CN111617046A

CN111617046A - Azilsartan dispersible tablet and preparation process thereof

Info

Publication number: CN111617046A
Application number: CN202010656007.4A
Authority: CN
Inventors: 胡海波; 殷学治
Original assignee: Zhejiang Nord Pharmaceutical Co ltd
Current assignee: Zhejiang Nord Pharmaceutical Co ltd
Priority date: 2020-07-09
Filing date: 2020-07-09
Publication date: 2020-09-04

Abstract

The invention provides an azilsartan dispersible tablet and a preparation process thereof, wherein micronized azilsartan is mixed with a filler glucose binder and a part of disintegrant, wet granulation is carried out by adopting a binder solution added with a stabilizer, then other fillers and the rest of disintegrant are added, and a lubricant is added for tabletting, wherein the azilsartan raw material is micronized so as to be more effectively combined with the glucose binder to improve the dissolution speed. The adoption of the glucose binding agent improves the hydrophilicity of the medicine, so that the azilsartan dispersible tablet still has higher dissolution rate under higher hardness, and the bioavailability is improved. And the process is simple and is suitable for industrial mass production.

Description

Azilsartan dispersible tablet and preparation process thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to an azilsartan dispersible tablet and a preparation method thereof.

Background

Azilsartan (Azilsartan) is an angiotensin II receptor Antagonist (ARB) antihypertensive drug developed by wutian pharmaceutical company of japan (Takeda), and is used for the treatment of hypertension.

Chemical name of azilsartan: 2-ethoxy-1- [ [ 2' - (4, 5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl) biphenyl-4-yl ] methyl ] benzimidazole-7-carboxylic acid. CAS number: 147403-03-0. The chemical structural formula is as follows:

CN103933000A discloses AN azilsartan tablet and a preparation method thereof, the azilsartan tablet contains micronized azilsartan, anhydrous lactose 21AN, anhydrous lactose 24AN, a disintegrating agent and a lubricant, and is prepared by direct compression. The content difference between tablets is easily caused because the particle size of the raw material is greatly different from that of lactose.

CN104306344B discloses a tablet containing azilsartan and its preparation process, wherein the tablet is prepared by mixing micronized azilsartan (D90 ═ 30-60 μm) and microcrystalline cellulose KG1000, then adding other auxiliary materials, mixing, and direct tabletting by dry method. The patent optimizes the particle size difference between raw and auxiliary materials, solves the problem of tablet content uniformity, but introduces the problem of poor fluidity, is not beneficial to tabletting and is more not beneficial to industrial production.

CN101528262A discloses a pharmaceutical composition containing azilsartan, which incorporates a low melting point oily substance and a low viscosity binder, and is mainly characterized in that the low viscosity binder is used to improve the dissolution of azilsartan. However, the use of low viscosity binders to enhance the in vitro dissolution of azilsartan is very limited.

CN104523632B discloses an azilsartan tablet, which is prepared by dissolving azilsartan and povidone in diethylene glycol monoethyl ether, adding gas silicon dioxide for adsorption, then mixing with pharmaceutically acceptable auxiliary materials, and pressing by adopting a direct tabletting process. The tablet is combined with the solubilizer and the adsorbent through a solid dispersion technology, so that the in-vitro dissolution is improved, but the process is complex, and an organic solvent is introduced, so that extra burden is brought to detection, and the industrial production is not facilitated.

