TW201028150A - Solid pharmaceutical composition comprising amlodipine and losartan and process for producing same - Google Patents

Abstract

The present invention relates to a solid pharmaceutical composition for preventing or treating cardiovascular disorders comprising amlodipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof, which exhibits high dissolution rates of amlodipine and losartan even under a low pH condition and improved storage stability.

Description

201028150 VI. Description of the Invention: [Technical Field] The present invention relates to an amlodipine or a pharmaceutically acceptable 5-salt thereof and losartan or a pharmaceutically acceptable salt thereof. A solid pharmaceutical composition for preventing or treating a cardiovascular disorder, and a method of producing the same. L· Body Chair] Background of the Invention In the treatment of blood pressure, the blood pressure itself is relatively simple, and the blood pressure is maintained within a normal range on a consistent basis, for reducing the risk of complications such as coronary heart disease and Cardiovascular diseases such as stroke, heart failure and myocardial infarction. Thus, antihypertensive agents must be effective for long-term treatment of hypertension. Further, advanced treatment using a combination of two or more drugs having different pharmacological effects can improve the preventive effect or the therapeutic effect, 15 while reducing the side effects caused by long-term administration of the mono-drug. Antihypertensive drugs worthy of the idea include diuretics, sympathetic inhibitors, and vasodilators. Vasodilators are the most widely prescribed anti-high-pressure drugs, and are classified into several categories according to their pharmacological effects, including ACE (angiotensin-converting 6|) inhibitors, angiotensin receptor antagonists, and calcium channel blockade. Agent. 2〇Ammonia level is 3-ethyl-5-methyl-2-(2-aminoethoxy-methylphenyl)-6-methyl-1,4-dihydro-3,5- The common name for pyridine dicarboxylate. Ammoniapine besylate is currently sold under Novasc (trade name). Ammoniadipine is a long-acting calcium channel blocker' which can be used to treat cardiovascular disorders such as angina, hypertension, and congestive heart failure. 3 201028150 Losartan is 2-butyl-4-气-1-[[2,_(ih-tetrazol-5-yl)[1,1,_biphenyl]-4-yl]methyl]_iH The common name of _imidazole _5_methanol is disclosed in U.S. Patent Nos. 5,608,075; 5,138,069; and 5,153,197. Losartan potassium is commercially available from Cozaar (trade name). Losartan blocks the interaction between vasopressin 5 and its receptor, mainly in the treatment of hypertension, heart failure, ischemic peripheral circulatory disorders, myocardial ischemia (angina), diabetic neuropathy and glaucoma. Also used to prevent heart failure after myocardial infarction. The inventors have found that a combination formulation comprising amlodipine and losartan having different pharmacological activities can be used for the prevention or treatment of cardiovascular disorders, and has been developed to have such an optimized aerobic and phytochemical properties. Satan combination composition. SUMMARY OF THE INVENTION SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a solid pharmaceutical composition comprising amlodipine and a losar 15 tan, which has a high dissolution rate of ammonia gas and losartan even under low pH conditions. And improved storage stability. According to one aspect of the present invention, there is provided a solid pharmaceutical composition for preventing or treating a cardiovascular disorder comprising amlodipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof. The composition of the present invention 2 includes amlodipine and losartan, preferably in a form separated from each other, and more preferably in a granular form separated from each other. Further, controlling the amount of losartan results in the optimum solubility of ammonia sulphate and losartan in the compositions of the present invention. Brief Description of the Drawings 4 201028150 The foregoing and other objects and features of the present invention will be more apparent from the following description of the invention together with the accompanying drawings, which are shown in the accompanying drawings: 5 10 15 Figure 1: Preparation of Example 1 and Comparative Example 1 The dissolution rate of amlodipine at 0.01 N HCl (pH 2.0) was observed in the ingot and the ammonia gas (trade name) ingot (Test Example 1); Fig. 2: Ammonia gas was observed for the ingots prepared in Examples 1 to 4. The dissolution rate of the ground at 0.01 N HC1 (pH 2.0) (Test Example 2); Figure 3: The ammonia gas level was observed in the artificial gastric juice (pH 1.2) for the ingots prepared in Examples 1, 3 and 7 and Comparative Examples 1 and 2. And the dissolution rate of 1·〇1Ν HC1 (pH 2.0) (Test Example 3); Figure 4: Ammonia observed for the ingots prepared in Examples 4 to 6 and Comparative Example 2 and the ammonia gas (trade name) ingot The dissolution rate of sputum in 〇〇1N HC1 (pH 2.0) (Test Example 4); and Figure 5: Ingots prepared in Examples 1, 3 and 7 and Comparative Examples 2 and 2 and Koza (trade name) ingots The dissolution rate of losartan in artificial gastric juice (pH 丨 2) and 〇〇 1N HC1 (pH 2.0) was observed (Test Example 5). t embodiment; J. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The solid pharmaceutical composition of the present invention comprising amlodipine and losartan has a high dissolution rate of ammonia gas and losartan even at a low pH, thereby comparing The conventional single-formulation 'achieves the preventive or therapeutic effect of an improved cardiovascular condition while reducing the side effects of both drugs. The amlodipine used in the present invention may be in a variety of pharmaceutically acceptable salt forms. The pharmaceutically acceptable salts of ammodipine include hydrogen acid 20 201028150 salts, hydrobromides, sulfates, phosphates, acetates, maleates, fumarates, lactates, oxalic acid Salt, citrate, gluconate, besylate and camphor sulfonate, but not limiting. Among these salts, ammoxipine benzenesulfonate and camphorsulfonate are preferred, and an ammoxigenate 5 brain acid salt is more preferred. Meanwhile, the ammonia gas level used in the present invention may be an ammonia gas racemate and an S-ammonia level. The losartan used in the present invention may be one of a plurality of pharmaceutically acceptable salt forms. A pharmaceutically acceptable salt of the preferred losartan useful in the present invention is losartan. 