Melasartan potassium tablet with high stability and high dissolution rate and preparation method of Melasartan potassium tablet
Preparing measartan potassium tablets through specific formulas and process methods solves the problems of poor stability, low dissolution and high production costs in the prior art, and achieves high stability, high dissolution and suitable for industrial production.
Patent Information
- Application Number
- CN202510351578.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-24
- Publication Date
- 2025-06-06
AI Technical Summary
The existing Measartan potassium tablets have poor stability, low dissolution during the preparation process, and are high in production costs, making it difficult to meet the quality requirements and the needs of industrial production.
Measartan potassium tablets are prepared using specific formulas and processes, including the use of raw materials such as mannitol, croscarmellose sodium, anhydrous citric acid, sodium hydroxide, hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate. Through the fluidized bed granulation and tableting process, the pH value and granulation conditions of the adhesive are controlled to ensure the stability and dissolution of the tablet.
It has achieved high stability and fast dissolution of Measartan potassium tablets, and is suitable for industrial production, reducing production costs, and ensuring the stability and efficacy of the drug activity.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical technology, and particularly relates to a mesartan potassium tablet with high stability and high solubility and a preparation method thereof. Background Art
[0002] 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.
[0003] Both bissartan potassium and azilsartan are poorly soluble drugs, and their solubility is relatively low. Therefore, when being prepared as oral preparations, it is necessary to have a good dissolution curve to be well absorbed by the gastrointestinal tract, otherwise, its absorption and bioavailability will be greatly hindered. Conventional micronization process increases its hydrophobicity while increasing specific surface area, so there is no obvious improvement on dissolution behavior. In addition, bissartan potassium is an ester salt, which is easily hydrolyzed to azilsartan under high temperature and high humidity conditions. Therefore, it is necessary to strictly control temperature and humidity during granulation, which will inevitably lead to an extension of granulation time and increase production cost. Therefore, it is urgent to develop a preparation process of bissartan potassium tablets, which can not only meet quality requirements, but also reduce production costs. Summary of the invention
[0004] The technical problem to be solved by the present invention is to provide a mesartan potassium tablet with high stability and high solubility, the drug activity remains stable and the dissolution is fast. The technical problem to be solved by the present invention is to provide a method for preparing mesartan potassium tablet with high stability and high solubility, the method is simple and suitable for industrial production.
[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:
[0006] A measartan potassium tablet with high stability and high solubility. The measartan potassium tablet is prepared from the following raw materials in parts by weight: 42-86 parts of measartan potassium tablets, 95-192 parts of mannitol, 13-28 parts of cross-linked sodium carboxymethyl cellulose, 0.5-2 parts of anhydrous citric acid, 0.4-0.5 parts of sodium hydroxide, 5-11 parts of hydroxypropyl cellulose, 19-40 parts of microcrystalline cellulose, and 1-4 parts of magnesium stearate.
[0007] Furthermore, the lasartan potassium tablets are made of the following raw materials in parts by weight: 85.36 parts of lasartan potassium, 191.26 parts of mannitol, 13.8 parts of cross-linked carboxymethyl cellulose sodium, 1.6-1.8 parts of anhydrous citric acid, 0.41 parts of sodium hydroxide, 10.8 parts of hydroxypropyl cellulose, 39.37 parts of microcrystalline cellulose, and 3.6 parts of magnesium stearate.
[0008] Furthermore, the method for preparing the high stability and high solubility Asartan potassium tablets comprises the following steps:
[0009] 1) Add anhydrous citric acid and sodium hydroxide into pure water and stir to dissolve to obtain a buffer solution;
[0010] 2) then adding hydroxypropyl cellulose to the buffer solution of step 1), adjusting the pH, and stirring until completely dissolved to obtain an adhesive;
[0011] 3) mixing the binder obtained in step 2) with mannitol, part of croscarmellose sodium and mesartan potassium in a fluidized bed for granulation, and then drying and granulating to obtain intermediate material granules;
[0012] 4) The intermediate material particles obtained in step 3) are mixed with the remaining cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, and the mixture is tableted and dried to obtain mesartan potassium tablets.
[0013] Furthermore, in step 2), the pH is adjusted to 3.8-4.5.
[0014] Furthermore, in step 3), mannitol, croscarmellose sodium and mesartan potassium are added to the fluidized bed for preheating, the air inlet temperature is set above 40° C. for preheating for 10 min, and a binder is used for granulation.
