KR20050045630A - Pharmaceutical composition and manufacturing process containing micronized glimepiride drug - Google Patents

Abstract

The present invention relates to a formulation containing glymepiride finely divided into particles having an average particle size of 5 μm or less, and a method of finely granulating glymepiride. And effectively improve the dissolution rate to increase the bioavailability of the drug.

Description

Micronized glimepiride, a method of micronization, and a preparation containing the same {Pharmaceutical composition and manufacturing process containing micronized glimepiride drug}

The present invention relates to glymepiride finely divided into particles having an average particle size of 5 mu m or less, a method of finely granulating glymepiride, and a formulation containing finely divided glymepiride.

In the present invention, the glymepiride formulation prepared by granulating the average particle size of the poorly soluble glymepiride to be 5 μm or less can effectively improve the solubility and dissolution rate, thereby increasing the bioavailability of the drug.

German Patent No. 2951135 describes a method for preparing Glimepiride.

Glymepyride described in the German patent is a sulfonyl urea compound, and the compound name is trans-3-ethyl-2,5-dihydro-4-methyl-N- [2- [4-[[[[(4-methylcyclo hexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl] -2-oxo-1-carboxamide is -1H- pyrrole (molecular weight 490.63), indicated an insulin secretion promoting action trade name Amaryl current (Amaryl ^R) It is a type 2 diabetes drug marketed by the company.

In general, drugs used to treat diabetes require rapid expression of the effect of the drug in the human body to maintain normal blood glucose levels in the living body, and it is necessary to formulate the drug to rapidly reach the effective concentration in the blood. In particular, poorly soluble drugs, such as the drug of the present invention is commonly used for solubilization of drugs, microemulsions and solid dispersions through the grinding of drug particles, the addition of surfactants, etc. to improve the dissolution rate.

However, glymepiride formulations prepared according to the method described in the German patent or commercially available glymepiride raw materials prepared in a conventional manner have an average solubility of 5.14 µg / ml in a buffer of pH 7.8 and 65.71% (1 hour). It has been a problem that it is difficult to expect the effective expression of the drug in vivo because it shows the dissolution rate of.

Nevertheless, the solubilization of the conventional poorly soluble drug, glymepiride, is described in European Patent No. 649660 only for formulation methods suitable for in-body administration. .

As mentioned above, a method for improving the dissolution rate of poorly soluble drugs, which can be selected for increasing the surface area by granulation, is mechanical grinding or dissolving in an organic solvent and then drying. Grinding by dry mills, such as jet mills, ball mills, vibrating mills, hammer mills, etc., is used to increase or solidify the cohesiveness and adhesion of particles, thereby limiting fine grinding to a certain level.

As a result of measuring the average particle size of the conventionally available glymepiride and available glymepiride raw materials, it was confirmed that the particle size was 16 to 60 μm. The average particle size of the raw material is 5 to 8 µm, but the size is reduced by about 1/6 times.

When formulated with 5 ~ 8 ㎛ glymepiride obtained by a dry mill, solubility of 15 ~ 17 ㎍ / ml in the solubility test of pH7.8 buffer, which is shown in the body dissolution rate of the same formulation as shown in Table 2 It has a dissolution rate of less than 70% and does not show a satisfactory dissolution rate.

Table 1

manufacturer Mean particle size Chinese raw materials1 56.308 μm Chinese raw materials2 50.187㎛ Chinese raw materials3 43.817㎛ Chinese raw materials4 23.540 μm Indian raw materials1 41.158 μm India Raw Materials2 16.298㎛ Indian Raw Materials3 34.576 μm Spain raw materials 26.040㎛ Canadian raw materials 20.344 ㎛

[Table 2]

Time (min) Unpretreated formulation Ball Mill Pretreatment Pretreatment with Jet Mill Micronized Formulation Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 3 45.65 1.47 51.53 0.92 52.32 2.72 89.91 0.84 6 51.59 2.75 55.86 0.92 58.27 1.14 92.45 1.09 9 52.46 2.24 58.48 1.91 63.09 1.59 92.14 1.08 12 54.58 0.72 60.37 2.22 64.52 0.85 92.21 1.83 15 55.37 0.22 63.14 0.19 66.52 2.56 92.18 1.32 30 60.47 2.35 65.07 0.71 69.23 0.85 92.24 1.32 60 65.71 0.38 69.58 1.54 70.17 0.25 91.58 0.74

 As can be seen above, the low solubility and dissolution rate of the conventionally prepared glymepiride and the glymepiride formulated from the available glymepiride raw materials are due to the particle size, and the size of the glymepiride particle has a great effect on the bioavailability of the drug. It can be seen that it is mad.