10 In the composition of the present invention, the amount of amlodipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof is expressed in a weight ratio of 1:2.5 to 1:20, And preferably in the range of: 5 to 丨: 1〇. The compositions of the present invention provide improved prophylactic or therapeutic effects of cardiovascular disorders such as angina pectoris, hypertension, arterial vasospasm, deep venous blood thrombosis, cardiac hypertrophy, cerebral infarction, congestive heart failure, and myocardial infarction. When a combination formulation of ammonia gas and losartan is prepared simply by mixing two drugs, the gelation of losartan is disadvantageously occurred. Losartan is readily soluble in pure water or is extremely easy to release at relatively high pH (e.g., pH 6 8), but at low pH (e.g., ΡΗ2·0 or pH 1.2) it is extremely slow to release due to gelation. 2 In the case of the commercially available losartan preparation, that is, the Koza (trade name), the dissolution rate in the pH range of 1.2 to 2.0 at 30 minutes is less than 3%. In a combination formulation of amlodipine and losartan, the ammonia level may be latched inside the formulation due to the gelation of losartan. Further, the group 6 201028150 formulation prepared by simply mixing ammonia gas and losartan has extremely poor storage stability, mainly due to undesired chemistry between amlodipine, losartan and excipients. The reaction is so. In order to overcome the aforementioned problems such as losartan gelation and stability reduction, a combination formulation of amlodipine and losartan must be prepared by isolating amlodipine from losartan. As an example of the physical separation of amlodipine from losartan to prepare a combined formulation, the two-layer ingot is prepared by blending the separated particles of ammonia flat into one ingot' with the mixture containing losartan. Mix and mix the resulting mixture into a two-layer ingot. However, there are several problems with this method. 10 A special double-layer press is required, and double mass deviation often occurs, resulting in a decrease in productivity due to a decrease in the speed of the spindle. Thus, research and development of a pharmaceutical composition which can be formulated by a conventional tablet press and a preparation method thereof are required. Also included within the scope of the invention is a combination formulation of amlodipine and losartan wherein the amlodipine or a pharmaceutically acceptable salt thereof and a losartan or a pharmaceutically acceptable salt thereof are physically separated and Separate granulation reduces contact between the two drugs. Thus, it is preferred that the present invention provide a solid pharmaceutical composition comprising the amlodipine and losartan particles separated from each other. According to an embodiment of the present invention, the amlodipine and losartan combination formulation in which the particles of amlodipine and losartan are opened to each other can be prepared by a method comprising the following steps (1) Ammoniadipine or its pharmaceutically acceptable salt and losartan or its pharmaceutically acceptable salt are separately obtained to obtain individual fractions; sigh (2) mixed lions. Through the foregoing, the combination formulation of the present invention prepared by the method of the present invention does not have a decrease in stability. The problem is that the specific surface area of the particles is reduced and the individual drugs are surrounded by the excipients used for 201028150, so the ammonia gas granules and Luo The mixing of the sultan particles reduces the contact size between the two drugs. Compare the comparison! The combined formulation is a tablet obtained by simply mixing ammonia gas and losartan, and the combined formulation of Examples 1 to 7 prepared by the method has a dissolution rate of amlodipine (refer to the first 1)) also has the high stability of ammonia level (refer to Table 2). The compositions of the present invention comprise a pharmaceutically acceptable carrier or excipient in each of the ammoniapine particles and losartan particles. Pharmaceutically acceptable carriers or traits include microcrystalline cellulose, lactose, mannitol, sodium citrate, calcium citrate, glycine, sucrose, disintegrating agents (eg sodium starch glycolate, cross-linking) Cellulose sodium, complex bismuth and cross-povidone and board-forming binders (eg, polyethylidene carbaryl, propylmethylcellulose (HPMC), hydroxypropyl cellulose) (HPC), sucrose, gelatin and acacia gum. Further, the composition further comprises a lubricant such as magnesium stearate 'stearic acid, glyceryl citrate and talc. Although this is the case, the particles are separated from each other. The solid pharmaceutical composition of amlodipine and losarzil is still at risk of unsatisfactory release of losartan due to the gelation of losartan under low p 。 conditions. The bioavailability of the formulation is expected to be a problem. The undesired effect is caused by the fact that when the 2 〇 formulation is administered orally, the formulation is first exposed to acidic gastric juice having a low pH value. Thus, the pH value of a normal adult stomach is considered to be in the range of 1.0 to 3.5. Loss of Cmax of Losartan after food absorption About 10%, there is a need to develop a formulation that has a high losartan dissolution rate in the normal pH range of the stomach 'ie pH 1.0 to 3.5. 8 201028150 The inventors found that the dissolution rate of ammonia and losartan is large. This is particularly the case depending on the amount of losartan, especially at low pH. Therefore, the scope of the present invention also includes a solid pharmaceutical composition containing a specific amount of losartan which optimizes the dissolution rate of amlodipine and losartan. 5 having the pH value from L〇 to 2·0, that is, the pH value of the normal adult stomach having the high dissolution rate of ammonia gas and losartan, the composition of the invention comprising ammonia gas and losartan And the amount of losartan in a range of from 3% to 25% by weight, more preferably from 5% to 22.3% by weight, relative to the total weight of the composition. When the losartan content is 25% by weight or less , ammonia gas and Luo 10 Shatan increase the solubility rate at low pH. In particular, it contains 25% by weight.

