A process for the preparation of azilsartan solid dispersion and pharmaceutical compositions thereof

Abstract

The application relates to a preparation method of an azilsartan solid dispersion and a medicinal composition thereof, and belongs to the technical field of pharmaceutical preparations. A unit dose of the azilsartan solid dispersion comprises azilsartan 20 mg, povidone K30 50-105 mg, sodium acetate trihydrate 4.9-5.7 mg, microcrystalline cellulose 210-270 mg, mannitol 65.6-83.2 mg, and sodium croscarmellose 8-24 mg which is added internally, and the preparation method is wet granulation; a unit dose of the azilsartan medicinal composition comprises the solid dispersion 429.5 mg, sodium croscarmellose 16 mg which is added externally, magnesium stearate 4.5 mg, and film coating premix 18 mg. The preparation process of the azilsartan solid dispersion is simple, almost all pharmaceutical factories have the hardware conditions, and no first and second class organic solvents are used, so that the safety and bioavailability of the azilsartan preparation are effectively improved; the stability of the azilsartan solid dispersion is good, and the dissolution rate and related substances do not obviously decrease after long-time storage.

Description

Technical Field

[0001] This invention relates to a method for preparing an azisartan solid dispersion and its pharmaceutical composition, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Azisartan is a new generation of selective AT1 subtype angiotensin II receptor antagonist. It achieves its 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] Azisartan belongs to BCS Class IV and has low bioavailability, limited by dissolution rate. Solid dispersion technology can significantly improve the dissolution rate and bioavailability of poorly soluble drugs. Amorphous solid dispersions are the most common, which reduce the drug particle size to the molecular level and highly disperse it in a suitable soluble carrier. The main methods include melt dispersion, solvent dispersion, and grinding. Patents CN104721147A and CN103705510A both use grinding, grinding azisartan and carrier materials with water to the micron level of the active pharmaceutical ingredient. However, most of the active pharmaceutical ingredient does not dissolve to form a molecular state, thus failing to form an amorphous solid dispersion. Furthermore, azisartan has poor stability; vigorous and prolonged grinding can easily lead to a sharp increase in related substances.

[0004] Patent CN111643461A involves adding azilsartan to a molten polyethylene glycol solution, followed by granulation of the molten suspension with other excipients. Azilsartan has a melting point of approximately 190°C. When heated above this melting point, azilsartan decomposes significantly; therefore, this method does not melt the active pharmaceutical ingredient. However, when heated far below the melting point, azilsartan remains in a solid powder state, making effective and uniform mixing difficult, and it cannot form an amorphous solid dispersion.

[0005] Patent CN108096195A describes the preparation of amorphous azilsartan solid dispersions using a supercritical antisolvent method. To improve the solubility of the active pharmaceutical ingredient (API), a large amount of organic mixed solvent is used in the preparation of the azilsartan-carrier mixed solution, containing acetone, dichloromethane, and dimethyl sulfoxide in a volume ratio of 1:1:0.1. Dichloromethane is classified as a Class II solvent (ICH recommends limiting its use), and dimethyl sulfoxide has a high boiling point (189°C), posing a risk of excessive residual solvent. Furthermore, this method requires highly sophisticated equipment, which most pharmaceutical manufacturers lack, limiting its widespread application.

[0006] Patent CN103260605A prepared azilsartan solid dispersion using a solvent method, preferably using a large amount of methanol as the solvent and vacuum drying. The mass concentration of azilsartan in methanol was only 0.0125 g / mL. At the same time, vacuum drying required maintaining a temperature of 40°C for more than 24 hours. After repeated experiments, it was found that the prepared azilsartan solid dispersion was difficult to peel off from the container, and the levels of related substances increased significantly.

[0007] Considering the aforementioned patents for azilsartan formulations and the inherent instability of the active pharmaceutical ingredient (API) under vigorous pulverization or high-temperature conditions, solvent-based methods should be preferred for preparing solid dispersions. Currently, the main reasons limiting the widespread application of solvent-based methods include the following three aspects: First, azilsartan API has very poor solubility; it is not only insoluble in water but also has unsatisfactory solubility in many commonly used organic solvents (see Table 1). Therefore, the consumption of organic solvents is enormous, easily leading to significant safety, quality, and environmental pollution problems. Second, high-temperature drying time should not be too long; therefore, vacuum drying and reduced-pressure drying are not preferred. Third, the equipment requirements are relatively high; for example, freeze drying and spray drying require specialized equipment, which some formulation manufacturers lack the necessary hardware for.

