoxomil. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted so as to have a weight of 310 mg, and the olmesartan medoxomil-containing tablet of Comparative Example 1 was obtained.

(Comparative Example 2)
As Comparative Example 2, the same production method as in Example 1 except that 35.0 g of low-substituted hydroxypropyl cellulose (L-HPC (21), Shin-Etsu Chemical Co., Ltd.) was used instead of carmellose in Example 1. Thus, an orally disintegrating tablet containing olmesartan medoxomil was obtained.

(Comparative Example 3)
In Comparative Example 3, the powder before tableting was tableted to a weight of 320.0 mg by the same production method as in Example 1 except that the amount of crospovidone was 10.0 g, and the oral cavity containing olmesartan medoxomil An internally disintegrating tablet was obtained.

(Comparative Example 4)
In Comparative Example 4, 208.0 g of D-mannitol was added, and the weight was 320.0 mg according to the same production method as Example 1 except that 3.0 g of aspartame (Ajinomoto) was used instead of neucillin. The powder before tableting was tableted so that an orally disintegrating tablet containing olmesartan medoxomil was obtained.

(Comparative Example 5)
In Comparative Example 5, before tableting to give a weight of 320.0 mg by the same production method as in Example 1 except that 3.0 g of thaumatin (Saneigen FFI) was used instead of neucillin. The powder was tableted to obtain an orally disintegrating tablet containing olmesartan medoxomil.

(Evaluation of bitterness)
The bitterness was evaluated for Example 1 and Comparative Examples 1 to 5 described above. As a taste sensor, Insent Corporation, MODEL: TS-5000Z, was used to evaluate acid bitterness (prior taste), astringency (prior taste), hydrochloride bitterness, acidic bitter taste (aftertaste), and astringency (aftertaste). The evaluation results of individual astringency in Example 1 and Comparative Examples 1 to 5 are shown in Table 1. Moreover, the evaluation result of the acidic bitterness (prior taste) of Example 1 and Comparative Examples 1-5 is shown in FIG.

From the results of Table 1 and FIG. 1, the olmesartan medoxomil-containing orally disintegrating tablet of Example 1 to which carmellose was added has an acidic bitter taste (prior taste), astringency (prior taste), hydrochloride bitter taste, acidic bitter taste (after taste), It became clear that all of astringency (aftertaste) were suppressed significantly compared with Comparative Examples 1-5.

(Example 2)
In Example 1, carmellose was added in the fluidized bed granulation step, but in Example 2, the effect of suppressing bitterness was examined by adding (post-addition) after granulation. In a fluidized bed granulator, olmesartan medoxomil 40.0 g, D-mannitol 218.0 g, low-substituted hydroxypropylcellulose (L-HPC (21), Shin-Etsu Chemical) 35.0 g, crystalline cellulose (KG1000, Asahi Kasei Chemicals) ) After mixing 10.0 g, an aqueous solution in which 1.0 g of hydroxypropyl cellulose and 3.0 g of sucralose were dissolved was sprayed to perform fluidized bed granulation. The granulated product obtained in the fluidized bed granulation step was dried at 60 ° C.

After the dried granulated product is sized with sieve No. 22, 15.0 g of carmellose (Nichirin Chemical) and 3.0 g of calcium stearate (Japanese oil) are added to the sized product and mixed in a plastic bag to contain olmesartan medoxomil. A powder before tableting was obtained. Using a tableting machine (VELA5, Kikusui Seisakusho), the powder before tableting was tableted to a weight of 325 mg to obtain an orally disintegrating tablet containing ormesartan medoxomil of Example 2.

(Comparative Example 6)
In Comparative Example 6, the powder before tableting was adjusted to a weight of 325.0 mg by the same production method as in Example 2 except that 15.0 g of carmellose calcium (ECG505, Gotoku Pharmaceutical) was used instead of carmellose. Was tableted to obtain an orally disintegrating tablet containing olmesartan medoxomil.

