CN105079815A - A kind of azilsartan medoxomil potassium composition and preparation method thereof - Google Patents

Abstract

The invention provides an azilsartan medoxomil potassium composition with angiotensin II receptor antagonism and a preparation method thereof. The invention also provides a method for preparing the composition.

Description

A kind of azilsartan medoxomil potassium composition and preparation method thereof

technical field

The invention relates to the field of pharmacy, in particular to a composition comprising azilsartan medoxomil potassium, a pH control agent and pharmaceutically acceptable auxiliary materials and a preparation method thereof.

Background technique

Azilsartan medoxomil potassium, whose 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-carboxylic acid Potassium ethyl ester. Its structure is as follows:

Azilsartan medoxomil potassium is disclosed in the patent document (WO2005/080384, wherein the relevant technology is cited as a reference), has angiotensin II receptor antagonistic effect, and is a drug for treating hypertension.

Azilsartan medoxomil potassium is unstable under neutral conditions, and its solubility in solid pharmaceutical preparations is relatively low under its stable pH conditions. Azilsartan medoxomil potassium has both good stability and dissolution in solid pharmaceutical preparations is its safe and effective requirements. It is difficult to prepare the pharmaceutical preparation of azilsartan medoxomil potassium meeting the above requirements under the usual method for preparation of preparations under neutral conditions.

Chinese patent CN101677961 discloses a solid pharmaceutical preparation comprising benzimidazole-7-carboxylate derivatives, fumaric acid and sodium hydroxide or monosodium fumarate and other auxiliary materials as a pH control agent, and the pH range is controlled at 2 Between -5. According to the above-mentioned prior art, benzimidazole-7-carboxylate derivatives have both excellent stability and dissolution properties in their solid pharmaceutical preparations.

Contents of the invention

The present invention provides another pH control agent, which prepares the azilsartan medoxomil potassium composition under pH conditions different from those of the prior art (CN101677961B, wherein the relevant technology is cited as a reference), so that the azilsartan medoxomil potassium composition can be The prepared solid preparations have both excellent stability and dissolution properties.

Summary of the invention

The first aspect of the present invention provides an azilsartan medoxomil potassium composition excellent in both stability and dissolution properties.

Another aspect of the present invention is to provide a preparation method of the azilsartan medoxomil potassium composition with excellent stability and dissolution.

Definition of Terms

In the present invention, room temperature means that the temperature is about 18°C to about 35°C, or about 20°C to 30°C, or about 25°C.

In the present invention, the pH value of the pH control agent: add the pH control agent into purified water and stir until clear, then stir until clear, the obtained solution. The above solution was measured with a pH meter at 25°C.

In the present invention, w/w means mass to mass ratio.

In the present invention, w/v means that 1 g of substance is dissolved in 100 ml of solution.

In the present invention, mg means milligram, ml means milliliter, and μl means microliter.

In the foregoing context of this disclosure, whether or not the word "about" or "approximately" is used, all numbers disclosed herein are approximations. The value of each number may have a difference of less than 10%, such as a difference of 1%, 2%, 3%, 4% or 5%, according to the common knowledge of those skilled in the art.

Detailed description of the invention

In the long-term development and research, the inventor tried to make azilsartan medoxomil potassium have excellent stability and dissolution in the composition by constantly trying different pH control agents and screening different excipients.

Therefore, the first aspect of the present invention provides a composition of azilsartan medoxomil potassium, which comprises azilsartan medoxomil potassium, a pH control agent and pharmaceutically acceptable auxiliary materials.

In the present invention, the pH control agent is an organic acidic substance. The organic acid can be selected from one or more of tartaric acid, citric acid, lactic acid, fumaric acid, malic acid, ascorbic acid, acetic acid, and acidic amino acids. In some embodiments, the pH control agent is citric acid. The pH control agent is used in an amount of about 0.20% to about 0.76% by mass in the entire composition; in some embodiments, about 0.20% to about 0.38%; in some embodiments, about 0.28%.

The pH control agent needs to be configured into an aqueous solution with a pH value of about 2 to 3 to be sprayed into the formulation system during use.

In some embodiments, the pH control agent is citric acid, wherein the amount of citric acid is about 0.20% to about 0.76% by mass in the entire composition; in some embodiments, about 0.20% to about 0.38%; in some embodiments, about 0.28%.