[0008]

[0009] In summary, breakthroughs are urgently needed in developing a solvent-friendly, low-volume azilsartan solid dispersion, pharmaceutical composition, and preparation method that is suitable for conventional granulation methods and industrial production, and has excellent quality in terms of related substances and dissolution. Summary of the Invention

[0010] This invention provides an azisartan solid dispersion, pharmaceutical composition, and preparation method that are solvent-friendly, require less dosage, are suitable for conventional wet granulation, and produce excellent quality.

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

[0012] This invention uses the conventional and excellent carrier material, povidone K30, for detailed description. However, it should be noted that this invention is not limited to povidone. Other conventional carrier materials, such as poloxamer, hydroxypropyl cellulose, and polyethylene glycol, can also be applied after simple exploration and adjustment.

[0013] Table 1 shows the measured solubility data of the active pharmaceutical ingredient (API). It was found that dissolving 1g of azilsartan requires approximately 160mL of ethanol. Based on the ICH guidelines requiring a minimum pilot-scale batch size of 100,000 tablets and the minimum specification of this product being 20mg, it is estimated that a single pilot-scale batch would require approximately 320L of ethanol. This enormous solvent consumption implies extremely high material, energy, and labor costs, as well as safety hazards, significantly limiting the scale-up of this product. To improve the solubility of azilsartan in ethanol and reduce solvent usage, the applicant dispersed azilsartan in a carrier material (such as povidone K30). By increasing the carrier concentration in ethanol or the solution temperature, the solubility of azilsartan in this solvent system was effectively improved, to the point that dissolving 1g of azilsartan requires approximately 20mL of ethanol. Furthermore, azilsartan does not precipitate after brief heating and rapid cooling to room temperature in this system. Furthermore, through extensive experimentation, the applicant unexpectedly discovered that adding an appropriate amount of alkaline salt (such as sodium acetate trihydrate) significantly increased the solubility of azilsartan, remarkably requiring only about 7 mL of ethanol to dissolve 1 g of azilsartan, far exceeding expectations. However, azilsartan exhibits poor stability in strongly alkaline solutions. To ensure the safety and efficacy of the drug, by controlling the amount of alkaline salt and adjusting the solution pH to 6.5–7.5, the stability of azilsartan remained unaffected. However, pH values ​​outside this range negatively impacted stability to varying degrees.

[0014] It should be noted that the combined application of (1) increasing the solution temperature, (2) using high concentrations of povidone K30, and (3) using appropriate amounts of alkaline salts for solubilization can significantly increase the solubility of azisartan in ethanol by more than 15 times, thus significantly reducing the amount of solvent used. However, 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 using solvent methods is significantly improved. In addition to the continued availability of conventional techniques such as freeze drying, spray drying, and fluidized bed one-step granulation, wet granulation technology, which is limited by the amount of solvent used, may also be realized. It should be noted that wet granulation technology is most widely used in ordinary oral solid dosage forms, but its application in the preparation of solid dispersions is relatively rare. To better explain the innovation of this invention, the most conventional and economical wet granulation and fluidized bed drying processes were selected for the preparation of solid dispersions. The study found that this process does not destroy the formation of solid dispersions, and the related substances do not grow rapidly and the dissolution rate is significantly improved, indicating good bioavailability.

[0015] The technical solution of this invention is:

[0016] A solid dispersion of azilsartan suitable for wet granulation, wherein a unit dose of the solid dispersion of azilsartan contains 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 croscarmellose sodium (added internally). Azilsartan, povidone K30, and sodium acetate trihydrate are co-dissolved in 75%-100% ethanol solvent under heating conditions to prepare a solution with a pH of 6.5-7.5.

[0017] Preferably, 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 croscarmellose sodium (added internally).

[0018] Preferably, the solution contains azisartan at a concentration of not less than 0.1 g / mL and povidone K30 at a concentration of 0.35~0.75 g / mL.

[0019] Preferably, the solvent is 75% ethanol, the mass concentration of povidone K30 is preferably 0.5 g / mL, and the heating temperature is preferably 60°C.

[0020] An azilsartan solid dispersion suitable for wet granulation is prepared by the following method:

[0021] Step 1: Prepare the solution

[0022] Under the condition of heating in a 60°C water bath, add povidone K30 to the solvent while stirring until completely dissolved. Then add azisartan and sodium acetate trihydrate and stir until completely dissolved. Set aside at room temperature for later use.

