Melsartan potassium tablet and preparation method thereof

Abstract

The invention discloses a Milsartan potassium tablet. The Milsartan potassium tablet is obtained by coating a Milsartan potassium tablet with a moisture-proof coating solution, the Milsartan potassium tablet is prepared from the following raw materials in parts by weight: 76.8 to 93.9 parts of Milsartan potassium, 204 to 250 parts of a filling agent, 4.84 to 5.92 parts of a pH (Potential of Hydrogen) regulator, 9.7 to 11.9 parts of an adhesive, 24.8 to 30.4 parts of a disintegrating agent and 3.2 to 4.0 parts of a lubricating agent, the moisture-proof coating liquid is a dispersion liquid with the concentration of 15-20% prepared by dispersing a moisture-proof coating premixing agent in water; the weight of the moisture-proof coating premix is 4-6% of the total weight of the raw materials of the Milsartan potassium tablet. The storage hygroscopicity of the Milsartan potassium tablet is obviously reduced, meanwhile, the requirement for an inner bag is reduced, the Milsartan potassium tablet is easy to store and transport and good in stability, and the process is simple and easy to control.

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to a medicine and a preparation method thereof, and in particular to a mesartan potassium tablet and a preparation method thereof. Background Art

[0002] Azilsartan Potassium is an angiotensin II receptor antagonist (ARB) drug developed by Takeda Pharmaceuticals of Japan. It exerts its antihypertensive effect by blocking angiotensin II receptors. Azilsartan Potassium is a prodrug that can be quickly converted into the active ingredient azilsartan after oral absorption. Like all other sartan antihypertensive drugs, azilsartan can reduce urine protein and protect the heart and kidneys while lowering blood pressure. It is the first choice for the treatment of hypertension in young and middle-aged people, hypertension with diabetes, hypertension with kidney disease, and hypertension with cardiovascular disease. Compared with traditional sartan antihypertensive drugs, azilsartan has a unique oxadiazole ring structure, which increases its affinity with angiotensin II receptors by more than 10,000 times. It also binds more tightly to the receptors and dissociates more slowly, thereby exerting a strong, stable and lasting antihypertensive effect.

[0003] Asartan 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, the structural formula is as follows:

[0004]

[0005] Asartan Potassium is an ester salt, which is almost insoluble in water and sensitive to light, moisture and heat. It is prone to degradation, especially under high moisture or high humidity conditions. At present, the inner packaging system of existing products on the market, whether blister packaging or bottle packaging, requires the addition of desiccant. Therefore, it is very important to develop a relatively stable formulation of Asartan Potassium Tablets in medicine for the long-term storage of Asartan Potassium Tablets.

[0006] The preparation process of the original formulation of this product disclosed in CN101677961A is as follows: weigh the amount of the prescription, add part of the raw and auxiliary materials, put them into a fluidized bed granulator, spray the binder to granulate, mix the granules with the external auxiliary materials, and then press the tablets, and then vacuum dry the tablets and blister pack them. The packaging material is an aluminum blister with an integrated desiccant, and the storage condition is 25°C, sealed and dark. In addition, the preparation process requires up to 16 hours of reduced pressure drying to ensure that the moisture content of the product is at an absolutely low level, and the production conditions are relatively harsh.

[0007] Chinese invention patent application CN 117503719 A provides a method for preparing lasartan potassium tablets, wherein micronized lasartan potassium is mixed with an appropriate amount of a flow aid and dextrin to prepare a lasartan potassium cyclodextrin inclusion compound; the lasartan potassium cyclodextrin inclusion compound is mixed with a filler and a disintegrant, a lubricant is added and mixed evenly, and the mixture is directly compressed to obtain lasartan potassium tablets. This method ensures the stability of the active ingredient of the drug by preparing the lasartan potassium cyclodextrin inclusion compound, but the inclusion compound is easily uneven during the preparation process, resulting in drug exposure and uneven quality between sample batches.

[0008] Chinese invention patent CN117122570A discloses a method for preparing mesartan potassium tablets, which improves product stability by introducing meglumine as an alkaline agent together with acidic tartaric acid. However, this method only improves the effect of pH on product stability, and does not solve the problem of product degradation caused by moisture or humidity.

