Melsartan potassium capsule and preparation method thereof

Abstract

The invention provides a Milsartan potassium capsule and a preparation method thereof, the Milsartan potassium capsule is prepared by filling a Milsartan potassium micro-tablet into a hollow capsule, the compliance of a patient is improved, and compared with a common tablet, the micro-tablet can improve the dissolution rate and increase the contact area with gastrointestinal mucosa after oral administration, so that the bioavailability of a medicine can be improved, and the bioavailability of the medicine is improved. In addition, the micro-tablets are filled into hollow capsules, so that the exposure of the tablets can be reduced, the influence of moisture can be reduced, and the stability of the medicines can be improved.

Description

Technical Field

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

[0002] Asartan Potassium Tablets (trade name ) was first approved by the US FDA in 2011 and is now available in more than 15 countries around the world, including Canada, France, and the United Kingdom, for the treatment of hypertension. ) was approved for marketing in China in January 2021. The manufacturer is Takeda Ireland Ltd. (Bray Business Park, Kilruddery, Co Wicklow, Ireland). Currently, only tablets of Asartan Potassium are available in the United States.

[0003] Azilsartan potassium is a prodrug that can be rapidly converted into the active ingredient azilsartan after oral absorption. The latter can block the effects of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors in various tissues. Angiotensin II is the main pressor substance of 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. Azilsartan potassium blocks the vasoconstriction and aldosterone secretion of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors in many tissues such as vascular smooth muscle and adrenal glands. Therefore, its effects are unrelated to the angiotensin II synthesis pathway. The affinity of Azilsartan potassium for AT1 receptors is more than 10,000 times higher than that for AT2 receptors.

[0004] In in vitro studies, acesartan potassium significantly inhibited the specific binding of angiotensin II to the AT1 receptor, and compared with other AT1 receptor antagonists (olmesartan, telmisartan, valsartan and irbesartan), its inhibitory effect on AT1 receptors was persistent even after washout. These results show that acesartan potassium is a potent and selective antagonist of AT1 receptors, and dissociates more slowly from AT1 receptors than other angiotensin II receptor antagonists (ARBs). These binding characteristics may be the reason why acesartan potassium has a significant and lasting antihypertensive effect in vivo compared with other ARBs.

[0005] Asartan potassium belongs to BCS IV compounds, which means it has low solubility and low permeability. When it is made into an oral preparation, only when Asartan potassium is quickly and efficiently dissolved or dispersed in water can it be well absorbed in the gastrointestinal tract and improve the bioavailability of the drug. Therefore, it is very important to improve its solubility without changing its pharmacological properties.

[0006] Both Azilsartan Potassium and Azilsartan are poorly soluble drugs with low solubility. The solubility of this product can be effectively improved by adding solubilizers to the formula or through other methods such as ultrafine grinding and solid dispersion.

[0007] Azilsartan potassium is an oral prodrug, which can be rapidly metabolized to the active ingredient azilsartan by esterase in the body during absorption. Azilsartan potassium is an ester salt, which is easily hydrolyzed to azilsartan under moisture or high humidity conditions. Therefore, it is very important to develop a relatively stable Azilsartan potassium tablet formula in pharmacy for the long-term preservation of Azilsartan potassium tablets. In addition, Azilsartan potassium and Azilsartan are both poorly soluble drugs, and their solubility is relatively low. At present, the inner packaging system (aluminum-plastic blister or bottled) of existing products on the market all need to add desiccant.

[0008] Chinese patent CN101677961A discloses that a pH regulator, i.e., a combination of fumaric acid and sodium hydroxide, can improve both tablet stabilizer and dissolution. However, the preparation method of the tablet is relatively complicated. When preparing the tablet, it is necessary to reduce the pressure and dry it for up to 16 hours to ensure that the moisture content of the product is controlled at an absolutely low level, thereby further ensuring the stability of the tablet. The production conditions are relatively harsh.

