Stable Milsartan potassium tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses a stable Milsartan potassium tablet and a preparation method thereof, the tablet is composed of the following raw materials by weight: 20-30% of Milsartan potassium, 1-2% of a stabilizer, 40-80% of a filler, 1-5% of an adhesive, 5-15% of a disintegrating agent, and 0.5-3% of a lubricant. The stabilizer is a mixture of maleic acid and sodium hydroxide. The mixture of maleic acid and sodium hydroxide is used as the stabilizer, so that the increase of decomposition products of Milsartan potassium can be better inhibited, and the stability of the Milsartan potassium composition is better than that of preparations on the market. The preparation process provided by the invention is simple and suitable for commercialized batch production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, relates to the preparation of a potassium salsartan tablet preparation, and particularly relates to a stable potassium salsartan tablet and a preparation method thereof. Background Art

[0002] Azilsartan Medoxomil Potassium, chemical name is (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate potassium salt.

[0003] Azilsartan potassium is a prodrug that can be rapidly converted into the active ingredient azilsartan after oral absorption. Azilsartan can block the effects of angiotensin II by selectively blocking the binding of angiotensin II to type 1 receptors (AT1 receptors) in various tissues. Angiotensin II is the main pressor substance of the renin-angiotensin-aldosterone system (RAAS), which has the effects of constricting blood vessels, stimulating the synthesis and release of aldosterone, exciting the heart, and reabsorb sodium by the kidneys.

[0004] Permeability is a key factor for drugs to reach the target from the gastrointestinal tract and exert their efficacy. The difference from azilsartan is that the azilsartan medoxomil tablets formed by esterification of mesartan potassium have improved permeability (the ability of a compound to pass through the cell membrane), greatly improving the drug absorption and absorption rate (faster and more stable than azilsartan). Compared with azilsartan, the bioavailability of azilsartan medoxomil tablets is increased by 30%.

[0005] Different from the tetrazole ring structure of traditional ARB drugs, Asartan Potassium uses a unique oxadiazole ring to replace the acidic group tetrazole ring, further improving the drug's binding affinity with the AT1 receptor, reducing acidity, increasing lipid solubility, and thus improving bioavailability.

[0006] Asartan Potassium was first approved by the FDA in February 2011. (Trade name: EDARBI), available in 40mg and 80mg. It is currently available in more than 15 countries around the world, including the United States, Canada, France, and the United Kingdom. On January 19, 2021, Takeda Pharmaceutical's Class 1 new drug Asartan Potassium Tablets was approved by the National Medical Products Administration for the treatment of essential hypertension. Trade name: The specifications are 40mg and 80mg, and will be included in medical insurance in March 2023.

[0007] Azilsartan potassium is a prodrug of azisartan. The compound structure contains ester bonds and ether bonds. It is a water-sensitive compound and has potential stability risks. Summary of the invention

[0008] In view of the deficiencies of the prior art, the object of the present invention is to provide a stable mersartan potassium tablet. The present invention adopts a combined stabilizer of maleic acid and sodium hydroxide, which can better inhibit the increase of mersartan potassium decomposition products and show better stability than marketed preparations. Another object of the present invention is to provide a method for preparing the mersartan potassium tablet.

[0009] The present invention is achieved through the following technical solutions:

[0010] A stable lasartan potassium tablet is composed of the following raw materials in percentage by weight: 20-30% of lasartan potassium, 1-2% of a stabilizer, 40-80% of a filler, 1-5% of a binder, 5-15% of a disintegrant, and 0.5-3% of a lubricant; the stabilizer is a mixture of maleic acid and sodium hydroxide.

[0011] A further improvement of the present invention is:

[0012] The filler is one or a mixture of two or more of microcrystalline cellulose, mannitol, lactose, starch, and phosphates;

[0013] And / or, the binder is one or a mixture of two or more of hydroxypropyl cellulose, hypromellose, and povidone K30;

[0014] And / or, the disintegrant is one or a mixture of two or more of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone XL, and sodium starch glycolate;

[0015] And / or, the lubricant is one or a mixture of two or more of magnesium stearate, stearic acid, aluminum stearate, calcium stearate and talc.

