JP5241510B2 - Solid preparation - Google Patents

Description

  The present invention relates to a stable solid formulation containing 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 vascular smooth muscle by the calcium channel antagonist, and Secondary sodium excretion action makes it possible to simultaneously suppress the causes of multiple hypertension and is expected to show a stable and sufficient treatment or prevention effect of hypertension 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, and contains olmesartan medoxomil 5 mg, 10 mg, 20 mg or 40 mg as an active ingredient, and low-substituted hydroxypropylcellulose, hydroxypropylcellulose, crystalline cellulose, lactose as additives And magnesium stearate.

  Olmesartan medoxomil has an ester group on the imidazole ring and thus is susceptible to hydrolysis and the like, and is hydrolyzed under acidic or basic conditions to give 4- (1-hydroxy-1-methylethyl) -2 which is an active metabolite. -Propyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylic acid (hereinafter referred to as RNH-6270).

RNH-6270

(±) -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 combining olmesartan medoxomil and azelnidipine is known (WO 2004/067003 pamphlet), but a stable solid preparation containing olmesartan medoxomil and azelnidipine of the present invention is not known.
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 stable solid preparation containing olmesartan medoxomil and azelnidipine, a method for stabilizing a solid preparation containing olmesartan medoxomil and azelnidipine, and the like.

  In recent years, hypertensive patients tend to use a plurality of drugs including drugs for treating complications, and it has been pointed out that this may contribute to poor blood pressure control. As the number of drugs to be taken increases, the compliance is lowered. Therefore, in order to realize reliable blood pressure control, it is considered important to improve the patient's compliance. Olmesartan medoxomil, an angiotensin II receptor antagonist, and azelnidipine, a calcium channel antagonist, are widely used in the medical field as a combination that can be expected to have a more reliable antihypertensive effect, so as to improve patient compliance The development of a combination of both drugs is strongly desired.

  In general, when developing a solid preparation (compound formulation) containing two kinds of drugs, a formulation in which the other active ingredient is added to the formulation of either one is often used. However, in the solid preparation containing olmesartan medoxomil and azelnidipine, the physical or chemical properties of olmesartan and / or azelnidipine, regardless of the formulation of Olmetec (registered trademark) or Calblock (registered trademark) It has been found that the mixing stability becomes worse. This is because olmesartan medoxomil has an alkaline and unstable property, but azelnidipine has an alkaline and stable property, so when the other active ingredient is added to one of the formulations, the added active ingredient is not effective. It seems that it became stable. In other words, since the formulation of Calblock (registered trademark) tablets is alkaline, adding olmesartan medoxomil to this makes olmesartan medoxomil unstable, and conversely, the formulation of Olmetec (registered trademark) tablets is not alkaline. It is considered that azelnidipine became unstable when it was added.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have stabilized the solid preparation containing olmesartan medoxomil and azelnidipine by separately blending each active ingredient so as not to contact each other. As a result, the present invention has been completed.

  The present invention produces a stable solid preparation containing olmesartan medoxomil and azelnidipine (particularly, a preparation for treating or preventing hypertension), and said solid preparation (particularly, a preparation for treating or preventing hypertension). Use of olmesartan medoxomil and azelnidipine for the treatment of a disease (particularly hypertension) in which a solid preparation containing pharmacologically effective amounts of olmesartan medoxomil and azelnidipine is administered to a warm-blooded animal (particularly human) And a method for stabilizing a solid preparation containing olmesartan medoxomil and azelnidipine (particularly, a preparation for treatment or prevention of hypertension).

That is, the present invention
(1) A solid preparation containing olmesartan medoxomil and azelnidipine, wherein the active ingredients are separated and blended so as not to contact each other,
(2) The solid preparation according to (1), wherein the solid preparation is in the form of a tablet,
(3) The solid preparation according to (2), wherein the tablet is a multilayer tablet, and olmesartan medoxomil and azelnidipine are blended in separate layers,
(4) The solid preparation according to (3), wherein the multilayer tablet is a bilayer tablet, containing olmesartan medoxomil in the first layer and azelnidipine in the second layer,
(5) The solid preparation according to (3), wherein the multi-layered tablet is a three-layered tablet and contains olmesartan medoxomil in the first layer and azelnidipine in the other layer sandwiching the intermediate layer,
(6) The solid tablet according to (3), wherein the multilayer tablet is a dry-coated tablet comprising an inner core and an outer layer, the inner core contains olmesartan medoxomil, and the outer layer contains azelnidipine,
(7) The solid preparation according to (3), wherein the multilayer tablet is a dry-coated tablet comprising an inner core and an outer layer, the inner core contains azelnidipine, and the outer layer contains olmesartan medoxomil.
(8) The solid preparation according to (6) or (7), which has an intermediate layer between the inner core and the outer layer,
(9) The solid preparation according to (5) or (8), which contains an excipient in the intermediate layer,
(10) The solid preparation according to (9), wherein the excipient is one or more selected from the group consisting of lactose, crystalline cellulose, and light anhydrous silicic acid,
(11) The solid preparation according to any one of (1) to (10) for treating or preventing hypertension,
(12) A method for stabilizing a solid preparation containing olmesartan medoxomil and azelnidipine,
(13) A method for stabilizing a solid preparation containing olmesartan medoxomil and azelnidipine, wherein the solid preparation according to any one of (1) to (11) is used,
(14) Provided is a method for stabilizing olmesartan medoxomil, which comprises using the solid preparation according to any one of (1) to (11).

