KR20090094288A - Solid preparation - Google Patents

Abstract

Disclosed is a stable solid preparation containing olmesartan medoxomil and azelnidipine. Specifically disclosed is a solid preparation wherein olmesartan medoxomil and azelnidipine are separately arranged so that they are not in contact with each other.

Description

Solid Formulation {SOLID PREPARATION}

The present invention relates to a stable solid formulation containing olmesaltan medoxomil and azelnidipine.

Currently, angiotensin II receptor antagonists and calcium channel antagonists are widely used as medicines for the treatment or prevention of hypertension or heart disease. Angiotensin II receptor antagonists, renin-angiotensin-based inhibitors, are particularly effective in renin-dependent hypertension and have a protective effect against cardiovascular and renal failure. In addition, the calcium channel antagonist has an effect of sodium diuresis in addition to the vasodilation action, and thus is effective for body fluid retention (renin-independent) hypertension. Therefore, in combination with an angiotensin II receptor antagonist and a calcium channel antagonist, in addition to the inhibitory effect of the renin-angiotensin system by an angiotensin II receptor antagonist, calcium channel antagonism in vascular smooth muscle by a calcium channel antagonist, and secondary sodium excretion As a result, it is expected that a plurality of adults of hypertension can be simultaneously suppressed and stable and exhibit sufficient therapeutic or prophylactic effect of hypertension regardless of the etiology.

(5-methyl-2-oxo-1,3-dioxoren-4-yl) methyl4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 '-(1H-tetra Zol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylate (hereinafter referred to as olmesaltan medoxomil) is an excellent angiotensin II receptor antagonist for the treatment or prevention of hypertension and heart disease. It is known to be useful as a medicine (Japanese Patent Publication No. 2082519, US Patent Publication No. 5,616,599).

[Formula 1]

Olmesaltan Medocsomil

Olmesaltan Medoxomil is sold as Ormetec® and contains 5 mg, 10 mg, 20 mg or 40 mg of Olmesaltan Medoxomil as an active ingredient, and low-substituted hydroxypropyl cellulose, hydroxy as an additive. Propyl cellulose, crystalline cellulose, lactose, magnesium stearate.

Olmesaltan medoxomil is susceptible to hydrolysis, etc., because it has an ester group on the imidazole ring, and is hydrolyzed under acidic or basic conditions, resulting in the active metabolite 4- (1-hydroxy-1-methylethyl) -2-propyl. -1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazol-5-carboxylic acid (hereinafter referred to as RNH-6270).

[Formula 2]

In addition, (±) -2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine- 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 and heart disease, etc. (Japanese Patent Publication No. 1666755) US Patent Publication No. 4,772,596).

[Formula 3]

Azelnidipine

Azelnidipine is sold as a carbloc (trademark) tablet and contains 8 mg or 16 mg of azelnidipine as an active ingredient, and D-mannitol, carmellose calcium, low-substituted hydroxypropyl cellulose and hydrogen carbonate as additives. Sodium, polysorbate 80, magnesium metasilicate aluminate, hard silicic anhydride, hydroxypropyl cellulose, talc, magnesium stearate.

In the prior art, medicaments combining olmesaltan medoxomil and azelnidipine are known (International Publication No. 2004/067003 pamphlet), but stable solid formulations containing olmesaltan medoxomil and azelnidipine of the present invention are known. Not.

Patent Document 1: Japanese Patent Publication No. 2082519 (US Patent Publication No. 5,616,599)

Patent Document 2: Japanese Patent Publication No. 1666755 (US Patent Publication No. 4,772,596)

Patent Document 3: International Publication No. 2004/067003 Pamphlet

Disclosure of Invention

Problems to be Solved by the Invention

An object of the present invention is to provide a stable solid preparation containing olmesaltan medoxomil and azelnidipine, a stabilization method of a solid preparation containing olmesaltan medoxomil and azelnidipine, and the like.