[0016] Furthermore, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose to mannitol is 1:3-7.

[0017] Furthermore, the mass ratio of the sodium hydroxide to the maleic acid is 1:2-4.

[0018] Furthermore, the sartan potassium is a particle with a particle size range D90 of 3-35 um.

[0019] A further improvement of the present invention is:

[0020] A method for preparing a stable lasartan potassium tablet comprises the following steps: adding lasartan potassium and a filler into a fluidized bed, spraying a binder solution containing a stabilizer for granulation, mixing the granules with an external filler, a disintegrant and a lubricant after granulation, and then tabletting and drying under reduced pressure to obtain lasartan potassium tablets.

[0021] Furthermore, the granulation process needs to control the air inlet temperature at 45-70°C, the material temperature at 20-45°C, the atomization pressure at 0.5-3 bar, and the spray speed at 10-25 g / min; and / or, the drying process needs to control the drying temperature at 30-50°C and the drying time at 8-24 h.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention adopts a mixture of maleic acid and sodium hydroxide as a stabilizer, which can better inhibit the increase of decomposition products of mesartan potassium and show better stability than marketed preparations.

[0024] The preparation process of the invention is simple and suitable for commercial batch production. DETAILED DESCRIPTION

[0025] The present invention is described in detail below in conjunction with specific embodiments.

[0026] Example 1

[0027] Prescription composition

[0028]

[0029] Preparation process:

[0030] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0031] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0032] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, stopping liquid supply after 20min of granulation, continuing granulation after granulation through 40-mesh sieve, drying in fluidized bed after granulation, controlling moisture content ≤1.2% after drying.

[0033] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0034] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0035] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.350 g).

[0036] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0037] Example 2

[0038] Prescription composition

[0039]

[0040]

[0041] Preparation process:

[0042] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0043] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0044] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, stopping liquid supply after 20min of granulation, continuing granulation after granulation through 40-mesh sieve, drying in fluidized bed after granulation, controlling moisture content ≤1.2% after drying.

[0045] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0046] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0047] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.370 g).

[0048] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0049] Example 3

[0050] Prescription composition

[0051]

[0052] Preparation process:

[0053] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0054] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0055] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, drying in fluidized bed at the end of granulation, controlling moisture content ≤1.2% after drying.

[0056] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0057] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0058] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.350 g).

[0059] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0060] Example 4

[0061] Prescription composition

[0062]

[0063] Preparation process:

[0064] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0065] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0066] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, drying in fluidized bed at the end of granulation, controlling moisture content ≤1.2% after drying.

[0067] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0068] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0069] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.350 g).

[0070] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0071] Example 5

[0072] Prescription composition

[0073]

[0074] Preparation process:

[0075] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0076] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0077] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, stopping liquid supply after 20min of granulation, continuing granulation after granulation through 40-mesh sieve, drying in fluidized bed after granulation, controlling moisture content ≤1.2% after drying.

[0078] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0079] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0080] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.350 g).

[0081] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0082] Example 6

[0083] Prescription composition

[0084]

[0085]

[0086] Preparation process:

[0087] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0088] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0089] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, stopping liquid supply after 13min of granulation, continuing granulation after granulation through 40-mesh sieve, and drying in fluidized bed after granulation, controlling moisture content ≤1.2% after drying.

[0090] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0091] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0092] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.350 g).

[0093] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0094] Example 7

[0095] Prescription composition

[0096]

[0097] Preparation process:

[0098] (1) Preparation of adhesive: Add maleic acid and sodium hydroxide to purified water and stir to dissolve to prepare a buffer solution. Stir to dissolve hydroxypropyl cellulose in the buffer to prepare an adhesive solution.

[0099] (2) Premixing: Mix mannitol and mesartan potassium in a mixer.