(Comparative Example 7)
In Comparative Example 7, a weight of 325.0 mg was obtained by the same production method as in Example 2 except that 15.0 g of croscarmellose calcium sodium (Accizol, DSP Gokyo Food & Chemical) was used instead of carmellose. The powder before tableting was tableted to obtain olmesartan medoxomil-containing orally disintegrating tablets.

(Comparative Example 8)
In Comparative Example 8, before tableting to give a weight of 325.0 mg by the same production method as in Example 2, except that 15.0 g of sodium starch glycolate (Primogell, DMV) was used instead of carmellose. The powder was tableted to obtain an orally disintegrating tablet containing olmesartan medoxomil.

(Evaluation of bitterness)
The bitterness was evaluated by the method described above for Examples 1-2 and Comparative Examples 6-8 described above. Table 2 shows the evaluation results of individual astringency in Examples 1-2 and Comparative Examples 6-8. Moreover, the evaluation result of the acidic bitterness (prior taste) of Examples 1-2 and Comparative Examples 6-8 is shown in FIG.

From the results shown in Table 2 and FIG. 2, the ormesartan medoxomil-containing orally disintegrating tablet of Example 2 in which carmellose was added to the granulated product was compared with Example 1 in terms of acid bitterness (prior taste), astringency ( It has been clarified that it is possible to further suppress the taste (taste), hydrochloride bitterness, acidic bitterness (aftertaste) and astringency (aftertaste). Further, from the results of Comparative Examples 6 to 8, olmesartan medoxomil-containing intraoral disintegration can be obtained by using carmellose salts such as carmellose calcium and calcium sodium instead of carmellose, or using a cross-linked polymer of carmellose such as croscarmellose sodium. It was revealed that the acidic bitter taste of the tablets could not be sufficiently suppressed.

As described above, it was clarified that the bitterness can be significantly suppressed in the orally disintegrating orally disintegrating tablet containing olmesartan medoxomil by adding carmellose, and therefore the effects of carmellose content and other additives were further examined.

Example 3
In Example 3, instead of crospovidone, corn starch (Corn Starch XX16W, Nippon Shokuhin Kako) was used, except that 5.0 g was used. Tablet powder was tableted to obtain an orally disintegrating tablet containing olmesartan medoxomil.

Example 4
In Example 4, except that crospovidone 2.5 g and corn starch 2.5 g were used, the pre-tablet powder was tableted to a weight of 320.0 mg by the same production method as Example 1, and olmesartan Medoxomil-containing orally disintegrating tablets were obtained.

(Example 5)
In Example 5, the same production as in Example 1 except that carmellose was 25.0 g in the fluidized bed granulation step, 10.0 g corn starch was added, and crospovidone was not added after granulation. By the method, the powder before tableting was tableted so as to have a weight of 320.0 mg to obtain an orally disintegrating tablet containing olmesartan medoxomil.

(Example 6)
In Example 6, in place of hydroxypropylcellulose, except that 1.0 g of polyvinyl alcohol (GOHSENOL EG-05, Nippon Synthetic Chemical) was used, the production method was the same as in Example 5 and the weight was 320.0 mg. The powder before tableting was tableted so that an orally disintegrating tablet containing olmesartan medoxomil was obtained.

(Example 7)
In Example 7, except that carmellose was 20.0 g and corn starch 15.0 g was added, the pre-tablet powder was tableted to a weight of 320.0 mg by the same production method as Example 5, An orally disintegrating tablet containing olmesartan medoxomil was obtained.

(Example 8)
In Example 8, in place of corn starch, except for using 15.0 g of low-substituted hydroxypropylcellulose (L-HPC (21), Shin-Etsu Chemical Co., Ltd.), the same production method as in Example 7, The powder before tableting was tableted to a weight of 320.0 mg to obtain an orally disintegrating tablet containing olmesartan medoxomil.