[0009] Chinese invention patent application CN117883396A discloses a potassium tablet of Asartan, which improves product stability by adding soybean oil, castor oil, stearin, liquid paraffin or dimethyl silicone oil as a stabilizer. However, it only proves that high temperature conditions are conducive to product stability and cannot guarantee stability under high humidity conditions.

[0010] In summary, the mersartan potassium tablets prepared by the prior art still cannot achieve good stability of the product under high humidity conditions. Therefore, there is an urgent need for a prescription to improve the stability of mersartan potassium tablets, solve the current problems of difficult storage of mersartan potassium tablets or demanding industrial production conditions, and also solve the problem of poor solubility. Summary of the invention

[0011] The purpose of the present invention is to solve the problem that the existing bisartan potassium tablets are insufficiently stable under high humidity conditions, and to provide a bisartan potassium preparation and a preparation method thereof.

[0012] The objective of the present invention is achieved through the following technical solutions:

[0013] A measartan potassium tablet is obtained by coating measartan potassium tablets with a moisture-proof coating liquid; the measartan potassium tablet is prepared from the following raw materials in parts by weight: 76.8-93.9 parts of measartan potassium, 204-250 parts of a filler, 4.84-5.92 parts of a pH regulator, 9.7-11.9 parts of a binder, 24.8-30.4 parts of a disintegrant, and 3.2-4.0 parts of a lubricant; the moisture-proof coating liquid is a dispersion liquid with a concentration of 15-20% prepared by dispersing a moisture-proof coating premix in water; the weight of the moisture-proof coating premix is ​​4-6% of the total weight of the raw materials of the measartan potassium tablet; the moisture-proof coating premix consists of a gastric-soluble film coating premix and a pH regulator; the gastric-soluble film coating premix is ​​a gastric-soluble film coating premix with polyvinyl alcohol as a film-forming agent.

[0014] Preferably, the bisartan potassium tablets are made of the following raw materials in weight fractions: 85.36 parts of bisartan potassium, 227.26 parts of filler, 5.38 parts of pH adjuster, 10.8 parts of binder, 27.6 parts of disintegrant, and 3.6 parts of lubricant.

[0015] The D90 particle size of the mesartan potassium is less than 20 μm, preferably less than 15 μm.

[0016] The filler comprises a granulation filler and an external mixing filler; the weight ratio of the granulation filler to the external mixing filler is 5:1-5.5:1; the granulation filler is mannitol, and the external mixing filler is microcrystalline cellulose.

[0017] Specifically, the preferred type of microcrystalline cellulose is PH112 (i.e., microcrystalline cellulose PH112).

[0018] In the described mesartan potassium tablets, the described pH regulator comprises an acidic regulator and an alkaline regulator; the weight ratio of the described acidic regulator to the alkaline regulator is 2.5:1 to 3.3:1; the described acidic regulator is selected from at least one of tartaric acid, fumaric acid and malic acid, preferably fumaric acid; the described alkaline regulator is selected from at least one of sodium hydroxide, sodium bicarbonate and malic acid, preferably sodium hydroxide.

[0019] The binder is at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose, preferably hydroxypropyl cellulose.

[0020] The disintegrant is cross-linked sodium carboxymethyl cellulose.

[0021] The lubricant is magnesium stearate.

[0022] In the moisture-proof coating premix, the amount of the pH regulator is 20-40% of the total weight of the moisture-proof coating premix.

[0023] The gastric soluble film coating premix comprises at least polyvinyl alcohol, titanium dioxide, polyethylene glycol and talcum powder, and the mass fraction of the polyvinyl alcohol is 35-45%, preferably 40%.

[0024] Preferably, the gastric soluble film coating premix is ​​a composition of polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc in a weight ratio of 10:6:5:4.

[0025] Specifically, the model of the polyvinyl alcohol is 05-88, and the polyethylene glycol is selected from polyethylene glycol 4000.