[0009] Chinese patent CN117122570A provides a measartan potassium tablet with improved stability and a preparation method thereof. The measartan potassium tablet is made of the following raw materials: measartan potassium, a stabilizer, a solubilizer, a filler, a disintegrant, a binder and a lubricant; the stabilizer is selected from at least one of tartaric acid, fumaric acid, citric acid, lactic acid and malic acid; the solubilizer is selected from at least one of meglumine, poloxamer, polysorbate and sodium lauryl sulfate. The preparation method is as follows: measartan potassium, a filler and a disintegrant are mixed in a wet granulator, and an aqueous solvent of a binder, a stabilizer and a solubilizer is sprayed to granulate the mixture, and fluidized bed drying is performed; the obtained granules are sized using a 1.5 mm screen; a lubricant is added and mixed; and the uniformly mixed total mixed granules are tableted using a rotary tablet press with a theoretical tablet weight of 360 mg.

[0010] Although the above prior art has improved the stability and solubility of Asartan Potassium to a certain extent, there is still room for improvement. Since there are only tablets on the market and no other dosage forms, and Asartan Potassium has a special smell, it is not conducive to patient compliance if the tablets still have this special smell. Summary of the invention

[0011] The purpose of the present invention is to provide a mesartan potassium capsule on the basis of the prior art, which is prepared by filling mesartan potassium microtablets into hollow capsules, which not only improves the patient's compliance, but also the microtablets can improve the dissolution rate compared with ordinary tablets, and the contact area with the gastrointestinal mucosa after oral administration is increased, thereby improving the bioavailability of the drug, and can also reduce or eliminate the irritation of certain drugs to the gastrointestinal tract. In addition, filling the microtablets into the hollow capsules can reduce the exposure of the tablets, reduce the influence of moisture, and improve the stability of the drug.

[0012] Another object of the present invention is to provide a method for preparing the above-mentioned Asartan Potassium Capsules.

[0013] The technical solution of the present invention is as follows:

[0014] A measartan potassium capsule is prepared by filling measartan potassium microtablets into hollow capsules, wherein the measartan potassium microtablets are prepared from the following components in parts by weight: 40-45 parts of measartan potassium, 80-130 parts of a filler, 4-12 parts of a stabilizer, 2-8 parts of a binder, 10-20 parts of a disintegrant, and 2-6 parts of a lubricant.

[0015] For the present invention, the filler is one or more of microcrystalline cellulose, mannitol, lactose or starch. Preferably, microcrystalline cellulose and mannitol are used. The stabilizer is anhydrous citric acid and sodium citrate; the binder is one or more of hydroxypropyl cellulose, povidone or hydroxypropyl methylcellulose, preferably hydroxypropyl cellulose; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked povidone or low-substituted hydroxypropyl cellulose, preferably cross-linked sodium carboxymethyl cellulose, wherein the disintegrant is divided into internal disintegrant and external disintegrant according to the order of addition. The lubricant is magnesium stearate.

[0016] Asartan potassium contains ester bonds and is easily hydrolyzed. In the present invention, anhydrous citric acid and sodium citrate are used as stabilizers. In the formula, sodium citrate is used to control pH and forms a buffer pair with anhydrous citric acid to maintain the stability of the product.

[0017] For the mesartan potassium capsules provided by the present invention, in the preparation process, mesartan potassium, a filler and an internal disintegrant are firstly mixed uniformly to obtain a mixed material, the obtained mixed material is subjected to fluidized bed granulation using a binder solution made of a stabilizer, a binder and purified water, the obtained granules are dried and granulated, and then uniformly mixed with an external disintegrant and a lubricant to obtain total mixed granules, which are pressed into micro-tablets and filled into hollow capsules to obtain mesartan potassium capsules.

[0018] In the present invention, the particle size D90 of Asartan Potassium is controlled to be no higher than 15 μm, i.e. ≤15 μm, so as to improve the bioavailability of the drug.

[0019] In the present invention, microcrystalline cellulose and mannitol are used as fillers, and cross-linked sodium carboxymethyl cellulose is used as a disintegrant. According to the order of addition, they are divided into internal disintegrants and external disintegrants, which can reduce the phenomenon of equipment adhesion during the granulation process. In a preferred embodiment, the weight ratio of the internal disintegrant to the external disintegrant is 1:2-4, and in a more preferred embodiment, the weight ratio of the internal disintegrant to the external disintegrant is 1:3.

[0020] In the present invention, mesartan potassium and auxiliary materials are prepared into micro-tablets and filled into capsules, that is, one dose of the drug is dispersed in a plurality of independent micro-units. After oral administration, the contact area with the gastrointestinal mucosa is increased, thereby improving the bioavailability of the drug and reducing or eliminating the irritation of certain drugs to the gastrointestinal tract.