Meanwhile, another conventional method for atomization may be applied by spray drying to atomize or adsorb to a porous material.

However, when the glymepiride is dissolved in an organic solvent in the above-mentioned micronization method and then slowly dried in a rotary evaporator or the like to be formulated, even if completely dissolved in an organic solvent as shown in FIG. If not dried at high pressure or not adsorbed onto the porous material, the particle size is rather large, resulting in a lower dissolution rate at pH 7.8 than when formulated without pretreatment.

Therefore, the method of micronization of glymepiride is a drug having solubility and dissolution rate so that the micronization method such as particle size having solubility and dissolution rate, dissolution of glymepiride, rapid drying of dissolved glymepiride or adsorption on porous material can exhibit high bioavailability. It can be seen that it acts as an important variable in the granulation.

Accordingly, the present inventors have studied the particle size of the glymepiride, and as a result, it was confirmed that the solubility and dissolution rate of glymepiride can be improved by making the average particle size of the glymepiride to 5 μm or less, thereby completing the present invention.

Therefore, an object of the present invention is a glymepiride fine particles having an average particle size of less than 5㎛.

It is another object of the present invention to make the glymepiride fine particles having an average particle size of 5 mu m or less.

In addition, an object of the present invention is to formulate glymepiride finely divided to an average particle size of less than 5㎛ to effectively improve the solubility and dissolution rate of the poorly soluble drug glymepiride to increase the bioavailability of the drug.

In order to achieve the above object, the present invention effectively improves the solubility and dissolution rate of the poorly soluble drug glymepiride to increase the bioavailability of the drug, and the pharmaceutical composition containing glymepiride finely divided to an average particle size of 5㎛ or less To provide.

The present invention also provides a method of dissolving poorly soluble glymepiride in an organic solvent and adsorbing the spray-dried or porous material at high temperature and high pressure to finely granulate the glymepiride with an average particle size of 5 μm or less.

In the present invention, the glymepiride raw material having an average particle size of 5 μm or less can be achieved by dissolving glymepiride and available glymepiride prepared in the prior art in an organic solvent and then adsorbing the spray-dried or porous material at high temperature and high pressure. .

In the present invention, the organic solvent used to prepare the glymepiride finely divided to an average particle size of 5 μm or less is a general organic solvent (relative to the solvents described in Drug Residual Solvent Standard Guidelines-KFDA Proposition 65607-79: Solvents of low toxicity and class 3: ideally low toxicity), such as acetone, methanol, ethanol, hexane, chloroform and acetonitrile, t-butyl ethyl ether, ethyl acetate, heptane and the like.

In addition, in the present invention, the glymepiride is completely dissolved in an organic solvent and dried by high temperature and high pressure spray drying, or the glymepiride is completely dissolved in an organic solvent and adsorbed onto a porous material. It can manufacture.

The present invention does not increase the dissolution rate, as can be seen in Figure 5 and Table 8, when glymepiride is completely dissolved in an organic solvent and dried, but is dried and formulated without adsorption to high-temperature, high-pressure spray drying or porous materials.

Porous materials used in the present invention are sugars or sugar alcohols including xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, mannose, galactose, sucrose, corn starch, cellulose And one or more substances selected from the group consisting of crospovidone, microcrystalline cellulose, methacryl copolymer and colloidal silicon dioxide and lactose, but are not limited thereto.

Meanwhile, a high speed rotary stirrer or a fluidized bed granulator may be used to adsorb the porous material, but is not limited thereto.

The atomized glymepiride formulation obtained by the above method is a formulation having an average particle diameter of 5 탆 or less, unlike the particle size obtained in the conventional grinding and atomization, as shown in Table 3.

In addition, the present invention is added to the pharmaceutically acceptable additives, such as lactose, polyvinylpyrrolidol, microcrystalline cellulose, sodium gluconate starch, magnesium stearate, and the like, by adding conventional excipients, the average particle size is less than 5㎛ glymepiride It can be formulated into a composition containing.