In recent years, patients with hypertension tend to use a plurality of drugs, including drugs for treating complications, and it has been pointed out that this may be a cause of poor blood pressure control. Since the medication compliance decreases when the number of medications to be taken is large, it is considered that it is important to improve the medication compliance of the patient in order to realize reliable blood pressure control. Olmesaltan 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 certain antihypertensive effect, so as to improve the patient's medication compliance. There is a strong demand for the development of pharmaceutical formulations.

In general, when developing a solid preparation (mixing agent) containing two kinds of drugs, a prescription in which one active ingredient is added to the prescription of one monosaccharide is often used. However, in solid formulations containing olmesaltan medoxomil and azelnidipine, olmesartan and / or azelnidipine, even when based on either prescription of Ormetec® or Carbloc® It was found that the physical or chemical formulation stability of the compound deteriorated. This is because olmesaltan medoxomil has alkaline and unstable properties, but since azelnidipine has alkaline and stable properties, when one of the other active ingredients is added to a prescription, the added active ingredient becomes unstable. I can think of it. In short, since the carbloc (registered trademark) definition formulation is alkaline, adding olmesaltan medoxomill to it will make the olmesaltan medoxomill unstable, whereas the ormetec (registered trademark) definition formulation is not alkaline. Putting azelnidipine in can be thought to be unstable.

Means to solve the problem

MEANS TO SOLVE THE PROBLEM As a result of earnestly researching in order to solve the said subject, the present inventors discovered that the solid formulation containing olmesartan medoxomil and azelnidipine stabilized by isolate | separating and mixing so that each active ingredient may not contact each other, The invention has been completed.

The present invention provides stable solid preparations (particularly for the treatment or prevention of hypertension) containing olmesaltan medoxomil and azelnidipine, olme for preparing said solid preparations (particularly for the treatment or prevention of hypertension). Method of treating or preventing diseases (especially hypertension) of using saltan medoxomil and azelnidipine, administering said solid preparations containing pharmacologically effective amounts of olmesaltan medoxomil and azelnidipine to warm-blooded animals (especially humans) And stabilizing methods for solid preparations (particularly for the treatment or prevention of hypertension) containing olmesaltan medoxomil and azelnidipine.

That is, the present invention,

(1) a solid formulation containing olmesaltan medoxomil and azelnidipine, wherein the solid formulation is separately blended so that the active ingredients do not come into contact with 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, in which olmesaltan medoxomil and azelnidipine are blended in each layer,

(4) The solid preparation according to (3), wherein the multilayer tablet contains two-layered tablets, which contains 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-layer tablet, which contains olmesaltan medoxomil in the first layer and azelnidipine in the other layer sandwiched between the intermediate layers,

(6) The solid preparation according to (3), wherein the multilayer tablet includes an inner core and an outer layer, wherein the inner core contains olmesaltan medoxomil and the outer layer contains azelnidipine;

(7) The solid preparation according to (3), wherein the multilayer tablet comprises a nucleus tablet consisting of an inner core and an outer layer, wherein the inner core contains azelnidipine and the outer layer contains olmesartan medoxomill;

(8) the solid preparation according to (6) or (7) having 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 two or more selected from the group consisting of lactose, crystalline cellulose, and hard silicic anhydride,

(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 olmesaltan medoxomil and azelnidipine,

(13) A method for stabilizing a solid preparation containing olmesaltan medoxomil and azelnidipine, comprising using the solid preparation according to any one of (1) to (11).

(14) It provides the stabilization method of olmesartan medoxomil etc. which use the solid preparation in any one of (1)-(11).

Effects of the Invention

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

Best Mode for Carrying Out the Invention

The active ingredients of the solid preparations of the present invention are olmesaltan medoxomil and azelnidipine.

Olmesaltan 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 Publication No. 2082519 (US Pat. No. 5,616,599) or the like.