Or the combination of the following contents of losartan, the release of ammonia level even under low pH conditions is excellent, especially the formulation can meet the dissolution standard of ammonia level, that is, at pH 1. 〇~2.0 Dissolve 80% or more in 30 minutes (refer to Figures 2 to 4). In addition, comparing the Koza (trade name) bond, that is, the conventional single 15 losartan formulation, the combination formulation containing 25% by weight or less of losartan has a significantly higher Loxa at low pH. Tan dissolution rate (refer to Figure 5). Thus, it is expected that the combined formulation of the present invention will exhibit significantly higher bioavailability of ammonia terpine and losartan. At the same time, when the losartan is less than 3% by weight, the overall size of the formulation is too large, which is not conducive to the patient's compliance. According to another embodiment of the present invention, the scope of the present invention also includes a solid pharmaceutical composition comprising particulate ammoniapine and losartan which are separated from each other and based on the total weight of the composition. The amount of losartan is in the range of 3% to 25% by weight. 201028150 Further 'the present invention provides a solid pharmaceutical composition comprising particulate losartan' wherein the percentage of fine particles passing through a 75 micron mesh is less than 50%, preferably less than 25%, and more preferably less than 1%. %. In this respect, the inventors have found that the dissolution rate of ammoniapine and losartan, except for the total amount of losartan, clearly depends on the particle size of the losartan particles, especially at low pH. In particular, it has been found that a decrease in the ratio of fine particles in the losartan granules leads to an improvement in the dissolution rate of the ammonia level and the losartan. Thus, in accordance with yet another embodiment of the present invention, the scope of the present invention also provides a solid pharmaceutical composition of particulate ammoniapine and losartan separated from each other, wherein the losartan granule portion passes through 75 micrometers. The percentage of fine particles is less than 50%. The present invention further encompasses a stabilizer such as an antioxidant which acts to enhance the stability of the ammonia level against undesirable reactions between the ammonia level and its pharmaceutically acceptable excipient during the blending process, and Fight against deformation of ammonia level due to light or moisture over time. Representative examples of the antioxidant used in the present invention include butylated hydroxyindole benzene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitic acid, and ethyldiaminetetraacetic acid (EDTA). , sodium metabisulfite and mixtures thereof. Among the above antioxidants, the butylated hydroxy oxime is preferred in the present invention. According to still another embodiment of the present invention, a method of preparing a solid pharmaceutical composition comprising particulate amlodipine and losartan separated from each other in the scope of the present invention includes the following steps: a) A mixture of losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable 10 201028150 excipient is granulated and dried to obtain losartan granules; ^ ammonia chloride or its (iv) acceptable salt and _ The age of the excipients can be granulated with the granules and the money (4) 氯 氯 氯 氯 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 1 pay t 干 dry = Γ. In the granulation method, the conventional wet granulation technique or the composition of the present invention can be administered orally, in a form of a tablet, a capsule or a multiparticulate, including oral, oral, and sublingual administration. Give. (d) The route of administration of the composition must be determined by the clinician based on the patient's symptoms and needs. = It is difficult to formulate the composition of the invention into an ingot type. From the hair 2#, her W coat layer can be made up of urrr high molecular weight compounds that can be formed. In order to facilitate the administration of drugs and the amount of cockroaches, the amount should be minimized, based on the total weight of the formulation, = can be about 1% to the weight ratio of the broth, preferably to the amount of the coating, according to the conventional method of coating Any amount = line. Prepared by the above method. 1 Reduced under conditions. (4) The composition is simple and extremely light under conventional storage conditions, and is resistant to light and water. Wai. The following examples are intended to illustrate the invention without limiting its example 1: Preparation of a combination tanning agent. (1) - Losartan granule fraction _ 50.0 mg Losartan unloading 11 201028150 10 15 Microcrystalline cellulose cross-linking Villon-Ammonia flat granules part - Ammonia sulphate camphor sulfonate butylation Benzyl phthalocyanine cellulose mannitol glycolic acid powder Nano-polyethylene ° Bilosterone pure water - lubricant - hard Magnesium sulphate-coated part - hypromellose hydroxypropyl cellulose titanium dioxide talc ethanol 175.0 mg 12.0 mg 7.84 mg (ammonia level 5 mg) 0.1 mg 9 〇. 〇 mg 40.0 mg 17.0 mg 5.0 mg ( 65.0 mg) 3.0 mg 8.0 mg 2.0 mg 2.0 mg 0.1 mg (200.0 mg)

