TW200835525A - Method for improvement of elution - Google Patents

Abstract

The present invention provides a method for improving dissolution of the solid preparation comprising olmesartan medoxomil and azelnidipine. The said solid preparation is prepared by the separate way of olmesartan medoxomil and azelnidipin each other being out of contact.

Description

200835525 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a method for improving the solubility of a solid preparation containing olmesartan medoxomil and azelnidipine. [Prior Art] Angiotensin I I receptor antagonists and calcium ion channel antagonists are widely used today as medicines for the treatment or prevention of hypertension or heart disease. Angiotensin I I receptor antagonists, which are inhibitors of the renin-angiotensin system, are particularly effective against renin-dependent hypertension and exhibit protective effects against cardiovascular or renal pelvic disorders. Further, since the calcium ion channel antagonist has a sodium diuretic action in addition to the vasodilating action, it is also effective for humoral storage (renin non-dependent) hypertension. Therefore, if an angiotensin receptor antagonist and a calcium channel antagonist are used, in addition to the inhibitory effect of the renin-angiotensin system derived from an angiotensin II receptor antagonist, plus calcium ion Channel antagonists of vascular smooth muscle calcium channel sputum resistance and secondary sodium excretion, while inhibiting the formation of multiple hypertension causes, and expect to show the treatment or preventive effect of hypertension regardless of the disease . (5-Methyl-2-keto-1,3-dioxolan-4-yl)methyl 4-(1.hydroxy-1-methylethyl b-2-propyl-1-[2' -(1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate (hereinafter referred to as olmesartan medoxomil) is an excellent angiotensin II receptor antagonist, It is known to be useful as a medicine for the treatment or prevention of hypertension, heart disease, etc. (Japanese Patent No. 2082 5 19, 200835525, US Pat. No. 5,616,599)

(Omesartan has been sold under the 〇lme tec® (registered trademark) ingot, containing the active ingredient olmesartan medoxomil 5 mg, 10 mg, 20 mg or 40 mg, and low-substituted hydroxypropyl cellulose as an additive. , hydroxypropyl cellulose, crystalline cellulose, lactose, magnesium stearate. Further, (earth)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl) 3-(1-Diphenylmethylazetidin-3-yl)ester 5-isopropyl 5-carboxylate (hereinafter referred to as adipine), which is an excellent calcium ion channel An antagonist is known to be useful as a medicine for the treatment or prevention of hypertension, heart disease, etc. (Japanese Patent No. 1 6667 5 5, US Pat. No. 4,772, 5 96). II (h3c>2hc-oc,

Adipine has been sold as Calblock® (registered trademark) ingots containing 200835525 active ingredient adipine 8mg or i6mg, and contains D-mannitol and carboxymethylcellulose calcium as additives. Low-substituted hydroxypropyl cellulose, sodium hydrogencarbonate, polysorbate 80, magnesium metasilicate aluminate, light phthalic anhydride, hydroxypropyl cellulose, talc, magnesium stearate. In the prior art, the combination of olmesartan medoxomil and adipine is known (International Publication No. 2004/067003), but the solid preparation containing olmesartan medoxomil and adipine is not known. The dissolution improvement method. Patent Document 1: Japanese Patent No. 20825 1-9 (U.S. Patent No. 5,6,6,5,99) Patent Document 2: Japanese Patent No. 1 66675 5 (U.S. Patent No. 4,772,5,96) Patent Document 3: International Publication No. 2004/067003 booklet. Disclosure of the Invention Problems to be Solved by the Invention An object of the present invention is to provide a method for improving the dissolution property of a solid preparation containing olmesartan medoxomil and aflatabine. In recent years, patients with hypertension have a tendency to use a plurality of agents containing a drug for the treatment of phlegm, which is considered to be a cause of poor blood pressure control. Since the medication compliance is reduced once the number of medications taken is reduced, in order to achieve accurate blood pressure control, it is considered important to improve the patient's medication compliance. The vasopressin II receptor antagonist olmesartan medoxomil and the calcium channel antagonist adendipine are widely used in medical facilities because they can be expected to have a more effective combination of therapeutic effects of hypertension, so that 