[0021] Since Asartan Potassium has a rather unpleasant smell, the smell is still strong after being made into tablets. The existing dosage form is an uncoated tablet. When taking it, it is difficult to swallow due to the smell. In view of the above problem, the present invention makes it into micro-tablets and fills it into capsules, which can not only mask the smell, but also improve its stability, which is better than other dosage forms such as tablets and granules. In particular, Asartan Potassium contains ester bonds and is easily hydrolyzed. After being made into a preparation, it needs to avoid storage under relatively humid conditions, and preparing it into capsules is more conducive to moisture-proof.

[0022] In a preferred embodiment, the present invention provides a measartan potassium capsule, which is prepared by filling a measartan potassium microtablet into a hollow capsule, wherein the measartan potassium microtablet is made of the following components in parts by weight: 40-45 parts of measartan potassium, 85-95 parts of mannitol, 15-25 parts of microcrystalline cellulose, 3-5 parts of anhydrous citric acid, 3-6 parts of sodium citrate, 3-6 parts of hydroxypropyl cellulose, 12-16 parts of cross-linked sodium carboxymethyl cellulose, and 3-4 parts of magnesium stearate; wherein the weight ratio of the internal disintegrant cross-linked sodium carboxymethyl cellulose to the external disintegrant cross-linked sodium carboxymethyl cellulose is 1:1-4.

[0023] In a more preferred embodiment, the lasartan potassium capsule provided by the present invention is prepared by filling lasartan potassium microtablets into hollow capsules, wherein the lasartan potassium microtablets are made of the following components in parts by weight: 42.28 parts of lasartan potassium, 86.77-90.26 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 2.66-5.15 parts of sodium citrate, 3.6-5.4 parts of hydroxypropyl cellulose, 14 parts of cross-linked sodium carboxymethyl cellulose, and 3-4 parts of magnesium stearate; wherein the weight ratio of the internal disintegrant cross-linked sodium carboxymethyl cellulose to the external disintegrant cross-linked sodium carboxymethyl cellulose is 1:1-3.

[0024] In a particularly preferred embodiment, the lasartan potassium capsule provided by the present invention is prepared by filling lasartan potassium micro-tablets into hollow capsules, wherein the lasartan potassium micro-tablets are made of the following components in parts by weight:

[0025] For example, 42.28 parts of mesartan potassium, 87.77 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, and 3 parts of magnesium stearate. The weight ratio of the internal disintegrant croscarmellose sodium to the external disintegrant croscarmellose sodium is 1:3.

[0026] For example, 42.28 parts of mesartan potassium, 90.26 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 2.66 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, and 3 parts of magnesium stearate. The weight ratio of the internal disintegrant croscarmellose sodium to the external disintegrant croscarmellose sodium is 1:3.

[0027] For example, 42.28 parts of mesartan potassium, 86.77 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, and 4 parts of magnesium stearate. The weight ratio of the internal disintegrant croscarmellose sodium to the external disintegrant croscarmellose sodium is 1:3.

[0028] For example, 42.28 parts of mesartan potassium, 89.57 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 3.6 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, and 3 parts of magnesium stearate. The weight ratio of the internal disintegrant croscarmellose sodium to the external disintegrant croscarmellose sodium is 1:3.

[0029] 42.28 parts of mesartan potassium, 87.77 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 7 parts of internal disintegrant croscarmellose sodium, 7 parts of external disintegrant croscarmellose sodium, and 3 parts of magnesium stearate. The weight ratio of the internal disintegrant croscarmellose sodium to the external disintegrant croscarmellose sodium is 1:1.

[0030] The present invention also provides a method for preparing the above-mentioned Asartan Potassium Capsules, comprising the following steps:

[0031] (1) dispersing a stabilizer in purified water, adding a binder and stirring evenly to prepare a binder solution;

[0032] (2) sieving the potassium arachidonic acid, filler and internal disintegrant, adding them into a fluidized bed, and subjecting them to fluidized bed granulation with the binder solution obtained in step (1), and drying and granulating the obtained granules;

[0033] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant and a lubricant to obtain a total mixed granule, which is then pressed into micro-tablets and filled into hollow capsules to obtain mesartan potassium capsules.

