CN111643461A

CN111643461A - Tablet for treating hypertension and preparation method thereof

Info

Publication number: CN111643461A
Application number: CN201910160855.3A
Authority: CN
Inventors: 张贵民; 郝贵周; 庞晓娟
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2019-03-04
Filing date: 2019-03-04
Publication date: 2020-09-11
Anticipated expiration: 2039-03-04
Also published as: CN111643461B

Abstract

The invention belongs to the technical field of medicinal preparations, and particularly relates to a tablet for treating hypertension and a preparation method thereof. The tablet for treating hypertension comprises a solid dispersion prepared from azilsartan and polyethylene glycol, a filler, a disintegrating agent and a lubricant; the tablet is prepared by the following method: adding azilsartan into polyethylene glycol melt, stirring uniformly, adding into filler and disintegrant, stirring and granulating, adding lubricant into the prepared granules, mixing and tabletting. Compared with the prior art, the invention has the advantages of simple preparation process, better dissolution rate and stable and controllable quality.

Description

Tablet for treating hypertension and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to a tablet for treating hypertension and a preparation method thereof.

Background

Azilsartan is an angiotensin II receptor antagonist drug for treating hypertension, is mostly used for treating hypertension, and is the only angiotensin II receptor antagonist (sartan) drug in the end-stage clinic at present. The medicine is marketed by Wutian pharmaceutical company in Japan in 2012, and the curative effect of the medicine in the clinical stage is obvious.

Azilsartan belongs to a poorly soluble drug, and has a solubility in water of less than 9 mug/ml. The structural formula is as follows:

the bioavailability of a drug in the body is greatly affected by the dissolution of the drug. Azilsartan is almost insoluble in water and is a poorly soluble drug, and when the azilsartan is prepared into a pharmaceutical preparation, micronized azilsartan particles are usually adopted, and the particle size is controlled to be below 15 mu m, so that the absorption of the drug in a body and the clinical curative effect of the drug are ensured.

CN101528262A discloses a stable pharmaceutical composition with excellent dissolution property, which contains a low melting point oily and no substance, and a low viscosity adhesive, and is mainly characterized in that the low viscosity adhesive is used to improve the dissolution of azilsartan, but the low viscosity adhesive is used to improve the in vitro dissolution of azilsartan, which is often limited.

CN103705510A discloses a preparation method of an azilsartan solid composition. The preparation method comprises the steps of preparing the azilsartan into a suspension solution, adding the suspension solution into a diluent of the pharmaceutical composition in a spraying mode after wet grinding, and drying to prepare particles and powder of the azilsartan pharmaceutical composition; finally, the granules and the powder are prepared into the azilsartan medicinal minimum dosage unit. Solves the problem that the impurity is increased sharply when the azilsartan particles are prepared by a conventional crushing method, but the process is more complex.

CN102895205A discloses a fast-dissolving azilsartan pharmaceutical preparation, the particle size D90 of azilsartan is less than or equal to 20 mu m, the method improves the dissolution by controlling the particle size, but the dissolution rate still needs to be improved, and the stability of micronized active ingredients is reduced.

CN102793680A discloses an azilsartan solid dispersion, a preparation method and a pharmaceutical composition thereof, wherein the solid dispersion system is prepared by azilsartan and pharmaceutically acceptable carrier materials thereof, and the dissolution rate of the tablets prepared by the method is still low.

CN106333930A discloses an azilsartan pellet tablet and a preparation method thereof, wherein the azilsartan pellet tablet is prepared by tabletting azilsartan pellets and pharmaceutical excipients, so as to improve the dissolution rate and bioavailability of the drug, but in the preparation process of the fluidized bed pellet tablet, the drug may be loaded on the pellet core in the form of crystal transition, partial crystal transition or amorphous crystal, which affects the exertion of drug effect.

CN104306344A discloses an azilsartan tablet and a preparation method thereof, wherein the azilsartan tablet is prepared by compressing azilsartan, microcrystalline cellulose, KG1000 and other pharmaceutically acceptable auxiliary materials by a dry direct compression process, and the dissolution rate of the prepared tablet needs to be improved.

CN104523632A discloses an azilsartan tablet, which is prepared by dissolving azilsartan and povidone in diethylene glycol ethyl ether, adding silicon dioxide for adsorption, and then mixing with other auxiliary materials and directly pressing. However, the azilsartan tablets directly pressed by powder are difficult to ensure the mixing uniformity although the process is simple, and the problem of in vitro dissolution is not substantially solved because the layering phenomenon is easily generated in the tabletting process.