Pure water (50.0 mg) 20 The components of the losartan granules were dry granulated using a roller compactor to prepare a losartan granule portion having a fine particle content of 20% by weight through a 75 micron sieve. Or below. Each of the components of the ammonia-level granule portion was wet-granulated with 65.0 mg/poule of pure water, sieved through a sieve, and dried to prepare an ammonia gas-level granule portion having a prescribed amount of each component. Ammonia Floor Granules 12 201028150 Partially mixed 3G (10) with a mixer in the difficult part of Losartan. Subsequently, a hard fat secret lubricant was added to the corresponding amount to 5 minutes. The resulting mixture is formulated as a _, and the resulting tablet is coated with a prescribed amount. A combination tablet is obtained by coating a short coating of various components of Pi. The combination tablet contains 5 mg of amlodipine and 5 mg of losartan, wherein the losartan-containing lanthanide is equivalent to about the weight of the tablet but about 12.5% excluding the coated portion.

20 Example 2: Preparation of a combined tablet-(IJ) 10 - Losartan granule fraction - Losartan slant 50.0 mg calcium dihydrogen phosphate Π 5.0 mg cross-linked Pvillon 12.0 mg - Ammonia granules - Ammoniapine camphor sulfonate 7.84 mg (ammoniadipine 5 mg) Butylated hydroxytoluene. 1 mg bisulphate dihydrogen about 90.0 mg mannitol 4 〇〇 glycolic acid; Temple powder nano 17.0 mg polyethylene η Pilotidone 5.0 mg pure water (65.0 mg) -lubricant - magnesium stearate 3.0 mg The combined lozenge was prepared by repeating the procedure of Example 1, but in the case of Luoshating and the position of the lions Microcrystalline cellulose. 13 201028150 The combined tablet contains 5 mg of amlodipine and 50 mg of losartan, wherein the losartan content is equivalent to the weight of the tablet but about 12.5% except for the coated portion. Example 3: Combination Preparation of tablets - (III) - Losartan granules _ 5 Losartan potassium 50.0 mg Microcrystalline cellulose 175.0 mg Crosslinked Pvillon 12.0 mg - Amlodipine granules _ Amlodipine camphor sulfonate 15.68 mg (ammonia level 10 mg) 10 Hydroxyphenylbenzene 0.2 mg Microcrystalline cellulose 90.0 mg Mannitol 40.0 mg Sodium glycolate sodium starch 17.0 mg Polyethylene 吼 ° Each biting ketone 5.0 mg 15 Pure water (65.0 mg) - Lubricant - Magnesium stearate 3.0 Mg-coated portion _ Haibo Milo 8.0 mg 20 Hydroxypropyl cellulose 2.0 mg Titanium dioxide 2.0 mg Talc 0.1 mg Ethanol (200.0 mg) Pure water (50.0 mg)

