CN106913545B

CN106913545B - Glimepiride tablet and preparation method thereof

Info

Publication number: CN106913545B
Application number: CN201511003500.1A
Authority: CN
Inventors: 张贵民; 丁兵; 陈美丽; 臧营
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2015-12-28
Filing date: 2015-12-28
Publication date: 2021-06-22
Anticipated expiration: 2035-12-28
Also published as: CN106913545A

Abstract

The invention relates to a glimepiride tablet and a preparation method thereof, wherein the tablet is prepared by the following method, glimepiride is dissolved in sodium hydroxide solution, mesoporous silicon dioxide is added, the mixture is uniformly stirred, glacial acetic acid is added into the solution under the stirring condition, the compound of the glimepiride and the mesoporous silicon dioxide is separated out, filtered and dried, then the mixture is mixed with a filler and a disintegrating agent, granulated, dried, a lubricant is added into dry granules, and the tablet is prepared by tabletting. Compared with the prior art, the tablet prepared by the invention is fast dissolved in water, has simple preparation process and is suitable for industrial production.

Description

Glimepiride tablet and preparation method thereof

Technical Field

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

Background

Glimepiride is a novel sulfonylurea hypoglycemic agent, the chemical name of which is 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido) ethyl ] benzenesulfonyl ] -3- (trans-4-methylcyclohexyl) urea, and the structural formula is as follows:

the molecular formula is as follows: c₂₄H₃₄N₄O₅S molecular weight: 490.62

Glimepiride was developed by Hoechst Marion Roussel (HMR) in germany, first marketed in sweden under the trade name Amaryl in 1995 for 9 months and approved by the FDA for entry into the us market in 1996 for the treatment of type ii diabetes mellitus, which is uncontrollable in diet and exercise, and is the first sulfonylurea drug approved by the FDA to be used with insulin. The action time of the medicine and a receptor is short, so that the islet cord secretion time is shortened, the medicine has a strong insulin-saving effect, and the secondary failure of islet cells can be overcome to a certain extent. The glimepiride has the advantages of high efficiency, long acting, small dosage, small side effect and the like, and is the best sulfonylurea hypoglycemic agent in clinical evaluation at present.

Glimepiride is a poorly soluble drug, but its solubility in alkaline media tends to increase.

After the oral solid preparation enters the body, the oral solid preparation can be absorbed by the organism through the biological membrane after the oral solid preparation is dissolved out. However, because the glimepiride is a poorly soluble drug and is almost insoluble in water, the problem of low dissolution rate or even unqualified glimepiride in the actual production of the oral solid preparation of the glimepiride is often encountered; and because the content of the glimepiride in the preparation is low, the glimepiride is difficult to be fully mixed in the preparation process, and the problems of high and low content and large dissolution difference among tablets are often existed in the dissolution rate detection. When quick-acting and high-efficiency preparations are urgently needed in clinic, the problem of low bioavailability of insoluble medicines caused by low solubility and slow dissolution is always a big problem in pharmaceutical industry.

CN102379855A discloses a glimepiride dispersible tablet and a preparation method thereof, the dispersible tablet is prepared by micronizing the drug glimepiride to control the particle diameter below 10 μm and adding auxiliary materials.

CN102512388B provides a glimepiride orally disintegrating tablet, which is prepared by adopting an inclusion technology, the glimepiride is included by polypropylene resin S100, and the prepared tablet is quickly disintegrated but has poor dissolution effect.

CN102600106A relates to a glimepiride nanoparticle capsule and a preparation method thereof, which can effectively solve the problems of poor water solubility, short half-life period, instability, low bioavailability and poor targeted treatment effect of glimepiride, and the technical proposal for solving the problems is as follows: calculated by weight ratio: 1 part of glimepiride, 1-30 parts of surfactant and 3-60 parts of freeze-drying protective agent; the preparation method comprises the steps of dissolving glimepiride or a mixture of glimepiride and the surfactant in an organic solvent to prepare an initial suspension, and obtaining the suspension with the average particle size of 300 +/-60 nm by adopting a high-pressure homogenization method or an emulsification diffusion method; freeze drying and sieving the nanometer suspension, and filling the nanometer suspension into a capsule shell. The preparation process is complicated and a large amount of surfactant is used.

In the prior art, the dissolution rate of the medicament is improved by methods such as micronization of glimepiride, co-grinding and crushing with water-soluble or hydrophilic auxiliary materials or addition of a large amount of surfactant and the like. But the drug is easy to aggregate after micronization, and the uniform mixing of the drug is difficult to ensure; the addition of large amounts of surfactants leads to increased gastrointestinal side effects.