CN108553433A, selected from Azilsartan, diluent (I), diluent (II), diluent (III), stabilizer, disintegrant, lubricant and adhesive. The prepared azilsartan medoxomil tablet has smooth appearance, good hardness, small tablet weight difference and uniform content, but the process is complex, and the in-vitro dissolution needs to be improved.

So far, the problem of poor dissolution rate of azilsartan still cannot be solved by adopting pharmaceutic adjuvants and preparation technologies in the prior art. The prepared azilsartan tablets still have the problems of poor stability, improved safety and the like.

Disclosure of Invention

Aiming at the defects of the prior art, the inventor finds that the drug dispersion degree and the hydrophilicity of the azilsartan can be improved by adopting a solid dispersion melt granulation technology, and further finds that the solid dispersion, a mixture of specific fillers, namely lactose and corn starch, and a low-substituted hydroxypropyl cellulose serving as a disintegrant are mixed and pressed into tablets, so that the water penetration into the tablets can be further accelerated, the disintegration is accelerated, and the dissolution rate and the stability of the azilsartan are improved.

Specifically, the invention is realized by the following technologies:

a solid dispersion for treating hypertension, which comprises a solid dispersion prepared from azilsartan and polyethylene glycol, wherein the weight ratio of the azilsartan to the polyethylene glycol is 1: 1.2-1.8.

The polyethylene glycol specification is selected from one or more of PEG 200-8000.

Preferably, the polyethylene glycol is one or more of PEG 1500-6000.

The solid dispersion for treating hypertension can be further prepared into dosage forms such as tablets, capsules or granules according to textbooks and/or other methods in the prior art, and the original characteristics are still maintained.

The invention further provides a tablet for treating hypertension, which comprises the solid dispersion prepared from the azilsartan and polyethylene glycol, a filler, a disintegrant and a lubricant.

The filler is one or more of lactose, corn starch, microcrystalline cellulose, sucrose, pregelatinized starch, mannitol, and sorbitol.

The filler is one or more of lactose, corn starch and microcrystalline cellulose.

Preferably, the filler is a mixture of lactose and corn starch.

Further preferably, the weight ratio of the lactose to the corn starch is 1: 2-3.

More preferably, the weight ratio of lactose to corn starch is 1: 2.5.

The disintegrant is low-substituted hydroxypropyl cellulose.

The lubricant is magnesium stearate.

The tablet for treating hypertension specifically comprises the following components in parts by weight:

preferably, the tablet for treating hypertension specifically comprises the following components in parts by weight:

the invention also provides a preparation method of the tablet for treating hypertension, which comprises the following steps: adding azilsartan into polyethylene glycol melt, stirring, adding filler and disintegrant into the obtained suspension melt, stirring, granulating, adding lubricant, mixing, and tabletting.

Preferably, the preparation method of the tablet for treating hypertension is prepared by the following steps: adding azilsartan into the polyethylene glycol melt, and uniformly stirring to obtain a suspension melt; weighing the filler and the disintegrant according to the prescription amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding the lubricant into the prepared granules, mixing and tabletting.

Compared with the prior art, the invention has the advantages of simple preparation process, rapid tablet disintegration, rapid drug dissolution and better stability.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.

Example 1

1) Prescription

2) Preparation method

Adding azilsartan into the melt of polyethylene glycol 4000 and PEG1500, and uniformly stirring to obtain a suspension melt;

weighing the corn starch, the lactose and the low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding the magnesium stearate into the prepared granules, mixing and tabletting.

Example 2

1) Prescription

2) Preparation method

Adding azilsartan into the polyethylene glycol 2000 molten liquid, and uniformly stirring to obtain a suspension molten liquid;

Example 3

1) Prescription

2) Preparation method

Adding azilsartan into polyethylene glycol 6000 melt, and uniformly stirring to obtain suspension melt;

Example 4

1) Prescription

2) Preparation method

Adding azilsartan into polyethylene glycol 8000 melt, and stirring uniformly to obtain suspension melt;

Example 5

1) Prescription

2) Preparation method

Adding azilsartan into the polyethylene glycol 200 melt, and uniformly stirring to obtain a suspension melt;

Example 6

1) Prescription

2) Preparation method

Example 7

1) Prescription

2) Preparation method

Adding azilsartan into polyethylene glycol 10000 molten liquid, and uniformly stirring to obtain suspension molten liquid;

Example 8

1) Prescription

2) Preparation method

Example 9

1) Prescription

2) Preparation method

Example 10

1) Prescription

2) Preparation method

weighing microcrystalline cellulose and croscarmellose sodium in the prescribed amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding talcum powder into the prepared granules, mixing, and tabletting.

