JPWO2013100112A1 - Solid pharmaceutical composition containing a compound having angiotensin II antagonistic activity - Google Patents

Abstract

The solid pharmaceutical composition of the present invention contains a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof. The solid pharmaceutical composition of the present invention has excellent stability and particularly excellent moisture resistance.

Description

  The present invention relates to a solid pharmaceutical composition containing a compound having an angiotensin II antagonism.

  Valsartan, one of the compounds having an angiotensin II antagonism used as a therapeutic agent for hypertension, is marketed as “Dioban (registered trademark) tablet” (Non-patent Document 1).

  Patent Document 1 describes that the content of valsartan in the preparation is increased, and if necessary, hydrochlorothiazide is added to the preparation.

JP 2007-238637 A

“Diovan (registered trademark) lock” package insert

  An object of the present invention is to provide a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action and having excellent stability.

  In order to solve the above problems, the present inventors have formulated a solid pharmaceutical composition by blending an alkaline earth metal salt and / or a hydrate thereof with a solid pharmaceutical composition containing a compound having an angiotensin II antagonistic action. The present inventors have found that the stability of a product, particularly moisture resistance, can be improved, and the present invention has been completed.

  The present invention is a solid pharmaceutical composition comprising a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof.

  In one embodiment, the compound having angiotensin II antagonism is a group consisting of losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof At least one compound selected from the group consisting of:

  In one embodiment, content of the said compound which has the angiotensin II antagonism is 30 mass% or more on the basis of the mass of the said composition.

  In one embodiment, the alkaline earth metal is at least one metal selected from the group consisting of calcium, strontium, barium, radium, magnesium, and beryllium.

  In one embodiment, the alkaline earth metal salt and / or hydrate thereof is calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, precipitated calcium carbonate, calcium lactate. Hydrate, anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium monohydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dried magnesium sulfate, magnesium gluconate , Magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide alumina, magnesium sulfate hydrate, magnesium metasilicate aluminate, and magnesium carbonate, and combinations thereof Is at least one compound-option.

  In one embodiment, content of the said alkaline-earth metal salt and / or its hydrate is 2 mass%-10 mass% on the basis of the mass of the said composition.

  ADVANTAGE OF THE INVENTION According to this invention, it is a solid pharmaceutical composition containing the compound which has an angiotensin II antagonism, Comprising: The solid pharmaceutical composition excellent in stability can be provided.

  The solid pharmaceutical composition of the present invention contains a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof.

  The compound having an angiotensin II antagonistic action is not particularly limited, and examples thereof include losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof, and These combinations are mentioned.

  The content of the compound having an angiotensin II antagonistic action in the solid pharmaceutical composition of the present invention is not particularly limited, but is preferably 30% by mass or more, more preferably 30% by mass based on the mass of the composition. It is 70 mass% or less.

  In the present invention, alkaline earth metal refers to calcium, strontium, barium, radium, magnesium, or beryllium.

  The alkaline earth metal salt and / or hydrate thereof of the present invention is not particularly limited, and examples thereof include calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, and precipitated carbonic acid. Calcium, calcium lactate hydrate, anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium monohydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dry magnesium sulfate , Magnesium gluconate, magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium magnesium hydroxide, magnesium sulfate hydrate, magnesium magnesium metasilicate, and magnesium carbonate, and combinations thereof And the like. Preferably, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium carbonate, magnesium oxide, or a combination thereof. These are preferable because they can be obtained at low cost.

  The content of the alkaline earth metal salt and / or hydrate thereof in the solid pharmaceutical composition of the present invention is not particularly limited, but is preferably 2% by mass to 10% by mass based on the mass of the composition, More preferably, it is 3 mass%-7 mass%.

  The shape of the solid pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, capsules, pills, troches, granules, and powders. A tablet is preferred.

  The solid pharmaceutical composition of the present invention includes other excipients, disintegrants, binders, fluidizers, lubricants, colorants, solubilizers, sweeteners, fragrances, foaming agents, surfactants, preservatives. And additives such as a pH adjusting agent and a coating agent.

  The excipient is not particularly limited, and examples thereof include crystalline cellulose, low-substituted hydroxypropyl cellulose, starch, corn starch, saccharides (such as glucose, fructose, lactose, sucrose, reduced maltose, trehalose), and sugar alcohol (D -Mannitol, erythritol, sorbitol, xylitol, maltitol, lactitol, etc.), and combinations thereof.