[0034] For the present invention, the filler is one or more of microcrystalline cellulose, mannitol, lactose or starch. Preferably, microcrystalline cellulose and mannitol are used. The stabilizer is anhydrous citric acid and sodium citrate; the binder is one or more of hydroxypropyl cellulose, povidone or hydroxypropyl methylcellulose, preferably hydroxypropyl cellulose; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked povidone or low-substituted hydroxypropyl cellulose, preferably cross-linked sodium carboxymethyl cellulose, wherein the disintegrant is divided into internal disintegrant and external disintegrant according to the order of addition. The lubricant is magnesium stearate.

[0035] In the present invention, microcrystalline cellulose and mannitol are used as fillers, and crosslinked sodium carboxymethyl cellulose is used as a disintegrant. According to the order of addition, they are divided into internal disintegrants and external disintegrants, which can reduce the phenomenon of equipment adhesion during the granulation process. In a preferred embodiment, the weight ratio of the internal disintegrant to the external disintegrant is 1:1-4, and in a more preferred embodiment, the weight ratio of the internal disintegrant to the external disintegrant is 1:1-3.

[0036] In the present invention, the particle size D90 of Asartan Potassium is controlled to be no higher than 15 μm, i.e. ≤15 μm, so as to improve the bioavailability of the drug.

[0037] For the present invention, in step (2), the fluidized bed granulation parameters are as follows: the inlet air temperature is 60±10°C, the spray speed is 40-100rpm, the wind frequency is 20-40Hz, and the material temperature is controlled at 30-50°C during the entire granulation process; during drying, the inlet air temperature is controlled at 60±10°C, and the moisture content is below 0.8%.

[0038] In the present invention, in step (3), when pressing into micro-tablets, a 3 mm round punch die is used, the tablet weight is 20 mg / tablet, and the hardness is 15-30N.

[0039] Adopt the technical scheme of the present invention, the advantages are as follows:

[0040] (1) The mesartan potassium capsule provided by the present invention uses microcrystalline cellulose and mannitol as fillers and cross-linked sodium carboxymethyl cellulose as a disintegrant. According to the order of addition, the disintegrants are divided into internal disintegrants and external disintegrants, which can reduce the phenomenon of equipment adhesion during the granulation process.

[0041] (2) The lasartan potassium capsule provided by the present invention is prepared by preparing lasartan potassium and excipients into micro-tablets and filling them into capsules, that is, a dose of the drug is dispersed in a plurality of mutually independent micro-units. After oral administration, the contact area with the gastrointestinal mucosa is increased, thereby improving the bioavailability of the drug and reducing or eliminating the irritation of certain drugs to the gastrointestinal tract.

[0042] (3) Since bisartan potassium has a rather unpleasant odor, the odor is still strong even after it is made into tablets. The existing dosage form is an uncoated tablet. When taking it, it is difficult to swallow due to the odor. In view of the above problem, the present invention makes it into micro-tablets and fills it into capsules, which can not only mask the odor, but also improve its stability, which is better than other dosage forms such as tablets and granules. In particular, bisartan potassium contains ester bonds and is easily hydrolyzed. After being made into a preparation, it needs to avoid storage under relatively humid conditions, and preparing it into capsules is more conducive to moisture resistance.

[0043] (4) The lasartan potassium capsule provided by the present invention controls the particle size D90 of lasartan potassium to be no higher than 15 μm, which can improve the bioavailability of the drug. DETAILED DESCRIPTION

[0044] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0045] Example 1

[0046] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0047]

[0048] The preparation method thereof comprises the following steps:

[0049] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0050] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0051] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0052] Example 2

[0053] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0054]

[0055] The preparation method thereof comprises the following steps:

[0056] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0057] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0058] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0059] Example 3

[0060] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0061]

[0062] The preparation method thereof comprises the following steps:

[0063] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0064] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0065] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0066] Example 4

[0067] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0068]

[0069]

[0070] The preparation method thereof comprises the following steps:

[0071] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0072] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0073] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0074] Example 5

[0075] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0076]

[0077] The preparation method thereof comprises the following steps:

[0078] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0079] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0080] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0081] Comparative Example 1

[0082] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0083]

[0084] The preparation method thereof comprises the following steps:

[0085] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0086] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0087] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0088] Comparative Example 2

[0089] A kind of Asartan potassium tablet, the tablet is made of the following components in parts by weight:

[0090]

[0091] The preparation method thereof comprises the following steps:

[0092] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0093] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0094] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked carboxymethyl cellulose sodium, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then compressed into tablets using an 8 mm round punch die with a tablet weight of 180 mg / tablet and a hardness of 60-110 N to obtain mesartan potassium tablets.