[0023] Step 2: Wet granulation

[0024] Microcrystalline cellulose, mannitol, and cross-linked sodium carboxymethyl cellulose were placed in a wet granulator and premixed for 3 minutes at a stirring speed of 100 rpm. Then, the stirring speed was adjusted to 200 rpm, the cutter speed to 1000 rpm, and the peristaltic pump speed to 70 rpm. The solution obtained in step 1 was sprayed into the wet granulator and granulated for 8 minutes to obtain wet granules.

[0025] Step 3: Fluidized bed drying

[0026] Transfer the wet particles obtained in step 2 to a fluidized bed, set the inlet air volume to 35Hz and the inlet air temperature to 50℃, and collect the material when the moisture content is dried to below 2%.

[0027] Step 4: Granulation

[0028] Granulation was performed using a granulator with a screen aperture of 1.2 mm and a rotation speed of 600 rpm. The granules were then collected to obtain the azisartan solid dispersion.

[0029] A pharmaceutical composition of an azisartan solid dispersion, wherein a unit dose of the pharmaceutical composition comprises 429.5 mg of the solid dispersion, 16 mg of croscarmellose sodium (added), 4.5 mg of magnesium stearate, and 18 mg of film-coating premix.

[0030] A pharmaceutical composition of azisartan solid dispersion, prepared by the following method:

[0031] Step 5: Total Mixing

[0032] Azisartan solid dispersion and croscarmellose sodium (added externally) were placed in a hopper mixer and mixed at 10 rpm for 5 min. Then magnesium stearate was added and mixed for 3 min to obtain the total mixture.

[0033] Step 6: Tableting

[0034] The total mixture obtained in step 5 is compressed into tablets with a hardness of 45~80N to obtain plain tablets.

[0035] Step 7: Coating

[0036] The uncoated tablets obtained in step 6 are coated with a film to obtain azisartan solid dispersion tablets.

[0037] Compared with the prior art, the present invention has the following advantages:

[0038] (1) Using ethanol-water, which has good biocompatibility, as a solvent is safer and easier to remove than other organic solvents;

[0039] (2) The new solvent system increases the solubility of azisartan by more than 15 times, significantly reducing the amount of solvent used and production costs;

[0040] (3) Thanks to the significant reduction in solvent usage, the wet granulation process was used for the first time to prepare amorphous azisartan solid dispersion. The quality stability of related substances and dissolution was good. At the same time, the hardware requirements were reduced, the operation was simple, the efficiency was higher, and it was suitable for industrial production. Detailed Implementation

[0041] Experimental Example 1: Investigation of Factors Affecting the Solubility of Azisartan

[0042] Under water bath heating conditions, povidone K30 and sodium acetate trihydrate were added to the solvent while stirring until completely dissolved. Azilsartan was then added in portions of 0.1g each time until it could not be completely dissolved, and the amount of azilsartan added that had been dissolved was recorded.

[0043] The specific inspection plan is as follows:

[0044]

[0045] As shown in Table 2, the solubility of azisartan was most significantly improved only when the water bath temperature, ethanol concentration, povidone K30, and sodium acetate trihydrate dosage all met the requirements. Under the same solvent volume (140 mL), the maximum solvent volume of azisartan in Experiments 1-2 (water bath temperature of 30℃), Experiments 1-3 (no sodium acetate trihydrate added), Experiments 1-4 (solvent of 50% ethanol), and Experiments 1-7 (lower concentration of povidone K30) was all less than 10 g, and the mass concentration was less than 0.1 g / mL, but still much higher than the required concentration. Table 1 shows that the mass concentration of azisartan in anhydrous ethanol alone is 0.0063 g / mL. The difference between test examples 1-1, 1-5, 1-6, and 1-7 lies in the mass concentration of povidone K30. When the mass concentration is greater than 0.35 g / mL, the solubility of azisartan is significantly improved. Further increasing the mass concentration of povidone K30 to 0.5 g / mL and 0.75 g / mL results in a slower increase in the solubility of azisartan. Therefore, to ensure the stability of subsequent processes, the optimal mass concentration of povidone K30 is 0.5 g / mL.

[0046] All experiments in Example 1 investigated the maximum solubility of azisartan under the corresponding conditions. The dissolution process took a long time. Considering that the required azisartan solid dispersion pharmaceutical composition specification is 20mg, the amount of azisartan used in subsequent Experiment 1-1 was reduced to 20g for testing.