[0100] (3) Fluidized granulation: Add the premixed materials into the fluidized bed and set the air volume to 500±100m 3 / h, air inlet temperature 60±10℃, atomization pressure 0.8bar, liquid supply speed 15g / min, spraying binder solution for granulation, controlling material temperature at 25-40℃ during granulation, stopping liquid supply after 13min of granulation, continuing granulation after granulation through 40-mesh sieve, and drying in fluidized bed after granulation, controlling moisture content ≤1.2% after drying.

[0101] (4) Dry granulation: The granules after drying were sieved using a 0.8 mm pore size screen.

[0102] (5) Total mixing: Add the whole granules, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing bucket and mix well.

[0103] (6) Tableting: The mixture was tableted using a 9.5 mm φ punch (tableting pressure 7.0 KN / punch, tablet weight 0.350 g).

[0104] (7) Drying: The tablets were dried in a vacuum oven at 40°C under reduced pressure for 16 h.

[0105] Example 8: Stability Study

[0106] Stability study of marketed preparations and example tablets

[0107] According to the fourth guideline of the 2020 edition of the Chinese Pharmacopoeia, 9001-Guidelines for Stability Testing of Raw Materials and Preparations, the stability was tested for 1, 2, 3, and 6 months at a temperature of 40±2°C and a relative humidity of 75±5%. The growth of decomposition products was detected by HPLC. The results of the inspection of the marketed preparation (batch number 12343797, licensed manufacturer Takeda) and the tablets of Examples 1-6 are as follows:

[0108]

[0109] According to the results of the investigation on the increase in the amount of decomposition products, the increase in the amount of decomposition products of Examples 1-3 is lower than that of the marketed preparations, and the tablet stability is better than that of the marketed preparations; compared with the tablets of Examples 1-2, the increase in the amount of decomposition products of Example 4 is significantly higher; compared with the tablets of Example 2, the decomposition products of Examples 5-6 are significantly increased; compared with the tablets of Example 2, the decomposition products of Example 7 are significantly increased.

[0110] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A stable asartan potassium tablet, characterized in that: The invention is composed of the following raw materials in percentage by weight: 20-30% of potassium sartan, 1-2% of a stabilizer, 40-80% of a filler, 1-5% of a binder, 5-15% of a disintegrant, and 0.5-3% of a lubricant; the stabilizer is a mixture of maleic acid and sodium hydroxide.

2. A stable mesartan potassium tablet according to claim 1, characterized in that: The filler is one or a mixture of two or more of microcrystalline cellulose, mannitol, lactose, starch, and phosphates; And / or, the binder is one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone K30, or a mixture of two or more thereof; and / or, the disintegrant is one of cross-linked sodium carboxymethyl cellulose, cross-linked povidone XL, and sodium starch glycolate, or a mixture of two or more thereof; And / or, the lubricant is one or a mixture of two or more of magnesium stearate, stearic acid, aluminum stearate, calcium stearate and talc.

3. The pharmaceutical composition containing the active ingredient of Asartan Potassium according to claim 2, characterized in that: The filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose to mannitol is 1:3-7.

4. A stable mesartan potassium tablet according to claim 1, characterized in that: The mass ratio of the sodium hydroxide to the maleic acid is 1:2-4.

5. A stable mesartan potassium tablet according to claim 1, characterized in that: The mesartan potassium is particles with a particle size range D90 of 3-35 um.

6. A method for preparing a stable mesartan potassium tablet according to any one of claims 1 to 5, characterized in that: The method comprises the following steps: adding mesartan potassium and a filler into a fluidized bed, spraying a binder solution containing a stabilizer for granulation, mixing the granules with an external filler, a disintegrant and a lubricant after granulation, and then tabletting and drying under reduced pressure to obtain mesartan potassium tablets.

7. The method for preparing a stable Asartan potassium tablet according to claim 6, characterized in that: The granulation process needs to control the air inlet temperature at 45-70°C, the material temperature at 20-45°C, the atomization pressure at 0.5-3bar, and the spray speed at 10-25g / min; and / or, the drying process needs to control the drying temperature at 30-50°C and the drying time at 8-24h.

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