200835525 The patient's medication compliance improved, and the development of the two agents was strongly expected. In general, when a solid preparation (mixture) containing two types of pharmaceuticals is developed, it is often necessary to add a prescription for the other active ingredient or a two-layer tablet to a single dose. However, in the solid preparation containing olmesartan medoxomil and adipine, the dissolution of olmesartan medoxomil over time is known as the basis of the Olmetec® (registered trademark) ingot and Calblock® (registered trademark) ingot. Will become lower. Means for Solving the Problems As a result of intensive research to solve the above-mentioned problems, the present inventors have found that by separating and disposing the respective active ingredients in the preparation, a layer in which the two main drugs are inactive is sandwiched into a three-layer ingot. The reduction in the dissolution of olmesartan meitoxide at the time is improved, and the present invention has been completed. The present invention provides a method for improving the dissolution of olmesartan medoxomil containing a solid preparation of olmesartan medoxomil and aflatabine (particularly a preparation for prevention or treatment of hypertension), and the manufacture of the aforementioned solid preparation (especially hypertension) For the prophylactic or therapeutic use), the use of olmesartan medoxomil and adipine in a pharmacologically effective amount of the aforementioned solid preparation containing olmesartan medoxomil and adipine is administered to a warm-blooded animal (especially human) A method of preventing or treating a disease, particularly hypertension. That is, the present invention provides: (1) A method for improving the dissolution property of a solid preparation comprising olmesartan medoxomil and adipine; (2) (1), which is characterized by olmesartan medoxomil and 200835525 The method described in (1) or (2), wherein the solid preparation is in the form of a tablet; (4) the method described in (3), wherein the tablet is in the form of a tablet; (5) The method described in (4), wherein the multi-layer ingot is a three-layer ingot, the first layer contains olmesartan medoxomil, and the other layer sandwiching the intermediate layer contains abdipine; (6) (4) In the method described, the multi-layer ingot is a core ingot composed of an inner core and an intermediate layer and an outer layer, wherein the inner core contains olmesartan medoxomil and the outer layer contains adipine; the method described in (7) (4), the multi-layer ingot is a core a core ingot comprising an intermediate layer and an outer layer, wherein the inner core contains a dextromethine, and the outer layer contains olmesartan medoxomil; the method according to any one of (8) to (7), wherein the intermediate layer contains an excipient (9) The method according to (8), wherein the excipient is selected from the group consisting of lactose and crystalline fiber (1) The method according to any one of (1) to (9), which is for improving the dissolution property of olmesartan medoxomil; (11) The method according to any one of (1) to (1) for use in the treatment or prevention of hypertension or the like. EFFECT OF THE INVENTION According to the present invention, it is possible to provide a method for improving the dissolution property of a solid preparation containing olmesartan medoxomil and aflatabine. 200835525 [Embodiment] The best form for carrying out the invention The active ingredient of the solid preparation of the present invention is olmesartan medoxomil and apodamine zp. olmesartan medoxomil which is one of the active ingredients in the solid preparation of the present invention can be based on Japanese patent It is easy to manufacture by the method described in the publication of U.S. Patent No. 5,6,6,5,9,9, and the like. Adesodipine, which is one of the active ingredients in the solid preparation of the present invention, can be easily produced by the method described in Japanese Patent No. 1666755 (U.S. Patent No. 4,772,596). Adesodipine forms an acid addition salt, and such acid addition salts are also included in the present invention. The acid portion of the adipine acid addition salt is not particularly limited as long as it can form an acid addition salt with adipine, and examples of such an acid include hydrochloric acid, hydrobromic acid, and hydroiodic acid. Sulfuric acid, 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 It is 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 