14 201028150 A combined tablet was prepared by repeating the procedure of Example 1, but using twice the amount of amlodipine and butylated hydroxyindole. The combination tablet contains 10 mg of ammodipine and 50 mg of losartan, wherein the losartan content is equivalent to the weight of the tablet but about 12.3% except for the coated portion. 5 Example 4: Preparation of combined tablets - (IV)

- Losartan granule fraction - Losartan potassium microcrystalline cellulose cross-linked Pirillon 10 - Amlodipine granule fraction - Amlodipine camphor sulfonate Butylated hydroxytoluene Microcrystalline cellulose Mannitol 15 Glycolic acid Starch sodium Polyethylene 吼 13 each bite ketone pure water 100.0 mg 350.0 mg 24.0 mg 15.68 mg (amlodipine 10 mg) 0.2 mg 90.0 mg 40.0 mg 17.0 mg 5.0 mg (65.0 mg) - Lubricant - Magnesium stearate 20 - Coated portion - 5.0 mg of Hypomitol Hydroxypropyl Cellulose Titanium Oxide Talc 8.0 mg 2.0 mg 2.0 mg 0.1 mg 15 201028150 Ethanol (200.0 mg) Pure water (50.0 mg) A combined lozenge was prepared by repeating the procedure of Example 3, However, each of the two portions of the losartan granule portion and 5 mg of magnesium stearate were used. The combined ingot 5 contains 10 mg of ammodipine and 100 mg of losartan, wherein the losartan content is equivalent to the weight of the tablet but about 15.5% except for the coated portion. Example 5: Preparation of a combined tablet-(V) 50.0 mg 25.0 mg 12.0 mg 7.84 mg (ammoniapine 5 mg) 0.1 mg 90.0 mg 40.0 mg 17.0 mg 5.0 mg (65.0 mg)

- Losartan Granules - Losartan Potassium 10 Microcrystalline Cellulose Crosslinked Pvillon - Ammonia Diffused Granules - Amlodipine Camphor Sulfate Butylated Hydroxytoluene 15 Microcrystalline Cellulose Mannitol Glycolic Acid Sodium starch, polyvinylpyrrolidine, ketal, pure water 20 -lubricant - magnesium stearate 3.0 mg - coated portion - hapomilo 8.0 mg hydroxypropyl cellulose 2.0 mg 16 201028150 5 titanium dioxide 2.0 mg talc 0.1 mg ethanol (200.0 mg) Pure water (50.0 mg) By repeating the procedure of Example 1, but using the ingredients specified in the amounts specified above, a combination comprising a losartan content of about 20% of the weight of the tablet except for the coated portion was prepared. Lozenges. Example 6: Preparation of a combined tablet - (VI) Ref 10 15 20 - Losartan granule fraction - Losartan unloading 50.0 mg of microcrystalline cellulose 350.0 mg of crosslinked Povillon 24.0 mg - Amlodipine granules - Ammoniapine camphor sulfonate 7.84 mg (ammoniapine 5 mg) Butylated hydroxytoluene 0.1 mg microcrystalline cellulose 90.0 mg mannitol 40.0 mg sodium glycolate sodium 17.0 mg polyethylene ° 嘻 ° ketene 5.0 mg Pure water (65.0 mg) - Lubricant - Magnesium stearate 5.0 mg - Coated part - Hypoamyl 8.0 mg 17 201028150 Hydroxypropyl cellulose 2.0 mg Titanium dioxide 2.0 mg Talc 0.1 mg Ethanol (200.0 mg) 5 Pure water (50.0 mg) A combined tablet containing a losartan content of about 8.5% by weight of the tablet except for the portion of the coating was prepared by repeating the procedure of Example 1, but using the ingredients specified in the amounts specified above. Example 7: Preparation of a combined tablet-(VII) 10 - Losartan granule fraction - Losartan unloading 50.0 mg Crosslinked Povillon 12.0 mg - Ammoniapine granule fraction _ Amlodipine camphor sulfonate 7.84 mg (Ammonia level 5 mg) 15 Butylated hydroxytoluene 0.1 mg Microcrystalline cellulose 90.0 mg Mannitol 40.0 mg Sodium glycolate sodium starch 17.0 mg Polyvinyl sulfonate 5.0 mg 20 Pure water (65.0 mg) - Lubricant - Magnesium stearate 3.0 mg - Coated portion - Hypermagmule 8.0 mg 18 201028150 Hydroxypropyl cellulose 2.0 mg Titanium dioxide 2.0 mg Talc 0.1 mg Ethanol (200.0 mg) Pure water (50.0 mg) Procedure by repeating Example 1 However, a combination tablet containing a losartan content of about 22.2% by weight of the tablet except for the coated portion was prepared using the ingredients in the amounts specified above.