In the present invention, the pharmaceutically acceptable auxiliary materials include disintegrants, binders, lubricants and excipients. Wherein the disintegrant can be selected from amino acid, starch, cornstarch, calcium carbonate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose One or more of them; the binder can be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, starch, gum arabic, gum tragacanth, carboxymethylcellulose, Sodium alginate, one or more in pullulan; Described lubricant can be selected from magnesium stearate, stearic acid, calcium stearate, purified talc etc.; Described excipient can be selected from lactose, One or more of sucrose, glucose, starch, corn starch, sucrose, microcrystalline cellulose, powdered licorice, mannitol, sorbitol, sodium bicarbonate, calcium phosphate, calcium sulfate, and calcium silicate. In some embodiments, the pharmaceutically acceptable excipient is selected from one or more of mannitol, hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose and magnesium stearate.

In some embodiments, the azilsartan medoxomil potassium composition is calculated by weight percentage, and the mass percentages of each component in the entire composition are about 23.0% to about 24.0% of azilsartan medoxomil potassium, and mannose Alcohol from about 50.0% to about 60.0%, hydroxypropyl cellulose from about 2.0% to about 6.0%, microcrystalline cellulose from about 5.0% to about 15.0%, croscarmellose sodium from about 2.0% to about 8.0%, magnesium stearate from about 0.5% to about 2.0%, citric acid from about 0.20% to about 0.76%.

In some embodiments, the azilsartan medoxomil potassium composition is calculated by weight percentage, and the mass percentages of each component in the entire composition are about 23.0% to about 24.0% of azilsartan medoxomil potassium, and mannose Alcohol is about 55.0%, hydroxypropyl cellulose is about 2.0% to about 4.0%, microcrystalline cellulose is about 10.0%, croscarmellose sodium is about 5.0% to about 8.0%, citric acid is about 0.20% to about 0.76%. Wherein the content of citric acid is preferably about 0.20% to about 0.38%, more preferably about 0.28%.

Obtain composition among the present invention, with the 0.1M hydrochloric acid solution containing the sodium lauryl sulfate of 0.6% (w/v) as stripping medium, 37 ± 0.5 ℃, 900ml, basket method, 100rpm, before starting test Within 5 minutes, the dissolution rate of the total content of azilsartan medoxomil potassium in the composition is at least 34.7 ± 7.7%; within 10 minutes before starting the test, the dissolution rate of the total content of azilsartan medoxomil potassium in the composition At least 52.6 ± 10.3%; within the first 15 minutes of starting the test, the dissolution rate of the total content of azilsartan medoxomil potassium in the composition is at least 62.8 ± 10.4%; within the first 30 minutes of starting the test, Azilsartan medoxomil potassium The dissolution rate of the total content of tansylate potassium in the composition is at least 78.6±8.7%; within 45 minutes before starting the test, the dissolution rate of the total content of azilsartan medoxomil potassium in the composition is at least 90.3±4.6%.

The azilsartan medoxomil potassium composition provided by the present invention, owing to adopting citric acid as the pH control agent, under the condition of limiting pH about 2 to about 3, makes azilsartan medoxomil potassium obtain very good in the composition For stability, see the results in Stability Test 2 of this specification.

The azilsartan medoxomil potassium composition provided by the invention can be used for treating hypertension.

The azilsartan medoxomil potassium composition provided by the invention can be made into dosage forms such as pharmaceutical tablets, granules and capsules.

Another aspect of the present invention provides a method for preparing the composition of azilsartan medoxomil potassium described in the first aspect. The method includes the following steps:

1) Weigh the PH regulator and add an appropriate amount of purified water to stir until clear, and measure the pH value to be about 2 to about 3; then add the binder to make a solution;

2) Take an appropriate amount of excipient to pass through a 30-mesh sieve, and set aside;

3) Azilsartan medoxomil potassium, an appropriate amount of disintegrant and an appropriate amount of excipients obtained in 2) are uniformly mixed to obtain a premix;

4) Take an appropriate amount of the excipient obtained in 2) and pour it into the fluidized bed to preheat for 2 minutes, then pour the above premix into the fluidized bed and preheat it. Spray 1) solution obtained under the condition;

5) Drying, when the moisture content of the particles in the fluidized bed is less than 1.0%, discharge;

6) Use a granulator to granulate the above-mentioned materials and pass through a sieve;

7) uniformly mixing the granules prepared in 6) with an appropriate amount of lubricant and an appropriate amount of excipients to obtain a final mixture;

8) The above-mentioned final mixture is made into dosage forms such as tablets, granules and capsules.