or methanesulfonic acid. Acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably hydrobromic acid, methanesulfonic acid, or p-toluenesulfonic acid, more preferably hydrobromic acid or methanesulfonic acid, most preferably hydrogen Bromo acid. The term "improvement in dissolution" in the present invention means improvement in a solid preparation in a stability test (60 ° C and/or 40 ° C 7 5 % relative humidity, and / or 25 ° C 60% relative humidity). The dissolution of olmesartan medoxomil is preferably 75. After the stability test, the dissolution rate of olmesartan medoxomil in the dissolution test of the sample is -10-200835525, more than 75%, preferably 8 0% or more, more preferably 85% or more. The dissolution property of the solid preparation of the present invention is measured in accordance with the second method of the dissolution test method (paddle method) of the general test method of the Japanese market. For example, the slurry is rotated 75 times per minute, and the second liquid (JP-2, pH 6.8) is used as the test liquid. The test liquid after 30 minutes from the start of the test is used, and the pore size is 0.45 μηι. The membrane filter was filtered, and the filtrate was quantified by high-speed liquid chromatography, and the dissolution rate of olmesartan medoxomil was calculated. Examples of the "solid preparation" of the present invention include a tablet (including a sublingual tablet, an orally disintegrating ingot), a capsule (including a soft capsule, a microcapsule), a granule, a fine granule, a powder, and a lozenge. A tongue tablet or the like is preferably a tablet. In the present invention, the "multilayer ingot" is a type of index component which is formed by laminating in layers and compressed and formed into a tablet (layered ingot) in the same dosage form, preferably having two main drugs to contain inactive A tablet of the olmesartan medoxomil layer and the three layers of the adipine layer separated by an intermediate layer of the additive. Further, an additional layer may be present on the outer side of the olmesartan medolate layer and/or the adipine layer. These additional layers may be aesthetically pleasing, or may be intended to mask the medicinal taste and contain other active ingredients. The "three-layer ingot" in the present invention is a laminated layer composed of a first layer containing one active ingredient, a second layer containing an inactive additive (intermediate layer), and a third layer containing the other active ingredient. . The intermediate layer can avoid direct contact between drugs and improve dissolution. The "nuclear ingot" in the present invention is a tablet containing a core containing a drug of the other side, and the core is connected to the outer layer, and serves as a direct contact between drugs. You can set the middle layer of the kernel with a high score of -11-200835525 or sugar. The inactive additive to be used in the intermediate layer is not particularly limited as long as it does not react with the active ingredient, and examples thereof include additives used as usual excipients. As such an additive, for example, a sugar derivative such as lactose, lactose (granulated powder), white sugar, glucose, mannitol or sorbitol; a starch derivative such as corn starch, potato starch, α-starch or dextrin; a cellulose derivative such as a crystalline cellulose, a crystalline cellulose, and a spray dried product of light phthalic anhydride; an arabic gum; a dextran; or an organic excipient such as a diglycan; or a light phthalic anhydride, synthetic a phthalate derivative such as aluminum citrate, calcium citrate or magnesium bismuth phthalate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; or an inorganic excipient such as a sulfate such as calcium sulfate. Preferred is lactose (granulated powder), spray dried product of crystalline cellulose and light phthalic anhydride, D-mannitol, magnesium metasilicate aluminate, light phthalic anhydride, more preferably crystalline cellulose and light sand A spray dried product of an acid anhydride. Also, a lubricant can be used for the intermediate layer. Examples of the lubricant include stearic acid derivatives such as magnesium stearate, calcium stearate, and sodium fumarate; mineral resources such as talc; and fatty acid derivatives such as sucrose fatty acid esters, preferably stearic acid. Magnesium acid. The solid preparation of the present invention may, if necessary, contain a suitable pharmacologically acceptable additive such as an excipient, a lubricant, a