[0026] In the moisture-proof coating premix, the pH regulator is composed of an acidic regulator and an alkaline regulator in a weight ratio of 2.5:1 to 3.3:1; the acidic regulator is selected from at least one of tartaric acid, fumaric acid and malic acid, preferably fumaric acid; the alkaline regulator is selected from at least one of sodium hydroxide, sodium bicarbonate and malic acid, preferably sodium hydroxide.

[0027] According to one embodiment of the present invention, the lasartan potassium tablets are obtained by coating lasartan potassium tablets with a moisture-proof coating liquid; the lasartan potassium tablets are made of the following raw materials by weight: 85.36 parts of lasartan potassium; 191.26 parts of mannitol; 36 parts of microcrystalline cellulose; 4 parts of fumaric acid; 1.38 parts of sodium hydroxide; 10.8 parts of hydroxypropyl cellulose; 27.6 parts of cross-linked carboxymethyl cellulose sodium; 3.6 parts of magnesium stearate; the The moisture-proof coating liquid is prepared by dispersing a moisture-proof coating premix in purified water to form a dispersion of 15%, 18%, and 20%; the weight of the moisture-proof coating premix is ​​5% of the total weight of the raw materials of the mesartan potassium tablets, and the moisture-proof coating premix is ​​composed of a gastric-soluble film coating premix with polyvinyl alcohol as a film-forming agent, fumaric acid and sodium hydroxide in a weight ratio of 12.6:4:1.4, 14.4:2.68:0.92, and 10.8:5.35:1.85.

[0028] Another object of the present invention is to provide a method for preparing the asartan potassium tablets, comprising the following steps:

[0029] Step (1), adding a pH regulator and a binder into water to prepare a binder solution containing a pH regulator with a binder concentration of 5 to 8%; adding mesartan potassium and a filler for granulation into a fluidized bed, and spraying the binder solution containing a pH regulator into the fluidized bed for granulation;

[0030] The granulated particles obtained in step (2) and step (1) are granulated; an additional mixing filler, a disintegrant and a lubricant are added, mixed evenly, and tableted to obtain mesartan potassium tablets;

[0031] Step (3), preparing a moisture-proof coating solution containing a pH regulator with water; coating the lasartan potassium tablets with the moisture-proof coating solution containing the pH regulator to obtain lasartan potassium tablets, wherein the moisture content of the lasartan potassium tablets is less than 1.0%.

[0032] In step (1), the moisture content of the granulated particles is below 1.0%.

[0033] Preferably, mesartan potassium and a filler for granulation are added to a fluidized bed, and a binder solution containing a pH regulator is sprayed into the fluidized bed for granulation. The material temperature is controlled at 30-40° C. during the granulation process, and after the spraying is completed, the granulated particles are dried until the moisture content is below 1.0%.

[0034] In step (2), the granulated particles are sized using a 1.5 mm sieve.

[0035] The tablet pressing pressure is 2-4KN.

[0036] In step (3), preferably, the Asartan potassium tablets are placed in a GBB-48C high-efficiency coating machine, and a moisture-proof coating liquid containing a pH regulator is sprayed into the coating machine for coating. During the coating process, the inlet air humidity is controlled at 10 g / m 3 Next, the material temperature is controlled at 38-42° C. during the coating process, and drying is continued after the coating is completed until the moisture content of the Asartan Potassium tablets is below 1.0%.

[0037] The water described in the present invention can be purified water.

[0038] Beneficial effects of the present invention:

[0039] The present invention coats the prepared lasartan potassium tablets by adding a pH regulator as a moisture-proof coating premix to a gastric soluble film coating premix with polyvinyl alcohol as a film-forming agent, and controls the moisture content of the lasartan potassium tablets to be below 1.0%. The storage hygroscopicity of the obtained lasartan potassium tablets is significantly reduced, and the requirements for the inner package are reduced. The tablets are easy to store and transport, have good stability, and have a simple process and are easy to control. DETAILED DESCRIPTION

[0040] In order to more clearly understand the present invention, the present invention is described in detail below by means of preferred embodiments, but the present invention is not limited thereby in any way.

