JPWO2008078727A1 - Pharmaceutical composition with improved dissolution - Google Patents

Abstract

Disclosed is a pharmaceutical composition with improved dissolution comprising olmesartan medoxomil and azelnidipine. A pharmaceutical composition comprising (A) olmesartan medoxomil, (B) azelnidipine and (C) polyvinyl alcohol or a vinyl alcohol copolymer.

Description

  The present invention relates to a pharmaceutical composition comprising olmesartan medoxomil and azelnidipine.

  Currently, angiotensin II receptor antagonists and calcium channel antagonists are widely used as medicaments for the treatment or prevention of hypertension or heart disease. Angiotensin II receptor antagonists, which are inhibitors of the renin-angiotensin system, are particularly effective for renin-dependent hypertension and have a protective effect against cardiovascular and renal damage. Further, since the calcium channel antagonist has a natriuretic action in addition to a vasodilatory action, it is also effective for fluid retention (renin-independent) hypertension. Therefore, when an angiotensin II receptor antagonist and a calcium channel antagonist are used in combination, in addition to the inhibitory effect of the renin-angiotensin system by the angiotensin II receptor antagonist, the calcium channel antagonistic action in the vascular smooth muscle and the two The next sodium excretion action makes it possible to simultaneously suppress the origin of multiple hypertension, and is expected to show a stable and sufficient hypertension treatment or prevention effect regardless of the etiology.

   (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazole-5- Yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate (hereinafter referred to as olmesartan medoxomil) is an excellent angiotensin II receptor antagonist and is useful as a medicament for the treatment or prevention of hypertension, heart disease and the like (Patent No. 2082519, US Pat. No. 5,616,599).

Olmesartan Medoxomil

  Olmesartan medoxomil is sold as Olmetec (registered trademark) tablets, containing 5 mg, 10 mg, 20 mg or 40 mg of olmesartan medoxomil as an active ingredient, and low-substituted hydroxypropylcellulose, hydroxypropylcellulose, crystalline cellulose, lactose as additives And magnesium stearate.

  (±) -2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) Ester 5-isopropyl ester (hereinafter referred to as azelnidipine) is an excellent calcium channel antagonist and is known to be useful as a medicament for the treatment or prevention of hypertension, heart disease and the like (Japanese Patent No. 1666755). No., US Pat. No. 4,772,596).

Azelnidipine

  Azelnidipine is sold as Calblock (registered trademark) tablets, containing 8 mg or 16 mg of azelnidipine as an active ingredient, and D-mannitol, carmellose calcium, low-substituted hydroxypropylcellulose, sodium bicarbonate, polysorbate as an additive 80, containing magnesium aluminate metasilicate, light anhydrous silicic acid, hydroxypropylcellulose, talc, magnesium stearate.

In the prior art, a medicine in which olmesartan medoxomil and azelnidipine are combined is known (WO 2004/067003 pamphlet). There is no known pharmaceutical composition that contains a vinyl alcohol copolymer and / or improved dissolution properties.
Japanese Patent No. 2082519 (US Pat. No. 5,616,599) Japanese Patent No. 1666755 (US Pat. No. 4,772,596) International Publication No. 2004/067003 Pamphlet

  An object of the present invention is to provide a pharmaceutical composition with improved dissolution, comprising (A) olmesartan medoxomil, (B) azelnidipine and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer.

  In recent years, hypertensive patients tend to use a plurality of antihypertensive drugs having different mechanisms of action in order to achieve more reliable blood pressure control. Among them, olmesartan medoxomil, which is an angiotensin II receptor antagonist, and azelnidipine, which is a calcium channel antagonist, are widely used in the medical field as a combination that can be expected to have a more reliable therapeutic effect on hypertension. However, it was found that olmesartan medoxomil and azelnidipine interact with each other to form a poorly soluble compound, and the dissolution property of olmesartan medoxomil decreases.

  As a result of intensive studies to solve the above problems, the present inventors have found that a pharmaceutical composition with improved dissolution can be obtained by blending polyvinyl alcohol or a vinyl alcohol copolymer. The present invention has been completed.