Table 3

Raw material name Mean particle size Raw material 28.795㎛ Raw material pretreated by ball mill 8.972 μm Raw material pretreated with jet mill 7.218㎛ Atomized raw materials 4.788 μm

Drugs formulated with glymepiride raw material in which the average particle size prepared by the above micronization method is micronized to 5 μm or less are solubilized as can be seen in Tables 5, 7, 9, 4, 5 and 7. , Dissolution rate and bioavailability were improved.

In addition, it was confirmed that the crystal form of the firstly supplied glymepiride raw material of 5㎛ size or more does not cause deformation and is very stable in terms of formulation (FIG. 6, 8A, 8B, 8C, 8D, 8E, and Table 10).

The glymepiride composition of the present invention may be formulated in a conventional pharmaceutical formulation, and may be formulated in the form of tablets, granules or capsules, which are conventional oral formulations.

The following examples embody the invention, but the invention is not limited to these examples.

<Example 1>

10 glymepiride

Polyvinylpyrrolidone K25 5g

Yellow Iron Oxide 1g

Blue No. 2 Aluminum Lake 3g

Lactose-R (686g)

100 g of microcrystalline cellulose

40 g sodium starch gluconate

5 g magnesium stearate

10 g of glimepiride and 5 g of polyvinylpyrrolidone were dissolved in an organic solvent, and then spray-dried in a spray dryer to obtain a granulated glymepiride composition, which was distributed with yellow iron oxide, blue No. 2 aluminum lake, and direct lactose, followed by lactose and gluconic acid. It was compressed by mixing with sodium starch, microcrystalline cellulose and magnesium stearate.

<Example 2>

10 glymepiride

Polyvinylpyrrolidone K25 5g

Yellow Iron Oxide 1g

Blue No. 2 Aluminum Lake 3g

Lactose-R (686g)

100 g of microcrystalline cellulose

40 g sodium starch gluconate

5 g magnesium stearate

10 g of glimepiride was dissolved in an organic solvent and spray-dried in a spray dryer to obtain a granulated glimepiride composition, which was then dispersed with yellow iron oxide, blue No. 2 aluminum lake, and direct lactose, followed by lactose, polyvinylpyrrolidone, and gluconic acid starch. It was compressed by mixing with sodium, microcrystalline cellulose and magnesium stearate.

<Example 3>

10 glymepiride

Polyvinylpyrrolidone K25 5g

Yellow Iron Oxide 1g

Blue No. 2 Aluminum Lake 3g

Lactose-R (686g)

100 g of microcrystalline cellulose

40 g sodium starch gluconate

5 g magnesium stearate

10 g of glimepiride, 5 g of polyvinylpyrrolidone, and 5 g of magnesium stearate were dissolved in an organic solvent, and then spray-dried in a spray dryer to obtain a granulated glymepiride composition, which was then dispersed in yellow iron oxide, blue No. 2 aluminum lake, and direct lactose, followed by direct application. Lactose, polyvinylpyrrolidone, sodium gluconate starch, microcrystalline cellulose and magnesium stearate were mixed and compressed into tablets.

<Example 4>

10 glymepiride

Polyvinylpyrrolidone K25 5g

Yellow Iron Oxide 1g

Blue No. 2 Aluminum Lake 3g

Lactose-R (686g)

100 g of microcrystalline cellulose

40 g sodium starch gluconate

5 g magnesium stearate

10 g of glimepiride, 5 g of polyvinylpyrrolidone, and 2.5 g of magnesium stearate were dissolved in an organic solvent, and then spray-dried in a spray dryer to obtain a granulated glymepiride composition, which was then dispersed with yellow iron oxide, blue No. 2 aluminum lake, and direct lactose. It was compressed by mixing with other lactose, polyvinylpyrrolidone, sodium gluconate starch, microcrystalline cellulose and magnesium stearate.