Example 11

1) Prescription

2) Preparation method

weighing lactose and low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing, and tabletting.

Example 12

1) Prescription

2) Preparation method

weighing the corn starch and the low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing and tabletting.

Example 13

1) Prescription

2) Preparation method

weighing the starch and the low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing, and tabletting.

Example 14

1) Prescription

2) Preparation method

Example 15

1) Prescription

2) Preparation method

weighing mannitol and low-substituted hydroxypropyl cellulose in the formula amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing, and tabletting.

Example 16

1) Prescription

2) Preparation method

weighing sorbitol and low-substituted hydroxypropyl cellulose in the formula amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing, and tabletting.

Example 17

1) Prescription

2) Preparation method

weighing sucrose and low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing, and tabletting.

Example 18

1) Prescription

2) Preparation method

weighing the pregelatinized starch and the low-substituted hydroxypropyl cellulose in the formula amount, uniformly mixing, adding the suspension melt, stirring and granulating, adding magnesium stearate into the prepared granules, mixing, and tabletting.

Comparative example 1

1) Prescription

2) Preparation method

Weighing the azilsartan and povidone PVP-K30 according to the formula amount, adding 400mL of methanol, stirring until the azilsartan and the povidone-PVP-K30 are dissolved, transferring the azilsartan and the povidone-PVP-K30 into a vacuum drying oven, keeping the temperature at 40 ℃, drying under reduced pressure for 24 hours, then crushing, and sieving by a 60-mesh sieve to obtain the azilsartan solid dispersion, wherein the solid dispersion according to the formula amount and auxiliary materials except magnesium stearate are weighed. After uniformly mixing, sieving by a 30-mesh sieve, mixing again, adding the magnesium stearate in the formula amount, uniformly mixing, punching by using a 9.5mm punching die, and tabletting the mixture under the weight of 350mg and the pressure of 7-9 kg.

Comparative example 2

1) Prescription

2) Preparation method

Adding 400mL of methanol into azilsartan and polyethylene glycol 6000, stirring until the azilsartan and the polyethylene glycol are dissolved, transferring the mixture into a vacuum drying oven, keeping the temperature at 40 ℃, drying under reduced pressure for 24 hours, then crushing, and sieving by a 60-mesh sieve to obtain an azilsartan solid dispersion;

weighing the corn starch, the lactose and the low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing with the azilsartan solid dispersion, adding magnesium stearate into the prepared granules, mixing and tabletting.

Comparative example 3

1) Prescription

2) Preparation method

Adding azilsartan into the povidone melt, and uniformly stirring to obtain a suspension melt;

Comparative example 4

1) Prescription

2) Preparation method

The azilsartan is subjected to jet milling, the milling pressure is 0.4Mpa, D90 is 38 micrometers, the azilsartan is weighed according to the prescription amount, then the azilsartan and pregelatinized starch KG1000 according to the prescription amount are uniformly mixed in a multi-item motion mixer, then the crosslinked povidone, lactose 100 and talcum powder according to the prescription amount are uniformly mixed, and the azilsartan is prepared by pressing the azilsartan and the pregelatinized starch KG1000 according to the prescription amount on a rotary tablet press through a direct tabletting process.

Comparative example 5

1) Prescription

2) Preparation method

Azilsartan is micronized, D90 is controlled to be less than 20 micrometers, and the azilsartan is weighed according to the prescription; sieving anhydrous lactose 21AN with 65 mesh sieve, removing granules, and weighing according to the prescription; the micronized azilsartan and the anhydrous lactose are uniformly mixed, the anhydrous lactose 24AN, the magnesium stearate, the sodium carboxymethyl starch, the low-substituted hydroxypropyl cellulose and the silicon dioxide with the prescription amount are added, and the mixture is uniformly mixed and tabletted.

Verification examples

1. Dissolution testing

The azilsartan formulations prepared in examples 1 to 18 of the present invention and comparative examples 1 to 5 were left for a long period of 12 months at 25 ℃ and 60% RH, and the dissolution rates were measured for 0 month and 12 months, respectively.

