CN116421571A

CN116421571A - Azilsartan pharmaceutical composition

Info

Publication number: CN116421571A
Application number: CN202310426255.3A
Authority: CN
Inventors: 杨德斌; 张友凯; 郝宪宵
Original assignee: Disha Pharmaceutical Group Co Ltd
Current assignee: Disha Pharmaceutical Group Co Ltd
Priority date: 2023-04-20
Filing date: 2023-04-20
Publication date: 2023-07-14

Abstract

The invention relates to an azilsartan pharmaceutical composition and a preparation method thereof, and the azilsartan pharmaceutical composition specifically comprises 20% of azilsartan, 6-10% of sodium caprate, 3-9% of glycerogelatin, 40-62.5% of filler, 2-9% of microcrystalline wax, 6-10% of crosslinked povidone and 0.5-2% of magnesium stearate. The azilsartan pharmaceutical composition disclosed by the invention not only can ensure uniform release of the medicament in vivo, but also has excellent stability, and realizes stable control of blood pressure after administration.

Description

Azilsartan pharmaceutical composition

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an azilsartan tablet and a preparation method thereof.

Background

Azilsartan (Azilsartan) is an angiotensin II receptor antagonist for treating hypertension, and blocks the vasoconstrictor effect of angiotensin II by selectively blocking the binding of angiotensin II to vascular smooth muscle AT1 receptor, thereby producing a hypotensive effect. Compared with Angiotensin Converting Enzyme Inhibitor (ACEI) antihypertensive drugs, azilsartan has the advantages of stable depressurization and no dry cough. The medicine is marketed in 2012 by the Japanese Wuta-tsai pharmaceutical company, and has remarkable clinical effects.

Azilsartan is almost insoluble in water, the solubility in water is less than 9 mug/mL, and when a poorly soluble drug is prepared into a pharmaceutical preparation, special treatment is often required, so that the in-vitro dissolution speed of the drug is improved, and the drug can reach an effective concentration in blood to realize the expected clinical curative effect.

Chinese patent No. CN103260605B discloses a method for preparing azilsartan compositions by solid dispersion technology. Dissolving the raw materials and the carrier in methanol, drying under reduced pressure to obtain solid dispersion powder, and mixing with pharmaceutically acceptable diluents, disintegrants and binders to obtain corresponding compositions. The method improves the dissolution of the medicine in the medium with the pH of 4.5, but the method uses an organic solvent, has complex process and high risk coefficient of workshop mass production.

Chinese patent CN104523632a discloses a method for preparing azilsartan tablets by combining solid dispersion technology with solubilizer and adsorbent. Azilsartan is dissolved in diethylene glycol monoethyl ether, and povidone is added for preparation, so that the diethylene glycol monoethyl ether is a high-boiling-point very-commonly-used pharmaceutical auxiliary material, and solvent residues in products are easy to cause, so that the safety problem is brought.

Chinese patent No. 102895205A discloses a pharmaceutical composition of azilsartan, wherein the pharmaceutical composition is prepared by mixing the pre-micronized (D90 is less than or equal to 12 um) and the corresponding auxiliary materials, and directly tabletting the powder. Although the dissolution rate of the drug can be increased by reducing the particle size of the drug using micronization techniques, the micronization process may damage the crystal form, resulting in an increase in impurities (Lipeng Sui is pointed out in j.chip.pharm.sci.2014, 23 (5), 302-305). Meanwhile, during the storage process of the micronized raw materials, particles are easy to agglomerate, the particle size becomes large, and the particle size difference between different batches of raw materials is increased, so that the disintegration, the dissolution and the bioavailability are affected.

According to the scheme, the azilsartan preparation is prepared by a technology of preprocessing a main medicine or forming a solid dispersion with other components, although the dissolution rate of the azilsartan can be improved, the solid dispersion technology easily causes great change of the physicochemical property of the medicine, the absorption speed of the medicine in a body can be excessively high, excessive depressurization and aggravation adverse reaction are caused, and the medicine effect maintenance time is short. The problem of poor drug stability easily occurs when the drug is purely micronized.

For patients with hypertension, the improvement of the in vivo absorption rate of the medicine is only one aspect, and a specific preparation method is also needed to control the uniform release of the medicine so as to realize the stable control of the blood pressure after taking the medicine.