Example 5

10 glymepiride

Polyvinylpyrrolidone K25 5g

Yellow Iron Oxide 1g

Blue No. 2 Aluminum Lake 3g

Lactose-R (686g)

100 g of microcrystalline cellulose

40 g sodium starch gluconate

5 g magnesium stearate

Glymepiride, polyvinylpyrrolidone k25, yellow iron oxide, and blue No. 2 aluminum lake were dissolved in an organic solvent, and then combined with lactose and starch gluconate sodium in a high speed rotary stirrer to obtain a granulated glymepiride composition. Microcrystalline cellulose and magnesium stearate were mixed and compressed into tablets.

<Example 6>

10 glymepiride

Polyvinylpyrrolidone K25 5g

Yellow Iron Oxide 1g

Blue No. 2 Aluminum Lake 3g

Lactose-R (686g)

100 g of microcrystalline cellulose

40 g sodium starch gluconate

5 g magnesium stearate

Glymepiride, polyvinylpyrrolidone k25, yellow iron oxide, and blue No. 2 aluminum lake were dissolved in an organic solvent, and then lactose and starch gluconate sodium were added to a fluidized bed granulator, and the glimepiride solution was sprayed to obtain a granulated glycidide composition. Next, microcrystalline cellulose and magnesium stearate were mixed and compressed into tablets.

Experimental Example 1 Measurement of Average Particle Diameter

In general, the average particle diameters of the raw materials supplied with glymepiride, ball mill or jet mill, and granulated materials were measured with a particle analyzer. The results are shown in Table 4, and the measured values are shown in FIGS. 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1I, and 2A, 2B, 2C, and 2D. In general, the average particle diameter of the supplied glymepiride raw material was measured to be 16 ~ 60㎛ and the atomized raw material can be confirmed that the particle size is reduced to about 1/6 times.

 Table 4

Raw material name Mean particle size Chinese raw materials1 56.308 μm Chinese raw materials2 50.187㎛ Chinese raw materials3 43.817㎛ Chinese raw materials4 23.540 μm Indian raw materials1 41.158 μm India Raw Materials2 16.298㎛ Indian Raw Materials3 34.576 μm Spain raw materials 26.040㎛ Canadian raw materials 20.344 ㎛ Raw material 28.795㎛ Raw material pretreated by ball mill 8.972 μm Raw material pretreated with jet mill 7.218㎛ Atomized raw materials 4.788 μm

Experimental Example 2 Solubility Test

Solubility experiments were performed in pH7.8 buffer with formulations using unpretreated glymepiride raw materials, ball mill or jet mill pretreated raw materials, and granulated raw materials. After dissolving each formulation in pH 7.8 buffer, the supernatant was analyzed by high performance liquid chromatography (HPLC) to determine the solubility. The results are shown in Table 5.

It was found that the solubility of the preparation using the granulated raw material increased by about five times compared to the preparation using the raw material which was not pretreated.

Table 5

Formulation name Solubility (µg / mL) Unprepared formulations 5.14 Ball Mill Pretreatment 15.23 Pretreatment with Jet Mill 17.26 Micronized Formulation 25.89

Experimental Example 3 Dissolution Rate Test

The dissolution rate test was performed for each formulation as follows. With 6 tablets of each formulation, an elution test was carried out in 900 ml of eluate under the following conditions, and samples of 3, 6, 9, 12, 15, 30, and 60 minutes were taken. The collected sample was centrifuged to obtain an analytical table, and then analyzed by high performance liquid chromatography (HPLC).

Eluent: pH7.8 Buffer

Eluent Temperature: 37 ℃

RPM: 75rpm

HPLC conditions

Column: Superspher 100 C18 (4㎛, 4 ㅧ 15mm)

Mobile phase: Sodium dihydrogen phosphate: Acetonitrile: Water = 0.5 g: 500 ml: 500 ml

Detector: UV Absorbance Photometer (228nm)