  The present invention relates to a pharmaceutical composition comprising (A) olmesartan medoxomil, (B) azelnidipine, and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer (particularly, a composition for preventing or treating hypertension). Use of olmesartan medoxomil and azelnidipine for the preparation of the above pharmaceutical composition (especially a composition for the prevention or treatment of hypertension), the pharmaceutical composition comprising a pharmacologically effective amount of olmesartan medoxomil and azelnidipine For the prevention or treatment of diseases (especially hypertension) administered to warm-blooded animals (especially humans), pharmaceutical compositions containing olmesartan medoxomil and azelnidipine (especially compositions for the treatment or prevention of hypertension) A method for improving the dissolution property of

That is, the present invention
(1) (A) olmesartan medoxomil; (B) azelnidipine; and (C) a pharmaceutical composition containing one or more compounds selected from polyvinyl alcohol and vinyl alcohol copolymers,
(2) The component (C) is one or more compounds selected from polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Pharmaceutical composition,
(3) The pharmaceutical composition according to (1), wherein component (C) is polyvinyl alcohol,
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the pharmaceutical composition is blended into a single preparation,
(5) The pharmaceutical composition according to (4), wherein the preparation is a solid preparation,
(6) The pharmaceutical composition according to (4), wherein the preparation is a powder, fine granules, granules, capsules or tablets,
(7) The pharmaceutical composition according to (4), wherein the preparation is a tablet,
(8) The pharmaceutical composition according to any one of (1) to (7), which is coated;
(9) The pharmaceutical composition according to (8), wherein component (C) is contained in the coating,
(10) The pharmaceutical composition according to any one of (1) to (9) for treating or preventing hypertension,
(11) A method for improving the dissolution property of olmesartan medoxomil using the pharmaceutical composition according to any one of (1) to (10).

  According to the present invention, it is possible to provide a pharmaceutical composition with improved dissolution, comprising (A) olmesartan medoxomil, (B) azelnidipine and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer. It becomes.

  The active ingredients of the pharmaceutical composition of the present invention are olmesartan medoxomil and azelnidipine.

  Olmesartan medoxomil, which is one of the active ingredients in the pharmaceutical composition of the present invention, can be easily produced according to the method described in Japanese Patent No. 2082519 (US Pat. No. 5,616,599) and the like.

  Azelnidipine which is one of the active ingredients in the pharmaceutical composition of the present invention can be easily produced according to the method described in Japanese Patent No. 1666755 (US Pat. No. 4,772,596) and the like. Azelnidipine can form acid addition salts, and these acid addition salts are also encompassed by the present invention. The acid part of the acid addition salt of azelnidipine is not particularly limited as long as it is an acid that can form an acid addition salt with azelnidipine. Examples of such acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like. , Nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid , Preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably Is hydrobromic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably Hydrobromic acid, methanesulfonic acid, or p-toluenesulfonic acid, still more preferably hydrobromic acid or methanesulfonic acid, and most preferably hydrobromic acid.

  Examples of the “polyvinyl alcohol and / or vinyl alcohol copolymer” in the pharmaceutical composition of the present invention include, for example, polyvinyl alcohol (OPADRY II 85F18422 manufactured by Colorcon), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR manufactured by BASF). Etc.), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT (registered trademark) manufactured by Daido Kasei Kogyo Co., Ltd.), and preferably polyvinyl alcohol. In the present invention, these can be used alone or in combination of two or more. The blending amount of polyvinyl alcohol and / or vinyl alcohol copolymer in the pharmaceutical composition is not particularly limited, but is preferably 1 to 90% by weight, more preferably 5 to 85% by weight of the formulation weight. It can mix | blend within the range. The polyvinyl alcohol and / or the vinyl alcohol copolymer may be uniformly contained in the whole preparation or may be contained in a part of the preparation. When providing a film coating layer, it may be contained in the film coating layer.

  The pharmaceutical composition of the present invention further comprises, as necessary, appropriate pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, and the like. Additives can be included.

  Examples of “excipients” used include sugar derivatives such as lactose, sucrose, sucrose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; Cellulose derivatives; gum arabic; dextran; or organic excipients such as pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; such as calcium hydrogen phosphate An inorganic excipient such as phosphate; carbonate such as calcium carbonate; or sulfate such as calcium sulfate can be used.

  Examples of “lubricants” used include stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bead wax or gay wax; boric acid; adipic acid Sulfates such as sodium sulfate; glycols; fumaric acid; sodium benzoate; D, L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrates; Or the above starch derivatives.

  Examples of the “binder” used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the same compound as the excipient.

  “Disintegrants” used include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or carboxymethyl starch or carboxymethyl starch Mention may be made of starch and cellulose modified chemically such as sodium.

  “Emulsifiers” used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate A cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

  “Stabilizers” used include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol or cresol Such phenols; thimerosal; dehydroacetic acid; or sorbic acid.

  Examples of the “flavoring agents” used include sweeteners such as sodium saccharin or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon or orange. it can.

  Examples of the “diluent” used include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, and polyvinylpyrrolidone. And magnesium aluminate metasilicate or mixtures thereof.