  The disintegrant is not particularly limited, and for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid Synthetic aluminum silicate crystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, and hydroxypropyl starch, and combinations thereof.

  The binder is not particularly limited, and examples thereof include gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, Examples include pullulan, partially pregelatinized starch, and saccharides, and combinations thereof.

  Examples of the fluidizing agent include silicates such as calcium silicate, silicic anhydride such as light anhydrous silicic acid, hydrated silicon dioxide, and talc, and combinations thereof.

  The lubricant is not particularly limited, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, Examples include sodium stearyl fumarate, sodium benzoate, L-leucine, and L-valine, and combinations thereof.

  The colorant is not particularly limited, and examples thereof include iron sesquioxide, yellow iron sesquioxide, edible red No. 2, edible red No. 3, edible yellow No. 4, and edible yellow No. 5, and combinations thereof.

  The solubilizing agent is not particularly limited, and examples thereof include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium hydrogen carbonate, and combinations thereof.

  The sweetener is not particularly limited and includes, for example, aspartame, sodium saccharin, dipotassium glycyrrhizin, stevia, and thaumatin, and combinations thereof.

  The fragrance is not particularly limited, and examples thereof include mint, lemon, and orange, and combinations thereof.

  The foaming agent is not particularly limited, and examples thereof include tartrate, citrate, bicarbonate, and combinations thereof.

  The surfactant is not particularly limited, and examples thereof include anionic surfactants such as sodium alkyl sulfate, sucrose fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives. Nonionic surfactants and the like can be mentioned.

  The preservative is not particularly limited, and examples thereof include benzoic acid, paraoxybenzoic acid, and salts thereof.

  The pH regulator is not particularly limited, and examples thereof include organic acids such as citric acid, tartaric acid, acetic acid and lactic acid, inorganic acids such as hydrochloric acid and phosphoric acid, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate and sodium hydroxide. Can be mentioned.

  The coating agent is not particularly limited, and examples thereof include hydroxypropyl methylcellulose (hypromellose), titanium oxide, and polyethylene glycol (Macrogol 6000), and combinations thereof.

  The content of the additive in the solid pharmaceutical composition of the present invention is appropriately set depending on the purpose of blending the additive.

  The method for producing the solid pharmaceutical composition of the present invention is not particularly limited, and for example, the steps included in the method for producing a solid pharmaceutical preparation usually used by those skilled in the art can be used. The granulation step, the tableting step, or the coating step And the like.

  As the granulation step that can be used in the present invention, for example, granulation by wet granulation or dry granulation can be employed. Conventionally, a solid pharmaceutical composition containing a compound having an angiotensin II antagonism was sometimes produced by a dry granulation method, but the method for producing a solid pharmaceutical composition of the present invention is limited to the dry granulation method. Alternatively, a wet granulation method can be selected. The wet granulation method is not particularly limited. For example, a granulating means such as a fluidized bed granulator / dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulating / coating machine, or a spray dryer is used. Granulation can be employed. It does not specifically limit as a dry granulation method, For example, granulation using granulation means, such as a roller compactor, can be employ | adopted.

The tableting process that can be used in the present invention is not particularly limited. For example, using a tableting mortar, a tableting upper punch and a lower punch, a hydraulic hand press machine, a single-shot tableting machine, a rotary type Tableting using a tableting means such as a tableting machine may be employed. The tableting pressure is not particularly limited, and is, for example, in the range of ² kN / cm ^{2 to 7} kN / cm ² .

  The coating process that can be used in the present invention is not particularly limited. For example, a coating method in which a coating agent is dissolved or dispersed in a solvent such as water to prepare a coating solution, and the coating solution is sprayed onto the main agent particles, a film Coating using a method such as a coating machine, a pan coating method, a fluid coating method, and a rolling coating method may be employed.

  The solid pharmaceutical composition of the present invention is granulated by mixing, for example, an angiotensin II antagonistic compound, an alkaline earth metal salt and / or hydrate thereof, an excipient, a disintegrant and a binder. It is manufactured by adding and mixing a fluidizing agent, lubricant, if necessary, disintegrating agent to tablets, and coating the resulting uncoated tablet with a coating agent and, if necessary, a coloring agent. .