Azelenidipine, 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 Publication No. 1666755 (US Pat. No. 4,772,596) and the like. Azelnidipine can form acid addition salts, and these acid addition salts are also included in the present invention. The acid portion of the acid addition salt of azelnidipine is not particularly limited as long as it is an acid capable of forming an acid addition salt with azelnidipine. Examples of such acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and 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 hydrobromic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid. Preferably hydrobromic acid, methanesulfonic acid, or p-toluenesulfonic acid, still more preferably hydrobromic acid or methanesulfonic acid, Chapter preferably hydrobromic acid.

The term "stable solid formulation" in the present invention refers to a solid formulation in which the chemical stability of olmesartan medoxomil and / or azelnidipine in the solid formulation is maintained, and the content of RNH-6270 is preferably 8.66% (w / The content of less than w) and / or total impurities is less than 13.20% (w / w), more preferably, the content of RNH-6270 is less than 2.65% (w / w) and / or the content of total impurities is 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 RNH-6270 The content of is less than 1.10% (w / w) and / or the content of total impurities is less than 3.39% (w / w).

Stability can be measured using high performance liquid chromatography. From the chromatogram, the relative holding time, which is the ratio of the holding time of the standard material olmesartan medoxomill and the holding time of various flexible substances, is calculated, and the flexible substance can be identified from the relative holding time. have. From the ratio of the peak area of the various lead materials and the peak area of the standard material, the lead material content for the main drug is calculated. Stability is preferably determined by the content of the flexible material measured after being left at 40 ° C. 75% relative humidity for one month, and more preferably the content of the flexible material measured after being left at 40 ° C. 75% relative humidity for 6 months. Determined by

"Total impurity" in this invention means the sum total of the flexible substance derived from olmesaltan medoxomil and azelnidipine.

Examples of the "solid preparation" in the present invention include tablets (including sublingual tablets and disintegrating tablets in the oral cavity), capsules (including soft capsules and microcapsules), granules, fine granules, and powders. ), Pills, troches and the like, and are preferably tablets.

The term "multilayered tablet" in the present invention refers to a tablet (laminated tablet) in which various kinds of prescription ingredients are layered and compressed in a stepwise manner and accommodated in the same formulation, and preferably, both main medicines contain an inert additive. It is a tablet consisting of three layers having an olmesaltan medoxomil layer and an azelnidipine layer separated into an intermediate layer. Furthermore, you may have an additional layer on the outer side of an olmesaltan medoxomil layer and / or an azelnidipine layer. These additional layers may be for aesthetic purposes or may be for the purpose of masking the taste of the drug or of containing other active ingredients.

The "two-layered tablet" in this invention means the laminated tablet which consists of a 1st layer containing one active ingredient, and a 2nd layer containing the other active ingredient.

The "three-layered tablet" in this invention means the laminated tablet which consists of the 1st layer containing one active ingredient, the 2nd layer (intermediate layer) containing an inert additive, and the 3rd layer containing the other active ingredient. . Direct contact between the drugs can be avoided by the interlayer, thereby providing a more stabilized solid preparation.

The "nucleated tablet" in this invention means the tablet which coat | covered so that the inner core containing one drug may be wrapped by the outer layer containing another drug, and the inner core and outer layer may contact, and also avoid direct contact between drugs. For this purpose, the inner core may be covered with a polymer or a sugar to form an intermediate layer.