[0015] Furthermore, in the step 3), the material temperature is controlled to be ≤70°C during the granulation process.
[0016] Furthermore, in step 3), the drying temperature is 50-90° C. and the moisture content is ≤1.0%.
[0017] Furthermore, in step 3), the granulation is performed through a 24-mesh sieve.
[0018] Furthermore, the specific process of mixing in step 4) is: adding the intermediate material particles and cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing barrel and mixing for 5 minutes.
[0019] Furthermore, in step 4), the tableting speed is 60,000 to 200,000 tablets per hour, the drying temperature is 40°C ± 5°C, and the tablets are dried to a moisture content of ≤ 0.8%.
[0020] Compared with the prior art, the present invention has the following advantages:
[0021] The preparation method of the tablet containing mesartan potassium of the present invention ensures the stability of the tablet during storage by controlling the pH value of the binder; the fluidized bed granulation process shortens the contact time between the raw material and water, the prepared granules have good fluidity and compressibility, and have good disintegration performance, and can stably prepare products with the same efficacy and quality as the reference preparation. DETAILED DESCRIPTION
[0022] The present invention is further illustrated below in conjunction with specific examples. The examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.
[0023] Example 1
[0024] A method for preparing mesartan potassium tablets with high stability and high solubility. The specific product formula is shown in Table 1.
[0025] Table 1 Specific product formula
[0026]
[0027] Production operation steps:
[0028] 1) Add anhydrous citric acid and sodium hydroxide to pure water in a stainless steel barrel and stir continuously until they are completely dissolved to obtain a buffer solution.
[0029] 2) Add hydroxypropyl cellulose to the buffer solution, adjust the pH to 3.8-4.5, and continue stirring to completely dissolve it to obtain an adhesive.
[0030] 3) Pour mannitol, cross-linked sodium carboxymethyl cellulose (added internally), and mesartan potassium into a multifunctional granulating coating machine for preheating, set the air inlet temperature to above 40°C for preheating for 10 minutes, and use a binder for granulation. The atomization pressure is 0.2-0.4 Mpa, adjust the fan frequency and spray frequency, and control the material temperature to ≤70°C. After granulation, dry to a material temperature of 40°C (moisture ≤1.0%) and discharge. Sieve through a 24-mesh sieve for granulation.
[0031] 4) Add the granulated material into the hopper mixer, add the prescribed amount of cross-linked carboxymethyl cellulose sodium (external), microcrystalline cellulose, and magnesium stearate and mix. The tableting speed is 60,000 to 200,000 tablets / hour, and the pressed tablets are dried in a drying oven at 40 ℃±5 ℃ to a moisture content of ≤0.8%.
[0032] Example 2
[0033] A method for preparing mesartan potassium tablets with high stability and high solubility. The specific product formula is shown in Table 2.
[0034] Table 2 Specific product formula
[0035]
[0036] The production operation steps are the same as in Example 1.
[0037] Example 3
[0038] A method for preparing mesartan potassium tablets with high stability and high solubility. The specific product formula is shown in Table 3.
[0039] Table 3 Specific product formula
[0040]
[0041] The production operation steps are the same as in Example 1.
[0042] Example 4
[0043] A method for preparing mesartan potassium tablets with high stability and high solubility. The specific product formula is shown in Table 4.
[0044] Table 4 Specific product formula
[0045]
[0046] The production operation steps are the same as in Example 1.
[0047] Example 5
[0048] A method for preparing mesartan potassium tablets with high stability and high solubility. The specific product formula is shown in Table 5.
[0049] Table 5 Specific product formula
[0050]
[0051] The production operation steps are the same as in Example 1.
[0052] Comparative Example 1
[0053] A method for preparing mesartan potassium tablets with high stability and high solubility. The specific product formula is shown in Table 6.
[0054] Table 6 Specific product formula
[0055]
[0056] The production operation steps are the same as in Example 1.
[0057] Comparative Example 2
[0058] A method for preparing a highly stable mesartan potassium tablet. The specific product formula is shown in Table 7.
[0059] Table 7 Specific product formula
[0060]
[0061] The production operation steps are the same as in Example 1.
[0062] Example 6
[0063] The relevant properties of the tablets of Examples 1 to 5 and the Asartan potassium tablets obtained in Comparative Examples 1 to 2 were measured, and the specific results are shown in Table 8 below.