Flow rate: 1.0ml / min

 ① Comparative dissolution test among commonly supplied glymepiride raw materials

Table 6

Time (min) Chinese raw material 1 Chinese raw material 2 Chinese raw material 3 Indian Raw Materials1 Indian Raw Materials 2 Mean SD Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 0 0 3 6.23 0.76 9.52 0.95 9.46 0.84 10.52 0.66 39.02 0.52 6 7.50 0.57 11.38 1.07 14.02 0.68 13.46 0.85 45.51 0.56 9 9.31 0.86 14.45 1.08 14.42 0.74 15.38 0.45 50.01 0.42 12 9.99 0.23 14.58 0.51 16.64 0.52 17.74 0.44 51.59 0.50 15 11.95 0.36 15.88 0.13 18.27 0.61 18.44 1.45 55.32 0.75 30 15.77 0.45 18.17 0.35 24.43 1.14 24.78 0.78 68.43 0.57 60 20.16 0.33 21.38 0.94 34.94 0.64 35.29 0.56 75.08 0.43 Time (min) Indian Raw Materials3 Spanish raw materials Chinese raw materials 4 Canadian raw materials Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 3 8.82 0.90 26.17 0.63 34.81 0.57 30.55 0.61 6 14.00 0.56 26.61 0.20 38.02 0.75 40.19 0.35 9 15.41 0.49 25.25 0.19 40.91 1.07 44.19 0.65 12 17.07 0.14 30.33 0.19 44.59 0.45 45.04 0.82 15 20.95 0.56 31.30 0.24 49.93 0.19 48.40 0.22 30 25.05 0.78 35.47 0.28 54.23 0.67 53.92 0.47 60 33.01 0.51 50.27 0.17 62.30 0.95 65.04 0.47

As shown in Table 6, the dissolution rate in the pH7.8 buffer solution does not reach an average of 70%, and when formulated as raw materials, the desired bioavailability cannot be reached.

② Comparative dissolution test between glymepiride raw material without pretreatment and raw material pre-treated with ball mill or jet mill and granulated raw material

Table 7

Time (min) Unpretreated formulation Ball Mill Pretreatment Pretreatment with Jet Mill Micronized Formulation Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 3 45.65 1.47 51.53 0.92 52.32 2.72 89.91 0.84 6 51.59 2.75 55.86 0.92 58.27 1.14 92.45 1.09 9 52.46 2.24 58.48 1.91 63.09 1.59 92.14 1.08 12 54.58 0.72 60.37 2.22 64.52 0.85 92.21 1.83 15 55.37 0.22 63.14 0.19 66.52 2.56 92.18 1.32 30 60.47 2.35 65.07 0.71 69.23 0.85 92.24 1.32 60 65.71 0.38 69.58 1.54 70.17 0.25 91.58 0.74

As shown in Table 7, the average dissolution rate is not more than 70% in the formulations which are not mechanically pulverized but also mechanically pulverized using a ball mill or jet mill to reduce the particle size to about 1/6 times. It can be seen that the average dissolution rate is significantly improved to 90% or more in the case of the granulated particles to an average of 5㎛ or less.

③ Comparative dissolution test in the case of formulating by completely drying after completely dissolved in organic solvent and not adsorbing on porous material

In order to determine the effect of the presence or absence of adsorption on the porous material in the present invention was dissolved in each of the solvents used in the present invention and compared with the elution rate without adsorption or adsorption on the porous material.

Table 8

Time (min) Formulated without adsorption to porous materials Formulation after adsorption on porous material Mean SD Mean SD 0 0 0 0 0 3 8.47 1.21 76.95 1.55 6 9.72 1.14 88.20 0.54 9 12.09 0.16 90.45 0.86 12 13.18 1.05 90.53 0.74 15 14.01 1.50 91.16 1.15 30 19.16 0.67 92.79 0.67 60 31.35 2.87 92.12 0.75

As shown in Table 8, even when all the glymepiride raw material was dissolved in the organic solvent used in the present invention, it can be seen that the dissolution rate varies depending on the presence or absence of adsorption drying.

Experimental Example 4 Effect of Atomization Process on Absorption in vivo

Animal experiments were performed to examine the correlation between the increase in dissolution rate in vitro and the increase in absorption in vivo.

The micronized and unpretreated preparations were orally administered in 8-week-old male rats suspended in water at a dose of 7 μg / g per unit body weight (as glimepiride) and pharmacokinetics were evaluated. Number of animals n = 5 Rats fasted one day before the test and took 0.5 ml of blood at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48 hours to assess pharmacokinetics It was. Glymepiride blood concentration / time data between the respective formulations were obtained, and the blood concentration profile is shown in FIG. 7. As shown in Table 9, the blood concentration (Cmax, ng / ml) of the formulation using the micronized raw material was 10 times higher than that of the formulation using the untreated raw material and the area under the curve (AUC, ng · hr / ml). Showed a 6.5-fold increase. This means that the granulated raw material increases the solubility and dissolution rate and consequently increases the bioavailability by increasing the absorption in vivo.