[0095] Comparative Example 3

[0096] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0097]

[0098]

[0099] The preparation method thereof comprises the following steps:

[0100] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0101] (2) Mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose are passed through a 60-mesh sieve and added to a wet granulation pot, and wet granulated with the binder solution obtained in step (1). The wet granulation parameters are as follows: stirring speed 90 rpm, shear speed 1000 rpm, mixing for 5 minutes, spraying the binder solution to make a soft material, the spraying time is controlled within 3 minutes, and granulation is continued for 1 minute; the obtained wet granules are added to a fluidized bed for drying. During drying, the inlet air temperature is controlled at 60±10°C and the moisture content is less than 0.8%; a swing granulator is used to granulate with a 20-mesh sieve;

[0102] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0103] Comparative Example 4

[0104] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0105]

[0106]

[0107] The preparation method thereof comprises the following steps:

[0108] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0109] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0110] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0111] Comparative Example 5

[0112] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0113]

[0114] The preparation method thereof comprises the following steps:

[0115] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0116] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0117] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0118] Comparative Example 6

[0119] A sartan potassium capsule, which is prepared by filling sartan potassium micro-tablets into hollow capsules, wherein the sartan potassium micro-tablets are made of the following components in parts by weight:

[0120]

[0121] The preparation method thereof comprises the following steps:

[0122] (1) dispersing anhydrous citric acid and sodium citrate in 82 parts of purified water, adding hydroxypropyl cellulose as a binder and stirring evenly to prepare a binder solution;

[0123] (2) passing mesartan potassium, filler and internal disintegrant cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve, adding them into a fluidized bed, and subjecting the binder solution obtained in step (1) to fluidized bed granulation. The fluidized bed granulation parameters are as follows: inlet air temperature is 60±10° C., spray speed is 40-100 rpm, wind frequency is 20-40 Hz, and the material temperature is controlled at 30-50° C. during the whole granulation process; the obtained granules are dried. During drying, the inlet air temperature is controlled at 60±10° C. and the moisture content is reduced to below 0.8%; a swing granulator is used to granulate the granules through a 20-mesh sieve;

[0124] (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant, cross-linked sodium carboxymethyl cellulose, and a lubricant, magnesium stearate, to obtain a total mixed granule, which is then pressed into micro-tablets using a 3 mm round punch die with a tablet weight of 20 mg / tablet and a hardness of 15-30 N. The micro-tablets are then filled into hollow capsules with a filling specification of 9 tablets / capsule and a 1# capsule shell to obtain mesartan potassium capsules.

[0125] Comparative Example 7

[0126] The mesartan potassium tablets were prepared by referring to the formula and method of Example 1 in patent CN101677961A.

[0127] The dissolution curves of the finished products in the examples and comparative examples and the original formulation Takeda (batch 12355773, licensee: Takeda) in pH 6.8 phosphate buffer + 0.2% CTAB medium (basket method, rotation speed 100 rpm) were investigated, and the specific dissolution results are as follows:

[0128] Group 5min 10min 15min 20min 30min 45min Original preparation 45.1 65.4 84.3 90.1 93.7 95.7 Example 1 42.3 62.5 87.7 92.3 94.1 96.1 Example 2 38.7 60.5 81.3 89.3 92.3 94.1 Example 3 41.3 62.5 88.7 90.3 94.9 95.3 Example 4 41.3 62.5 88.7 90.3 94.9 95.3 Example 5 44.3 67.5 86.7 95.3 95.1 95.7 Comparative Example 1 31.3 55.3 75.7 81.2 87.9 94.5 Comparative Example 2 28.2 60.2 78.9 87.3 90.4 93.2 Comparative Example 3 29.7 50.3 67.9 77.9 84.8 90.4 Comparative Example 4 30.1 53.8 69.3 72.3 80.1 88.6 Comparative Example 5 48.3 68.7 86.3 90.6 91.7 94.9 Comparative Example 6 33.1 54.6 70.3 81.2 86.9 90.6 Comparative Example 7 45.8 66.0 80.2 92.6 94.3 95.2

[0129] From the dissolution data, it can be seen that the capsules provided in Examples 1-5 of the present invention have a relatively consistent dissolution curve trend with the original preparation, the capsules in Comparative Example 5 and the tablets in Comparative Example 7, with no significant difference, and have a good dissolution effect.