  According to the present invention, it is possible to provide a stable solid preparation containing olmesartan medoxomil and azelnidipine.

  The active ingredients of the solid preparation of the present invention are olmesartan medoxomil and azelnidipine.

  Olmesartan medoxomil which is one of the active ingredients in the solid preparation 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 solid preparation 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.

  The “stable solid preparation” in the present invention refers to a solid preparation in which the chemical stability of olmesartan medoxomil and / or azelnidipine in the solid preparation is maintained, and preferably the content of RNH-6270 is 8.66%. (w / w) and / or total impurities content is less than 13.20% (w / w), more preferably RNH-6270 content is less than 2.65% (w / w) and And / or the content of total impurities is less than 7.35% (w / w), more preferably the content of RNH-6270 is less than 1.59% (w / w) and / or the content of total impurities Is less than 5.89% (w / w), most preferably the content of RNH-6270 is less than 1.10% (w / w) and / or the content of total impurities is 3.39% (w / w).

  Stability can be measured using high performance liquid chromatography. From the chromatogram, the relative retention time, which is the ratio of the retention time of olmesartan medoxomil, which is the standard substance, and the retention time of various related substances is calculated, and the related substance can be identified from the relative retention time. The content of the related substance relative to the main drug is calculated from the ratio of the peak areas of the various related substances and the peak area of the standard substance. Stability is preferably determined by the content of related substances measured after standing at 40 ° C. and 75% relative humidity for 1 month, more preferably after standing at 40 ° C. and 75% relative humidity for 6 months. Determined by the content of related substances.

  The “total impurities” in the present invention refers to the sum of related substances derived from olmesartan medoxomil and azelnidipine.

  Examples of the “solid preparation” in the present invention include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, fine granules, powders, pills, and troches. An agent etc. can be mentioned, A tablet is preferred.

  The “multi-layer tablet” in the present invention refers to a tablet (layered tablet) in which several kinds of prescription ingredients are layered in layers and compression-molded and stored in the same dosage form. A tablet consisting of three layers having an olmesartan medoxomil layer and an azelnidipine layer separated by an intermediate layer containing an inert additive. Further, an additional layer may be provided outside the olmesartan medoxomil layer and / or the azelnidipine layer. These additional layers may be aesthetic purposes, may be masking the taste of the drug, or may contain other active ingredients.

  The “bilayer tablet” in the present invention refers to a laminated tablet comprising a first layer containing one active ingredient and a second layer containing the other active ingredient.

  The “three-layer tablet” in the present invention comprises a first layer containing one active ingredient, a second layer (intermediate layer) containing an inert additive, and a third layer containing the other active ingredient. This is a laminated tablet. The intermediate layer can avoid direct contact between drugs and provide a more stable solid formulation.

  The “nucleated tablet” in the present invention refers to a tablet in which an inner core containing one drug is covered with an outer layer containing another drug, and the inner core and the outer layer may be in contact with each other. For the purpose of avoiding direct contact between them, the inner core may be provided by coating the inner core with a polymer or sugar.

  The inactive additive used in the intermediate layer is not particularly limited as long as it is an additive that does not react with the active ingredient, and examples thereof include additives that are usually used as excipients. Examples of such additives include sugar derivatives such as lactose, lactose (granulated powder), sucrose, sucrose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; Cellulose derivatives, such as spray-dried products of cellulose, crystalline cellulose and light anhydrous silicic acid; gum arabic; dextran; or organic excipients such as pullulan; or light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or metasilicate aluminum Silicate derivatives such as magnesium acid; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or inorganic excipients such as sulfates such as calcium sulfate. Is lactose (granulated powder), crystalline cellulose and light anhydrous Acid spray-dried products, D- mannitol, magnesium metasilicate aluminate, a light anhydrous silicic acid, more preferably a spray-dried product of crystalline cellulose and light silicic anhydride. Further, a lubricant may be used for the intermediate layer. Examples of the lubricant include stearic acid derivatives such as magnesium stearate, calcium stearate and sodium stearate fumarate; mineral resources such as talc; and fatty acid derivatives such as sucrose fatty acid ester. Is magnesium stearate.