Table 9

Unpretreated formulation Micronized Formulation Cmax (ng / ml) 66.84 645.43 Tmax (hr) 2.17 2.00 AUC (nghr / ml) 897.32 5857.29

Experimental Example 5 Determination of Change of Crystal Form (DSC)

In the process of micronization according to the present invention, DSC was measured to determine whether the crystalline form of the drug was changed to amorphous. As shown in FIG. Since there is no reaction peak and the melting point is almost unchanged, it is judged that there is no change in amorphous form. Only decrease of binding energy between particles seems to affect the increase of solubility and dissolution rate.

Experimental Example 6 Stability Test of the Formulation

Tablets formulated using the granulated raw materials were subjected to stability tests in packaging (HDPE, silica gel) and unpacked at room temperature, 40 ° C, 40 ° C and 75%. The dissolution rate and the content test of the dissolution rate over time for 1, 2, 3, 4 and 6 months were performed and the results are shown in Table 10, Figure 8a, 8b, 8c, 8d, 8e.

As shown in Table 10, there was no change in dissolution rate at room temperature, 40 ° C., 40 ° C. and 75%, and no change in content occurred. It was found that the preparations according to the invention are stable even in severe temperatures and humidity.

 Table 10

<1 month stability>

Time (min) Packing Unpacked Packing Room temperature 40 degrees 40 degrees 70% 40 degrees 40 degrees 75% Mean SD Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 0 0 3 89.45 0.66 89.33 1.30 89.93 0.49 88.15 0.42 89.03 0.64 6 89.47 4.22 89.46 0.74 88.98 0.71 88.56 1.26 89.50 0.70 9 90.99 1.62 89.51 1.53 88.84 1.94 88.80 0.15 91.01 1.15 12 91.18 1.46 90.01 1.83 88.45 0.75 88.60 1.67 90.10 0.40 15 91.20 1.38 91.44 0.11 89.96 0.63 89.39 0.31 91.20 0.54 30 92.13 0.16 90.27 2.29 90.62 1.38 92.70 2.44 91.06 0.87 60 91.26 0.45 91.12 1.47 91.28 2.34 90.23 2.40 90.56 0.86

<2 months stability>

Time (min) Packing Unpacked Packing Room temperature 40 degrees 40 degrees 70% 40 degrees 40 degrees 75% Mean SD Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 0 0 3 89.90 0.02 88.12 2.44 89.00 0.49 89.83 0.06 87.52 1.32 6 90.97 2.10 87.43 1.17 88.98 0.71 86.82 1.44 88.02 0.35 9 91.36 1.10 88.34 1.15 89.26 1.40 88.36 1.22 88.05 0.30 12 91.05 1.65 88.70 0.80 87.81 1.86 88.08 0.26 88.86 0.09 15 91.37 1.14 89.46 0.46 89.21 0.11 89.34 0.26 89.44 0.20 30 90.07 3.07 89.67 0.04 89.94 0.16 89.70 0.02 90.22 0.71 60 91.26 0.45 89.70 0.16 89.82 0.15 90.62 0.14 89.78 0.01

<3 months stability>

Time (min) Packing Unpacked Packing Room temperature 40 degrees 40 degrees 70% 40 degrees 40 degrees 75% Mean SD Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 0 0 3 90.08 0.24 88.49 2.90 88.22 0.33 89.04 0.71 88.35 1.22 6 91.12 1.89 88.32 1.13 87.49 0.71 87.07 1.69 89.08 0.90 9 90.46 2.37 89.68 0.19 89.18 0.99 87.99 0.09 89.44 0.39 12 91.23 1.39 88.78 1.80 89.09 2.21 88.57 1.03 89.28 0.03 15 91.03 1.62 90.48 0.33 89.46 0.37 88.54 0.87 89.65 0.09 30 91.45 1.13 89.60 1.56 89.84 0.35 90.56 1.25 89.51 0.34 60 91.26 0.45 88.93 2.04 89.99 1.02 89.54 1.80 89.44 0.87