[0130] However, the capsules in Comparative Example 1, Comparative Examples 3-4, Comparative Example 6, and the tablets in Comparative Example 2 had poor dissolution effects and slow dissolution trends. The larger particle size of Asartan Potassium in the capsule of Comparative Example 1 will lead to a slower dissolution rate; the tablets in Comparative Example 2 are made into ordinary tablets with less contact area with the medium than in Example 1, and the 5-min dissolution rate is slower, indicating that ordinary tablets are not conducive to the dissolution of Asartan Potassium; the granulation method of the capsule in Comparative Example 3 is changed to wet granulation, and the obtained granules are tighter than those of the fluidized bed, resulting in a slower dissolution rate, indicating that the wet granulation method is not conducive to the dissolution of Asartan Potassium; the amount of sodium citrate in Comparative Example 4 is low, and the dissolution rate is slow, indicating that a lower amount of sodium citrate is not conducive to the dissolution of Asartan Potassium; in Comparative Example 6, the ratio of the internal disintegrant to the external disintegrant of the disintegrant cross-linked carboxymethyl cellulose sodium is adjusted to 1:0.33 in the capsule, and the disintegration rate of the tablet slows down, and the dissolution rate slows down, indicating that the ratio of the internal and external additions of the disintegrant cross-linked carboxymethyl cellulose sodium needs to be controlled.

[0131] The finished products in the examples and comparative examples and the original formulation Takeda (batch 12355773, licensee: Takeda) were placed under high temperature conditions to examine their stability. The specific stability results are as follows:

[0132]

[0133] From the stability data, it can be seen that the stability of the capsules provided in Examples 1-5 of the present invention is not significantly different from that of the capsules in Comparative Examples 1 and 6, the content of related substances is low, and the content of related substances does not increase much under high temperature conditions of 40°C and 60°C, and the stability is relatively high.

[0134] Since the tablets in Comparative Example 2 were made into ordinary tablets without capsule filling, the stability results were worse than those of the embodiments and the original preparation; the capsules in Comparative Example 3 were prepared by wet granulation, and the stability results were worse than those of the fluidized bed granulation method; the dosage of the stabilizer sodium citrate in Comparative Examples 4 and 5 was too high or too low, and the related substances increased significantly, and the stability was poor; the stability results of the tablets in Comparative Example 7 (prepared with reference to patent CN101677961A) were worse than those of the embodiments.

[0135] In summary, the present invention prepares mesartan potassium, a filler, a stabilizer, a binder, a disintegrant and a lubricant in the form of microtablets and fills the microtablets into capsules. The stabilizers are anhydrous citric acid and sodium citrate. The prepared microtablets do not need to be dried under reduced pressure and can be directly filled into capsules, thereby maintaining high stability and high solubility of the preparation at the same time.

[0136] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A mesartan potassium capsule, characterized in that: The capsule is prepared by filling bissartan potassium microtablets in hollow capsules. The bissartan potassium microtablets are made of the following components in parts by weight: 40-45 parts of bissartan potassium, 80-130 parts of fillers, 4-12 parts of stabilizers, 2-8 parts of binders, 10-20 parts of disintegrants, and 2-6 parts of lubricants; wherein the filler is one or more of microcrystalline cellulose, mannitol, lactose or starch; the stabilizer is anhydrous citric acid and sodium citrate; the binder is one or more of hydroxypropyl cellulose, povidone or hydroxypropyl methylcellulose; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked povidone or low-substituted hydroxypropyl cellulose; wherein the disintegrant is divided into internally added disintegrants and externally added disintegrants according to the order of addition; and the lubricant is magnesium stearate.

2. The Asartan potassium capsule according to claim 1, characterized in that: During its preparation process, the potassium mesartan, a filler and an internal disintegrant are first mixed uniformly to obtain a mixture, and the mixture is subjected to fluidized bed granulation using a binder solution made of a stabilizer, a binder and purified water. The obtained granules are dried and granulated, and then mixed uniformly with an external disintegrant and a lubricant to obtain total mixed granules, which are pressed into microtablets and filled into hollow capsules to obtain potassium mesartan capsules.