Therefore, a nontoxic method is sought for increasing the dissolution rate of glimepiride, and a method for improving the dissolution rate of glimepiride is imminent.

Disclosure of Invention

For the poorly soluble drug glimepiride, the dissolution rate can be naturally improved if the solubility can be improved, and the method for improving the solubility is most commonly used for reducing the particle size of the raw material. The inventors first considered that glimepiride is pulverized, but even if the powder is pulverized to D90 ═ 20 μm, it is still difficult to dissolve rapidly. The inventor adopts a multiple micronization technology, the particle size is crushed until the D90 is about 450nm, the dissolution rate of the preparation is 80% in 3min, the dissolution is still incomplete, and the quick effect cannot be achieved.

Specifically, the invention is realized by the following technologies:

the glimepiride tablet is prepared by the following method, glimepiride is dissolved in sodium hydroxide solution, mesoporous silicon dioxide is added, the mixture is uniformly stirred, glacial acetic acid is added into the solution under the stirring condition, a glimepiride and mesoporous silicon dioxide compound is separated out, filtered and dried, then the mixture is mixed with a filling agent and a disintegrating agent, the mixture is granulated and dried, a lubricating agent is added into dry granules, and the glimepiride tablet is formed by tabletting.

The concentration of the sodium hydroxide solution is 40-55% (m/v); preferably, the concentration of the sodium hydroxide solution is 50%.

The weight ratio of the glimepiride to the sodium hydroxide solution is 1: 4-6; preferably, the weight ratio is 1: 5.

The weight ratio of the glimepiride to the mesoporous silica is 1: 0.3-0.5; preferably, the weight ratio is 1: 0.4.

The weight ratio of the glimepiride to the glacial acetic acid is 1: 3-5; preferably, the weight ratio is 1: 4;

The filler is one or more of lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch and starch-lactose compound.

The disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.

The lubricant is one or more of magnesium stearate, sodium stearyl fumarate and zinc stearate.

Compared with the prior art, the invention has simple preparation process and rapid drug dissolution, and is suitable for industrial production.

Detailed Description

The following examples further illustrate the benefits of the present invention, and the examples are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art in light of the present disclosure are intended to be included within the scope of the present invention.

Example 1

The preparation process comprises the following steps:

dissolving glimepiride in sodium hydroxide solution, adding mesoporous silicon dioxide, stirring uniformly, adding glacial acetic acid into the solution under the condition of stirring, separating out a glimepiride and mesoporous silicon dioxide compound, filtering, drying at 60 ℃, then uniformly mixing with mixed powder of microcrystalline cellulose and sodium carboxymethyl starch, adding magnesium stearate, mixing, and tabletting.

Example 2

The preparation process comprises the following steps:

dissolving glimepiride in sodium hydroxide solution, adding mesoporous silicon dioxide, stirring uniformly, adding glacial acetic acid into the solution under the stirring condition, separating out a glimepiride and mesoporous silicon dioxide compound, filtering, drying at 65 ℃, then uniformly mixing with mixed powder of microcrystalline cellulose and crospovidone, adding magnesium stearate, mixing, and tabletting.

Example 3

The preparation process comprises the following steps:

Comparative example 1

The preparation process comprises the following steps:

dissolving glimepiride in sodium hydroxide solution, stirring, adding glacial acetic acid into the solution under stirring to precipitate glimepiride, filtering, drying at 60 deg.C, mixing with mixed powder of microcrystalline cellulose and crospovidone, adding magnesium stearate, mixing, and tabletting.

Comparative example 2

The preparation process comprises the following steps:

jet milling glimepiride to D90 ═ 15.3 μm, mixing with microcrystalline cellulose and crospovidone, adding magnesium stearate, mixing, and tabletting.

Comparative example 3

The preparation process comprises the following steps:

jet milling glimepiride for 3 times, D90-450 nm, mixing with microcrystalline cellulose and crospovidone, adding magnesium stearate, mixing, and tabletting.

Comparative example 4

The preparation process comprises the following steps:

dispersing polyacrylic resin S100 in 95% ethanol of a prescribed amount, adding glimepiride, stirring for dissolving, performing rotary evaporation at 60 ℃ to obtain a glimepiride inclusion compound, uniformly mixing with mannitol, ethyl cellulose and croscarmellose sodium, preparing a soft material by using a 10% pregelatinized starch solution, granulating by using a 20-mesh sieve, drying at 60 ℃, granulating by using a 24-mesh sieve, adding croscarmellose sodium and magnesium stearate, mixing, and tabletting.