binder, a breaker, an emulsifier, a stabilizer, a flavoring agent, a diluent, and the like. Examples of the "excipient" to be used include sugar derivatives such as lactose, white sugar, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; and crystallization. Cellulose derivatives such as cellulose, gum arabic; dextran; or organic -12-200835525 excipients such as meglucan; or light phthalic anhydride, synthetic aluminum citrate, calcium citrate or partial An inorganic excipient such as a citrate derivative such as magnesium citrate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; or a sulfate such as calcium sulfate. Examples of the "lubricant" to be used include stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal vermiculite; waxes such as beeswax or cetyl wax; Boric acid; adipic acid; sulfate such as sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; D, L-leucine; dodecyl sulfate such as sodium dodecyl sulfate or dodecyl magnesium sulfate a tannic acid such as phthalic anhydride or citric acid water; or the above starch derivative. Examples of the "binding agent" to be used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the same excipients as described above. Compound. Examples of the "cracking agent" to be used include cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, or internal cross-linked carboxymethylcellulose sodium; Cross-linked polyvinylpyrrolidone; or chemically modified starch/cellulose such as carboxymethyl starch or sodium carboxymethyl starch. Examples of the "emulsifier" to be used include a clay clay such as bentonite or VEE GUM®; a metal hydroxide such as magnesium hydroxide or aluminum hydroxide; and an anion such as sodium dodecyl sulfate or calcium stearate. a surfactant; a cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as a polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid ester or a sucrose fatty acid ester. Examples of the "stabilizer" to be used include, for example, methyl p-hydroxybenzoate or p-hydroxybenzoic acid ester such as propyl-p-propyl alcohol, chlorohydrin, benzyl alcohol or phenylethyl alcohol; Benzyl ammonium chloride; phenols such as phenol or cresol; sulfur sulphate; dehydroacetic acid; or sorbic acid. Examples of the "flavoring and odorizing agent" to be used include a sweetener such as saccharin sodium or aspartame; a sour material such as citric acid, malic acid or tartaric acid; or a flavoring agent such as menthol, lemon or orange. Examples of the "diluent" to be used include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, and propylene glycol. Glycerin, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate or a mixture of these. The method for producing the preparation of the present invention can be produced by using the general method described in Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier Science Pub. Co ( December 1, 1993)), etc., without particular limitation. . The multilayer ingot of the present invention can be directly compression-molded, for example, by a method known per se, or each of the active ingredients can be produced in each layer by a usual wet granulation or dry granulation (compression) method, and then, by Each layer was produced by compression molding. The three-layer ingot of the present invention can be used, for example, by a method known per se, by using the usual direct ingot granules or wet granulation or dry granulation by using the first layer, the second layer (intermediate layer) and the third layer. The (compression) method is produced, and then the first layer, the second layer, and the third layer are compressed, and each layer is produced by bonding using a usual three-layer ingot forming apparatus. Further, the three-layer ingot of the present invention may be provided with at least one film coating. -14- 200835525 The core ingot of the present invention can be produced, for example, by forming a core ingot of a core portion by a method known per se, and then coating the core ingot with a core ingot machine. Further, the core ingot (core) may be coated with a film before being coated on the outer layer. Further, the above-mentioned core ingot may have one core ingot in one preparation, or may have plural. Further, the core ingot of the present invention may be provided with at least one film coating. The coating is carried out, for example, by using a film coating device, and examples of the film coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a slow release film coating base, and the like. . The sugar-based base may be one or