Therefore, there is an urgent need to find a preparation method of azilsartan tablets which can ensure uniform release of the drug in vivo and has excellent stability.

Disclosure of Invention

The invention aims to: provides an azilsartan pharmaceutical composition which can ensure the uniform release of the medicament in vivo and has excellent stability.

The applicant finds that azilsartan is added into a gel matrix formed by sodium caprate aqueous solution and glycerogelatin, uniformly dispersed and sprayed into a material containing a filler and microcrystalline wax for granulating, dried, added with a disintegrating agent and a lubricant, and tableted. Can obviously improve the dissolubility of the azilsartan in digestive juice and can achieve the aim of uniform release.

The in vitro dissolution experiment using artificial gastric juice and artificial intestinal juice as medium proves that the dissolubility of the tablet obtained by the scheme in digestive juice is obviously improved, the drug release speed is uniform, and the aim of uniform release can be basically achieved. Accelerated tests prove that the addition of a proper amount of microcrystalline wax can obviously improve the stability of the medicine.

The principle of analysis may be: sodium caprate is used as an intestinal penetration promoter and an anionic surfactant, has strong hydrophilicity and wettability, can obviously reduce the hydrophobicity of the medicine, changes the solubility of the medicine in digestive juice, forms a stable gel state with glycerogelatin water, and can control the release rate of the medicine after being fully combined with azilsartan, thereby achieving the aim of uniform release. The microcrystalline wax is used as a plastic material, so that the damage of mechanical force to the main medicine can be reduced in the preparation process, and the effect of improving the medicine stability is achieved.

The technical scheme of the invention is as follows: an azilsartan composition contains 20% of azilsartan, 6-10% of sodium caprate, 3-9% of glycerogelatin (the same applies below in terms of anhydrate), 40-62.5% of filler, 2-9% of microcrystalline wax, 6-10% of crosslinked povidone and 0.5-2% of magnesium stearate.

The glycerogelatin is formed by adding water to 100% from 20% glycerol and 2% gelatin and heating.

The filler is selected from lactose-microcrystalline cellulose complex and mannitol-microcrystalline cellulose complex.

In the present invention, purified water is used as a solvent, and is removed during the process without taking into account the composition ingredients.

Preferably, the azilsartan composition comprises 20% of azilsartan, 7-9% of sodium caprate, 4-8% of glycerogelatin, 46.8-57.2% of filler, 4-6% of microcrystalline wax, 7-9% of crosslinked povidone and 0.8-1.2% of magnesium stearate.

Preferably, the azilsartan composition comprises 20% of azilsartan, 8% of sodium caprate, 6% of glycerogelatin, 52% of filler, 5% of microcrystalline wax, 8% of crosslinked povidone and 1% of magnesium stearate.

The preparation method of the azilsartan composition comprises the following steps:

the first step: dissolving sodium caprate in purified water to form 5% (w/w) sodium caprate aqueous solution, adding glycerogelatin, and stirring to obtain colloidal liquid;

and a second step of: adding azilsartan into the colloidal liquid prepared in the first step, and stirring at a high speed for 2min by using a homogenizer at a rotating speed of 10000r/min to uniformly disperse the azilsartan to obtain emulsion;

and a third step of: adding filler and microcrystalline wax into a fluidized bed granulator (manufacturer: chongqing English lattice, model: WBG-2G), setting air inlet temperature at 60 ℃, air quantity at 40 m/h, atomization pressure at 1.5MPa and liquid inlet speed at 12rpm, spraying the emulsion prepared in the second step into the fluidized bed granulator to prepare particles, wherein the water content of the particles is required to be less than or equal to 1.5%;

fourth step: the granules are sized by using a screen with the aperture of 1.0 mm;

fifth step: adding the crosslinked povidone and magnesium stearate into the granules after finishing, and uniformly mixing by using a three-dimensional motion mixer;

sixth step: tabletting the granules, and adopting a 7mm shallow concave die, wherein the hardness of the tablets is 40-60N.

Examples

1000 tablets are prepared according to the preparation method of the technical scheme, and the specific steps are as follows.

Example 2:

preparation 1000 tablets preparation method reference example 1.

Example 3:

preparation 1000 tablets preparation method reference example 1.