  As described above, the solid pharmaceutical composition of the present invention can be produced, for example, as a tablet.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Example 1
Tablets containing valsartan were produced according to the formulation described in Table 1 below. Valsartan (Patent Document 1) 800 g, magnesium carbonate 100 g, low-substituted hydroxypropyl cellulose 770 g, crystalline cellulose 100 g, light anhydrous silicic acid 100 g, and magnesium stearate 30 g The mixture was mixed and the mixture was consolidated using a roller compactor (TF-MINI manufactured by Freund Sangyo Co., Ltd.) at a compaction force of 60 kg / cm ² and a roller speed of 4 rpm. The compacted mixed compact is passed through a granulator (P-02S manufactured by Dalton Co., Ltd.) to form granules (dry granulation), 50 g of low-substituted hydroxypropylcellulose, 10 g of light anhydrous silicic acid, 20 g of talc and 20 g of magnesium stearate was added and mixed, and the mixture was put into a tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.), and a tablet weight of 200 mg at a tableting pressure of 7 kN / cm ² using a 8.5 mm diameter punch. Tableting was performed to obtain an uncoated tablet (core tablet part). Next, this uncoated tablet was put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 128 g of hydroxypropylmethylcellulose, 16 g of polyethylene glycol and 16 g of titanium oxide in 1600 g of purified water was 8 mg per tablet. Film coating was performed by spraying the uncoated tablets so that the solid content was coated, and tablets were obtained.

(Example 2)
Tablets containing valsartan were produced according to the formulation described in Table 2 below. Production was carried out in the same manner as in Example 1 except that the magnesium carbonate in Example 1 was replaced with precipitated calcium carbonate.

(Example 3)
Tablets containing valsartan were produced according to the formulation described in Table 3 below. 200 g of Valsartan (Patent Document 1), 25 g of magnesium carbonate, 210 g of low-substituted hydroxypropyl cellulose and 25 g of crystalline cellulose are put into a stirring granulator (VG-05 manufactured by Paul Wrec Co., Ltd.) and mixed, and further 15 g of hydroxypropyl cellulose is added. Wet granulation was performed by adding a solution dissolved in purified water. 12.5 g of low-substituted hydroxypropylcellulose, 2.5 g of light anhydrous silicic acid, 5 g of talc and 5 g of magnesium stearate were added to and mixed with the resulting granulated product, and this mixture was mixed with a tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.). VIRGO) and tableting was performed using a punch with a diameter of 8.5 mm at a tableting pressure of 6 kN / cm ² to obtain an uncoated tablet (core tablet part). Next, this uncoated tablet is put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 32 g of hydroxypropylmethylcellulose, 4 g of polyethylene glycol and 4 g of titanium oxide in 400 g of purified water is sprayed on the uncoated tablet. Film coating was performed to obtain tablets.

Example 4
Tablets containing valsartan were prepared according to the formulation described in Table 4 below. Production was carried out in the same manner as in Example 3 except that magnesium carbonate in Example 3 was replaced with magnesium oxide.

(Comparative Example 1)
Tablets containing valsartan were prepared according to the formulation described in Table 5 below. 800 g of Valsartan (Patent Document 1), 870 g of low substituted hydroxypropyl cellulose, 100 g of crystalline cellulose, 100 g of light anhydrous silicic acid and 30 g of magnesium stearate are charged into a container rotation type mixer (S-3, manufactured by Tsutsui Rika Kikai Co., Ltd.) The mixture was consolidated using a roller compactor (TF-MINI manufactured by Freund Sangyo Co., Ltd.) at a compaction force of 60 kg / cm ² and a roller speed of 4 rpm. The compacted mixed compact is passed through a granulator (P-02S manufactured by Dalton Co., Ltd.) to form granules (dry granulation), 50 g of low-substituted hydroxypropylcellulose, 10 g of light anhydrous silicic acid, 20 g of talc and 20 g of magnesium stearate was added and mixed, and the mixture was put into a tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.), and a tablet weight of 200 mg at a tableting pressure of 7 kN / cm ² using a 8.5 mm diameter punch. Tableting was performed to obtain an uncoated tablet (core tablet part). Next, this uncoated tablet was put into a film coating machine (HCT-48N manufactured by Freund Sangyo Co., Ltd.), and a solution obtained by dissolving 128 g of hydroxypropylmethylcellulose, 16 g of polyethylene glycol and 16 g of titanium oxide in 1600 g of purified water was 8 mg per tablet. Film coating was performed by spraying the uncoated tablets so that the solid content was coated, and tablets were obtained.