As an inert additive used for an intermediate | middle layer, if it is an additive which does not react with an active ingredient, it will not specifically limit, The additive etc. which are normally used as an excipient are mentioned. Such additives include, for example, sugar derivatives such as lactose, lactose (granulated powder), white sugar, glucose, mannitol or sorbitol; corn starch, potato starch, Starch derivatives such as starch or dextrins; cellulose derivatives such as crystalline cellulose, spray dry products of crystalline cellulose and hard silicic anhydride; gum arabic; dextran; or organic excipients such as pullulan; or hard silicic anhydride, synthetic aluminum silicate , Silicate derivatives such as calcium silicate or magnesium metasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or inorganic excipients such as sulfates such as calcium sulfate, preferably lactose (granulated powder). ), A spray dry product of crystalline cellulose and hard silicic anhydride, D-mannitol, magnesium aluminate silicate, and hard silicic anhydride, more preferably a spray dry product of crystalline cellulose and hard silicic anhydride. In addition, a lubricant may be used for the intermediate layer. Examples of the lubricant include, for example, stearic acid derivatives such as magnesium stearate, calcium stearate and sodium stearate; mineral resources such as talc; fatty acid derivatives such as sucrose fatty acid esters, and preferably magnesium stearate. to be.

The solid preparation of the present invention may further contain additives such as suitable pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, copulation agents, diluents, etc., as needed.

Examples of the "excipient" to be used include sugar derivatives such as lactose, white sugar, glucose, mannitol or sorbitol; corn starch, potato starch, Starch derivatives such as starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or organic excipients such as pullulan; or hard silicic anhydride, synthetic aluminum silicate, calcium silicate or magnesium aluminate silicate Silicate derivatives; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or inorganic excipients such as sulfates such as calcium sulfate.

As the "lubricant" to be used, for example, stearic acid; metal stearic acid salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or sperm; boric acid; adipic acid; sodium sulfate and The same sulfate; glycol; fumaric acid; sodium benzoate; D, L-leucine; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or the starch derivatives.

As a "binder" used, a compound similar to hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, or the said excipient is mentioned, for example.

Examples of the "disintegrant" to be used include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or internally crosslinked carboxymethyl cellulose sodium; crosslinked polyvinylpyrrolidone; or carboxy And chemically modified starches and celluloses such as methyl starch or carboxymethyl starch sodium.

Examples of the "emulsifier" to be used include, for example, colloidal clay such as bentonite or non-gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; and cationic interfaces such as benzalkonium chloride. Activator; or nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

Examples of the "stabilizer" to be used include, for example, parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; Merosal; dehydroacetic acid; or sorbic acid.

Examples of the "coating agent" used include sweeteners such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon or orange.

As the "diluent" to be used, for example, lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, Starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, or mixtures thereof.

As a manufacturing method of the formulation in this invention, what is necessary is just to manufacture using the general method described in publications, such as Powder Technology and Pharmaceutical Processes (D.Chulia et al., Elsevier Science Pub Co (December 1, 1993)), It is not particularly limited.

The multi-layered tablet of the present invention is, for example, by a method known per se, by direct compression molding of each layer containing the active ingredient, or by the conventional wet granulation or dry granulation of the active ingredient into each layer ( By compression) technique and then by compression molding each layer.

The two-layered tablet of the present invention can be prepared, for example, by the methods known per se, by the conventional wet granulation or dry granulation (compression) technique, respectively, followed by the first layer and the first layer. It can be prepared by compressing the second layer and joining both layers using a conventional two-layer tablet forming apparatus.

Moreover, you may form at least 1 layer of film coating in the two-layered tablet of this invention.

The three-layered tablet of the present invention can be used, for example, by means of a method known per se, by using conventional direct tableting granules or wet granulation or dry granulation, respectively. It can manufacture by a (compression) technique, and then, compresses a 1st layer, a 2nd layer, and a 3rd layer, and combines each layer using the conventional 3 layer tablet forming apparatus. Moreover, you may form at least 1 layer of film coating in the three layered tablet of this invention.

The nucleated tablet of the present invention can be produced by, for example, producing an inner core tablet to be an inner core part by a method known per se and then coating the inner core tablet with an outer layer using a nucleated tableting machine.

In addition, before the inner core tablet (inner core) is coated with an outer layer, a thin film coating may be performed. Moreover, the number of the said inner core tablets may be one, or multiple may be sufficient as one formulation. In addition, you may form at least 1 layer of film coating in the nucleated tablet of this invention.