Verification examples

And (4) determining the dissolution rate. In chromatographic conditions and system applicability tests, octadecylsilane chemically bonded silica is used as a filler, 0.1% sodium dihydrogen phosphate solution-acetonitrile (1:1, the pH value is adjusted to 3.5 by using 20% phosphoric acid) is used as a mobile phase, the detection wavelength is 228nm, the column temperature is set to be 25 ℃, the flow rate is adjusted to ensure that the retention time of a glimepiride peak is about 10 minutes, the number of theoretical plates is not less than 3000 calculated according to the glimepiride peak, and a tailing factor is not more than 1.5.

Taking the product, measuring by dissolution method (Paddle method), taking 900ml of disodium hydrogen phosphate-citric acid buffer solution (pH7.5) as solvent, rotating at 50 rpm, filtering at 3min, discarding at least 10ml of primary filtrate, taking appropriate amount of secondary filtrate, diluting with dissolving medium to obtain solution containing 1.1 μ g per 1ml, and using as sample solution. And precisely weighing 22mg of glimepiride reference substance, placing the glimepiride reference substance in a 100ml measuring flask, adding acetonitrile to dissolve and dilute the glimepiride reference substance to a scale, shaking up, precisely weighing 2ml, placing the glimepiride reference substance in the 100ml measuring flask, adding 8ml of acetonitrile, then adding a dissolution medium to dilute the glimepiride reference substance to the scale, shaking up, precisely weighing 10ml, placing the glimepiride reference substance in a 20ml measuring flask, adding the dissolution medium to dilute the glimepiride reference substance to the scale, and shaking up to obtain. Precisely measuring the two solutions by 50 μ l each, injecting into a liquid chromatograph, and recording chromatogram; the limit of the dissolution amount of each tablet calculated by peak area according to an external standard method is 75% of the marked amount and is in line with the regulation.

TABLE 1 measurement results of examples

Examples	0 day dissolution (%)	Dissolution after 6 months accelerated at 40 ℃ with 75% RH (%)
			Example 1	98.2	98.3
Example 2	97.9	98.5
			Example 3	98.3	98.1
Comparative example 1	66.9	63.1
			Comparative example 2	45.6	41.7
Comparative example 3	80.0	78.7
			Comparative example 4	79.5	76.8

As can be seen from Table 1, the drug in the examples of the present invention dissolves rapidly, and substantially completely dissolves in 3 min; in comparative example 1, the dissolution effect is poor without adding mesoporous silica gel; in comparative example 2, the raw material was jet-milled using the prior art, and the dissolution was slowest due to poor drug solubility; compared with the example 3, the dissolution rate is improved and still slower by adopting the prior art and carrying out airflow pulverization on the raw materials for 3 times; comparative example 4, which was prepared by inclusion technique, and in which glimepiride was included with polypropylene resin S100, the tablet prepared disintegrated rapidly, but the dissolution effect was not good.

Claims

1. The glimepiride tablet is characterized by comprising glimepiride, mesoporous silicon dioxide, a filler, a disintegrant and a lubricant; the filler is one or more of lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch and a starch-lactose compound; the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate and zinc stearate;

the preparation method of the glimepiride tablet comprises the steps of dissolving glimepiride in a sodium hydroxide solution, adding mesoporous silicon dioxide, uniformly stirring, adding glacial acetic acid into the solution under the stirring condition, separating out a glimepiride and mesoporous silicon dioxide compound, filtering, drying, then mixing with a filling agent and a disintegrating agent, granulating, drying, adding a lubricating agent into dry granules, and tabletting; the weight ratio of the glimepiride to the mesoporous silica is 1: 0.3-0.5.

2. The glimepiride tablet according to claim 1, wherein the weight ratio of glimepiride to mesoporous silica is 1: 0.4.

3. The method for preparing a glimepiride tablet according to claim 1, wherein the concentration of the sodium hydroxide solution is 40-55%.

4. The method for preparing a glimepiride tablet according to claim 1, wherein the concentration of the sodium hydroxide solution is 50%.

5. The method for preparing a glimepiride tablet according to claim 1, wherein the weight ratio of the glimepiride to the sodium hydroxide solution is 1: 4-6.

6. The method for preparing a glimepiride tablet according to claim 1, wherein the weight ratio of the glimepiride to the sodium hydroxide solution is 1: 5.

7. The method for preparing a glimepiride tablet according to claim 1, wherein the weight ratio of glimepiride to glacial acetic acid is 1: 3-5.

8. The method for preparing a glimepiride tablet according to claim 1, wherein the weight ratio of glimepiride to glacial acetic acid is 1: 4.