The examination method is the second method specified in Chinese pharmacopoeia 2010 edition, taking the product, according to the determination method of dissolution rate and release rate (second method of general rule 0931), taking 900ml of phosphate buffer solution with pH of 5.5 as dissolution medium, rotating speed of 50 r/min, operating according to the method, taking 10ml of solution after 5min, filtering, and taking the subsequent filtrate as the test solution. According to the chromatographic conditions under the content determination item, respectively taking 20 μ L of the test solution and the reference solution, respectively injecting into a liquid chromatograph, recording the chromatogram, and calculating the dissolution amount of each tablet.

2. Detection of related substances

The azilsartan formulations prepared in examples 1 to 18 of the present invention and comparative examples 1 to 5 were left for a long period of 12 months at 25 ℃ and 60% RH, and the substances of interest were measured for 0 month and 12 months, respectively.

Taking the product, grinding, taking a proper amount of fine powder (about 10mg of azilsartan), placing the fine powder into a 20ml brown measuring flask, adding methanol to dissolve and dilute the fine powder to a scale, shaking up, filtering, and taking a subsequent filtrate as a test solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml brown measuring flask, adding methanol to dilute the test solution to a scale, and shaking the test solution uniformly to serve as a control solution. Performing high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia). Octadecylsilane chemically bonded silica is used as a filling agent; mobile phase a was pH3.0 buffer (1.36 g potassium dihydrogen phosphate and 1.74g sodium pentane sulfonate were weighed, dissolved by adding 1000ml water, pH adjusted to 3.0 with phosphoric acid), mobile phase B was acetonitrile, linear gradient elution was performed according to the table below, detection wavelength was 251 nm. In addition, an appropriate amount of impurity 1, impurity 2, impurity 3, impurity 4, impurity 5 and azilsartan reference substance are respectively weighed, and methanol is added for dissolving and diluting to prepare a solution containing 0.5mg of azilsartan and 5 micrograms of known impurities per 1ml, and the solution is used as a system test solution; and precisely measuring 10 mu l of system test solution, injecting the system test solution into a liquid chromatograph, recording a chromatogram, and sequentially outputting peaks of the impurity 2, the impurity 1, the azilsartan, the impurity 3, the impurity 5 and the impurity 4, wherein the separation degree among the peaks of the substances meets the requirement. Injecting 10 mul of the contrast solution into a liquid chromatograph, and adjusting the detection sensitivity to ensure that the peak height of the main component chromatographic peak is 10-25% of the full scale; then precisely measuring 10 μ L of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram. After deducting the solvent peak, if there is impurity peak in the chromatogram of the sample solution, the peak area of the largest single unknown impurity should not be larger than 0.2 times (0.2%) of the main peak area of the control solution.

Table 1 test results of azilsartan tablets left for 0 month

Table 2 test results of azilsartan tablets left for 12 months

Claims

1. The solid dispersion for treating hypertension is characterized by comprising a solid dispersion prepared from azilsartan and polyethylene glycol, wherein the weight ratio of the azilsartan to the polyethylene glycol is 1: 1.2-1.8.

2. The solid dispersion for treating hypertension according to claim 1, wherein the polyethylene glycol specification is selected from one or more of PEG 200-8000.

3. The solid dispersion for treating hypertension according to claim 2, wherein the polyethylene glycol is one of PEG 1500-6000.

4. A tablet comprising the solid dispersion for treating hypertension according to claim 1, which comprises a solid dispersion prepared from azilsartan and polyethylene glycol, a filler, a disintegrant, and a lubricant.

5. The tablet according to claim 4, wherein the filler is one or more of lactose, corn starch, microcrystalline cellulose, sucrose, pregelatinized starch, mannitol, and sorbitol.

6. The tablet of claim 5, wherein the filler is a mixture of lactose and corn starch.

7. The tablet according to claim 6, wherein the weight ratio of lactose to corn starch is 1: 2-3.

8. The tablet according to claim 4, wherein the disintegrant is low-substituted hydroxypropylcellulose.

9. The tablet according to claim 4, wherein the tablet comprises the following components in parts by weight:

10. a process for preparing a tablet comprising the solid dispersion for hypertension treatment according to any one of claims 4 to 9, which is prepared by the following process: adding azilsartan into polyethylene glycol melt, stirring uniformly, adding the obtained suspension melt into filler and disintegrant, stirring, granulating, adding lubricant, mixing and tabletting.