more selected from the group consisting of talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, and trimeric glucose. . Examples of the water-soluble film coating base include celluloses such as hydroxypropylcellulose hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethylcellulose. Derivatives; polyvinyl alcohol, polyvinyl alcohol _ polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl acetal diethylamine acetate, aminoalkyl group A synthetic polymer such as a acrylate copolymer, a polyvinylpyrrolidone or a polyethylene glycol; a polysaccharide such as a trimeric glucose or the like. Examples of the enteric film coating base include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like. A cellulose derivative; an acrylic acid derivative such as a methacrylic acid copolymer L, a methacrylic acid copolymer LD or a methacrylic acid copolymer S; a natural product such as shellac or the like. -15- 200835525 As a slow release film coating base, for example, a cellulose derivative such as ethyl cellulose; an aminoalkyl methacrylate copolymer RS, ethyl acrylate·methyl methacrylate· An acrylic acid derivative or the like of a copolymer emulsion or the like. The above-mentioned coating base may be used in combination of two or more kinds in an appropriate ratio. Further, if necessary, it may contain additives such as a suitable pharmacologically acceptable plasticizer, excipient, lubricant, concealing agent, coloring agent, preservative, and the like. The administration amount and administration ratio of the olmesartan medoxomil and the adipine in the active ingredient of the solid preparation of the present invention may vary depending on the activity of the individual agent, the symptoms of the patient, the age, the body weight, and the like. The dosage varies depending on the symptoms, age, etc., and when administered orally, the daily dosage of olmesartan medoxomil 5 mg-80 mg (preferably 10 mg-40 mg) and adipine flat 8 mg-32 mg (preferably 8mg-16mg) can be administered from 1 to 6 times a day (preferably once a day). Moreover, the ratio of the dosage of the olmesartan medoxomil and the adipine in the active ingredient of the solid preparation of the present invention is also greatly changed, for example, the ratio of the ratio of the dose of olmesartan medoxomil to adipine is '1: In the range of 5 0 to 5 0 : 1, preferably 1: 5 to 5: 1. The most preferred form is a lozenge containing olmesartan medoxomil/ adipine in an amount of 20 mg/16 mg or l〇mg/8 mg. The solid preparation of the present invention is, for example, effective for preventing or treating hypertension or a disease derived from hypertension (more specifically, 'hypertension, palpitations, angina, myocardial infarction, arrhythmia, heart failure or heart Hypertrophy], renal pelvic disease [diabetic nephropathy, spheroid nephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]). Embodiments - 16 - 200835525 Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited thereto. (Example 1) Mixed particles 1 were produced using the same amounts of the components shown in Table 1 below. Olmesartan medoxomil, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and lactose are mixed with a speed-spreading machine (VG-10' Powrex' about 2kg scale) for 5 minutes, then mixed with pure water. 3 minutes, granulation. The obtained granules were granulated using a screening mill (Fiore, Deshou Work Station, a pore size sieve of 0 〇mm angle), and a fluidized bed dryer at a temperature of 90 °C (Glatt WST- After drying in 5, Powrex), the granules were obtained by granulating in a sieving machine (COMIL 197S, Powrex, apparatus 01.143 mm mesh). The granule 1, crystalline cellulose and magnesium stearate were weighed in the proportions shown in Table 1, and mixed with a V-type mixer to obtain mixed granules 1. Next, the mixed particles 2 were produced by using the same amounts as those shown in the following Table 2. Each scale 1 : 1 (weight ratio) of adipine and D-mannitol was mixed by a high-speed stirring granulator (Henschel Mixer FM-20, Mitsui Miike Co., Ltd.) for 5 minutes. The mixture was pulverized in a Hammer mill (Sample mill KII WG-1, Fuji Paudal). Further, magnesium metasilicate aluminate and light phthalic anhydride were mixed by a high-speed stirring granulator (Henschel mixer FM20, Mitsui Miike Seisakusho Co., Ltd.), and then polysorbate 80 was added to the mixture to obtain a polysorbate. 