Comparative Example 1: Preparation of a direct compression tablet containing a simple mixture of ammonia gas and losartan ❿ mixed portion - amlodipine camphor sulfonate losartan microcrystalline cellulose dihydrogen calcium glycolate sodium starch poly Vinyl hydrazine 11 π ketal ketone lubricant - 7.84 mg (amlodipine 5 mg) 50.0 mg 150.0 mg 60.0 mg 24.0 mg 3.0 mg magnesium stearate 2.0 mg All ingredients are mixed together according to the relative application amount, and the resulting mixture formula becomes direct Tablets are compressed. The direct compression tablet contains 5 mg of amlodipine and 50 mg of losartan, wherein the losartan content is about 16.8% by weight of the tablet. Comparative Example 2: Preparation of a combined tablet-(VIII) 19 201028150 - Losartan granule fraction - Losartan potassium 100.0 mg Microcrystalline cellulose 38.0 mg Crosslinked Pvillon 12.0 mg 5 - Ammoniapine granules - Amlodipine camphor sulfonate 7.84 mg (ammoniapine 5 mg) Butylated hydroxytoluene 0.1 mg microcrystalline cellulose 90.0 mg mannitol 40.0 mg 10 Sodium glycolate sodium 17.0 mg polyvinylpyrrolidone 5.0 mg pure water (65.0 mg) - Lubricant - Magnesium Stearate 3.0 mg 15 - Coated portion - Hypermagmule 8.0 mg propylcellulose 2.0 mg Titanium dioxide 2.0 mg Talc 0.1 mg 20 Ethanol (200.0 mg) Pure water (50.0 Mg) by repeating the procedure of Example 1, but using the quantities specified above

A combination tablet containing a losartan content of about 32.0% by weight of the tablet except for the coated portion was prepared. 20 201028150 The following is based on Examples 1 to 7 and Comparative Examples 1 and 2 Table 1. The nature of the formulation is shown in the weight of the formulation (mg). Example 1 400 Example 2 400 Example 3 408

5 Example 4 Example 5 Example 6 Example 7 Comparative Example 1 Comparative Example 2 647 589 225 297 313 Losartan Weight (mg) 50 50 50 50 Table 1 Percentage 12.5 12.5 12.3 15.5 20.0 8.5 22.2 16.8 Formulation type contains separate Loxa Tablets of amlodipine granules (sentences, right, lozenges containing separate losartan and ammonia granules (uncoated) containing lozenges of separate losartan and ammonia granules ( Coated) A lozenge containing separate losartan and ammodipine granules (sentence. Right, lozenges containing separate losartan and ammonia granules) (phrase. Right, 100 32.0 contains separate lozenges) Tablets of Satan and Ammoniapine Granules (Coated) Lozenges containing separate losartan and ammonia granules (Baoyou) Lozenges containing a mixture of losartan and ammonia sulphate (not packaged) a lozenge containing separate losartan and ammonia granules (by white, right,