Coating is performed using a film coating apparatus, for example, As a film coating base, For example, Sugar base, Water-soluble film coating base, Enteric film coating base, Sustained-release film coating A base etc. are mentioned.

White sugar is used as the base of the sugar, and may be used in combination of one or two or more selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like.

As a water-soluble film coating base, For example, Cellulose derivatives, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethylcellulose; Polyvinyl alcohol, Polyvinyl alcohol- Synthetic polymers such as polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methacrylate methyl copolymer, polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, macrogol; Polysaccharides, such as these, are mentioned.

Examples of the enteric film coating base include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L, methacrylic acid copolymer Acrylic acid derivatives, such as LD and methacrylic acid copolymer S; Natural products, such as shellac, etc. are mentioned.

As a sustained-release film coating base, cellulose derivatives, such as ethyl cellulose; acrylic acid derivatives, such as aminoalkyl methacrylate copolymer RS, ethyl acrylate, methyl methacrylate, and a copolymer emulsion, etc. are mentioned, for example.

The said coating base may mix and use the 2 or more types by an appropriate ratio. Furthermore, if necessary, additives such as suitable pharmacologically acceptable plasticizers, excipients, lubricants, concealing agents, coloring agents, and preservatives may be contained.

The dosage and ratio of olmesaltan medoxomil and azelnidipine, which are the active ingredients of the solid preparation of the present invention, can be changed by various conditions such as the activity of individual drugs, the symptoms, age, and weight of the patient. The dosage varies depending on symptoms and age, but in the case of oral administration, olmesaltan medoxomil 5mg-80mg (preferably 10mg-40mg) and azelnidipine 8mg-32mg (preferably 8mg-16mg) per adult Can be administered 1 to 6 times a day (preferably once a day) depending on the condition.

In addition, although the ratio of the dose of olmesaltan medoxomil and azelnidipine which is an active ingredient of the solid preparation of the present invention can also be drastically changed, for example, the dose ratio of olmesaltan medoxomil and azelnidipine is in terms of weight ratio. It may exist in the range of 1: 50-50: 1, Preferably it is 1: 5-5: 1. In the most preferred form, it is a tablet containing 20 mg / 16 mg or 10 mg / 8 mg of olmesaltan medoxomil / azellidipine.

The solid preparations of the present invention are, for example, a disease derived from hypertension or hypertension (more specifically, hypertension, heart disease [angina, myocardial infarction, arrhythmia, heart failure or cardiac hypertrophy], kidney disease [diabetic nephropathy (腎) I), glomerulonephritis or renal sclerosis] or cerebrovascular disease [cerebrovascular infarction or cerebral hemorrhage]).

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

(Example 1)

The mixed granules 1 were manufactured using the component shown in the following Table 1, and their quantity. Olmesaltan medoxomil, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and lactose were mixed for 5 minutes using a high-speed stirring granulator (VG-10, Faurek, about 2 kg scale), and then purified water was poured for 3 minutes. It was assembled by stirring. The obtained granulated material was confectioned using a screening mill (Fioremini, Tokuju Works, a sieve having a mesh of φ10 mm in width and width), and a fluidized bed dryer (Glatt WST-5, Faurek) having a blowing temperature of 90 ° C. After drying with, it was sized with a screening mill (comil 197S, Faurek, mesh mounting of? 1.143mm) to obtain granules (1). The granules (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 granules (1).