80 adsorption powder. The obtained adipine pulverized product, polysorbate 80 adsorption powder, D-mannitol, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, sodium hydrogencarbonate, light phthalic anhydride in high-speed stirring granulation The machine (VG-10, Powrex, about 2kg gauge -17-200835525 mold) was mixed, and an aqueous solution of hydroxypropylcellulose (solid concentration: 6.5%) was added to a high-speed stirring granulator (VG-10, Powrex). Granulation in 7.5 minutes. The resulting scouring compound was granulated by a sieving machine (Tornado Mill, F. J. Stokes Corp., apparatus with a pore size sieve of 10 mm), and a fluidized bed dryer was introduced at a temperature of 90 °C. After drying in Glatt WST-5, Powrex), the granules were granulated in a sifter (cyclone pulverizer, F. J. Stokes Corp., apparatus 0 1.143 mm mesh) to obtain granule 2. Granules 2, magnesium metasilicate aluminate, light phthalic anhydride, talc, and magnesium stearate were weighed in the proportions shown in Table 2, and mixed using a V-type mixer (Deshou Works) to obtain mixed particles 2. Next, in the formulation shown in Table 3, the lactose (granulated powder) and magnesium stearate were weighed and mixed in a V-type mixer (Deshou Work Station) for 1 minute to obtain mixed particles 3. Next, the 260 mg of the mixed granule 2 is mixed in the first layer, the 100 mg of the mixed granule 3 is in the second layer, and the 120 mg of the mixed granule 1 is formed in the third layer. In the machine, a special-shaped crucible having a long diameter of 15 mm and a short diameter of 7.3 mm was used, and the ingot was formed by a compression compression of 20.5 tons to obtain a tablet 1. The obtained tablet 1 was evaluated at 6 (the valence of the TC stability test, after 1 week, and after 2 weeks (the dissolution rate of olmesartan after 30 minutes), and the results are shown in Table 4. ( Comparative Example 1) The 260 mg of the mixed granule 2 obtained in the method shown in Example 1 was adjusted in the first layer and the 1200 mg of the mixed granule 1 in the second layer, and the long diameter was 1 in the rotary tableting machine. Shaped crucible with a diameter of 5 mm and a diameter of 7.3 mm, formed by compression compression of 2 · 5 tons -18- 200835525 Ingots 'obtained tablets 2. Evaluation of the obtained tablet 2 at the beginning of the stability test at 60 ° C, 1 The dissolution after week and after 2 weeks (the dissolution rate of olmesartan medoxomil after 30 minutes), the results are shown in Table 4. (Example 2) As shown in Table 3, the amount of crystalline cellulose • light 矽The anhydride spray-dried product, magnesium stearate, was mixed in a V-type mixer (Deshou Work Center) for 1 minute to obtain mixed particles 4. The 260 mg of the mixed granule 2 shown in Example 1 was mixed in the first layer, 100 mg. The granules 4 are adjusted in the second layer, and the 120 mg of the mixed granules 1 are adjusted in the third layer. In the rotary tableting machine, a profiled cymbal having a long diameter of 15 mm and a short diameter of 7.3 mm is used, and 2 5 The tablet was compressed and formed into a tablet to obtain a tablet 3. The dissolution of the obtained tablet 3 at the start of the stability test at 60 ° C, after 1 week, and after 2 weeks (the dissolution of olmesartan meitate after 30 minutes) The results are shown in Table 4. (Example 3) According to the prescription shown in Table 3, the amount of lactose (granulated powder), low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, crystalline cellulose, hard Magnesium citrate, mixed in a V-type mixer (Deshou Work Center) for 1 〇 minutes to obtain mixed granules 5. The 260 mg of the mixed granules 2 shown in Example 1 was mixed with the first layer, 100 mg of granules 5 In the second layer, 120 mg of the mixed particles 1 is adjusted in the manner of the third layer, and a shaped crucible having a long diameter of 15 mm and a short diameter of 7.3 mm is used in the rotary tableting machine, and the ingot is formed by a compression molding of 2.5 tons. Lozenges 4. Evaluating the dissolution of the obtained tanning agent 4 at the beginning of the stability test at 60 ° C, after 1 week, and after 2 weeks (the dissolution rate of olmesartan after 30 minutes), the results are shown in -19 - 200835525 Table 4. (Test Example) According to the 臼2 method (paddle stir t 190 m L as the test liquid, the liquid color layer is dissolved and tested in the tester) The dissolution test method described in the item of the 14th correction of the Bureau, the rotation of 75 times per minute 'use the second liquid (jP-2) test liquid for the test, and use the test 30 minutes after the start of the test. • A membrane filter of 4 5 μπι pore size was used for filtration, and the filtrate was subjected to high-speed precipitation to calculate the dissolution rate of olmesartan medoxomil (Varian: , Agilent technoloies: high-speed liquid chromatography). Line 3 ingots, expressed as their average 値. -20- 200835525 [Table l] Ingredient content (parts by weight) Olmesartan Medoxomil 20 Low-substituted hydroxypropylcellulose 20 Lactose 66.6 Hydroxypropylcellulose 2. 