  In the pharmaceutical composition of the present invention, (A) olmesartan medoxomil, (B) azelnidipine, and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer may be in separate preparations and mixed uniformly. A compounding agent (single preparation) may be used. A compounding agent is preferred.

  The pharmaceutical composition in the present invention is preferably a solid preparation. For example, tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, fine granules, and powders Pills, chewables, troches and the like, preferably powders, fine granules, granules, capsules or tablets, more preferably tablets, and even more preferably (A). , (B) and (C) are multi-layer tablets formulated in separate layers.

  As a method for producing the preparation in the present invention, a general method described in a publication such as Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier Science Pub Co (December 1, 1993)) is used. There are no special restrictions.

  The tablet of the present invention is prepared by, for example, granulating, drying, and sizing the active ingredient together with excipients, binders, etc. by a method known per se, adding a lubricant, etc., mixing, and tableting. obtain. Here, the granulation can be carried out by any of wet granulation, dry granulation, and heat granulation methods. Specifically, a high-speed agitation granulator, a fluidized granulator / dryer, an extrusion It is performed using a granulator, a roller compactor, etc. In addition, after granulation, operations such as drying and sizing may be performed as necessary. A mixture of the active ingredient and excipient, binder, lubricant, etc. can also be directly compressed. The tablet of the present invention may be provided with at least one film coating.

  Coating is performed using, for example, a film coating apparatus, and examples of the film coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like. Can be mentioned.

  As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like may be used in combination. it can.

  Examples of the water-soluble film coating base include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer, and polyvinylpyrrolidone. Molecule: polysaccharides such as pullulan.

  Examples of enteric film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic Acrylic acid derivatives such as acid copolymer S; natural products such as shellac.

  Examples of the sustained-release film coating base include cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate / copolymer emulsion, and the like.

  Two or more kinds of the coating bases may be mixed and used at an appropriate ratio. Further, if necessary, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents, preservatives and the like can be contained.

  The dissolution property of the pharmaceutical composition of the present invention is measured according to the second dissolution test method (paddle method) of the JP General Test Method. For example, the paddle rotation speed is 75 rotations per minute, 900 mL of JP II second liquid (JP-2, pH 6.8) is used as the test liquid, and the test liquid 30 minutes after the start of the test is collected, The elution rate of olmesartan medoxomil can be calculated by filtering using a membrane filter and quantifying the filtrate using high performance liquid chromatography.

  The dosage and administration ratio of olmesartan medoxomil and azelnidipine, which are the active ingredients of the pharmaceutical composition of the present invention, can vary depending on various conditions such as the activity of individual drugs, patient symptoms, age, body weight and the like. The dose varies depending on symptoms, age, etc., but in the case of oral administration, olmesartan medoxomil 5 mg-80 mg (preferably 10 mg-40 mg), azelnidipine 8 mg-32 mg (preferably 8 mg-16 mg) per day for adults. It can be administered 1 to 6 times a day (preferably once a day) according to symptoms.

  Further, the dose ratio of olmesartan medoxomil and azelnidipine, which are the active ingredients of the pharmaceutical composition of the present invention, can also vary greatly. For example, the dose ratio of olmesartan medoxomil and azelnidipine is 1:50 by weight. Up to 50: 1, and preferably 1: 5 to 5: 1. The most preferred form is a tablet containing 20 mg / 16 mg or 10 mg / 8 mg of olmesartan medoxomil / azelnidipine.

  The pharmaceutical composition of the present invention includes, for example, hypertension or a disease derived from hypertension (more specifically, hypertension, heart disease [angina, myocardial infarction, arrhythmia, heart failure or cardiac hypertrophy], kidney disease [ It is effective for the prevention or treatment of diabetic nephropathy, glomerulonephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]).

EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to this.

Example 1
A mixed granule 1 was prepared using the components shown in Table 1 below and their amounts. Olmesartan medoxomil, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and lactose were mixed for 5 minutes using a high-speed agitation granulator (VG-10, Paulek, approx. 2 kg scale), then purified water was added and stirred for 3 minutes. And granulated. The resulting granulated product is made into a condyle using a screening mill (Fiore mini, Deoksugaku Kosakusho, φ10mm square sieve sieve), and a fluidized bed dryer (Glatt WST-5, Paulek) with an inlet temperature of 90 ° C. And dried with a screening mill (Comil 197S, Paulek, equipped with a mesh of φ1.143 mm), and granules 1 were obtained. Granule 1, crystalline cellulose, and magnesium stearate were weighed in the proportions shown in Table 1, and mixed using a V-type mixer to obtain mixed granule 1.