The dispersible tablet is a new formulation produced in recent years and is collected in British pharmacopoeia and Chinese pharmacopoeia. The dispersible tablet can be rapidly disintegrated in water and dispersed into uniform suspension, and has the advantages of convenient administration and high bioavailability. The preparation method, production conditions and process of the dispersible tablet are simple and are beneficial to industrialization. The dispersible tablet can be administered flexibly, and can be swallowed as common tablet or dispersed in water. CN108096195A discloses a method for preparing azilsartan solid dispersion by supercritical anti-solvent method, comprising: step S1, dissolving the azilsartan and the water-soluble carrier in an organic solvent to obtain an azilsartan-carrier mixed solution; step S2, introducing CO2 into a crystallization kettle, and adjusting the temperature and pressure in the crystallization kettle; step S3, continuously introducing CO2, keeping the temperature and the pressure in the crystallization kettle unchanged, and simultaneously introducing the azilsartan-carrier mixed solution prepared in the step S1 into the crystallization kettle; step S4, after the azilsartan-carrier solution is introduced, continuously introducing CO2, maintaining the temperature and the pressure in the crystallization kettle unchanged, and releasing the pressure after a period of time; opening the crystallization kettle to collect the azilsartan solid dispersion after the pressure in the crystallization kettle is reduced to the atmospheric pressure; wherein the water-soluble carrier is PVP-K30. By the method, the azilsartan is dispersed in PVP-K30 in an amorphous form, so that the dissolution rate of the azilsartan can be improved, and the stability of the azilsartan can be improved. CN103260605A discloses an azilsartan solid dispersion, a preparation method and a pharmaceutical composition thereof. The azilsartan solid dispersion contains azilsartan and a carrier material, wherein the carrier material is selected from povidone, poloxamer, polyethylene glycol, hydroxypropyl cellulose and polyethylene oxide. The preparation method is a solvent method. The azilsartan and the carrier are dissolved in a solvent, and after all the azilsartan and the carrier are dissolved, the solvent is removed, dried and crushed to obtain the solid dispersion.

The azilsartan is almost insoluble in 0.1mol/L hydrochloric acid and water, the in vitro dissolution speed can be improved by using a dispersible tablet process, and the medicine can reach the required blood concentration in blood to realize the expected clinical effect.

Disclosure of Invention

The invention aims to provide an azilsartan dispersible tablet and a preparation method thereof, wherein azilsartan is almost insoluble in 0.1mol/L hydrochloric acid and water, and the azilsartan dispersible tablet is capable of being quickly dissolved out, and has a simple process and stable quality aiming at the problems of low water solubility of azilsartan and especially the problem of low dissolution of azilsartan in an acid environment.

In order to realize the purpose of the invention, the technical scheme adopted for solving the technical problem is as follows:

an azilsartan dispersible tablet is prepared by granulating micronized azilsartan and pharmaceutically acceptable auxiliary materials and tabletting; the micronized azilsartan has a particle size distribution D90 of less than 40 μm; the pharmaceutically acceptable auxiliary materials comprise a disintegrating agent, a filling agent, a bonding agent, a stabilizing agent and a lubricating agent. Wherein the disintegrating agent comprises one or more of low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; the filler comprises one or more of dextrates, mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose, starch, and pregelatinized starch; the binder comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvidone; the stabilizer is glycerol; the lubricant comprises one or more of magnesium stearate, pulvis Talci, stearic acid, and sodium fumarate stearate.

The dispersible tablet comprises the following raw materials in parts by weight: 10 parts of azilsartan, 2-12 parts of filler, 9-13 parts of disintegrating agent, 0.2-1 part of adhesive, 0.2-1 part of stabilizer and 0.1-0.5 part of lubricant.

Preferably, the weight parts of the components are as follows: 10 parts of azilsartan, 1-6 parts of dextrates, 1-6 parts of microcrystalline cellulose, 9-13 parts of low-substituted hydroxypropyl cellulose, 0.2-1 part of glycerol and 0.1-0.5 part of magnesium stearate.

More preferably, the components comprise, by weight, 10 parts of azilsartan, 3.2 parts of dextrates, 4 parts of microcrystalline cellulose, 11.25 parts of low-substituted hydroxypropylcellulose, 0.625 parts of glycerol and 0.3 parts of magnesium stearate.

In the dispersible tablet, preferably, the disintegrating agent is low-substituted hydroxypropyl cellulose; the filler comprises glucose binder and microcrystalline cellulose with equal mass; the adhesive is hydroxypropyl cellulose; the stabilizer is glycerol; the lubricant is magnesium stearate.