[0047] Experimental Example 2: Stability Study of Azisartan at Different Solution pH Levels

[0048] Under the condition of heating in a 60℃ water bath, povidone K30 was added to the solvent while stirring until completely dissolved. Then, azisartan and sodium acetate trihydrate were added and stirred until completely dissolved. The solution was placed at room temperature, and the pH of the solution was measured. Samples were taken at 0, 1, 2, 3, and 6 hours to detect related substances of azisartan.

[0049] The specific inspection plan is as follows:

[0050]

[0051] The results of the relevant substance test are as follows:

[0052]

[0053] Based on the above test results, the pH values ​​of Experiments 2-2, 2-3, and 2-4 were 6.5, 7.0, and 7.5, respectively. At these pH values, azisartan showed good stability in solution, with no significant increase in related substances after 6 hours at room temperature. In Experiments 2-1 and 2-5, the pH values ​​were 6.0 and 8.0, respectively, with significant increases in impurities A, J, and total impurities. In particular, the content of impurity A exceeded the limit after 6 hours. Since it is difficult to guarantee that the solution can be quickly moved to the next step after preparation in actual formulation production, ensuring the stability of the azisartan solution is extremely important. Based on the measured values, the pH of the solution needs to be stabilized between 6.5 and 7.5.

[0054] The composition will be further investigated below in conjunction with the studies in Experimental Example 1 and Experimental Example 2.

[0055] Prescription composition for Examples 1-6:

[0056]

[0057] Preparation method:

[0058] Step 1: Solution preparation: Under the condition of heating in a 60°C water bath, add the prescribed amount of povidone K30 to the solvent while stirring. After stirring until completely dissolved, add azisartan and sodium acetate trihydrate, and stir until completely dissolved. Set aside at room temperature for later use.

[0059] Step 2: Wet granulation: Place microcrystalline cellulose, mannitol, and croscarmellose sodium in a wet granulator, premix at 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. Spray the solution obtained in Step 1 into the wet granulator and granulate for 8 minutes to obtain wet granules.

[0060] Step 3: Fluidized bed drying: Transfer the wet particles obtained in step 2 to a fluidized bed, set the inlet air volume to 35Hz and the inlet air temperature to 50℃, and collect the material when the moisture content is below 2%.

[0061] Step 4: Granulation: Granulate using a granulator with a screen aperture of 1.2 mm and a rotation speed of 600 rpm, collect the particles to obtain azisartan solid dispersion.

[0062] Step 5: Mixing: Place the azisartan solid dispersion and cross-linked sodium carboxymethyl cellulose in a hopper mixer and mix at 10 rpm for 5 minutes. Then add magnesium stearate and mix for 3 minutes to obtain the final mixture.

[0063] Step 6: Tableting: The total mixture obtained in Step 5 is compressed into tablets with a hardness of 45~80N to obtain plain tablets.

[0064] Step 7: Coating: Coat the tablets obtained in Step 6 with a film to obtain azisartan solid dispersion tablets.

[0065] Comparative Examples 1-7: Prescription Composition:

[0066]

[0067] Preparation method:

[0068] Comparative Example 1 follows the preparation method of the previous example, except that in step 1, azisartan is not added to the ethanol solution, but rather to the premix in the wet granulation machine in step 2. Specifically, an ethanol solution containing povidone K30 and sodium acetate trihydrate is sprayed onto a mixture of azisartan, microcrystalline cellulose, mannitol, and croscarmellose sodium powder for wet granulation. The remaining steps are the same as those in steps 3-7 of the previous example.

[0069] Comparative Example 2 was prepared according to step 1 of the Example. After complete dissolution, the solution was placed in a vacuum drying oven and dried at 40°C for 24 hours. The solution was then removed and pulverized to obtain the azisartan solid dispersion. The remaining steps were the same as the preparation methods in steps 5-7 of the Example.

[0070] Comparative Example 3, referring to patent CN103260605A, involved dissolving azilsartan and povidone in methanol, placing the solution in a vacuum drying oven, drying it under vacuum at 40°C for 24 hours, and then pulverizing it to obtain the azilsartan solid dispersion. The remaining steps were the same as the preparation methods in steps 5-7 of the Examples.