In some embodiments, the pH regulator added in 1) is citric acid;

In some embodiments, the binder added in 1) is hydroxypropyl cellulose;

In some embodiments the excipient added in 2), 3) and 4) is mannitol;

In some embodiments 7) the added lubricant is magnesium stearate, and the added excipient is microcrystalline cellulose;

In some embodiments 8) the prepared dosage form is a tablet.

Detailed ways

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate used in the present invention meet the standards of pharmaceutical excipients in the Chinese Pharmacopoeia 2010 edition.

Example 1

Weigh 335g of mannitol, 44.8g of croscarmellose sodium and 142.2g of azilsartan medoxomil potassium, mix them evenly and place them on the Chongqing Zilong fluidized bed to preheat to 40°C, and then start the process at 35±3 Spray a mixed solution made of 12.2g hydroxypropyl cellulose, 1.2g citric acid and appropriate amount of water under the condition of ℃, the pH value is about 2.53, and dry on a fluidized bed, and then carry out granulation on a QUADRO granulator, Pass 055R sieve. 3.3 g of magnesium stearate and 62.4 g of microcrystalline cellulose were added and mixed together uniformly to obtain a mixture. Finally the resulting mixture was pressed into a composition with a hardness of 90N.

Composition of the preparation (370.1 mg per tablet)

Example 2

Weigh 329.0g of mannitol, 29.0g of croscarmellose sodium and 144.7g of azilsartan medoxomil potassium, mix them evenly and place them on the Chongqing Zilong fluidized bed to preheat to 40°C, and then start at 35± Spray a mixed solution made of 24.1g hydroxypropyl cellulose, 1.7g citric acid and appropriate amount of water at 3°C, the pH value is about 2.46, dry it on a fluidized bed, and then granulate it on a QUADRO granulator , through 055R sieve. 12.1 g of magnesium stearate and 59.6 g of microcrystalline cellulose were added and mixed together uniformly to obtain a mixture. Finally the resulting mixture was pressed into a tablet with a hardness of 90N.

Composition of the composition (359.5 mg per tablet)

Example 3

Weigh 325.6g of mannitol, 53.3g of croscarmellose sodium and 135.8g of azilsartan medoxomil potassium, mix them evenly and place them on the Chongqing Zilong fluidized bed to preheat to 40°C, and then start the process at 35± Spray a mixed solution made of 17.0g hydroxypropyl cellulose, 2.3g citric acid and an appropriate amount of water at 3°C, the pH value is about 2.38, dry it on a fluidized bed, and then granulate it on a QUADRO granulator , through 055R sieve. 6.1 g of magnesium stearate and 60.0 g of microcrystalline cellulose were added and mixed together uniformly to obtain a mixture. Finally the resulting mixture was pressed into a tablet with a hardness of 90N.

Composition of the composition (per 365.0mg)

Example 4

Weigh 329.8g of mannitol, 37.2g of croscarmellose sodium and 145.1g of azilsartan medoxomil potassium, mix them evenly and place them on the Chongqing Zilong fluidized bed to preheat to 40°C, and then start at 35± Spray a mixed solution made of 21.1g hydroxypropyl cellulose, 3.2g citric acid and appropriate amount of water at 3°C, the pH value is about 2.30, dry it on a fluidized bed, and then granulate it on a QUADRO granulator , through 055R sieve. 6.7 g of magnesium stearate and 57.1 g of microcrystalline cellulose were added and mixed together uniformly to obtain a mixture. Finally the resulting mixture is compressed into tablets.

Composition of the composition (per 353.3mg)

Example 5

Weigh 330.1g of mannitol, 43.3g of croscarmellose sodium and 158.9g of azilsartan medoxomil potassium, mix them evenly and place them on the Chongqing Zilong fluidized bed to preheat to 40°C, and then start the process at 35± Spray a mixed solution made of 11.8g hydroxypropyl cellulose, 4.6g citric acid and appropriate amount of water at 3°C, the pH value is about 2.22 and dry on a fluidized bed, then granulate on a QUADRO granulator, Pass 055R sieve. 9.7 g of magnesium stearate and 57.3 g of microcrystalline cellulose were added and mixed together uniformly to obtain a mixture. Finally the resulting mixture was pressed into a tablet with a hardness of 90N.

Composition of the composition (per 362.1mg)

Dissolution Test 1

The composition obtained in Examples 1-5 was investigated in vitro dissolution test, and the dissolution conditions were as follows: using 0.1M hydrochloric acid solution containing 0.6% (w/v) sodium lauryl sulfate as the dissolution medium, 37 ± 0.5 ° C, 900ml, basket method, 100rpm. The experiment was carried out according to the first method (basket method) of the second appendix XC dissolution determination of the Chinese Pharmacopoeia 2010 edition. The test solution was sampled at different time points, and the dissolution condition of the composition under the dissolution conditions was calculated by measuring the content of azilsartan medoxomil potassium in the sampled solution.