[0041] The D90 particle size of Asartan Potassium is 7.6 μm.

[0042] Example 1

[0043] Asartan Potassium Tablets (Specification 80mg) contain the following ingredients:

[0044]

[0045] Among them, the gastric soluble film coating premix is ​​a composition composed of polyvinyl alcohol 05-88, titanium dioxide, polyethylene glycol 4000 and talcum powder in a weight ratio of 10:6:5:4, wherein polyvinyl alcohol 05-88 is a film-forming agent.

[0046] Preparation process:

[0047] Step (1), adding fumaric acid, sodium hydroxide and hydroxypropyl cellulose to purified water to prepare a hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide with a hydroxypropyl cellulose concentration (mass fraction) of 5%; adding mesartan potassium and mannitol to a fluidized bed, spraying the hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide to granulate, controlling the material temperature at 30-40° C. during the granulation process, and continuing to dry the granulated particles after the spraying is completed until the moisture content of the granulated particles is 0.66%;

[0048] The granulated particles obtained in step (2) and step (1) are sieved using a 1.5 mm sieve; microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly, and tableted at a pressure of 2.6 KN to obtain mesartan potassium tablets;

[0049] Step (3), adding a gastric soluble film coating premix containing polyvinyl alcohol as a film-forming agent, fumaric acid and sodium hydroxide to purified water to prepare a moisture-proof coating solution having a gastric soluble film coating premix concentration (mass fraction) of 15%; placing the mesartan potassium tablets prepared in step (2) in a GBB-48C high-efficiency coating machine, spraying the moisture-proof coating solution into the tablets for moisture-proof coating, and controlling the inlet air humidity at 10 g / m 3 The temperature of the material is controlled at 38-42°C during the coating process (i.e., each cubic meter of air contains less than or equal to 10 grams of water). After the coating is completed, the tablets are dried until the moisture content is 0.83% to obtain Asartan Potassium tablets.

[0050] Example 2

[0051] Asartan Potassium Tablets (Specification 80mg) contain the following ingredients:

[0052]

[0053]

[0054] Preparation process:

[0055] Step (1), adding fumaric acid, sodium hydroxide and hydroxypropyl cellulose into purified water to prepare a hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide with a hydroxypropyl cellulose concentration of 6.5%; adding mesartan potassium and mannitol into a fluidized bed, spraying the hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide into the fluidized bed for granulation, controlling the material temperature at 30-40° C. during the granulation process, and continuing to dry the granulated particles after the spraying is completed until the moisture content of the granulated particles is 0.57%;

[0056] The granulated particles obtained in step (2) and step (1) are sieved using a 1.5 mm sieve; microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly, and tableted at a pressure of 2.8 KN to obtain mesartan potassium tablets;

[0057] Step (3), adding a gastric soluble film coating premix with polyvinyl alcohol as a film-forming agent (same as in Example 1), fumaric acid and sodium hydroxide into purified water to prepare a moisture-proof coating solution with a concentration of 18% of polyvinyl alcohol gastric soluble film coating premix; placing the mesartan potassium tablets prepared in step (2) in a GBB-48C high-efficiency coating machine, spraying the moisture-proof coating solution into the tablets for moisture-proof coating, and controlling the inlet air humidity at 10 g / m 3 Next, the material temperature was controlled at 38-42° C. during the coating process, and the tablets were dried until the moisture content was 0.86% to obtain Asartan potassium tablets.

[0058] Example 3

[0059] Asartan Potassium Tablets (Specification 80mg) contain the following ingredients:

[0060]

[0061] Preparation process:

[0062] Step (1), adding fumaric acid, sodium hydroxide and hydroxypropyl cellulose into purified water to prepare a hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide with a hydroxypropyl cellulose concentration of 8%; adding mesartan potassium and mannitol into a fluidized bed, spraying the hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide into the fluidized bed for granulation, controlling the material temperature at 30-40° C. during the granulation process, and continuing to dry the granulated particles after the spraying is completed until the moisture content of the granulated particles is 0.71%;