[0064] Table 8 Test results of relevant properties of Asartan Potassium Tablets
[0065]
[0066] The data in Table 8 above show that changing the pH adjuster does not affect the physical properties of the tablets, such as mixing uniformity, tablet appearance and disintegration time, which depend on the amount of filler and disintegrant used. Although the tablets of Comparative Example 2 have a slightly faster disintegration time, the final dissolution is lower (see Table 10), which is inferior to Examples 1 to 5.
[0067] The original preparation (12047035), the tablets of Examples 1 to 5 and the tablets of Comparative Examples 1 to 2 were examined for related substances using HPLC. The results are shown in Table 9 below.
[0068] The detection method for related substances was HPLC, and the chromatographic conditions were as follows: chromatographic column: octadecylsilane bonded silica gel as filler; mobile phase: 50 mmol / L diammonium phosphate buffer (pH adjusted to 3.0 with phosphoric acid)-acetonitrile (50:50); detection wavelength: 260 nm; flow rate: 1.5 mL / min; column temperature: 30 ℃; injection volume: 10 μL; solvent: acetonitrile-water-glacial acetic acid (80:20:1).
[0069] Table 9 Summary of inspection results of related substances
[0070]
[0071] It can be seen from Table 9 that when using anhydrous citric acid (1.4-1.8 parts), sodium hydroxide (0.4-0.5 parts) and fumaric acid and sodium hydroxide as pH regulators, the main degradation product azilsartan and total impurities of anhydrous citric acid are better than fumaric acid.
[0072] The original preparation, the tablets of Examples 1 to 5, and the tablets of Comparative Examples 1 to 2 were tested for dissolution using the UV method, and the results are shown in Table 10. Conditions of the UV method: dissolution method: second method; dissolution medium: pH 7.8 phosphate buffer 900 mL; rotation speed: 50 rpm; detection wavelength: 290 nm.
[0073] Table 10 Summary of dissolution curve test results
[0074]
[0075] As shown in Table 10, the use of different pH adjusters has no significant effect on the dissolution rate, indicating that the obtained Asartan potassium tablets have high stability and high solubility.
[0076] Example 7
[0077] Clinical trials
[0078] Miasartan Potassium Tablets have completed two bioequivalence studies, one on a fasting diet and the other on a meal. Both studies were randomized, open, two-period, double-crossover studies, and included 28 healthy subjects. Each study took one tablet of the test preparation Miasartan Potassium Tablets (specification: 80 mg; batch number: 20230502) or the reference preparation Miasartan Potassium Tablets (trade name: ; Licensee: Takeda Pharma A / S; Specification: 80 mg; Batch number: 12343793). All enrolled subjects were included in the full analysis set, safety analysis set, pharmacokinetic concentration set, pharmacokinetic parameter set, and bioequivalence analysis set. The test results are shown in Tables 11 to 14.
[0079] (1) Pharmacokinetic parameters
[0080] Fasting test
[0081] Table 11 Results of fasting pharmacokinetic test
[0082]
[0083] The data in Table 11 above show that the results of Asartan Potassium Tablets and the reference preparation Asartan Potassium Tablets (trade name: ) is absorbed at a rate and extent comparable to that in a healthy human body.
[0084] Postprandial test
[0085] Table 12 Pharmacokinetic postprandial test data
[0086]
[0087] The data in Table 12 above show that the results of Asartan Potassium Tablets and the reference preparation Asartan Potassium Tablets (trade name: ) is absorbed at a rate and extent comparable to that in a healthy human body.
[0088] (2) Bioequivalence results
[0089] Fasting test
[0090] Table 13 Bioequivalence fasting test results
[0091]
[0092] The data in Table 13 above show that the main pharmacokinetic parameters of azilsartan after the subjects took the test preparation and the reference preparation orally on an empty stomach were C max , AUC 0-t , AUC 0-∞ The 90% CI of GMR did not exceed the range of 80.00%~125.00%.
[0093] Postprandial test
[0094] Table 14 Results of postprandial bioequivalence test
[0095]
[0096] The data in Table 14 above show that the main pharmacokinetic parameters of azilsartan after oral administration of the test preparation and the reference preparation after meals are max , AUC 0-t , AUC 0-∞ The 90% CI of GMR did not exceed the range of 80.00%~125.00%.