Pipette an appropriate solution in the dissolution cup at the corresponding sampling time point to prepare a solution containing about 0.044 mg/ml of azilsartan medoxomil potassium for the test product, and use the UV method for detection, according to the Chinese Pharmacopoeia 2010 edition two appendix VD high performance liquid chromatography method. The chromatographic conditions are as follows:

Instrument: AgilentHPLC1260series

Chromatographic column: YMC-PackProC18, 4.6×150mm, 5μm

Mobile phase: 0.025mol/L potassium dihydrogen phosphate solution (adjust pH to 2.0 with phosphoric acid)-acetonitrile (35:65, v/v) mixed solution

Column temperature: 30°C

Flow rate: 1.0ml/min

Detection wavelength: 260nm

Injection volume: 10ul

Running time: 1.5 times the retention time of the main peak of azilsartan (about 6min)

The test results are shown in Table 1, which proves that the compositions prepared in Examples 1-5 have excellent dissolution properties.

Table 1

Sampling time Example 1 Example 2 Example 3 Example 4 Example 5 5min 34.7±7.7 38.7±6.3 46.4±2.1 44.8±1.1 44.0±2.9 10min 52.6±10.3 59.7±3.4 65.6±1.7 65.4±0.9 65.0±3.5 15min 62.8±10.4 69.7±3.4 75.2±1.3 76.3±0.9 76.4±3.1 30min 78.6±8.7 81.8±3.7 87.8±1.5 90.0±1.7 89.9±2.7 45min 92.2±7.8 90.3±4.6 93.8±1.5 98.8±2.7 99.0±3.6

Stability Test 2

The composition obtained in Examples 1-5 will be carried out in accordance with the Chinese Pharmacopoeia 2010 edition appendix XIX bulk drug and drug preparation stability guidelines to carry out the stability test investigation, the experimental conditions are as follows: the sample is packaged in a high-density polyethylene (HDPE) bottle, Add a desiccant inside; at a temperature of 40°C and a relative humidity of 75%; place it for 1 month and then take a spot check to investigate the impurity of the sample, and compare the comparative example 1, embodiment 1, 6 with the prescription dosage form disclosed in the Chinese patent CN101677961 . .

Get the composition of above-mentioned accelerated stability test sampling, with acetonitrile-water-glacial acetic acid (80:20:1, v/v/v) as diluent, prepare the test that concentration of azilsartan medoxomil potassium is about 1mg/ml Product solution, according to Chinese Pharmacopoeia 2010 edition two appendix VD high performance liquid chromatography to the sample of regular sampling inspection, chromatographic condition is as follows:

Instrument: AgilentHPLC1260series

Chromatographic column: Agilent ZORBAXSB-C18, 4.6×250mm, 5μm

Column temperature: 25°C

Sample tray temperature: 8°C

Flow rate: 1.0ml/min

Detection wavelength: 240nm

Injection volume: 10ul

Running time: 50min

Post run time: 5min

gradient elution

running time (min) Mobile phase A% (v/v) Mobile phase B% (v/v) 0 68.5 31.5 10 68.5 31.5 twenty two 52.5 47.2 30 52.5 47.5 40 22.0 78.0 50 22.0 78.0

Mobile phase A: a mixed solution of 0.050mol/L potassium dihydrogen phosphate solution (adjust the pH value to 3.5 with phosphoric acid)-acetonitrile (19:1, v/v)

Mobile Phase B: Acetonitrile

The stability data of the examples disclosed in Chinese patent CN101677961 are shown in Table 2 (see CN101677961B for detailed experimental methods), and the stability data of the examples of the present invention are shown in Table 3. It can be seen from the comparison of the stability data that the compositions obtained in Examples 1-5 have excellent stability during the investigation period of the stability experiment.

Table 2

Comparative example 1 Example 1A Example 6A Example 16A Example 17A Decomposition product increase (%) 3.84 0.52 1.28 0.56 0.84

table 3

Example 1 Example 2 Example 3 Example 4 Example 5 0 day total impurity content (%) 0.72 0.64 0.81 0.79 0.79 Total impurity content after 1 month (%) 1.73 0.81 1.42 1.39 1.39 Decomposition product increase (%) 1.01 0.17 0.61 0.60 0.60

In summary, the azilsartan medoxomil potassium composition provided by the present invention has excellent stability or dissolution rate.

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (12)

1. a composition of azilsartan medoxomil potassium, said composition comprises azilsartan medoxomil potassium, pH controller and pharmaceutically acceptable adjuvant; Described pH controller is an organic acidic substance, and said organic The acid can be selected from one or more of tartaric acid, citric acid, lactic acid, fumaric acid, malic acid, ascorbic acid, acetic acid, and acidic amino acids; the pH control agent needs to be configured so that the pH value is about 2 to 3 when used The aqueous solution is sprayed into the preparation system. 2. The composition according to claim 1, wherein the pH control agent is citric acid. 3. The composition according to claim 1 or 2, the amount of the pH control agent is about 0.20% to about 0.76% by mass in the entire composition; or about 0.20% to about 0.38%; or about 0.28%. 4. The composition according to any one of claims 1-3, wherein the pharmaceutically acceptable adjuvant comprises a disintegrant, a binding agent, a lubricant and an excipient. 5. composition according to claim 4, described disintegrant can be selected from amino acid, starch, cornstarch, calcium carbonate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked carboxymethyl cellulose One or more of plain sodium, low-substituted hydroxypropyl cellulose; the binder can be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, starch, gum arabic , tragacanth gum, carboxymethyl cellulose, sodium alginate, one or more of pullulan; the lubricant can be selected from magnesium stearate, stearic acid, calcium stearate, purified talc, etc. The excipient can be selected from lactose, sucrose, glucose, starch, corn starch, sucrose, microcrystalline cellulose, powdered licorice, mannitol, sorbitol, sodium bicarbonate, calcium phosphate, calcium sulfate, calcium silicate one or more of them. 6. according to the arbitrary described composition of claim 1-3, described pharmaceutically acceptable adjuvant is selected from mannitol, hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose and carboxymethyl cellulose One or several kinds of magnesium fatty acid. 7. The composition according to claim 6, calculated by weight percentage, the mass percent of each component in the whole composition is that azilsartan medoxomil potassium is about 23.0% to about 24.0%, and mannitol is about 24.0%. 50.0% to about 60.0%, hydroxypropyl cellulose from about 2.0% to about 6.0%, microcrystalline cellulose from about 5.0% to about 15.0%, croscarmellose sodium from about 2.0% to about 8.0% , magnesium stearate from about 0.5% to about 2.0%, and citric acid from about 0.20% to about 0.76%. 8. The composition according to claim 7, calculated by weight percentage, the mass percent of each component in the whole composition is that azilsartan medoxomil potassium is about 23.0% to about 24.0%, and mannitol is about 24.0%. 55.0%, hydroxypropyl cellulose from about 2.0% to about 4.0%, microcrystalline cellulose from about 10.0%, croscarmellose sodium from about 5.0% to about 8.0%, citric acid from about 0.20% to about 0.76%. 9. The composition according to any one of claims 1-8, which can be made into dosage forms such as pharmaceutical tablets, granules and capsules. 10. Use of the composition according to any one of claims 1-9 in the treatment of hypertension. 11. A method for preparing the composition according to any one of claims 1-9, the method comprising the following steps: 1) Weigh the PH regulator and add an appropriate amount of purified water to stir until clear, and measure the pH value to be about 2 to about 3; then add the binder to make a solution; 2) Take an appropriate amount of excipient to pass through a 30-mesh sieve, and set aside; 3) Azilsartan medoxomil potassium, an appropriate amount of disintegrant and an appropriate amount of excipients obtained in 2) are uniformly mixed to obtain a premix; 4) Take an appropriate amount of the excipient obtained in 2) and pour it into the fluidized bed to preheat for 2 minutes, then pour the above premix into the fluidized bed and preheat it. Spray 1) solution obtained under the condition; 5) Drying, when the moisture content of the particles in the fluidized bed is less than 1.0%, discharge; 6) Use a granulator to granulate the above-mentioned materials and pass through a sieve; 7) uniformly mixing the granules prepared in 6) with an appropriate amount of lubricant and an appropriate amount of excipients to obtain a final mixture; 8) The above-mentioned final mixture is made into dosage forms such as tablets, granules and capsules. 12. The method according to claim 11, wherein the pH regulator is citric acid; the binding agent is hydroxypropyl cellulose; the excipient is mannitol; the lubricant is magnesium stearate, and the excipient is micro Crystalline cellulose; the prepared dosage form is a tablet.