[0063] The granulated particles obtained in step (2) and step (1) are sieved using a 1.5 mm sieve; microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly, and tableted at a pressure of 2.5 KN to obtain mesartan potassium tablets;

[0064] Step (3), adding a gastric soluble film coating premix with polyvinyl alcohol as a film-forming agent (same as in Example 1), fumaric acid and sodium hydroxide into purified water to prepare a moisture-proof coating solution with a concentration of 20% of the gastric soluble film coating premix; placing the mesartan potassium tablets prepared in step (2) in a GBB-48C high-efficiency coating machine, spraying the moisture-proof coating solution into the tablets for moisture-proof coating, and controlling the inlet air humidity at 10 g / m 3 Next, the material temperature was controlled at 38-42° C. during the coating process, and the tablets were dried continuously after the coating was completed to obtain a moisture content of 0.82% to obtain Asartan potassium tablets.

[0065] Comparative Example 1

[0066] Referring to the original CN101677961A, Asartan Potassium Tablets (specification 80 mg) were prepared, which contained the following components:

[0067]

[0068] Preparation process:

[0069] Step (1), adding fumaric acid, sodium hydroxide and hydroxypropyl cellulose into purified water to prepare a hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide with a hydroxypropyl cellulose concentration of 6.5%; adding mesartan potassium and mannitol into a fluidized bed, spraying the hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide into the fluidized bed for granulation, controlling the material temperature at 30-40° C. during the granulation process, and continuing to dry the granulated particles after the spraying is completed until the moisture content of the granulated particles is 0.67%;

[0070] The granulated particles obtained in step (2) and step (1) are sieved using a 1.5 mm sieve; microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly, and tableted at a pressure of 2.5 KN to obtain mesartan potassium tablets;

[0071] Step (3) The lasartan potassium tablets obtained in step (2) are dried under reduced pressure at a temperature of 40° C. and a vacuum degree of −0.098 MPa for 16 hours, and the moisture content of the lasartan potassium tablets is finally 0.74%.

[0072] Comparative Example 2

[0073] Asartan Potassium Tablets (Specification 80mg) contain the following ingredients:

[0074]

[0075] Preparation process:

[0076] Step (1), adding fumaric acid, sodium hydroxide and hydroxypropyl cellulose into purified water to prepare a hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide with a hydroxypropyl cellulose concentration of 6.5%; adding mesartan potassium and mannitol into a fluidized bed, spraying the hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide into the fluidized bed for granulation, controlling the material temperature at 30-40° C. during the granulation process, and continuing to dry the granulated particles after the spraying is completed until the moisture content of the granulated particles is 0.61%;

[0077] The granulated particles obtained in step (2) and step (1) are sieved using a 1.5 mm sieve; microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly, and tableted at a pressure of 2.6 KN to obtain mesartan potassium tablets;

[0078] Step (3), adding a gastric soluble film coating premix with polyvinyl alcohol as a film-forming agent (same as in Example 1) to purified water to prepare a moisture-proof coating solution with a concentration of 16%; placing the mesartan potassium tablets prepared in step (2) in a GBB-48C high-efficiency coating machine, spraying the moisture-proof coating solution for moisture-proof coating, and controlling the inlet air humidity at 10 g / m 3 Next, the material temperature was controlled at 38-42° C. during the coating process, and the tablets were dried until the moisture content was 0.84% ​​to obtain Asartan potassium tablets.

[0079] Comparative Example 3

[0080] Asartan Potassium Tablets (Specification 80mg) contain the following ingredients:

[0081]

[0082]

[0083] Note: The formula ratio of the gastric soluble film coating premix with Hydroxypropyl Methylcellulose E5 as the film-forming agent is the same as that in Example 1, except that the polyvinyl alcohol is replaced by Hydroxypropyl Methylcellulose.