  If necessary, the solid preparation of the present invention may further contain appropriate pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, and the like. An agent can be included.

  “Excipients” used include, for example, 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 mentioned.

  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 agent” 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.

  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 multilayer tablet of the present invention can be prepared by, for example, directly compressing each layer containing an active ingredient by a method known per se, or by subjecting each layer of an active ingredient to a usual wet granulation or dry granulation (compression) technique. It can be manufactured by manufacturing and then compression molding each layer.

In the bilayer tablet of the present invention, for example, the first layer and the second layer are each produced by a conventional wet granulation or dry granulation (compression) technique by a method known per se. It can be produced by compressing the layers and combining the two layers using a conventional two-layer tableting machine.
The bilayer tablet of the present invention may be provided with at least one film coating.

  The trilayer tablet of the present invention uses, for example, conventional direct compression granules for the first layer, the second layer (intermediate layer), and the third layer, respectively, in a manner known per se, or wet granulation or dry type. It can be manufactured by granulating (compressing) technique, and then compressing the first layer, second layer, third layer and bonding each layer using a conventional three-layer tablet forming apparatus. The trilayer tablet of the present invention may be provided with at least one film coating.

The dry-coated tablet of the present invention is produced, for example, by preparing an internal core tablet that becomes an inner core part by a method known per se, and then coating the inner core tablet with an outer layer part using a dry-coated tableting machine. Can do.
The inner core tablet (inner core) may be coated with a thin film prior to coating with the outer layer. Further, the inner core tablet may be one in one preparation or a plurality thereof. Furthermore, the dry coated 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, sodium carboxymethylcellulose; polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid -Synthetic polymers such as methyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, macrogol; 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 dosage and administration ratio of olmesartan medoxomil and azelnidipine, which are the active ingredients of the solid preparation 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.

  The dose ratio of olmesartan medoxomil and azelnidipine, which are the active ingredients of the solid preparation of the present invention, can also vary greatly. For example, the dose ratio of olmesartan medoxomil and azelnidipine is from 1:50 to It can be in the range of 50: 1, 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 solid preparation of the present invention contains, 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 [diabetes mellitus]. Effective 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, approximately 2 kg scale), then purified water was added and the mixture was 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) each and 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 KIIWG- 1 and 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, the mixed granule 2 is adjusted to be filled to 260 mg in the first layer, the mixed granule 1 is adjusted to be filled to 120 mg in the second layer, and a φ9.5 mm punch is used with a rotary tableting machine. Molded and compressed with a compression pressure of 1.5 tons. The obtained tablets were coated with a coating solution (solid content concentration: 15%) composed of hydroxypropylcellulose, titanium oxide, talc, and purified water with a pan coating machine to obtain film-coated tablets 1.

100 tablets obtained were taken and subjected to a stability test for 1 month in a glass bottle (enclosed with 2 g of a desiccant) at 40 ° C. and 75% relative humidity. Table 3 shows the amount of RNH-6270 and the total amount of impurities of the one-month-old stability test.
(Comparative Example 1)
The mixed granule 1 and the mixed granule 2 shown in Example 1 were mixed at a ratio of 6:13 for 5 minutes with a V-type mixer, then put into a φ9.5 mm mortar, and punched with a rotary tableting machine. The tablet was molded and compressed at a compression pressure of 1.5 tons per unit. A film coat was applied in the same manner as shown in Example 1 to obtain a film-coated tablet 2.

  100 tablets obtained were taken and subjected to a stability test for 1 month in a glass bottle (enclosed with 2 g of a desiccant) at 40 ° C. and 75% relative humidity. Table 3 shows the amount of RNH-6270 and the total amount of impurities of the one-month-old stability test.

(Example 2)
260 mg of the mixed granule 2 shown in Example 1 was weighed, put into a mortar having a major axis of 14.0 mm and a minor axis of 6.5 mm, D-mannitol was laminated on the same mortar, and 120 mg of the mixed granule 1 was weighed Then, it was put into the same die and laminated, and a three-layer tablet was compressed with a compression pressure of 1.5 tons per punch with a hydraulic single-punch tableting machine. The obtained tableted product was coated in the same manner as shown in Example 1 to obtain film-coated tablets 3.