[0071] Comparative Examples 4-7 were prepared according to the methods described in the Examples. In Comparative Example 5, the excessive amount of povidone added resulted in excessively high solution concentration and viscosity. The solution quickly formed filaments after being sprayed from the wet granulation nozzle, making normal granulation impossible. In Comparative Example 6, due to the excessive amount of solvent, the material was too wet after wet granulation, and most of the particles formed spheres. After drying, the particles were hard and had poor compressibility, resulting in fragmentation. Therefore, no further investigation was conducted. In Comparative Example 7, after reducing the amount of solution and increasing the concentration of povidone, the solubility limit of azilsartan was exceeded, and azilsartan could not be completely dissolved. Therefore, no further experiments were conducted.

[0072] Experimental Example 3: Related substances investigation of azisartan solid dispersion pharmaceutical composition under accelerated conditions

[0073]

[0074]

[0075] Based on the test results of stability-related substances, when Examples 1-6 were placed under accelerated conditions for 6 months, the related substances did not exceed the limits.

[0076] Comparative Example 1 is a non-solid dispersion of azilsartan tablets prepared with the same formulation as in Example 1. The results of related substance testing showed that, compared to the non-solid dispersion, the related substances in azilsartan prepared as a solid dispersion using the formulation process of this invention did not increase significantly, and the growth rates of related substances at each time point (accelerated 1, 2, 3, and 6 months) were similar to those in the non-solid dispersion.

[0077] Comparative Examples 2 and 3 were prepared by vacuum drying. The related substances reached a high level at day 0, and no further stability was required for subsequent investigation.

[0078] Comparative Example 4 showed good results for the related substances at day 0, but its dissolution behavior at day 0 was poor (see Example 4 in the following test for details). Therefore, no further stability studies were conducted on the related substances.

[0079] Experimental Example 4: Investigation of the dissolution behavior of azisartan solid dispersion pharmaceutical composition

[0080] The dissolution behavior of the tablets prepared in Examples 1-6 and Comparative Examples 1 and 4 was evaluated under the following conditions:

[0081] 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 in the 2020 edition of the Chinese Pharmacopoeia, selecting the second method (i.e., paddle method), with a rotation speed of 50 rpm.

[0082]

[0083]

[0084] Based on the detection results of the above dissolution curves, the highest dissolution rates of Examples 1 to 6 can all reach over 90%, and there is no significant decrease under accelerated conditions.

[0085] Comparative Example 1 uses non-solid dispersion technology. In a dissolution medium without added surfactant, the dissolution rate is only about 10% within 60 minutes. Comparative Example 4 has a higher dissolution rate, but because the amount of povidone K30 is insufficient to form a complete solid dispersion with azilsartan, the dissolution rate of azilsartan in the partially crystalline state is significantly reduced.

Claims

1. An azilsartan solid dispersion suitable for wet granulation, characterized in that, A unit dose of azilsartan solid dispersion contains 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 internally added croscarmellose sodium. 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. The solution contains azilsartan at a concentration of not less than 0.1 g / mL and povidone K30 at a concentration of 0.35-0.75 g / mL. The specific preparation method is as follows: Step 1: Under the heating condition of 60℃ water bath, add povidone K30 to the solvent and stir until completely dissolved. Then add azisartan and sodium acetate trihydrate and stir until completely dissolved. Set aside at room temperature for later use. Step 2: Place microcrystalline cellulose, mannitol, and croscarmellose sodium cellulose in a wet granulator, premix them evenly, and then spray the solution obtained in Step 1 into the wet granulator to granulate, obtaining wet granules. Step 3: Transfer the wet granules obtained in Step 2 to a fluidized bed for drying. When the drying loss reaches less than 2%, collect the granules. The particles are then granulated to obtain the azisartan solid dispersion.

2. The azisartan solid dispersion according to claim 1, characterized in that, Each unit dose of azisartan solid dispersion contains 20 mg azisartan, 70 mg povidone K30, 5.3 mg sodium acetate trihydrate, 244 mg microcrystalline cellulose, 74.2 mg mannitol, and 16 mg of internally added croscarmellose sodium.

3. The azisartan solid dispersion according to claim 1, characterized in that, The mass concentration of povidone K30 in the solution is 0.5 g / mL.

4. The azisartan solid dispersion according to claim 1, characterized in that, The solvent is 75% ethanol.

5. The azisartan solid dispersion according to claim 1, characterized in that, The heating temperature is 60°C.

6. A pharmaceutical composition comprising the azisartan solid dispersion of claim 1 and a pharmaceutically acceptable pharmaceutical excipient.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition per unit dose comprises 429.5 mg of solid dispersion, 16 mg of added croscarmellose sodium, 4.5 mg of magnesium stearate, and 18 mg of film-coating premix.

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