[0084] Preparation process:

[0085] Step (1), adding fumaric acid, sodium hydroxide and hydroxypropyl cellulose into purified water to prepare a hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide with a hydroxypropyl cellulose concentration of 6.5%; adding mesartan potassium and mannitol into a fluidized bed, spraying the hydroxypropyl cellulose solution containing fumaric acid and sodium hydroxide into the fluidized bed for granulation, controlling the material temperature at 30-40° C. during the granulation process, and continuing to dry the granulated particles after the spraying is completed until the moisture content of the granulated particles is 0.49%;

[0086] (2) The granulated particles obtained in step (1) are sieved with a 1.5 mm sieve; microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly, and tableted at a pressure of 2.7 kN to obtain mesartan potassium tablets;

[0087] (3) Add a gastric soluble film coating premix containing hydroxypropyl methylcellulose as a film-forming agent, fumaric acid and sodium hydroxide into purified water to prepare a moisture-proof coating solution having a concentration of 12% of the gastric soluble film coating premix containing hydroxypropyl methylcellulose as a film-forming agent; place the mesartan potassium tablets prepared in step (2) in a GBB-48C high-efficiency coating machine, spray the moisture-proof coating solution into the tablets for moisture-proof coating, and control the air humidity at 10 g / m during the coating process. 3 Next, the material temperature was controlled at 38-42° C. during the coating process, and after the spraying was completed, the tablets were dried until the moisture content was 0.91%, thereby obtaining Asartan potassium tablets.

[0088] Example 4 Comparative study under high humidity conditions

[0089] The tablets of Examples 1 to 3 and Comparative Examples 1 to 3 were placed in a culture dish and placed in a container with a humidity of 75%±5%. The moisture content of the tablets was examined for 3 days and 5 days respectively. The results were analyzed as follows:

[0090] Table 1. Moisture test results of Asartan Potassium Tablets in Examples and Comparative Examples placed under high humidity conditions for different periods of time

[0091]

[0092] The results show that compared with Comparative Example 1, the moisture absorption of the asesartan potassium tablet samples prepared by moisture-proof coating in Examples 1 to 3 is greatly reduced; compared with Comparative Example 3, the moisture absorption of the asesartan potassium tablet samples prepared in Examples 1 to 3 is also lower, indicating that the moisture-proof effect of coating with a gastric-soluble film coating premix with polyvinyl alcohol as a film-forming agent is better than that of coating with a gastric-soluble film coating premix with hydroxypropyl methylcellulose as a film-forming agent.

[0093] Example 5 Comparative study under lighting conditions

[0094] The tablets of Example 1 and Comparative Example 1 were placed in a culture dish and placed in a light incubator with a light condition of 5000 lx. The relevant substances were examined for 15 days and 30 days respectively. The results were analyzed as follows:

[0095] Table 2. Detection results of related substances in the examples and comparative examples of Asartan Potassium tablets after exposure to light for different time periods

[0096]

[0097] The results show that compared with Comparative Example 1, the photostability of the Asartan potassium tablet sample prepared by moisture-proof coating in Example 1 is better.

[0098] Example 6 Accelerated stability study

[0099] The tablets of Example 1 and the tablets of Comparative Examples 1 and 2 were packed in double aluminum blister packaging (polyamide / aluminum / polyvinyl chloride cold-stamped solid medicinal hard tablets + medicinal aluminum foil), and subjected to accelerated stability test (the samples were placed in a stability test box at a temperature of 40°C ± 2°C and a humidity of 75% ± 5% for 3 months), and the related substances were detected. The results are analyzed as follows:

[0100] Table 3. Accelerated stability results of Asartan Potassium Tablets in Examples and Comparative Examples

[0101]

[0102] The results show that the impurity growth level in the related substances of the Asartan Potassium tablets obtained in Example 1 under accelerated conditions is comparable to that in Comparative Example 1, indicating that when double aluminum blister packaging is used, the Asartan Potassium tablets sample prepared by the present invention has comparable stability effects to the samples prepared by the original research process; however, the impurity growth level in the related substances of the Asartan Potassium tablets obtained in Example 1 is much lower than that in Comparative Example 2, indicating that when the moisture-proof coating component does not contain a pH regulator, although there is a moisture-proof effect (as can be seen from the results in Table 1), other stability problems will be caused.