[0097] (3) Safety results
[0098] During the trial, the researchers strictly followed the clinical trial protocol approved by the ethics committee to conduct various inspections, promptly observed and recorded adverse events, conducted timely follow-up after adverse events occurred, and increased safety visit time points and corresponding inspection items based on actual conditions.
[0099] Fasting test
[0100] During the trial, 9 cases and 13 adverse events occurred, with an adverse event rate of 32.1%; among them, 9 cases and 13 adverse events were "possibly related" to the trial drug and recorded as adverse reactions, with an adverse reaction rate of 32.1%. No serious adverse events occurred. No subject withdrew from the trial due to adverse events. The results showed that 28 healthy subjects were given a single oral fasting dose of 80 mg of the test preparation, Miasartan Potassium Tablets, and the reference preparation, Miasartan Potassium Tablets (trade name: ) after the safety is good.
[0101] Postprandial test
[0102] During the trial, 5 cases and 6 adverse events occurred, with an adverse event rate of 17.9%; among them, 3 cases and 4 adverse events were "possibly related" to the trial drug and recorded as adverse reactions, with an adverse reaction rate of 10.7%. No serious adverse events occurred. No subject withdrew from the trial due to adverse events. The results showed that 28 healthy subjects were given a single oral dose of 80 mg of the test preparation, Miasartan Potassium Tablets, and the reference preparation, Miasartan Potassium Tablets (trade name: ) after the safety is good.
[0103] in conclusion
[0104] Under fasting and postprandial conditions, the Asartan Potassium Tablets (specification: 80 mg; test preparation) provided in this application are bioequivalent to the Asartan Potassium Tablets (trade name: Edabi®; specification: 80 mg; reference preparation) held by Takeda Pharma A / S, and have good safety after being taken by the subjects.
[0105] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A mesartan potassium tablet with high stability and high solubility, characterized in that: The lasartan potassium tablets are made of the following raw materials in parts by weight: 42-86 parts of lasartan potassium tablets, 95-192 parts of mannitol, 13-28 parts of cross-linked carboxymethyl cellulose sodium, 0.5-2 parts of anhydrous citric acid, 0.4-0.5 parts of sodium hydroxide, 5-11 parts of hydroxypropyl cellulose, 19-40 parts of microcrystalline cellulose, and 1-4 parts of magnesium stearate.
2. The Asartan potassium tablets with high stability and high solubility according to claim 1, characterized in that: The lasartan potassium tablets are made of the following raw materials in parts by weight: 85.36 parts of lasartan potassium, 191.26 parts of mannitol, 13.8 parts of cross-linked carboxymethyl cellulose sodium, 1.6-1.8 parts of anhydrous citric acid, 0.41 parts of sodium hydroxide, 10.8 parts of hydroxypropyl cellulose, 39.37 parts of microcrystalline cellulose, and 3.6 parts of magnesium stearate.
3. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 1, characterized in that: The following steps are involved: 1) Add anhydrous citric acid and sodium hydroxide into pure water and stir to dissolve to obtain a buffer solution; 2) then adding hydroxypropyl cellulose to the buffer solution of step 1), adjusting the pH, and stirring until completely dissolved to obtain an adhesive; 3) mixing the binder obtained in step 2) with mannitol, part of croscarmellose sodium and mesartan potassium in a fluidized bed for granulation, and then drying and granulating to obtain intermediate material granules; 4) The intermediate material particles obtained in step 3) are mixed with the remaining cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, and the mixture is tableted and dried to obtain mesartan potassium tablets.
4. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: In the step 2), the pH is adjusted to 3.8-4.
5.
5. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: In the step 3), mannitol, cross-linked carboxymethyl cellulose sodium and mesartan potassium are added to the fluidized bed for preheating, the air inlet temperature is set above 40° C. and preheated for 10 min, and granulation is performed using a binder.
6. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: In the step 3), the material temperature is controlled to be ≤70°C during the granulation process.
7. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: The drying temperature of step 3) is 50-90°C, and the moisture content is ≤1.0%.
8. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: In the step 3), the granulation is performed through a 24-mesh sieve.
9. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: The specific mixing process in step 4) is as follows: adding the intermediate material particles and cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate into a mixing barrel and mixing for 5 minutes.
10. The method for preparing the Asartan potassium tablets with high stability and high solubility according to claim 2, characterized in that: In step 4), the tableting speed is 60,000 to 200,000 tablets per hour, the drying temperature is 40°C ± 5°C, and the tablets are dried to a moisture content of ≤ 0.8%.