Example 4:

preparation 1000 tablets preparation method reference example 1.

Example 5:

preparation 1000 tablets preparation method reference example 1.

Comparative example 1: sodium caprate is not contained in the prescription

1000 tablets were prepared according to the preparation method described in the following scheme.

The first step: adding glycerogelatin into purified water, and stirring until the glycerogelatin is uniformly dispersed;

and a second step of: adding azilsartan into the glycerol-containing gelatin liquid prepared in the first step, and stirring at a high speed for 2min by using a homogenizer at a rotating speed of 10000r/min to uniformly disperse the azilsartan to form a dispersion;

and a third step of: adding filler and microcrystalline wax into a fluidized bed granulator (manufacturer: chongqing English lattice, model: WBG-2G), setting air inlet temperature at 60 ℃, air quantity at 40 m/h and atomization pressure at 1.5MPa, spraying the dispersion liquid prepared in the second step into the fluidized bed granulator to prepare particles, wherein the water content of the particles is required to be less than or equal to 1.5%;

Comparative example 2: glycerol-free gelatin in prescription

The first step: dissolving sodium caprate in purified water to form a 5% (w/w) sodium caprate aqueous solution;

and a second step of: adding azilsartan into the sodium caprate aqueous solution prepared in the first step, and stirring at a high speed for 2min by using a homogenizer at a rotating speed of 10000r/min to uniformly disperse the azilsartan in the sodium caprate aqueous solution to form a dispersion;

and a third step of: adding filler and microcrystalline wax into a fluidized bed granulator (manufacturer: chongqing English, model: WBG-2G), setting air inlet temperature at 60 ℃, air quantity at 40 m/h, atomization pressure at 1.5MPa and liquid inlet speed at 12rpm, spraying the dispersion liquid prepared in the second step into the fluidized bed granulator to prepare particles, wherein the water content of the particles is required to be less than or equal to 1.5%;

Comparative example 3: no microcrystalline wax in the prescription

and a third step of: adding filler into a fluidized bed granulator (manufacturer: chongqing English, model: WBG-2G), setting air inlet temperature at 60 ℃, air quantity at 40 m/h, atomizing pressure at 1.5MPa, liquid inlet speed at 12rpm, spraying emulsion liquid prepared in the second step into the fluidized bed granulator to prepare particles, wherein the water content of the particles is required to be less than or equal to 1.5%;

Comparative example 4:

1000 tablets are prepared according to the preparation method of the technical scheme.

Comparative example 5:

Test example 1: release study

The release rates of the products of examples 1 to 5 and comparative examples 1 to 5 in artificial gastric juice and artificial intestinal juice, respectively, were measured and the results are recorded in Table 1.

Instrument name: full-automatic digestion test system

Instrument brand: sotax

The testing method comprises the following steps: reference is made to the United states pharmacopoeia dissolution assay, flow through Chi Fa, open loop.

Dissolution medium: artificial gastric juice and artificial intestinal juice.

Artificial gastric juice: taking 16.4mL of dilute hydrochloric acid, adding 800mL of water and 10g of pepsin, and diluting to 1000mL; wherein the diluted hydrochloric acid is diluted to 1000mL by adding water into 234mL of concentrated hydrochloric acid, and 9.5% -10.5% of diluted hydrochloric acid is obtained.

Artificial intestinal juice: dissolving 6.8g of monopotassium phosphate in 500mL of water, and regulating the pH to 6.8 by using 0.1mol/L sodium hydroxide solution; taking 10g of pancreatin, adding water to dissolve, and diluting with water to 1000 mL.

Sampling time: 2h,4h,6h,8h,10h (artificial gastric juice test 1-2h, artificial intestinal juice test 2-10 h).

Rotational speed: 50rpm.

The testing method comprises the following steps: HPLC chromatography.

Detection wavelength: 250nm.

Preparing a reference substance solution: about 10mg of azilsartan reference substance is precisely weighed, placed in a 200mL measuring flask, dissolved and diluted to a scale by adding methanol, and shaken uniformly to serve as a reference substance solution.