[0103] Example 7 Comparative Study of Different Packaging

[0104] The tablets of Example 1 and Comparative Example 1 were packaged in aluminum-plastic packaging (polyvinyl chloride solid pharmaceutical hard tablets + pharmaceutical aluminum foil) and subjected to an accelerated stability test (the samples were placed in a stability test box at a temperature of 40°C ± 2°C and a humidity of 75% ± 5% for 3 months), and the related substances were tested. The results are analyzed as follows:

[0105] Table 4. Accelerated stability results of different packaging of Asartan Potassium Tablets in Examples and Comparative Examples

[0106]

[0107] Combined with Table 3, it can be seen that the impurity growth level of the related substances in the mersartan potassium tablets obtained in Example 1 under accelerated conditions is much lower than that in Comparative Example 1, indicating that when aluminum-plastic packaging (which has poorer barrier properties than double aluminum packaging) is used, the mersartan potassium tablet sample prepared by the present invention still has a good stability effect, while the tablets of Comparative Example 1 prepared by the original research process, when using aluminum-plastic packaging, the impurities in the related substances increase significantly, indicating that the mersartan potassium tablets prepared by the present invention can still maintain good stability using conventional aluminum-plastic packaging, thereby reducing the requirements for packaging.

[0108] Example 8 In vitro dissolution curve investigation

[0109] Take the samples and reference preparations prepared in Examples 1 to 3 and Comparative Example 1, and refer to the dissolution and release determination method (Method 2, Part 4, General Rules 0931, Chinese Pharmacopoeia 2020 Edition). Use phosphate buffer (pH 7.8) (take 500 mL of 0.2 mol / L potassium dihydrogen phosphate and 445 mL of 0.2 mol / L sodium hydroxide solution, put them in a 2000 mL volumetric flask, dilute to the scale with water, shake well, adjust the pH to 7.8 ± 0.05 with 0.2 mol / L potassium dihydrogen phosphate or 0.2 mol / L sodium hydroxide solution, and perform ultrasonic degassing before use) 900 mL as the dissolution medium, the medium temperature is 37 ° C ± 0.5 ° C, the rotation speed is 50 revolutions per minute, operate according to the law, and pass 5, 10, 15, 2 At 0, 30, 45, and 60 minutes, take 20 mL of the dissolution solution, filter, accurately measure 10 mL of the filtrate, place it in a 20 mL volumetric flask, dilute it to the scale with the dissolution medium, shake well, and use it as the test solution; take about 59 mg of the reference substance of mesartan potassium, accurately weigh it, place it in a 50 mL brown volumetric flask, add the mixed solution (acetonitrile-water-glacial acetic acid = 80:20:1 V / V / V) to dissolve and dilute it to the scale, shake well, accurately measure 2 mL, place it in a 50 mL brown volumetric flask, dilute it to the scale with the dissolution medium, shake well, and use it as the reference solution. Take the reference solution and the test solution, and measure the absorbance at a wavelength of 290 nm according to the UV-visible spectrophotometry (General Rules 0401 of the Fourth Part of the 2020 Edition of the Chinese Pharmacopoeia), and calculate the dissolution amount of each tablet.

[0110] Table 5. Dissolution results of examples and comparative examples

[0111]

[0112] Note: N / A means not applicable.

[0113] The dissolution results show that compared with Comparative Example 1, the dissolution curves of the mesartan potassium tablets prepared in Examples 1 to 3 in the above-mentioned medium have no significant differences, and all have similar dissolution behaviors to the reference preparation, indicating that the moisture-proof coating does not affect the dissolution of this product.

[0114] In summary, the storage hygroscopicity of the Asartan Potassium Tablets of the present invention is significantly reduced, and at the same time, the tablets have good light stability, which reduces the requirements for packaging, is easy to store and transport, and has a simple process and is easy to control.