5 Granules 1 109.1 Crystalline cellulose 10 Magnesium stearate 0 9 Mixed particles 1 Total (mg) 120 [Table 2] Engineering name Ingredient content (parts by weight) Adipine adipine flat 16 Ground product D - Mannitol 16 Polysorbate polysorbate 80 40 80 Adsorption powder Magnesium metasilicate magnesium silicate 78 Light phthalic anhydride 20 D - Mannitol 3 Low-substituted hydroxypropyl cellulose 28 Intragranular component Carboxymethylcellulose calcium 15 Sodium hydrogencarbonate 12 Light phthalic anhydride 2 Hydroxypropyl fiber Prime 12 granule 2 242 magnesium metasilicate magnesium silicate 10 granule external component light phthalic anhydride 2 talc 2 magnesium stearate 4 mixed granule 2 total (mg) 260 -21 - 200835525 [Table 3] Example Example 1 Example 2 Example 3 Mixed granules mixed granules 3 Mixed granules 4 Mixed granules 5 Ingredient (parts by weight) Content (parts by weight) Content (parts by weight) Lactose (granulated powder) 99 - 66.6 Crystalline cellulose ·Light phthalic anhydride - 99 - Spray dried product Low substitution hydroxypropyl cellulose - 20 hydroxypropyl cellulose - 2.5 Crystalline cellulose - 10 Magnesium metasilicate magnesium aluminate — — — Light phthalic anhydride — — — magnesium stearate 1 1 0.9 Total (mg) 100 100 100 [Table 4] Example Example 1 Example 2 Example 3 Comparative Example 1 Mixed particles of the first layer mixed particles 2 Mixed particles 2 Mixed particles 2 Mixed particles 2 Mixed particles of the second layer Mixed particles 3 Mixed particles 4 Mixed particles 5 Mixed particles 1 Mixed particles of the third layer Mixed particles 1 Mixed particles 1 Mixed particles 1 Μ j\ \\ Formula name lozenge 1 Lozenge 3 Lozenges 4 Lozenges 2 Dissolution rate of olmesartan meitate after 30 minutes (%) At the beginning of stability test 95.9 86.1 91.6 87.4 60°C After 8 weeks of storage 89.2 79.1 87.4 70.5 60°C After 2 weeks of storage 87.8 76.1 83.9 64.8 As can be seen from Table 4, the solid preparation of the present invention improves the dissolution of olmesartan medoxomil. Industrial Applicability According to the present invention, the dissolution properties of the solid form -22-200835525 containing olmesartan medoxomil and adipine can be improved. [Simple description of the diagram] Μ . j \ \\ [Main component symbol description] 〇 J\ \\ -23

Claims (1)

200835525 X. Patent application scope: 1 · A method for improving the dissolution of a solid preparation, which comprises olmesartan medoxomil and azelnidipine. 2. The method of claim 1 of the patent scope, characterized in that olmesartan medoxomil and aflatoxin are separated and dispensed in a non-contact manner. 3. The method of claim 1 or 2, wherein the solid preparation is in the form of a tablet. 4. The method of claim 3, wherein the tablet is a multi-layered sharp. 5 · For example, the method of applying the patents to the four brothers, in which the multi-layered lake is a three-layer lake, the first layer contains olmesartan medoxomil, and the other layer sandwiching the middle layer contains a dextromethorphan. The method of item 4, wherein the multi-layer ingot is a core ingot composed of an inner core, an intermediate layer and an outer layer, wherein the inner core contains olmesartan medoxomil and the outer layer contains adipine. 7. The method of claim 4, wherein the multi-layer ingot is a core ingot, an intermediate layer, and a core ingot, wherein the core contains adipine, and the outer layer contains olmesartan medoxomil. The method of any one of claims 5 to 7, wherein the intermediate layer contains an excipient. 9. The method of claim 8, wherein the excipient is one or more selected from the group consisting of lactose, crystalline cellulose, and light phthalic anhydride. The method of any one of claims 1 to 9 for improving the dissolution of olmesartan medoxomil. The method of any one of claims 1 to 1 which is for the treatment or prevention of hypertension. -24- 200835525 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: Μ 〇 J V \\ 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: