Azilsartan solid dispersion and preparation method of pharmaceutical composition of azilsartan solid dispersion

Abstract

The invention discloses an azilsartan solid dispersion and a preparation method of a medicinal composition thereof, and belongs to the technical field of medicinal preparations. A unit dose of the azilsartan solid dispersion comprises 20 mg of azilsartan, 50 to 105 mg of povidone K30, 4.9 to 5.7 mg of sodium acetate trihydrate, 210 to 270 mg of microcrystalline cellulose, 65.6 to 83.2 mg of mannitol, and 8 to 24 mg of internally added croscarmellose sodium. The preparation method is wet granulation. A unit dose of the azilsartan pharmaceutical composition comprises 429.5 mg of a solid dispersion, 16 mg of cross-linked sodium carboxymethyl cellulose, 4.5 mg of magnesium stearate and 18 mg of a film coating premix. The preparation process of the azilsartan solid dispersion is simple, almost all preparation manufacturers have hardware conditions, first and second organic solvents are not used, the safety and bioavailability of the azilsartan preparation are effectively improved, the azilsartan solid dispersion is good in stability, and the dissolution rate and related substances are not obviously reduced after long-time storage.

Description

Technical Field

[0001] The invention relates to a preparation method of an azilsartan solid dispersion and a pharmaceutical composition thereof, and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Azilsartan is a new generation of selective AT1 subtype angiotensin II receptor antagonist, which achieves the antihypertensive effect by selectively blocking the binding of angiotensin II to AT1 receptors in multiple tissues and blocking the release of a series of pressor substances.

[0003] Azilsartan belongs to BCS IV class, has low bioavailability and is limited by dissolution. The dissolution rate and bioavailability of poorly soluble drugs can be greatly improved by solid dispersion technology, among which amorphous solid dispersions are the most common, which is to reduce the drug particle size to the molecular level and highly dispersed in a suitable soluble carrier. The main methods include melting method, solvent method and grinding method. Patents CN104721147A and CN103705510A both use grinding methods to grind azilsartan and carrier materials with water to the micron level of raw materials, but most of the raw materials do not dissolve to form a molecular state, so amorphous solid dispersions cannot be formed. In addition, the stability of azilsartan is poor, and strong and persistent grinding easily leads to a sharp increase in related substances.

[0004] Patent CN111643461A adds azilsartan to a polyethylene glycol melt, and then stirs the suspended melt with other excipients to granulate. The melting point of azilsartan is about 190°C. When the heating temperature is higher than the melting point, azilsartan will decompose in large quantities, so this method does not heat and melt the raw material; but when the heating temperature is much lower than the melting point, azilsartan still maintains a solid powder state, which is difficult to effectively mix evenly, and cannot form an amorphous solid dispersion.

[0005] Patent CN108096195A uses a supercritical antisolvent method to prepare amorphous azilsartan solid dispersion. In order to improve the solubility of the API, a large amount of organic mixed solvents are used in the preparation of the azilsartan-carrier mixed solution, including acetone, dichloromethane and dimethyl sulfoxide in a volume ratio of 1:1:0.1. Dichloromethane belongs to the second category of solvents (ICH recommends that its use should be restricted), and dimethyl sulfoxide has a high boiling point (189°C), which has a certain risk of excessive residual solvent. In addition, this method has extremely high requirements for equipment, and most formulation manufacturers do not have the hardware foundation, which limits its promotion and application.

[0006] Patent CN103260605A adopts a solvent method to prepare azilsartan solid dispersion, preferably a large amount of methanol as a solvent and a preparation method of reduced pressure drying. The mass concentration of azilsartan in methanol is only 0.0125 g / mL. At the same time, the reduced pressure drying needs to be maintained at 40°C for more than 24 hours. After repeated tests, it was found that the prepared azilsartan solid dispersion was difficult to peel off from the container, and the related substances were significantly increased.

[0007] Combined with the above-mentioned patents for azilsartan preparations and the unstable quality of the API under strong crushing or high temperature conditions, the solvent method should be preferred for preparing solid dispersions. At present, the main reasons for limiting the promotion and application of the solvent method include the following three aspects: First, the solubility of the API is very poor. It is not only insoluble in water, but also has unsatisfactory solubility in many commonly used organic solvents (see Table 1 for details). Therefore, the consumption of organic solvents is huge, which can easily bring great safety, quality risks and environmental pollution problems; second, the high-temperature drying time should not be too long, so reduced pressure drying and vacuum drying are not preferred; third, the equipment requirements are relatively high. For example, freeze drying and spray drying require corresponding special equipment, and some preparation manufacturers do not have the hardware conditions.

[0008]

[0009] In summary, there is an urgent need to develop a solid dispersion of azilsartan, a pharmaceutical composition and a preparation method that is solvent-friendly, has a low dosage, is suitable for conventional granulation methods and industrial production, and has excellent quality of related substances and dissolution. Summary of the invention

[0010] The invention provides a solvent-friendly solid dispersion of azilsartan, a pharmaceutical composition and a preparation method thereof, which has low usage amount, is suitable for conventional wet granulation and has high quality.

[0011] Azilsartan has poor solubility in conventional solvents such as water and ethanol. Improving its solubility without changing the pharmacological properties of the compound is crucial to the development of solid dispersions.

[0012] The present invention uses conventional excellent carrier material povidone K30 for detailed description, but it should be noted that the invention technology is not limited to povidone, and other conventional carrier materials such as poloxamer, hydroxypropyl cellulose, polyethylene glycol, etc. are also applicable after simple exploration and adjustment.

[0013] According to the measured data of the solubility of the API in Table 1, it is found that about 160 mL of ethanol is needed to dissolve 1 g of Azilsartan. According to the ICH guidelines requiring a minimum pilot batch of 100,000 tablets and the minimum specification of 20 mg for this product, a pilot batch requires about 320 L of ethanol. The huge amount of solvent means extremely high material, energy consumption, labor costs and safety hazards, which greatly limits the scale-up transformation of the product. In order to improve the solubility of Azilsartan in ethanol and reduce the amount of solvent used, the applicant dispersed Azilsartan in a carrier material (such as povidone K30). By increasing the carrier concentration or solution temperature in ethanol, the solubility of Azilsartan in the solvent system can be effectively improved, and it is increased to about 20 mL of ethanol to dissolve 1 g of Azilsartan. Moreover, Azilsartan will not precipitate after being heated and dissolved in the system for a short time and then quickly cooled to room temperature. In addition, the applicant unexpectedly discovered through a large number of experiments that adding an appropriate amount of alkaline salt (such as sodium acetate trihydrate) can significantly increase the solubility. It surprisingly takes only about 7 mL of ethanol to dissolve 1g of azilsartan, which is far beyond expectations. However, the stability of azilsartan in strong alkaline solutions is poor. In order to ensure the safety and effectiveness of the drug, the stability of azilsartan is not affected by controlling the amount of alkaline salt and adjusting the solution pH to 6.5-7.5. However, if the pH exceeds this range, the stability will be affected to varying degrees.

[0014] It should be noted that the combined use of (1) increasing the solution temperature, (2) high concentration of povidone K30, and (3) appropriate amount of alkaline salt solubilization can significantly increase the solubility of azilsartan in ethanol by more than 15 times, significantly reducing the amount of solvent used, while the solubilization effect of a single method is relatively limited. Due to the significant reduction in the amount of solvent used, the efficiency of preparing solid dispersions by solvent method has been significantly improved. In addition to conventional technologies such as freeze drying, spray drying, and fluidized bed one-step granulation, wet granulation technology, which is limited by the amount of solvent used, is also possible. It should be noted that wet granulation technology is most widely used in ordinary oral solid preparations, but is rarely used in the preparation of solid dispersions. In order to better explain the innovation of the present invention, the most conventional and economical wet granulation and fluidized bed drying process was selected for the preparation of solid dispersions. The study found that the process does not destroy the formation of solid dispersions, and at the same time, the related substances do not grow rapidly and the solubility is greatly improved, indicating good bioavailability.

[0015] The technical solution of the present invention is: A solid dispersion of azilsartan suitable for wet granulation, wherein a unit dose of the solid dispersion of azilsartan comprises 20 mg of azilsartan, 50-105 mg of povidone K30, 4.9-5.7 mg of sodium acetate trihydrate, 210-270 mg of microcrystalline cellulose, 65.6-83.2 mg of mannitol, and 8-24 mg of cross-linked sodium carboxymethyl cellulose (internal addition). Azilsartan, povidone K30, and sodium acetate trihydrate are co-dissolved in a 75%-100% ethanol solvent under heating conditions to prepare a solution with a pH of 6.5-7.5.

[0016] Preferably, a unit dose of azilsartan solid dispersion comprises 20 mg azilsartan, 70 mg povidone K30, 5.3 mg sodium acetate trihydrate, 244 mg microcrystalline cellulose, 74.2 mg mannitol, and 16 mg cross-linked sodium carboxymethyl cellulose (added internally).

[0017] Preferably, the mass concentration of azilsartan in the solution is not less than 0.1 g / mL, and the mass concentration of povidone K30 is 0.35-0.75 g / mL.

[0018] Preferably, the solvent is 75% ethanol, the mass concentration of povidone K30 is 0.5 g / mL, and the heating temperature is 60°C.

[0019] An azilsartan solid dispersion suitable for wet granulation, the preparation method being: Step 1: Prepare the solution Under the condition of heating in a water bath at 60°C, add povidone K30 to the solvent while stirring until completely dissolved, then add azilsartan and sodium acetate trihydrate, stir until completely dissolved, and place at room temperature for later use; Step 2: Wet granulation Place microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose in a wet granulator, premix at a stirring speed of 100 rpm for 3 minutes, adjust the stirring speed to 200 rpm, the cutter speed to 1000 rpm, and the peristaltic pump speed to 70 rpm, spray the solution obtained in step 1 into the wet granulator for granulation for 8 minutes to obtain wet granules; Step 3: Fluidized Bed Drying Transfer the wet granules obtained in step 2 to a fluidized bed, set the air volume to 35 Hz and the air temperature to 50°C, and collect the material when the moisture content is below 2%; Step 4: Whole grains The granules were granulated using a granulator with a sieve aperture of 1.2 mm and a rotation speed of 600 rpm. The granules were collected to obtain the azilsartan solid dispersion.

[0020] A pharmaceutical composition of azilsartan solid dispersion, wherein a unit dose of the pharmaceutical composition comprises 429.5 mg of the solid dispersion, 16 mg of cross-linked sodium carboxymethyl cellulose (external), 4.5 mg of magnesium stearate, and 18 mg of a film coating premix.

[0021] A pharmaceutical composition of azilsartan solid dispersion, prepared by: Step 5: Final Mixing Azilsartan solid dispersion and cross-linked sodium carboxymethyl cellulose (external) were placed in a hopper mixer, mixed at 10 rpm for 5 minutes, and magnesium stearate was added and mixed for 3 minutes to obtain a total mixed material; Step 6: Tablet The total mixed material obtained in step 5 is tableted to a hardness of 45-80N to obtain a plain tablet; Step 7: Coating The plain tablets obtained in step 6 are film-coated to obtain azilsartan solid dispersion tablets.

[0022] Compared with the prior art, the present invention has the following advantages: (1) Using ethanol water with good biocompatibility as the solvent is safer and easier to remove than other organic solvents; (2) The new solvent system increases the solubility of azilsartan by more than 15 times, significantly reduces the amount of solvent used, and significantly reduces production costs; (3) Thanks to the significant reduction in the amount of solvent used, the wet granulation process was used for the first time to prepare amorphous azilsartan solid dispersion, which had good quality stability in terms of related substances and dissolution. At the same time, the hardware requirements were reduced, the operation was simple, and the efficiency was higher, making it suitable for industrial production. DETAILED DESCRIPTION Test Example 1: Investigation of factors affecting the solubility of Azilsartan

[0023] Under heating conditions in a water bath, add povidone K30 and sodium acetate trihydrate to the solvent while stirring. After stirring until completely dissolved, add azilsartan in portions, 0.1 g each time, until it cannot be completely dissolved. Record the amount of azilsartan that has dissolved.

[0024] The specific inspection plan is as follows:

[0025] It can be seen from Table 2 that the solubility of azilsartan is most significantly improved only when the water bath temperature, ethanol concentration, povidone K30 and sodium acetate trihydrate dosage all meet the requirements. Under the same solvent dosage (140 mL), the maximum solvent amount of azilsartan in Test Example 1-2 (water bath temperature is 30 ° C), Test Example 1-3 (no sodium acetate trihydrate is added), Test Example 1-4 (solvent is 50% ethanol) and Test Example 1-7 (low povidone K30 concentration) is less than 10 g, and the mass concentration is less than 0.1 g / mL, but still much higher than In Table 1, the mass concentration of azilsartan in anhydrous ethanol alone is 0.0063 g / mL; the difference between Test Examples 1-1, 1-5, 1-6 and 1-7 is that the mass concentration of povidone K30 is different. When the mass concentration is greater than 0.35 g / mL, the solubility of azilsartan is greatly improved. When the mass concentration of povidone K30 is further increased to 0.5 g / mL and 0.75 g / mL, the solubility of azilsartan increases slowly. Therefore, in order to ensure the stability of subsequent processes, the most preferred mass concentration of povidone K30 is 0.5 g / mL.

[0026] Test Example 1 investigated the maximum solubility of azilsartan under corresponding conditions. The dissolution process took a long time. Considering that the required specification of the azilsartan solid dispersion pharmaceutical composition is 20 mg, the amount of azilsartan in the subsequent Test Example 1-1 was reduced to 20 g for testing.

[0027] Test Example 2: Study on the stability of azilsartan at different solution pH

[0028] Under the condition of heating in a 60°C water bath, add povidone K30 to the solvent while stirring until completely dissolved, then add azilsartan and sodium acetate trihydrate, stir until completely dissolved, and place at room temperature. Measure the pH of the solution, and take samples at 0, 1, 2, 3, and 6 hours to detect related substances of azilsartan.

[0029] The specific inspection plan is as follows:

[0030] The test results of the relevant substances are as follows:

[0031] According to the above test results, the pH values ​​of Test Examples 2-2, 2-3 and 2-4 were 6.5, 7.0 and 7.5, respectively. At this time, the stability of Azilsartan in the solution was good, and there was no significant increase in related substances after being placed at room temperature for 6 hours; the pH values ​​of Test Examples 2-1 and 2-5 were 6.0 and 8.0, respectively, and impurities A, J and total impurities increased significantly, especially at 6 hours, the content of impurity A exceeded the limit requirement. Since it is difficult to ensure that the solution can be quickly prepared and the next step can be carried out in the actual production process of the preparation, it is extremely important to ensure the stability of the Azilsartan solution. Combined with the measured values, the pH of the solution needs to be stabilized between 6.5 and 7.5.

[0032] The composition will be further investigated in combination with the research of Test Examples 1 and 2.

[0033] Example 1-6 Prescription composition:

[0034] Preparation method: Step 1: Prepare the solution: Add the prescribed amount of povidone K30 to the solvent while stirring in a 60°C water bath until completely dissolved, then add azilsartan and sodium acetate trihydrate, stir until completely dissolved, and place at room temperature for later use.

[0035] Step 2: Wet granulation: Place microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose in a wet granulator, premix at a stirring speed of 100 rpm for 3 minutes, then adjust the stirring speed to 200 rpm, the cutter speed to 1000 rpm, and the peristaltic pump speed to 70 rpm, and spray the solution obtained in step 1 into the wet granulator for granulation for 8 minutes to obtain wet granules.

[0036] Step 3: Fluidized bed drying: transfer the wet granules obtained in step 2 to a fluidized bed, set the air volume to 35 Hz and the air temperature to 50°C, and collect the material when the moisture content is below 2%; Step 4: Granulation: Granulate using a granulator with a sieve aperture of 1.2 mm and a rotation speed of 600 rpm to collect particles to obtain azilsartan solid dispersion.

[0037] Step 5: Total mixing: Place the azilsartan solid dispersion and cross-linked carboxymethyl cellulose sodium in a hopper mixer, mix at 10 rpm for 5 minutes, add magnesium stearate, and mix for 3 minutes to obtain a total mixed material.

[0038] Step 6: tableting: the total mixed material obtained in step 5 is tableted to a hardness of 45-80N to obtain a plain tablet.

[0039] Step 7: Coating: Film-coating the plain tablets obtained in step 6 to obtain azilsartan solid dispersion tablets.

[0040] Comparative Example 1-7 Prescription composition:

[0041] Preparation method: Comparative Example 1 refers to the preparation method of the embodiment, except that in step 1, azilsartan is not added to the ethanol solution, but is added to the premix of the wet granulator in step 2, that is, the ethanol solution containing povidone K30 and sodium acetate trihydrate is sprayed onto the mixed powder of azilsartan, microcrystalline cellulose, mannitol, and cross-linked sodium carboxymethyl cellulose for wet granulation. The remaining steps are the same as the preparation method of steps 3 to 7 of the embodiment.

[0042] Comparative Example 2: Prepare the solution with reference to step 1 of the embodiment. After complete dissolution, place the solution in a vacuum drying oven, vacuum dry it at 40° C. for 24 h, take it out, and grind it to obtain the solid dispersion of azilsartan. The remaining steps are the same as the preparation method of steps 5 to 7 of the embodiment.

[0043] Comparative Example 3 Referring to patent CN103260605A, azilsartan and povidone were dissolved in methanol, the solution was placed in a vacuum drying oven, vacuum dried at 40°C for 24 hours, taken out, and crushed to obtain azilsartan solid dispersion. The remaining steps were the same as the preparation method of steps 5 to 7 of the embodiment.

[0044] Comparative Examples 4 to 7 refer to the preparation method of the embodiment, wherein in Comparative Example 5, due to the excessive amount of povidone added, the solution concentration and viscosity are too high, and the solution quickly becomes filamentous after being sprayed out from the wet granulation gun, and granulation cannot be performed normally; in Comparative Example 6, due to the large amount of solvent used, the material is too wet after wet granulation, most of the particles are spherical, and after the whole particles are dried, the particles are hard, the compressibility is too poor, and there are cracks, so no subsequent investigation is carried out; in Comparative Example 7, after reducing the amount of solution and increasing the povidone concentration, the solubility upper limit of azilsartan has been exceeded, and azilsartan cannot be completely dissolved, so no subsequent tests are carried out.

[0045] Test Example 3: Investigation of related substances in azilsartan solid dispersion pharmaceutical composition under accelerated conditions

[0046]

[0047] According to the test results of stability-related substances, when Examples 1 to 6 were placed under accelerated conditions for 6 months, the related substances did not exceed the limits.

[0048] Comparative Example 1 is a non-solid dispersion of azilsartan tablets prepared by the same prescription as Example 1. The detection results of related substances show that, compared with the non-solid dispersion, there is no significant increase in related substances after azilsartan is prepared into a solid dispersion by the prescription process of the present invention, and the growth rate of related substances at each time point of 1, 2, 3, and 6 months of acceleration is similar to that of the non-solid dispersion.

[0049] Comparative Examples 2 and 3 used vacuum drying to prepare azilsartan solid dispersions, and the related substances had reached a relatively high level on day 0, and were no longer placed for subsequent stability investigation.

[0050] In Comparative Example 4, the results of the related substances on day 0 were good, but the dissolution behavior on day 0 was poor (see subsequent Test Example 4 for details), so the stability of the related substances was not investigated subsequently.

[0051] Test Example 4: Investigation of the dissolution behavior of azilsartan solid dispersion pharmaceutical composition The dissolution behavior of the tablets prepared in Examples 1-6 and Comparative Examples 1 and 4 was evaluated, and the dissolution conditions were as follows: Dissolution medium (pH 4.5 acetate buffer): Weigh 2.99 g of sodium acetate trihydrate, measure 1.6 mL of glacial acetic acid, add to 1.6 L of purified water, stir to dissolve, and adjust the pH to 4.5 ± 0.05 with saturated sodium hydroxide solution or glacial acetic acid. Dissolution method: Refer to the dissolution determination method of the Chinese Pharmacopoeia 2020 edition, select the second method (i.e., paddle method), and the rotation speed is 50 rpm.

[0052]

[0053]

[0054] From the test results of the above dissolution curves, it can be seen that the highest dissolution rates of Examples 1 to 6 can all reach more than 90%, and there is no significant decrease under accelerated conditions.

[0055] Comparative Example 1 adopts non-solid dispersion technology, and in the dissolution medium without adding surfactant, the dissolution amount within 60 minutes is only about 10%; the dissolution amount of Comparative Example 4 is improved, but because the amount of povidone K30 is not enough to form a solid dispersion with azilsartan, the solubility of azilsartan in the partial crystal state is significantly reduced.

Claims

1. A solid dispersion of azilsartan suitable for wet granulation, characterized in that: A unit dose of azilsartan solid dispersion comprises 20 mg of azilsartan, 50-105 mg of povidone K30, 4.9-5.7 mg of sodium acetate trihydrate, 210-270 mg of microcrystalline cellulose, 65.6-83.2 mg of mannitol, and 8-24 mg of added cross-linked sodium carboxymethyl cellulose, wherein azilsartan, povidone K30, and sodium acetate trihydrate are co-dissolved in 75%-100% ethanol under heating conditions to prepare a solution with a pH of 6.5-7.

5.

2. The azilsartan solid dispersion according to claim 1, characterized in that A unit dose of azilsartan solid dispersion contains 20 mg of azilsartan, 70 mg of povidone K30, 5.3 mg of sodium acetate trihydrate, 244 mg of microcrystalline cellulose, 74.2 mg of mannitol, and 16 mg of added cross-linked sodium carboxymethylcellulose.

3. The azilsartan solid dispersion according to any one of claims 1 or 2, characterized in that The mass concentration of azilsartan in the solution is not less than 0.1 g / mL, and the mass concentration of povidone K30 is 0.35-0.75 g / mL.

4. The azilsartan solid dispersion according to claim 3, characterized in that The mass concentration of povidone K30 in the solution is 0.5 g / mL.

5. The azilsartan solid dispersion according to claim 1, characterized in that: The solvent is preferably 75% ethanol.

6. The azilsartan solid dispersion according to claim 1, characterized in that: The heating temperature is 60°C.

7. A method for preparing the azilsartan solid dispersion according to claim 1, characterized in that: The following steps are involved: Step 1: Under the condition of heating in a water bath at 60°C, add povidone K30 to the solvent, stir until completely dissolved, then add azilsartan and sodium acetate trihydrate, stir until completely dissolved, and place at room temperature for later use; Step 2: placing microcrystalline cellulose, mannitol and cross-linked carboxymethyl cellulose sodium in a wet granulator, premixing them evenly, and then spraying the solution obtained in step 1 into the wet granulator for granulation to obtain wet granules; Step 3: The wet granules obtained in step 2 are transferred to a fluidized bed for drying. When the drying loss reaches less than 2%, the granules are collected and sized to obtain azilsartan solid dispersion.

8. A pharmaceutical composition comprising the azilsartan solid dispersion according to claim 1 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, characterized in that The unit dose of the pharmaceutical composition comprises 429.5 mg of the solid dispersion, 16 mg of additional cross-linked sodium carboxymethylcellulose, 4.5 mg of magnesium stearate, and 18 mg of a film coating premix.

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