Claims

1. A mesartan potassium tablet, characterized in that: The asesartan potassium tablets are obtained by coating asesartan potassium tablets with a moisture-proof coating liquid; the asesartan potassium tablets are prepared from the following raw materials in parts by weight: 76.8-93.9 parts of asesartan potassium, 204-250 parts of a filler, 4.84-5.92 parts of a pH regulator, 9.7-11.9 parts of a binder, 24.8-30.4 parts of a disintegrant, and 3.2-4.0 parts of a lubricant; the moisture-proof coating liquid is a dispersion prepared by dispersing a moisture-proof coating premix in water to form a dispersion with a concentration of 15-20%; the weight of the moisture-proof coating premix is ​​4-6% of the total weight of the raw materials of the asesartan potassium tablets; the moisture-proof coating premix consists of a gastric-soluble film coating premix and a pH regulator; the gastric-soluble film coating premix is ​​a gastric-soluble film coating premix with polyvinyl alcohol as a film-forming agent.

2. The Asartan Potassium Tablets according to claim 1, characterized in that: The lasartan potassium tablets are made of the following raw materials in weight fractions: 85.36 parts of lasartan potassium, 227.26 parts of fillers, 5.38 parts of pH regulators, 10.8 parts of binders, 27.6 parts of disintegrants, and 3.6 parts of lubricants.

3. The Asartan Potassium Tablets according to claim 1 or 2, characterized in that: The D90 particle size of the mesartan potassium is less than 20 μm, preferably less than 15 μm.

4. The Asartan Potassium Tablets according to claim 1 or 2, characterized in that: The filler includes a filler for granulation and an additional filler for mixing; the weight ratio of the filler for granulation to the additional filler for mixing is 5:1 to 5.5:1; in the mesartan potassium tablets, the pH regulator includes an acidic regulator and an alkaline regulator; the weight ratio of the acidic regulator to the alkaline regulator is 2.5:1 to 3.3:

1.

5. The Asartan Potassium Tablets according to claim 4, characterized in that: The granulation filler is mannitol, and the additional mixing filler is microcrystalline cellulose; the acid regulator is selected from at least one of tartaric acid, fumaric acid and malic acid, preferably fumaric acid; the alkaline regulator is selected from at least one of sodium hydroxide, sodium bicarbonate and malic acid, preferably sodium hydroxide.

6. The Asartan Potassium Tablets according to claim 1 or 2, characterized in that: The binder is at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose, preferably hydroxypropyl cellulose; the disintegrant is cross-linked sodium carboxymethyl cellulose; and the lubricant is magnesium stearate.

7. The Asartan Potassium Tablets according to claim 1, characterized in that: The gastric soluble film coating premix at least comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol and talcum powder, wherein the mass fraction of the polyvinyl alcohol is 35-45%; the dosage of the pH regulator is 20-40% of the total weight of the moisture-proof coating premix.

8. The Asartan Potassium Tablets according to claim 1 or 7, characterized in that: The gastric soluble film coating premix is ​​a composition of polyvinyl alcohol, titanium dioxide, polyethylene glycol and talcum powder in a weight ratio of 10:6:5:

4.

9. The Asartan Potassium Tablets according to claim 1 or 7, characterized in that: In the moisture-proof coating premix, the pH regulator is composed of an acidic regulator and an alkaline regulator in a weight ratio of 2.5:1 to 3.3:1; the acidic regulator is selected from at least one of tartaric acid, fumaric acid and malic acid, preferably fumaric acid; the alkaline regulator is selected from at least one of sodium hydroxide, sodium bicarbonate and malic acid, preferably sodium hydroxide.

10. A method for preparing the Asartan Potassium Tablets according to claim 1, characterized in that: The steps include: Step (1), adding a pH regulator and a binder into water to prepare a binder solution containing a pH regulator with a binder concentration of 5 to 8%; adding mesartan potassium and a filler for granulation into a fluidized bed, and spraying the binder solution containing a pH regulator into the fluidized bed for granulation; The granulated particles obtained in step (2) and step (1) are granulated; an additional mixing filler, a disintegrant and a lubricant are added, mixed evenly, and tableted to obtain mesartan potassium tablets; Step (3), preparing a moisture-proof coating solution containing a pH regulator with water; coating the lasartan potassium tablets with the moisture-proof coating solution containing the pH regulator to obtain lasartan potassium tablets, wherein the moisture content of the lasartan potassium tablets is less than 1.0%.

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