(Test example: Formulation stability evaluation Dissolution test before and after storage)
The tablets obtained in Examples 1 to 4 and Comparative Example 1 and “Diovan (registered trademark) 80 mg” (manufactured by Novartis) (Comparative Example 2) were subjected to a dissolution test of valsartan before and after storage. The test solution was 900 mL, and the elution rate (%) after 30 minutes was measured at a paddle rotation number of 50 rpm. "Dioban (registered trademark) tablet 80 mg" contains 8 components of hydroxypropyl cellulose, cellulose, silicic anhydride, talc, magnesium stearate, hypromellose, macrogol and titanium oxide in addition to valsartan.

  First, the tablets of Examples 1 to 4 and Comparative Example 1 were subjected to a valsartan dissolution test immediately before production, and the tablets of Comparative Example 2 were stored immediately after being obtained. Each test was performed three times. The results are shown in Table 6.

  As is apparent from Table 6, the tablets before storage of Examples 1 to 4 showed the dissolution properties of valsartan equivalent to the tablets of Comparative Examples 1 and 2 before storage.

  Subsequently, the tablets of Examples 1 to 4 and Comparative Examples 1 and 2 were stored for 3 days under conditions of 60 ° C., 75% humidity, and dark place, respectively, with aluminum packaging or without packaging. The tablets after storage were subjected to a dissolution test for valsartan. Each test was performed three times. The results are shown in Table 7.

  As is clear from Table 7, the tablets after storage in Comparative Examples 1 and 2 showed a significant decrease in the dissolution properties of valsartan compared to the tablets before storage. It did not elute. This result indicates that valsartan is vulnerable to high humidity.

  On the other hand, the tablets after storage in Examples 1 to 4 showed very stable results with little decrease in dissolution of valsartan in either aluminum packaging or non-packaging. By adding an alkaline earth metal salt and / or a hydrate thereof to a tablet containing valsartan, the stability of the tablet, particularly moisture resistance, could be increased.

  ADVANTAGE OF THE INVENTION According to this invention, it is a solid pharmaceutical composition containing the compound which has an angiotensin II antagonism, Comprising: The solid pharmaceutical composition excellent in stability can be provided.

Claims (6)

  A solid pharmaceutical composition comprising a compound having an angiotensin II antagonism and an alkaline earth metal salt and / or a hydrate thereof.   The compound having angiotensin II antagonistic activity is at least one selected from the group consisting of losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, tasosartan, azilsartan, and salts or esters thereof. The solid pharmaceutical composition according to claim 1, which is a seed compound.   The solid pharmaceutical composition according to claim 1, wherein the content of the compound having angiotensin II antagonistic activity is 30% by mass or more based on the mass of the composition.   The solid pharmaceutical composition according to claim 1, wherein the alkaline earth metal is at least one metal selected from the group consisting of calcium, strontium, barium, radium, magnesium, and beryllium.   The alkaline earth metal salt and / or hydrate thereof is calcium chloride hydrate, calcium citrate, calcium gluconate hydrate, calcium glycerophosphate, calcium carbonate, precipitated calcium carbonate, calcium lactate hydrate, anhydrous phosphorus Calcium hydrogen hydrogen, calcium hydrogen phosphate, calcium hydrogen hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, magnesium L-aspartate, magnesium chloride, dried magnesium sulfate, magnesium gluconate, magnesium silicate, silica At least selected from the group consisting of magnesium aluminum oxide, magnesium oxide, magnesium hydroxide, magnesium alumina hydroxide, magnesium sulfate hydrate, magnesium aluminate metasilicate, and magnesium carbonate, and combinations thereof It is a class of compounds, solid pharmaceutical composition of claim 1.   The solid pharmaceutical composition according to claim 1, wherein the content of the alkaline earth metal salt and / or hydrate thereof is 2% by mass to 10% by mass based on the mass of the composition.