<4 months stability>

Time (min) Packing Unpacked Packing Room temperature 40 degrees 40 degrees 70% 40 degrees 40 degrees 75% Mean SD Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 0 0 3 89.51 1.33 88.70 1.11 85.66 2.58 87.27 4.50 85.71 3.88 6 91.02 0.62 89.75 1.25 88.36 1.57 88.20 0.59 86.80 1.23 9 91.95 0.71 86.85 1.15 90.56 0.03 87.49 1.05 87.07 1.70 12 92.00 0.77 88.29 1.58 89.32 0.65 88.24 1.49 88.98 2.59 15 91.95 0.71 89.07 3.15 89.48 1.23 88.97 1.25 88.56 0.46 30 91.03 0.63 88.51 1.21 91.52 0.45 90.02 1.78 89.16 0.52 60 91.26 0.45 88.99 1.54 90.95 0.71 88.44 2.18 87.62 2.08

<6 months stability>

Time (min) Packing Unpacked Packing Room temperature 40 degrees 40 degrees 70% 40 degrees 40 degrees 75% Mean SD Mean SD Mean SD Mean SD Mean SD 0 0 0 0 0 0 0 0 0 0 0 3 89.75 0.23 86.47 1.43 77.69 1.25 86.44 1.56 82.04 0.30 6 82.00 0.65 87.33 0.80 79.62 1.17 87.52 1.89 87.26 0.32 9 92.19 0.08 91.76 0.91 88.04 1.05 88.33 2.48 87.88 0.98 12 92.33 0.17 90.63 2.76 89.07 1.09 90.70 0.90 90.03 0.78 15 91.86 0.45 91.75 1.41 91.23 2.15 91.45 1.58 91.28 0.23 30 92.25 0.01 92.05 1.21 92.52 1.60 91.00 1.43 92.06 0.27 60 92.01 0.62 92.42 0.62 93.21 0.76 92.57 1.06 91.17 0.67

In the present invention, the glymepiride is granulated with an average particle size of 5 μm or less, and the preparation using glymepiride having an average particle size of 5 μm or less shows an effect of effectively increasing solubility and dissolution rate and increasing bioavailability.

Figures 1a, 1a2, 1b1, 1b2, 1c1, 1c2, 1d1, 1d2, 1e1, 1e2, 1f1, 1f2, 1g1, 1g2, 1h, 1i are generally measured average particle size measurements of the supplied glymepile raw materials.

2A, 2B, 2C, and 2D are mean particle size measurement actual values of raw materials not pretreated, raw materials ball milled and jet milled, and granulated materials.

3 is a dissolution pattern of a formulation using a glymepiride raw material generally supplied.

4 is a comparative dissolution test result of a preparation using a raw material that has not been pretreated, a raw material pretreated with a ball mill or jet mill, and a raw material that has been granulated.

5 is a dissolution pattern when formulated without being completely dissolved in an organic solvent and not adsorbed on a porous material.

FIG. 6 is a DSC measurement value of a raw material spray-dried after completely dissolving in an organic solvent.

7 is a bioavailability test results in the animal of the present invention.

Figures 8a, 8b, 8c, 8d, 8e is the result of the stability test of the drug formulated by the present invention.

Claims (6)

Glymepiride is a method for granulating the glymepiride so that the average particle size is 5㎛ or less. The method of claim 1, wherein the glymepiride is dissolved in an organic solvent and spray-dried at high temperature and high pressure to granulate the glymepiride so that the average particle size is 5 mu m or less. The method of claim 1, wherein the glymepiride is dissolved in an organic solvent and then adsorbed onto a porous material to granulate the glymepiride so that the average particle size is 5 mu m or less. The method of claim 3, wherein the porous material is sugar or xylitol, mannitol, sugar alcohols including sorbitol, arabinose, ribose, xylose, glucose, mannose, galactose, sucrose, corn starch, A method of micronizing glymepiride to have an average particle size of 5 μm or less, characterized in that it is at least one selected from celluloses, crospovidone, microcrystalline cellulose, methacryl copolymers and colloidal silicon dioxide and lactose. A pharmaceutical composition comprising glymepiride finely divided to an average particle size of 5 μm or less by the method of claim 1. 6. The pharmaceutical composition for oral administration according to claim 5, wherein the formulation is a tablet, granule or capsule.