10 Test Example 1: Solubility Test of Ammonia Leveling Example 1 obtained a combination of 毫5 millifilaments of crustartan and a direct-pressed tablet containing the shoal Amodipin (trade name) was subjected to a drug conversion test under the following conditions in the form of ammonia-flattened cerebrorate. Test conditions - effluent: 500 ml 0.01 N HC1 (pH 2 〇) Dissolution test system: USP paddle method, 75 rpm Temperature: 37 ° C - Analysis conditions - 21 15 201028150 Column: Stainless steel column (inner diameter: 46 Millimeter, length: 15 cm) Filled with a dodecacinated silica gel with an octagonal base for the 5 micron liquid chromatography phase. Methanol and a mixture of G.G3M bismuth dihydrogen potassium (4) 〇: 400 , v/v) Detector: UV spectrophotometer (35 〇 nanometer) 5 Flow rate · 1.5 ml / min Injection volume: 20 μl - Dissolution rate - greater than 8 〇 % in 30 minutes _ Result - 10 as the first In the figure, the combined tanning agent prepared by using the separated ammonia gas and the losartan secret according to the example 1 is compared with the comparative example of the ice-connected ingot. The Weidiping rate is twice higher or secret. the above. Further, the dissolution rate of the tablet prepared in Comparative Example 1 did not satisfy the required standard, and the tablet of Example 1 satisfies the standard. Test Example 2: The temperate dissolution test of the formulations of Examples 1 to 4 The combination tablets of Examples 1 to 4 were each subjected to the mash dissolution test under the same test and knife-cut conditions of Test Example 1. Θ - Result - As can be seen from Fig. 3, the combined tablet obtained in Examples 2 to 4 has a high and safe amlodipine dissolution rate, which is similar to the performance of the tablet in 1N hci (pH). From this result, it was confirmed that the combined tablet has a high and stable ammonia gas level dissolution rate irrespective of the type of the excipient, and only the weight percentage of the combined tablet does not exceed the appropriate content. The content of the granules of the horizon or losartan is irrelevant. 22 201028150 Test Example 3: Ammonia flat dissolution test examples for the formulations of Examples 1, 3 and 7 and Comparative Examples 1 and 2 Examples of the tablets prepared in Examples 3 and 7 and Comparative Examples 1 and 2 were in Test Example 1 The drug dissolution test was carried out under the same test and analysis conditions. 5 - Test conditions - effluent: 900 ml artificial gastric juice (pH 1.2) or 0.01 N HC1 (pH 2.0)

Dissolution test system: USP paddle method, 50 rpm Temperature: 37 ° C 10 The aforementioned dissolution test system (USP paddle method, 50 rpm) is the most widely used

A system for assessing the drug dissolution rate of an oral formulation, the effluent (human gastric juice (pH 1.2) or 0.01 N HC1 (ρΗ2·0)) used has a pH similar to the pH of the gastrointestinal tract. As shown in Fig. 3, the combined tablet obtained in Examples 1, 3 and 7 had an amlodipine dissolution rate which was even higher than that of the tablets obtained in Comparative Examples 1 and 2. The results suggest that the dissolution rate of the formulation containing the separated losartan and amlodipine particles and containing the losartan content of 25% by weight or less at 3 minutes is 80 at low pH (pH 1.2 and pH 2). % or more, this value meets the standard. Test Example 4: Ammonia flat dissolution test for Examples 4 to 6 and Comparative Example 2 The combined tablet tablets obtained in Examples 4 to 6 and Comparative Example 2 were each subjected to drug dissolution under the same test and analysis conditions of Test Example 1. test. - Result - The dissolution rate of the combined tablet obtained in Examples 4 to 6 as shown in Fig. 4 was 80% or more at 3 minutes, which was the same as the result of Test Example 3. 23 201028150 Test Example S: For Examples 1, 3 and 7 and Comparative Examples! And losartan dissolution test of Examples 2, 3 and 7, Comparative Examples 1 and 2, and Koza (trade name) obtained tablets each received a drug dissolution test under the following conditions. - Test conditions - 5 Effluent · · 900 ml of artificial gastric juice (pH 1_2) or 〇.〇1 N HC1 (pH 2.0) Dissolution test system: USP paddle method, 50φπι Temperature: 37 ° C - Analysis conditions - Column: Stainless steel column (inner diameter: 4.6 mm, length: 15 cm) filled with 10 octadecyl decanoylated cerium oxide gel for 5 micron liquid chromatography phase: mobile phase A-phosphate buffer Liquid··Acetonitrile (85〇:15〇, v/v) Phase B-acetonitrile concentration gradient system time (minutes) — -- Phase A% Phase B% 0 80 20 10 40 60 11 80 20 15 80 20 Detector: UV spectrophotometer (25 〇 nanometer) Flow rate: 1.5 ml / min Injection volume: 10 μl 20 - Result - The aforementioned dissolution test system (USP paddle method, 5 rpm) is the most widely used. The effluent used in the system for estimating the drug dissolution rate of the oral formulation (human 24 201028150 gastric juice (pH 1.2) or 0.01 N HCl (pH 2.0)) has a pH similar to the pH of the gastrointestinal tract. As shown in Fig. 5, the combination tablets obtained in Examples 1, 3 and 7 had the dissolution ratios obtained in Comparative Examples 1 and 2 and the Koza (trade name) which was a single losartan compound 5 and the dissolution rate was even higher. The dissolution rate of losartan. Test Example 6: Safety test for chlorinated chlorine The combined tablet obtained in Example 1 was prepared by using separate amlodipine and losartan granules and comparatively obtained as a direct compression tablet, and was stabilized under the following conditions. Sex test. 10 Cultivation conditions: HDPE bottle is at 40. (:/75% relative humidity Incubation time: 0, 1, 2, 4 and 6 months Test subject: Ammonia leveling Analysis conditions: Analysis conditions of Example 1 The results are shown in Table 2. 15 Table 2