The preparation process of the azilsartan dispersible tablet comprises the following steps:

(1) uniformly mixing the micronized azilsartan, part of the filler and part of the disintegrant; the part of the filler accounts for half of the total mass of the filler, and the filler is a glucose binder; 1/3 parts of the disintegrant accounts for the total mass of the disintegrant;

(2) dissolving a stabilizer in a 3% adhesive solution for later use;

(3) adding the binder solution obtained in the step (2) into the mixed raw materials obtained in the step (1), and then granulating in a wet granulator;

(4) after sieving the wet granules, drying until the weight loss is less than or equal to 2.0 percent; granulating the dried particles by a 0.6mm screen for later use;

(5) adding the rest filler and disintegrant, mixing, adding magnesium stearate, mixing, and tabletting to obtain the final product, wherein the rest filler is microcrystalline cellulose.

(1) taking the micronized azilsartan, part of the filler and part of the disintegrant, and preheating to a temperature of not less than 30 ℃ in a fluidized bed; the part of the filler accounts for half of the total mass of the filler, and the filler is a glucose binder; 1/3 parts of the disintegrant accounts for the total mass of the disintegrant;

(2) dissolving the stabilizer in 3% adhesive solution for later use;

(3) adding the adhesive solution obtained in the step (2) into a fluidized bed for granulation, wherein the air inlet temperature is controlled to be 40-60 ℃ and the material temperature is controlled to be 27-35 ℃ in the granulation process; after the adhesive is added, the drying is continued until the drying weight loss is less than or equal to 2.0 percent; and (4) granulating the dried granules by a 0.6mm screen for later use.

(4) Adding the rest filler and the rest disintegrant, mixing, adding magnesium stearate, mixing, and tabletting; the rest filler is any one of mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose, starch and pregelatinized starch. Preferably, microcrystalline cellulose.

In the preparation method, the filler is a combination of glucose binder with equal mass and any one of mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose, starch and pregelatinized starch. The addition method is that the glucose binder is added before wet granulation, and other fillers are added after granulation. The two fillers are adopted and added respectively from front to back, so that the combination of the azilsartan and the glucose binder can promote the azilsartan to be quickly dissolved out, and other fillers (preferably microcrystalline cellulose) can ensure the smoothness of tabletting and the compressibility. In the addition mode, the azilsartan tablets can still rapidly collapse and dissolve out under higher tabletting hardness.

Has the advantages that:

(1) azilsartan is almost insoluble in water and is more hydrophobic after being micronized, but the micronized azilsartan is selected as a raw material medicament (given by Tianyu pharmaceutical industry Co., Ltd. in Zhejiang) for the purposes of ensuring the full combination of the raw material and a glucose binder and improving the dissolution speed.

(2) The hydrophilicity of the micronized azilsartan and the glucose binder is increased after wet granulation, the obtained azilsartan dispersible tablet can still rapidly collapse and dissolve out under higher hardness, and the dissolution amount in the first 15 minutes can reach more than 99% in a dissolution rate detection test. And the higher hardness is adopted to avoid the abrasion of the dispersible tablets in the transportation process.

(3) From the experimental data of the bioavailability in beagle dogs, the use of the dextrates and lactose as fillers can achieve higher bioavailability.

(4) The obtained azilsartan dispersible tablet has uniform raw material content, stable quality and simple process, and is suitable for industrial production.

Drawings

Fig. 1 is a plasma concentration-time curve of azilsartan in plasma after administration of samples of examples 1, 4 in bioavailability test.

Detailed Description

The present invention is further illustrated by the following specific examples, which are not intended to limit the invention.