Example 9
In Example 9, 17.5 g of carmellose and 17.5 g of low-substituted hydroxypropylcellulose were used, and the powder before tableting was adjusted to a weight of 320.0 mg by the same production method as in Example 8. Tableting was performed to obtain an orally disintegrating tablet containing olmesartan medoxomil.

(Example 10)
In Example 10, 15.0 g of carmellose and 20.0 g of low-substituted hydroxypropylcellulose were used, except that 1.0 g of polyvinyl alcohol (Gosenol EG-05, Nippon Synthetic Chemical) was used instead of hydroxypropylcellulose. By the same production method as in Example 9, the powder before tableting was tableted to a weight of 320.0 mg to obtain an orally disintegrating tablet containing ormesartan medoxomil.

(Example 11)
In Example 11, except that 5.0 g of crospovidone was added afterwards, the powder before tableting was tableted to a weight of 325.0 mg by the same production method as in Example 10, and the oral disintegration containing olmesartan medoxomil I got a tablet.

(Example 12)
In Example 12, except that 203.0 g of D-mannitol was added, the powder before tableting was tableted to a weight of 310.0 mg by the same production method as in Example 11, and the oral disintegration containing olmesartan medoxomil I got a tablet.

(Comparative Example 9)
In Comparative Example 9, the powder before tableting was tableted to a weight of 320.0 mg by the same production method as Example 10 except that 10.0 g of carmellose and 25.0 g of low-substituted hydroxypropylcellulose were added. Thus, an orally disintegrating tablet containing olmesartan medoxomil was obtained.

(Comparative Example 10)
In Comparative Example 10, the powder before tableting was pressed to a weight of 320.0 mg by the same production method as Comparative Example 9 except that 10.0 g of corn starch and 15.0 g of low-substituted hydroxypropylcellulose were added. The tablet was obtained to obtain an orally disintegrating tablet containing olmesartan medoxomil.

(Evaluation of bitterness)
The bitterness was evaluated by the method described above for Examples 3 to 12 described above. Table 3 shows the evaluation results of individual astringency in Examples 3 to 12. Table 3 also shows the results of Example 1 and Comparative Examples 2, 9, and 10 for comparison. Moreover, the evaluation result of the acidic bitterness (prior taste) of Example 1, Examples 3-12, and Comparative Examples 2, 9, and 10 is shown in FIG.

In addition, Examples 5 and 7, Examples 8 and 9, and Example 10 and Comparative Example 9 were plotted in FIG. 4 in order to examine the relationship between the amount of carmellose added and the bitterness suppressing effect.

From the results shown in Table 3 and FIG. It was revealed that taste (prior taste), hydrochloride bitterness, acidic bitterness (aftertaste), and astringency (aftertaste) can be suppressed. On the other hand, in Comparative Examples 9 and 10 in which the content of carmellose is 10 mg or less, the acidic bitterness (prior taste), astringency (prior taste), hydrochloride bitterness, acidic bitterness (aftertaste), and astringent taste (aftertaste) are not sufficient. It became clear that it could not be suppressed. From this result, it was revealed that the olmesartan medoxomil-containing orally disintegrating tablet according to the present invention can obtain a sufficient effect by containing more than 10 mg of carmellose. In addition, even when corn starch, low-substituted hydroxypropylcellulose, or low-substituted hydroxypropylcellulose and polyvinyl alcohol were added, it became clear that bitterness was suppressed according to the amount of carmellose added.

As described above, the ormesartan medoxomil-containing orally disintegrating tablet according to the present invention can significantly suppress the bitterness derived from olmesartan medoxomil by adding carmellose. Further, by adding carmellose to the granulated material later, acidic bitterness (prior taste), astringency (prior taste), hydrochloride bitterness, acidic bitterness (aftertaste), and astringent taste (aftertaste) can be further suppressed. .

Claims (1)

An oral disintegrating tablet containing olmesartan medoxomil, comprising olmesartan medoxomil and more than 10 mg and 35 mg or less of carmellose.

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