Formulation 0 1 month Example 1 100.0% 99.9% Comparative Example 1 100.2% 97.8% 2 months 4 months 6 months 99.6% -~~~__ 99.8% 99.5% 94.9% ^903% ------ 85.7% As shown in Table 2, the combined tablet obtained in Example 1 had a higher safety rating of ammonia chloride than the directly compressed tablet obtained by comparison. Although the present invention has been described in terms of the specific embodiments described above, it is to be understood by those skilled in the art that the invention is susceptible to various modifications and changes, and such modifications and variations are also within the scope of the invention as defined by the invention. [Simple description of the drawings] 25 20 201028150 Fig. 1 : The dissolution of the ammonia gas level in 0.01 N HC1 (ΡΗ 2·0) was observed for the ingot prepared in Example 1 and Comparative Example 1 and the ammonia gas (trade name) ingot. Rate (Ancient test case 1); Fig. 2 · The dissolution rate of ammonia gas at 5 0.01 N HCl (pH 2.0) observed for the ingots prepared in Examples 1 to 4 (Test Example 2); Fig. 3: Pair The ingots prepared in Examples 1, 3 and 7 and Comparative Examples and 2 were observed to have an ammonia gas level in artificial gastric juice (pH 1.2) and a dissolution rate in 0.01 N HC1 (pH 2.0) (Test Example 3); Figure 4: The dissolution rates of the ammonia gas level at 0.01 N HCl (pH 2.0) were observed for the ingots prepared in Examples 4 to 6 and Comparative Example 2 and the ammonia gas ❹ 10 (trade name) ingots (Test Example 4); and Figure 5 ················································ The dissolution rate (Test Example 5). 15 [Description of main component symbols] (none) ❹ 26

Claims (1)

201028150 VII. Patent application scope: I. A solid pharmaceutical composition for preventing or treating cardiovascular diseases, comprising amlodipine or a pharmaceutically acceptable salt thereof and losartan or its pharmacy Acceptable salt. 5 ❿ 10 15 20 2. The composition of claim 1 wherein ammoxipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof are separated from each other. 3. The composition of claim 2, wherein amlodipine or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof are in separate particle form. 4. The composition of claim 2 or 3, based on the total weight of the composition, comprising losartan or a pharmaceutically acceptable salt thereof in an amount of 3% to 25% by weight range. 5. The composition of claim 4, based on the total weight of the composition, comprising losartan or a pharmaceutically acceptable salt thereof in an amount ranging from 5% to 22.3% by weight. 6. The composition of claim 4, wherein the ammonia gas dissolution rate is 8% or more in 30 minutes in the pH range of 1 to 2 Torr. 7. The composition of the third paragraph of the patent scope, which comprises the granular form of losartan, wherein the percentage of fine particles which can pass through the 75 micron mesh is less than 50%. ·8. A lozentan in the form of particles, wherein the percentage of fine particles that can pass through a 75 micron mesh is less than 25%. 27 201028150 9. The composition of claim 8 wherein the composition comprises losartan in the form of particles wherein the percentage of fine particles which pass through the 75 micron mesh is less than 10%. 10. For the composition of claim 1 of the patent scope, wherein the salt of the aflatoxin 5 is a salt of amlodipine camsylate 〇 11. as claimed in claim 1 The composition, wherein the cardiovascular condition is selected from the group consisting of angina pectoris, hypertension, arteriolar vasospasm, deep vein thrombosis, cardiac hypertrophy, cerebral infarction, congestive heart failure, and myocardial infarction. 12. A method of preparing a composition comprising amlodipine and losartan in particulate form separated from each other as in claim 3, comprising the steps of: a) losartan or a pharmaceutically acceptable salt thereof Mixing and drying with a pharmaceutically acceptable excipient to obtain losartan granules; b) mixing ammoxipine or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient The particles are dried to obtain ammonia leveling particles; and c) the losartan particles obtained in step a) and the ammonia 20 gas level particles obtained in step b) are mixed.