The formulations used in example 1 and comparative examples 1 to 3 are shown in Table 1:

TABLE 1

The preparation process of example 1 is as follows:

taking micronized azilsartan crude drug (about 25 mu m of D90), dextrates and low-substituted hydroxypropyl cellulose, preheating to a temperature of not less than 30 ℃ in a fluidized bed, dissolving glycerol in 3% of hydroxypropyl cellulose solution of a binding agent, and adding the solution of the binding agent into the fluidized bed for granulation. The air inlet temperature is controlled to be 50 ℃ in the granulating process, and the material temperature is more than 27 ℃. And after the adhesive solution is added, continuously drying until the drying weight loss is less than or equal to 2.0 percent, starting a granulator, sieving by using a 0.6mm sieve at 500rpm, adding 200g of microcrystalline cellulose as an additional auxiliary material and 562.5g of low-substituted hydroxypropyl cellulose, mixing for 15 minutes, adding magnesium stearate, and mixing for 5 minutes. Circular at 7 mm.

Comparative example 1

The formulation of comparative example 1 was the same as example 1, except that no stabilizer glycerol was added to the binder during fluid bed granulation, and a post-granulation glycerol addition was used. In example 1, however, wet granulation was used and glycerol was mixed into the hydroxypropylcellulose binder solution and added prior to granulation.

COMPARATIVE EXAMPLE 2 (prescription of CN 103933000A)

Comparative example 2 used a method of direct lactose blend compression, specifically:

taking Azilsartan bulk drug (D90 is about 25 mu m), and sieving anhydrous lactose 21AN with a 20-mesh sieve and mixing uniformly. Adding anhydrous lactose 24AN and sodium carboxymethyl starch, mixing, adding magnesium stearate, mixing, and making into tablet with hardness of about 120N by 8mm round punch. The purpose of comparison is to investigate the influence of different preparation methods on the content uniformity of the dispersible tablets and related substances in the storage process.

COMPARATIVE EXAMPLE 3 (prescription of CN 104306344B)

The preparation process comprises the following steps: taking Azilsartan crude drug (about 50 mu m of D90), adding microcrystalline cellulose, mixing uniformly, adding crospovidone and lactose, mixing uniformly, adding magnesium stearate, mixing uniformly, and punching into tablets with hardness of about 120N in a 9mm circle. The purpose of comparison is to investigate the influence of different preparation methods on the flowability of the material and the related substances in the storage process.

Performance detection

1. Dissolution test: samples of example 1 and comparative examples 1 to 3 of the present invention were taken, respectively, and the amount of elution was measured by sampling 15 minutes at 50rpm using ph6.0 phosphate buffer as the elution medium.

2. The content uniformity is detected by a content uniformity detection method of 0941 in the four general rules of Chinese pharmacopoeia 2015 edition.

3. And (3) related substance detection: taking the azilsartan dispersible tablet prepared in example 1, grinding, weighing an appropriate amount, precisely weighing, adding an appropriate amount of diluent [ methanol-0.02 mol/L dipotassium hydrogen phosphate solution (pH value is adjusted to 8.0 by phosphoric acid) (50:50) ] for ultrasonic dissolution, and then adding the diluent for quantitative dilution to prepare a solution containing about 1.0mg in each 1ml to serve as a test solution; an appropriate amount was precisely measured, and diluted quantitatively with a diluent to give a solution containing about 1. mu.g per 1ml as a control solution. Respectively taking a proper amount of azilsartan, impurity A, impurity B, impurity C, impurity D, impurity E and impurity F, adding a proper amount of methanol, ultrasonically dissolving, and quantitatively diluting to prepare a solution containing 0.1mg of each of azilsartan, impurity A, impurity B, impurity C, impurity D, impurity E and impurity F in each 1ml, wherein the solution is used as an azilsartan impurity stock solution; taking about 10mg of azilsartan reference substance, precisely weighing, placing in a 100ml measuring flask, adding a proper amount of methanol for ultrasonic dissolution, adding 10ml of azilsartan impurity stock solution, and diluting to a scale with methanol to obtain a system applicability solution. Measuring by high performance liquid chromatography (0512 in the four-part general regulation of the 2015 edition of Chinese pharmacopoeia), and using octadecylsilane chemically bonded silica as filler; performing gradient elution by using potassium dihydrogen phosphate buffer solution (pH value is adjusted to 3.0) as a mobile phase A and acetonitrile as a mobile phase B; and (4) respectively taking 10 mu l of the test solution and the control solution, injecting into a liquid chromatograph, and recording the chromatogram.