Next, the mixed granules 2 were manufactured using the component shown in the following Table 2, and their quantity. Azelnidipine and D-mannitol were weighed in a ratio of 1: 1 (weight ratio), respectively, and mixed for 5 minutes using a high-speed stirring granulator (Hensel mixer FM-20, Mitsui-Mike Co., Ltd.), and then the mixture was hammer mill (sample mill KIIWG-1). And funni powder). Moreover, after mixing magnesium aluminate silicate and hard silicic acid anhydrous using a high speed stirring granulator (Hensel mixer FM20, Mitsui-Mike Co., Ltd.), polysorbate 80 was injected into this mixture and the polysorbate 80 adsorption powder was obtained. . The obtained azelnidipine pulverized product, polysorbate 80 adsorption powder, D-mannitol, carmellose calcium, low-substituted hydroxypropyl cellulose, sodium hydrogencarbonate, and hard silicic anhydride were subjected to a high-speed stirring granulator (VG-10, Faurek, 2 kg scale), the aqueous solution of hydroxypropyl cellulose (solid content concentration 6.5%) was added, and granulation was performed for 7.5 minutes by the high speed stirring granulator (VG-10, Faurek). The resulting union was baked using a screening mill (tornade mill, FJStokes Corp., a sieve with a square mesh of φ10 mm), dried with a fluid bed drier (Glatt WST-5, Faurek) with a blowing temperature of 90 ° C. The granules were grained with a screening mill (tornade mill, FJStokes Corp., mesh mounted with a diameter of 1.143 mm) to obtain granules (2). The mixed granules (2) were obtained by weighing the granules (2), magnesium metasilicate, hard silicic anhydride, talc, and magnesium stearate in the ratios shown in Table 2, and mixing them using a V-type mixer (Tokuju Works). . Next, the filling granules 2 were charged and adjusted to be 260 mg on the first layer, and the mixed granules 1 were charged and adjusted to be 120 mg on the second layer, and a rotary tableting machine was used to feed 1.5 tons of φ9.5 mm. Molding was compressed by compression. The obtained tablet was coated with a coating solution (solid content concentration: 15%) consisting of hydroxypropyl cellulose, titanium oxide, talc, and purified water with a pan coater to obtain a film-coated tablet (1).

100 tablets of the obtained tablet were separated and subjected to a stability test for 1 month in a glass bottle (2 g included of a desiccant) under 40 ° C and 75% relative humidity. Table 1 shows the RNH-6270 content and total impurity content of the 1 month trial product.

(Comparative Example 1)

The mixed granules 1 and the mixed granules 2 shown in Example 1 were each mixed for 5 minutes in a V-type mixer at a ratio of 6:13, and then charged into a mortar having a diameter of 9.5 mm, and then used per rotary ball to 1.5 per ball. Molding was compressed with a compression pressure of tons. Film coating was performed similarly to what was shown in Example 1, and the film coat tablet (2) was obtained.

100 tablets of the obtained tablet were separated and subjected to a stability test for 1 month in a glass bottle (2 g included of a desiccant) under 40 ° C and 75% relative humidity. Table 1 shows the RNH-6270 content and total impurity content of the test product for 1 month of stability.

(Example 2)

260 mg of the mixed granules 2 shown in Example 1 were weighed and placed in a mortar having a long diameter of 14.0 mm and a short diameter of 6.5 mm. Then, D-mannitol was laminated in the same mortar, and 120 mg of the mixed granules 1 were further weighed. Into the same mortar and laminated, three-layer tablets were compressed at a compression pressure of 1.5 tons per ball with a hydraulic single tablet. The obtained tablets were coated in the same manner as in Example 1 to obtain a film coated tablet (3).

100 tablets of the obtained tablet were separated and subjected to a stability test for 1 month in a glass bottle (2 g included of a desiccant) under 40 ° C and 75% relative humidity. Table 1 shows the RNH-6270 content and total impurity content of the test product for 1 month of stability.

(Example 3)

Lactose (granulated powder), crystalline cellulose, hard silicic anhydride spray dry product, and magnesium stearate were mixed for 5 minutes using a V-type mixer by the prescription shown in Table 4 below to obtain a mixed granule (4). The mixed granules (2) shown in Example 1 were charged and adjusted to 260 mg on the first layer, the mixed granules (4) were packed and adjusted to the second layer to 100 mg, and 120 mg of the mixed granules (1) was further added. After filling adjustment was carried out, three-layer tablets were formed into tablets by compression pressure of 2.5 ton using balls of 15.0 mm long diameter and 7.3 mm short diameter using a rotary tablet press. The obtained tablets were coated with a coating solution (solid content concentration: 20%) consisting of polyvinyl alcohol (partially saponified), titanium oxide, talc, polyethylene glycol, and purified water with a pan coater to obtain a film coated tablet (4).