  Next, the mixed granule 2 was produced using the components and their amounts shown in Table 2 below. Azelnidipine and D-mannitol were weighed 1: 1 (weight ratio), mixed for 5 minutes using a high-speed stirring granulator (Henschel mixer FM-20, Mitsui Miike Seisakusho), and the mixture was then hammer milled (sample mill K II). WG-1, Fuji powder). Moreover, after mixing magnesium aluminate metasilicate and light anhydrous silicic acid using a high-speed agitation granulator (Henschel mixer FM20, Mitsui Miike Seisakusho Co., Ltd.), polysorbate 80 is added to this mixture to obtain a polysorbate 80 adsorption powder. It was. The obtained azelnidipine pulverized product, polysorbate 80 adsorbed powder, D-mannitol, carmellose calcium, low-substituted hydroxypropylcellulose, sodium hydrogen carbonate, light anhydrous silicic acid, high speed stirring granulator (VG-10, Paulek, about 2 kg) (Scale), an aqueous solution of hydroxypropyl cellulose (solid content concentration 6.5%) was added, and granulation was performed for 7.5 minutes with a high-speed agitation granulator (VG-10, Paulek). The resulting kneaded product was made into a condyle using a screening mill (tornado mill, FJ Stokes Corp., equipped with a φ10 mm square mesh sieve), and a fluidized bed dryer (Glatt WST-5, Paulek, with an inlet temperature of 90 ° C). ), And the granules were sized using a screening mill (tornado mill, FJ Stokes Corp., φ1.143 mm mesh) to obtain granules 2. Granule 2, magnesium aluminate metasilicate, light anhydrous silicic acid, talc, magnesium stearate are weighed in the proportions shown in Table 2 and mixed using a V-type mixer (Tokuju Kogakusho). Obtained.

  Next, with the formulation shown in Table 3, lactose (granulated powder) and magnesium stearate were weighed and mixed for 10 minutes with a V-type mixer (Tokuju Kogakusho) to obtain mixed granules 3.

  Next, the mixed granule 2 was adjusted to be filled with 260 mg in the first layer, the mixed granule 3 with 100 mg in the second layer, and the mixed granule 1 with 120 mg in the third layer. Using a 7.3 mm variant punch, the tablet was molded with a compression pressure of 2.5 tons.

  The obtained tablets were coated with OPADRY II 85F18422 (Colorcon Co., Ltd.), which is a coating base containing PVA (using a pan coating machine (Paurec)), and film-coated tablets 1 were obtained.

The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Comparative Example 1)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 1 were evaluated. The results are shown in Table 4.

(Comparative Example 2)
The tablet obtained by the production method shown in Example 1 was film coated with OPADRY II 33K28628 (manufactured by Colorcon) containing HPMC to obtain film-coated tablet 2. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Example 2)
In the formulation shown in Table 3, crystalline cellulose / light anhydrous silicic acid spray-dried product and magnesium stearate were weighed and mixed for 10 minutes with a V-type mixer (Tokuju Kogakusho) to obtain mixed granules 4.

  The mixed granule 2 shown in Example 1 was adjusted to 260 mg in the first layer, the mixed granule 4 to 100 mg in the second layer, and the mixed granule 1 to 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The resulting tablet was coated with OPADRY II 85F18422 which is a coating base containing PVA (using a pan coating machine (Paurec)) to obtain film-coated tablet 3.

  The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Comparative Example 3)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 2 were evaluated. The results are shown in Table 4.

(Comparative Example 4)
The tablets obtained by the production method shown in Example 2 were film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablets 4. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Example 3)
Lactose (granulated powder), low-substituted hydroxypropylcellulose, hydroxypropylcellulose, crystalline cellulose, and magnesium stearate are weighed according to the formulation shown in Table 3 and mixed for 10 minutes with a V-type mixer (Tokuju Kosakusho). As a result, a mixed granule 5 was obtained.

  The mixed granule 2 shown in Example 1 was adjusted to be 260 mg in the first layer, the mixed granule 5 was 100 mg in the second layer, and the mixed granule 1 was 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The obtained tablets were coated with OPADRY II 85F18422, which is a coating base containing PVA (using a pan coating machine (Paurec)), and film-coated tablets 5 were obtained.

  The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Comparative Example 5)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 3 were evaluated. The results are shown in Table 4.

(Comparative Example 6)
The film obtained by the production method shown in Example 3 was film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablet 6. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.


Example 4
In the formulation shown in Table 3, weigh lactose (granulated powder), crystalline cellulose, light anhydrous silicic acid spray-dried product, and magnesium stearate, and mix by mixing for 10 minutes with a V-type mixer (Tokuju Kosakusho). Granule 6 was obtained.