Table 2 test results of examples and comparative examples

From the above results, it can be seen that the azilsartan dispersible tablets prepared in examples 1-2 and comparative example 1 of the present invention are rapidly dissolved out, and are basically completely dissolved out in 15 minutes. Example 1 accelerated test the relevant substances were essentially unchanged after 1 month of storage; while comparative example 1 shows a significant increase in the related substance under the acceleration condition, comparative example 2 shows a poor content uniformity, comparative example 3 shows a poor fluidity, complete dissolution cannot be achieved within 15 minutes, and the related substance shows a significant increase under the acceleration condition. The analysis reason is that the mode of adding glycerol after finishing the particles is adopted in the comparative example 1, and the glycerol cannot be effectively dispersed in the particles, so that the stability effect is poor; in the comparative example 2, no stabilizer is added, and the grain size difference between the auxiliary material and the API is large, so that the content uniformity is poor in the tabletting process, and related substances are remarkably increased; the raw materials in the comparative example 3 are directly tabletted after being mixed, the raw materials cannot be fully combined with hydrophilic materials, the dissolution improvement is not obvious, the flowability of the used materials is poor, and the weight difference of tablets in the tabletting process is large. Likewise, without the addition of a stabilizer, the relevant substances increase significantly.

Bioavailability test

EXAMPLE 1 and A study of the relative bioavailability of Azilsartan tablets on the market

Experimental formulation: a sample of azilsartan dispersible tablet prepared in example 1 (specification 40 mg);

reference formulation: azilsartan tablets (40 mg standard, wutian drug industries co., ltd.).

And (3) experimental design: the 6 beagle dogs are randomly divided into two groups, and a single-dose double-period cross test design is adopted, wherein the interval period between two tests is 1 week. The dose was 40mg administered per week, fasting was started for 12h 1 day in the evening before administration and the test was started about 8 am the following day. Collecting 4mL of elbow venous blood of a subject at 0.5, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 14 and 24 h (total 18 points) before and after administration, placing the elbow venous blood into an EDTA-K2 centrifuge tube, centrifuging the elbow venous blood at 3500rpm for 5min at-4 ℃ after collection, dividing the blood into two parts, taking 1mL of the blood plasma to be added into a formal tube, and adding the rest of the blood plasma to a backup tube. The sample was placed in a-20 ℃ freezer 1.5h after collection.

(II) data processing and statistical methods and pharmacokinetic parameters

The main kinetic parameters (Cmax, Tmax and AUC) of the azilsartan test formulation and the reference formulation were calculated to plot c-t curves from the plasma concentration-time data. Meanwhile, the mean value and the standard deviation of the drug concentration at each time point are tabulated, and the average blood concentration curve is drawn. Comparing whether the change of each index before and after administration has significant significance, and having statistical significance by taking P <0.05 as a difference.

	Example 1	Azilsartan tablets (commercially available)
			AUC0-t	7354	4050
AUC0-∞	7625	4220
			Cmax	927	582
Tmax	1.67	3.50
			F(％)	181	/

The difference in Tmax between example 1 and the commercial formulation was statistically significant, indicating that example 1 was absorbed more rapidly in beagle dogs than the commercial formulation. Cmax and AUC_0-∞The results of the logarithmic transformation and the analysis of variance show that the azilsartan dispersible tablets and the azilsartan tablets LnCmax and LnAUC obtained in example 1_0-∞The difference has statistical significance, and the relative bioavailability of the azilsartan dispersible tablets to the azilsartan tablets is 181%, which shows that the azilsartan dispersible tablet process can improve the bioavailability of the azilsartan, and the use of the glucose binding agent is more beneficial to the improvement of the absorption relative bioavailability of the medicine.