100 tablets obtained were taken and subjected to a stability test for 1 month in a glass bottle (enclosed with 2 g of a desiccant) at 40 ° C. and 75% relative humidity. Table 3 shows the amount of RNH-6270 and the total amount of impurities of the one-month-old stability test.
(Example 3)
Lactose (granulated powder), crystalline cellulose / light anhydrous silicic acid spray-dried product, and magnesium stearate were mixed in the formulation shown in Table 4 below for 5 minutes using a V-type mixer to obtain mixed granules 4. Filling adjustment of the mixed granule 2 shown in Example 1 to 260 mg in the first layer, filling adjustment of the mixed granule 4 to 100 mg, laminating in the second layer, and further mixing granule 1 to 120 mg After the filling was adjusted, a three-layer tablet was molded and compressed with a rotary tableting machine using a punch having a major axis of 15.0 mm and a minor axis of 7.3 mm at a compression pressure of 2.5 tons. The obtained tableted product is coated with a coating solution (solid content concentration: 20%) composed of polyvinyl alcohol (partially saponified), titanium oxide, talc, polyethylene glycol and purified water with a pan coating machine to obtain a film-coated tablet 4 It was.

100 tablets obtained were taken and subjected to a stability test for 1 month in a glass bottle (enclosed with 2 g of a desiccant) at 40 ° C. and 75% relative humidity. Table 3 shows the amount of RNH-6270 and the total amount of impurities of the one-month-old stability test.

Example 4
Lactose (granulated powder), crystalline cellulose / lightly anhydrous silicic acid spray-dried product, magnesium metasilicate magnesium aluminate, lightly anhydrous silicic acid, magnesium stearate with the formulation shown in Table 4 below, mixed for 5 minutes using a V-type mixer. A mixed granule 5 was obtained. In the same manner as shown in Example 3, the mixed granule 5 is used in the second layer to prepare a three-layer tablet, and the film-coated tablet using the coating solution (solid content concentration: 20%) shown in Example 3 5 was obtained.

100 tablets obtained were taken and subjected to a stability test for 1 month in a glass bottle (enclosed with 2 g of a desiccant) at 40 ° C. and 75% relative humidity. Table 3 shows the amount of RNH-6270 and the total amount of impurities of the one-month-old stability test.
(Test example)
The test was performed using high performance liquid chromatography. From the chromatogram, the relative retention, BR>, which is the ratio of the retention time of olmesartan medoxomil, the standard substance, and the retention time of various related substances is calculated, and the related substances are identified from the relative retention time. The content of related substances relative to the active ingredient was calculated from the ratio of the peak areas of various related substances and the peak areas of the standard substances.

As shown in Table 3, the content of the olmesartan medoxomil related substance (RNH-6270) and the total amount of impurities in the solid preparation of the present invention are lower than those of the single-layer tablet, and the chemical stability is improved. Are better.

  According to the present invention, a stable solid preparation containing olmesartan medoxomil and azelnidipine can be obtained.

Claims (11)

A solid preparation containing olmesartan medoxomil and azelnidipine, wherein the active ingredient is separated and blended into separate layers so as not to contact each other, comprising RNH-6270 in the multilayer tablet Is a solid preparation containing lactose only in the olmesartan medoxomil-containing layer as an active ingredient-containing layer, with a content of less than 2.65% (w / w) . The solid preparation according to claim 1 , wherein the multilayer tablet is a bilayer tablet, the first layer contains olmesartan medoxomil, and the second layer contains azelnidipine. 2. The solid preparation according to claim 1 , wherein the multilayer tablet is a three-layer tablet, and olmesartan medoxomil is contained in the first layer and azelnidipine is contained in the other layer sandwiching the intermediate layer. The solid preparation according to claim 1 , wherein the multilayer tablet is a dry-coated tablet comprising an inner core and an outer layer, the inner core contains olmesartan medoxomil, and the outer layer contains azelnidipine. The solid preparation according to claim 1 , wherein the multilayer tablet is a dry-coated tablet comprising an inner core and an outer layer, the inner core contains azelnidipine, and the outer layer contains olmesartan medoxomil. The solid preparation according to claim 4 or 5 , which has an intermediate layer between the inner core and the outer layer. The solid preparation according to claim 3 or 6 , wherein the intermediate layer contains an excipient. The solid preparation according to claim 7 , wherein the excipient is one or more selected from the group consisting of lactose, crystalline cellulose, and light anhydrous silicic acid. The solid preparation according to any one of claims 1 to 8 , for the treatment or prevention of hypertension. A method for stabilizing a solid preparation containing olmesartan medoxomil and azelnidipine, wherein the solid preparation according to any one of claims 1 to 9 is used. A method for stabilizing olmesartan medoxomil, comprising using the solid preparation according to any one of claims 1 to 9 .