  The mixed granule 2 shown in Example 1 was adjusted to 260 mg in the first layer, the mixed granule 6 to 100 mg in the second layer, and the mixed granule 1 to 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The obtained tablet was coated with OPADRY II 85F18422 which is a coating base containing PVA (using a pan coating machine (Paurec)) to obtain film-coated tablet 7.

  The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Comparative Example 7)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 4 were evaluated. The results are shown in Table 4.

(Comparative Example 8)
The film obtained by the production method shown in Example 4 was film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablet 8. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Example 5)
Lactose (granulated powder), crystalline cellulose / light anhydrous silicic acid spray-dried product, magnesium metasilicate aluminate, light anhydrous silicic acid, magnesium stearate were weighed according to the formulation shown in Table 3, and a V-type mixer (Tokuju Works) The mixed granule 7 was obtained by mixing for 10 minutes.

  The mixed granule 2 shown in Example 1 was adjusted to be 260 mg in the first layer, the mixed granule 7 was 100 mg in the second layer, and the mixed granule 1 was 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The obtained tablet was coated with OPADRY II 85F18422, which is a coating base containing PVA (using a pan coating machine (Paurec)), and film-coated tablets 9 were obtained.

  The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Comparative Example 9)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 5 were evaluated. The results are shown in Table 4.

(Comparative Example 10)
The film obtained by the production method shown in Example 5 was film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablet 10. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.

(Example 6)
Commercially available Olmetec tablets (20 mg) and Calblock tablets (16 mg) were placed in one vessel, and the dissolution properties of olmesartan medoxomil were evaluated. This dissolution evaluation was made by dissolving or suspending 100 mg of polyvinyl alcohol in advance as a test solution at 75 revolutions per minute according to the dissolution test method method 2 (paddle method) described in the 14th revision of the Japanese Pharmacopoeia. In addition, 900 mL of JP 2nd liquid (JP-2) was used. A test solution 30 minutes after the start of the test was collected, filtered using a membrane filter having a pore size of 0.45 μm, the filtrate was quantified using high performance liquid chromatography, and the dissolution rate of olmesartan medoxomil was calculated (Varian: dissolution test). Instrument, Agilent technoloies: high performance liquid chromatography). The results are shown in Table 5.

(Comparative Example 11)
In the same manner as in Example 6, 20 mg of commercially available Olmetec tablet and 16 mg of Calblock tablet were placed in one vessel, and the dissolution property of olmesartan medoxomil was evaluated. However, 900 mL of JP 2nd liquid (JP-2) was used for the test liquid. The results are shown in Table 5.

(Test example)
In accordance with dissolution test method method 2 (paddle method) described in the 14th revision of the Japanese Pharmacopoeia, the test was conducted using 75 mL / min and 900 mL of JP2 solution (JP-2) as the test solution. It was. A test solution 30 minutes after the start of the test was collected and filtered using a membrane filter having a pore size of 0.45 μm, and the filtrate was quantified using high performance liquid chromatography to calculate the dissolution rate of olmesartan medoxomil (Varian: elution). Tester, Agilent technoloies: high performance liquid chromatography).

The test is performed on 3 tablets, and the average value is shown.

From Table 4 and Table 5, the pharmaceutical composition of this invention has improved the dissolution property of olmesartan medoxomil.

ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition with improved elution property containing (A) olmesartan medoxomil, (B) azelnidipine, and (C) polyvinyl alcohol or a vinyl alcohol-type copolymer is obtained.

Claims (11)

(A) Olmesartan medoxomil;
(B) Azelnidipine; and (C) A pharmaceutical composition containing one or more compounds selected from polyvinyl alcohol and vinyl alcohol copolymers.   The pharmaceutical composition according to claim 1, wherein the component (C) is one or more compounds selected from polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. .   The pharmaceutical composition according to claim 1, wherein component (C) is polyvinyl alcohol.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is blended into a single preparation.   The pharmaceutical composition according to claim 4, wherein the preparation is a solid preparation.   The pharmaceutical composition according to claim 4, wherein the preparation is a powder, fine granules, granules, capsules or tablets.   The pharmaceutical composition according to claim 4, wherein the preparation is a tablet.   The pharmaceutical composition according to any one of claims 1 to 7, which is coated.   The pharmaceutical composition according to claim 8, wherein component (C) is contained in the coating.   The pharmaceutical composition according to any one of claims 1 to 9, for treating or preventing hypertension.   A method for improving the dissolution property of olmesartan medoxomil using the pharmaceutical composition according to any one of claims 1 to 10.