100 tablets of the obtained tablet were separated and subjected to a stability test for 1 month in a glass bottle (2 g included of a desiccant) under 40 ° C and 75% relative humidity. Table 1 shows the RNH-6270 content and total impurity content of the test product for 1 month of stability.

(Example 4)

Lactose (granulated powder), crystalline cellulose, hard silicic anhydride spray dry product, magnesium metasilicate aluminate, hard silicic anhydride, and magnesium stearate are mixed for 5 minutes using a V-type mixer according to the formulation shown in Table 4 below. Mixed granules (5) were obtained. As shown in Example 3, three-layered crystals were produced using the mixed granules 5 in the second layer, and a film-coated tablet 5 was obtained using the coating solution (solid content concentration: 20%) shown in Example 3. .

100 tablets of the obtained tablet were separated and subjected to a stability test for 1 month in a glass bottle (2 g included of a desiccant) under 40 ° C and 75% relative humidity. Table 1 shows the RNH-6270 content and total impurity content of the test product for 1 month of stability.

(Test example)

The test was carried out using high performance liquid chromatography. From the chromatogram, the relative holding time, which is the ratio of the holding time of the standard material olmesartan medoxomil and the holding time of the various flexible materials, is calculated, and the flexible material is identified from the relative holding time. The lead material content for the main drug was calculated from the ratio of the peak area of the various lead materials and the peak area of the standard material.

As shown in Table 3, the solid preparation of the present invention is low in content and total amount of impurities in the soft substance (RNH-6270) of olmesaltan medoxomil, and is excellent in chemical stability.

According to the present invention, a stable solid formulation containing olmesaltan medoxomil and azelnidipine is obtained.

Claims (14)

A solid preparation containing olmesaltan medoxomil and azelnidipine, wherein the active ingredient is separately blended so as not to contact each other. The method of claim 1, Solid preparation, wherein the solid preparation is in the form of a tablet. The method of claim 2, A solid formulation wherein the tablet is a multilayer tablet, in which olmesaltan medoxomil and azelnidipine are blended in each layer. The method of claim 3, wherein The multi-layered tablet is a two-layered tablet, wherein the first layer contains olmesaltan medoxomil and the second layer contains azelnidipine. The method of claim 3, wherein The multi-layered tablet is a three-layered tablet, in which the first layer contains olmesaltan medoxomil, and the other layer sandwiching the intermediate layer contains azelnidipine. The method of claim 3, wherein A solid preparation comprising a multi-layered tablet comprising an inner core and an outer layer, wherein the inner core contains olmesaltan medoxomil and the outer layer contains azelnidipine. The method of claim 3, wherein A solid preparation comprising a multi-layered tablet comprising an inner core and an outer layer, wherein the inner core contains azelnidipine and the outer layer contains olmesaltan medoxomil. The method according to claim 6 or 7, Solid preparation having an intermediate layer between the inner core and the outer layer. The method according to claim 5 or 8, Solid preparations containing excipients in the intermediate layer. The method of claim 9, A solid preparation wherein the excipient is one or two or more selected from the group consisting of lactose, crystalline cellulose and hard silicic anhydride. The method according to any one of claims 1 to 10, Solid preparations for the treatment or prevention of hypertension. A method of stabilizing a solid formulation containing olmesaltan medoxomil and azelnidipine. A method for stabilizing a solid preparation containing olmesaltan medoxomil and azelnidipine, wherein the solid preparation according to any one of claims 1 to 11 is used. The solid preparation of any one of Claims 1-11 is used, The stabilizing method of olmesartan medoxomil.