3. The Asartan potassium capsule according to claim 2, characterized in that: The particle size D90 of the mesartan potassium is not higher than 15 μm; the filler is microcrystalline cellulose and mannitol; the binder is hydroxypropyl cellulose; and the disintegrant is cross-linked sodium carboxymethyl cellulose.

4. The Asartan potassium capsule according to claim 3, characterized in that: The mesartan potassium microtablets are made of the following components in parts by weight: 40-45 parts of mesartan potassium, 85-95 parts of mannitol, 15-25 parts of microcrystalline cellulose, 3-5 parts of anhydrous citric acid, 3-6 parts of sodium citrate, 3-6 parts of hydroxypropyl cellulose, 12-16 parts of cross-linked sodium carboxymethyl cellulose, and 3-4 parts of magnesium stearate; wherein the weight ratio of the internal disintegrant to the external disintegrant is 1:1-4.

5. The Asartan potassium capsule according to claim 4, characterized in that: The mesartan potassium microtablets are made of the following components in parts by weight: 42.28 parts of mesartan potassium, 86.77-90.26 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 2.66-5.15 parts of sodium citrate, 3.6-5.4 parts of hydroxypropyl cellulose, 14 parts of cross-linked sodium carboxymethyl cellulose, and 3-4 parts of magnesium stearate; wherein the weight ratio of the internal disintegrant to the external disintegrant is 1:1-3.

6. The Asartan potassium capsule according to claim 4, characterized in that: The Asartan Potassium micro-tablets are made of the following components in parts by weight: 42.28 parts of mesartan potassium, 87.77 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, 3 parts of magnesium stearate; 42.28 parts of mesartan potassium, 90.26 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 2.66 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, 3 parts of magnesium stearate; 42.28 parts of mesartan potassium, 86.77 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, 4 parts of magnesium stearate; 42.28 parts of mesartan potassium, 89.57 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 3.6 parts of hydroxypropyl cellulose, 10.5 parts of internal disintegrant croscarmellose sodium, 3.5 parts of external disintegrant croscarmellose sodium, 3 parts of magnesium stearate; 42.28 parts of Asartan potassium, 87.77 parts of mannitol, 18 parts of microcrystalline cellulose, 4 parts of anhydrous citric acid, 5.15 parts of sodium citrate, 5.4 parts of hydroxypropyl cellulose, 7 parts of internal disintegrant croscarmellose sodium, 7 parts of external disintegrant croscarmellose sodium, and 3 parts of magnesium stearate.

7. The method for preparing the Asartan Potassium capsules according to claim 1, characterized in that: The steps include: (1) dispersing a stabilizer in purified water, adding a binder and stirring evenly to prepare a binder solution; (2) sieving the potassium sesartan, the filler and the internal disintegrant, adding them into a fluidized bed, and subjecting them to fluidized bed granulation with the binder solution obtained in step (1), drying and granulating; (3) The granules obtained in step (2) are then mixed evenly with an external disintegrant and a lubricant to obtain a total mixed granule, which is then pressed into micro-tablets and filled into hollow capsules to obtain mesartan potassium capsules.

8. The method for preparing Asartan Potassium Capsules according to claim 7, characterized in that: The particle size D90 of the mesartan potassium is not higher than 15 μm; the filler is microcrystalline cellulose and mannitol; the binder is hydroxypropyl cellulose; and the disintegrant is cross-linked sodium carboxymethyl cellulose.

9. The method for preparing Asartan Potassium Capsules according to claim 7, characterized in that: In step (2), the fluidized bed granulation parameters are as follows: the inlet air temperature is 60±10°C, the spray speed is 40-100rpm, the wind frequency is 20-40Hz, and the material temperature is controlled at 30-50°C during the entire granulation process; during drying, the inlet air temperature is controlled at 60±10°C and the moisture content is below 0.8%.

10. The method for preparing Asartan Potassium Capsules according to claim 7, characterized in that: In step (3), when pressing into microtablets, a 3 mm round punch die is used, the tablet weight is 20 mg / tablet, and the hardness is 15-30N.

Images