TABLE 1 results of the product Release test for examples 1-5 and comparative examples 1-5

FIG. 1 comparative graphs of the release profiles of the products of examples 1-5 and comparative examples 1-5

Table 1 data and fig. 1 illustrate: the azilsartan tablets of examples 1-5 prepared by adopting the technical scheme of the invention have basically linear release behaviors in artificial gastric juice and artificial intestinal juice, and are completely released finally; however, the release behavior of the azilsartan medoxomil tablets obtained in comparative examples 2, 4 and 5 is difficult to achieve a linear state, and the release is incomplete, which is not completely free from the problem of comparative example 1. The technical proposal is adopted, and the addition of 6 to 10 percent of sodium caprate and 3 to 9 percent of glycerogelatin can maintain the stable release of the medicine in artificial gastric juice and artificial intestinal juice, thus achieving the purpose of lasting effect.

Test example 2: stability study

The products of examples 1-5 and comparative examples 1-5 were respectively aluminum-plastic packaged, each sample was aluminum-plastic 10 plates, and the package specification was 12 pieces/plate, and the products were placed in an acceleration stability test box under the test conditions of 40℃and 75% humidity, and were sampled at the ends of 1 st, 2 nd, 3 rd and 6 th months, 2 plates were sampled at each time point, and the relevant substances were measured (total impurities required by the shelf life standard were not more than 1.5%), and the results are shown in Table 2.

TABLE 2 determination of total impurities/% for the products of examples 1-5 and comparative examples 1-5

Table 2 data illustrates: in the accelerated stability test, the growth rate of related substances of the products of examples 1-5 and comparative examples 1-2 prepared by adopting the technical scheme of the invention is obviously slower than that of the products of comparative examples 3-5, namely the products of examples 1-5 and comparative examples 1-2 are obviously better than that of the products of comparative examples 3-5, which proves that the addition of microcrystalline wax in the dosage range of 2-9% in the technical scheme can obviously improve the stability of the azilsartan tablet and reduce the adverse effect of impurities generated by drug degradation on the health of patients.

Claims

1. The pharmaceutical composition of azilsartan is characterized by comprising 20% of azilsartan, 6-10% of sodium caprate, 3-9% of glycerogelatin, 40-62.5% of filler, 2-9% of microcrystalline wax, 6-10% of crosslinked povidone and 0.5-2% of magnesium stearate.

2. The pharmaceutical composition according to claim 1, characterized in that the azilsartan composition comprises 20% of azilsartan, 7-9% of sodium caprate, 4-8% of glycerogelatin, 46.8-57.2% of filler, 4-6% of microcrystalline wax, 7-9% of crospovidone and 0.8-1.2% of magnesium stearate.

3. The pharmaceutical composition according to claim 1, characterized in that it comprises 20% of azilsartan, 8% of sodium caprate, 6% of glycerogelatin, 52% of filler, 5% of microcrystalline wax, 8% of crospovidone and 1% of magnesium stearate.

4. Pharmaceutical composition according to claim 1, characterized in that glycerogelatin is formed from 20% glycerol, 2% gelatin with water to 100% and heated.

5. Pharmaceutical composition according to claim 1, characterized in that the filler is selected from lactose-microcrystalline cellulose complexes, mannitol-microcrystalline cellulose complexes.

6. A process for preparing the pharmaceutical composition of claim 1, characterized in that:

the first step: dissolving sodium caprate in purified water to form sodium caprate aqueous solution, adding glycerogelatin, and stirring to form colloidal liquid;

and a second step of: adding azilsartan into the colloidal liquid prepared in the first step, and stirring at a high speed by using a homogenizer to uniformly disperse the azilsartan to obtain emulsion;

and a third step of: adding filler and microcrystalline wax into a fluid bed granulator, and spraying the emulsion liquid prepared in the second step into the fluid bed granulator to prepare granules;

fifth step: adding the crosslinked povidone and magnesium stearate into the granulated particles, and uniformly mixing;

sixth step: tabletting the granules.

7. The method of manufacturing according to claim 6, wherein:

and a third step of: adding filler and microcrystalline wax into a fluid bed granulator, setting the air inlet temperature to be 60 ℃, the air quantity to be 40 m/h, the atomization pressure to be 1.5MPa, the liquid inlet speed to be 12rpm, and spraying the emulsion liquid prepared in the second step into the fluid bed granulator to prepare particles, wherein the water content of the particles is required to be less than or equal to 1.5%;