The components used in examples 2-6 and the parts by weight of each component are shown in table 3:

TABLE 3

Claims

1. An azilsartan dispersible tablet is characterized in that the azilsartan dispersible tablet is prepared by granulating micronized azilsartan and pharmaceutically acceptable auxiliary materials and tabletting; the micronized azilsartan has a particle size distribution D90 of less than 40 μm; the pharmaceutically acceptable auxiliary materials comprise a disintegrating agent, a filling agent, a bonding agent, a stabilizing agent and a lubricating agent.

2. Azilsartan dispersible tablet according to claim 1, characterized in that the weight of each component is as follows: 10 parts of azilsartan, 2-12 parts of filler, 9-13 parts of disintegrating agent, 0.2-1 part of adhesive, 0.2-1 part of stabilizer and 0.1-0.5 part of lubricant.

3. The azilsartan dispersible tablet according to claim 1 or 2, wherein the disintegrant comprises one or more of low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium; the filler comprises dextrates and any one of mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose, starch and pregelatinized starch; the binder comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvidone; the stabilizer is glycerol; the lubricant comprises one or more of magnesium stearate, pulvis Talci, stearic acid, and sodium fumarate stearate.

4. Azilsartan dispersible tablet according to claim 2 wherein the disintegrant is low substituted hydroxypropylcellulose; the filler comprises glucose binder and microcrystalline cellulose with equal mass; the adhesive is hydroxypropyl cellulose; the stabilizer is glycerol; the lubricant is magnesium stearate.

5. Azilsartan dispersible tablets according to claim 4, characterised in that the components are in parts by weight as follows: 10 parts of azilsartan, 1-6 parts of dextrates, 1-6 parts of microcrystalline cellulose, 9-13 parts of low-substituted hydroxypropyl cellulose, 0.2-1 part of glycerol and 0.1-0.5 part of magnesium stearate.

6. An azilsartan dispersible tablet according to claim 4, wherein the components are, by weight, 10 parts of azilsartan, 3 parts of dextrates, 3 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropylcellulose, 0.8 parts of hydroxypropylcellulose, 0.5 parts of glycerin, and 0.3 parts of magnesium stearate.

7. The process for preparing azilsartan dispersible tablets according to claim 4, wherein the preparation method comprises the following steps:

uniformly mixing the micronized azilsartan, part of the filler and part of the disintegrant; the part of the filler accounts for half of the total mass of the filler, and the filler is a glucose binder; 1/3 parts of the disintegrant accounts for the total mass of the disintegrant;

dissolving a stabilizer in a 3% adhesive solution for later use;

adding the binder solution obtained in the step (2) into the mixed raw materials obtained in the step (1), and then granulating in a wet granulator;

after sieving the wet granules, drying until the weight loss is less than or equal to 2.0 percent; granulating the dried particles by a 0.6mm screen for later use;

adding the rest filler and disintegrant, mixing, adding lubricant, mixing, and tabletting, wherein the rest filler is any one of mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose, starch, and pregelatinized starch.

8. The process for preparing azilsartan dispersible tablets according to claim 2, wherein the preparation method comprises the following steps:

(2) dissolving the stabilizer in 3% adhesive solution for later use;

(3) adding the adhesive solution obtained in the step (2) into a fluidized bed for granulation, wherein the air inlet temperature is controlled to be 40-60 ℃ and the material temperature is controlled to be 27-35 ℃ in the granulation process; after the adhesive is added, the drying is continued until the drying weight loss is less than or equal to 2.0 percent; granulating the dried particles by a 0.6mm screen for later use;

(4) adding the rest filler and the rest disintegrant, mixing, adding magnesium stearate, mixing, and tabletting; the rest filler is any one of mannitol, xylitol, sorbitol, lactose, microcrystalline cellulose, starch and pregelatinized starch.