KR20190031660A - Wet granulation tablets with improved stability and method for preparing the same - Google Patents

Abstract

The present invention relates to a polaprezinc wet granule tablet with improved stability, and a method for manufacturing the same. A granule containing polaprezinc according to the present invention has excellent fluidity that tableting can be progressed smoothly, thereby faciliting mass production. In addition, a tablet, manufactured by using the granule is excellent in content uniformity and stability, since the production of flexible substances during storage and distribution is suppressed, thereby being usefully used.

Description

[0001] Wet Granule Tablets with Improved Stability and Preparation Methods Thereof [0002] Wet Granulation Tablets with Improved Stability and Methods for Preparing the Same [

The present invention relates to a Porphyrazine wet granule tablet having improved stability and a method for producing the same.

Polaprezinc is a complex of zinc and L-carnosine, and is used as a therapeutic agent for gastritis and gastric ulcer, which promotes healing of ulcers, promotes cell regeneration, regulates immunity, and has an anti-inflammatory action.

Korean Patent No. 10-1399514 relates to a polar repinque tablet prepared by a direct method, and the particle size (d90) of the main component, polar refinish, is limited to 500 탆 or less, preferably 30 to 300 탆. Such conventional tablets have poor flowability and uneven particle size distribution, which may result in a disability in mass production or poor uniformity of contents.

JP 1984-033270 A KR 10-1399514 B

It is an object of the present invention to provide a Porphyrazine wet granule tablet having improved flowability and stability, which comprises a polarized prink and an alcohol-bound liquid, and further, an excipient, a disintegrant and a glidant.

It is another object of the present invention to provide a method for producing the polar granule wet granule tablet.

In order to accomplish the above object, the present invention provides a stabilized polypregnix wet granule tablet characterized by comprising a polarizing agent and an alcohol-binding agent, and further an excipient, a disintegrant and a glidant.

According to an embodiment of the present invention, the alcohol may be at least one alcohol selected from the group consisting of ethanol, methanol, butanol, isopropanol and propanol.

According to an embodiment of the present invention, the granules may have a particle size (d90) corresponding to 90% of the maximum particle size in a cumulative particle size distribution of 250 mu m or less.

According to an embodiment of the present invention, the granules may have a particle size of 100 to 250 탆 corresponding to 80% of the particle size distribution.

According to one embodiment of the present invention, the excipient may be at least one selected from lactose, mannitol, starch and microcrystalline cellulose.

According to one embodiment of the present invention, the disintegrant may be at least one selected from starch, starch derivatives, carboxymethylcellulose calcium, carboxymethylcellulose derivatives, microcrystalline cellulose and crospovidone.

According to one embodiment of the present invention, the lubricant may be at least one selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG) and talc.

According to an embodiment of the present invention, the tablet may contain at least one binder selected from methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, starch, gelatin, povidone and gum arabic .

According to one embodiment of the present invention, the excipient and the disintegrant may be contained in a ratio of 60 to 80:20 to 40.

According to one embodiment of the present invention, the tablets may exhibit a Carr's compressibility value of 10 to 30% before tableting.

According to an embodiment of the present invention, the tablets may have a total amount of less than 0.22% by weight of the total amount of the suppositories when stored for 3 months at 40 ° C and 75% humidity.

The present invention also relates to a method for preparing a pharmaceutical composition comprising the steps of: (1) mixing an excipient and a disintegrant into a polar excipient; (2) mixing the mixture of step (1) with an alcohol-binding solution or an alcohol-binding solution containing a binder to prepare granules; (3) drying and granulating the granules to prepare a sized product; (4) mixing the sizing material with a lubricant; And (5) tableting the mixture of step (4). The present invention also provides a method for producing a polarophazine tablet having improved stability.

According to an embodiment of the present invention, in the step (4), one or more selected from excipients and disintegrants may be further mixed into the sized product.

The present invention also relates to a method of preparing a pharmaceutical composition comprising the steps of: (1) mixing an excipient into a polar prink; (2) mixing an alcohol-binding solution or an alcohol-binding solution containing a binder to the mixture of step (1) to prepare granules; (3) drying and granulating the granules to prepare a sized product; (4) mixing the disintegrant with a disintegrant and a lubricant; And (5) tableting the mixture of step (4). The present invention also provides a method for preparing the purified Porphyrazine wet granule tablets.

The granules containing the polar prinks according to the present invention are excellent in fluidity, so that the granules are smoothly advanced and easily mass-produced, the uniformity of the content is excellent, the generation of the soft substances during storage and distribution is suppressed and the stability is excellent So that it can be usefully used.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the particle size distribution of a pre-set mixture according to an embodiment of the present invention and a comparative example. Fig.
FIG. 2 is a graph showing the results of measurement of the amount of the generation of the soft materials after the initial and 3-month storage of tablets prepared according to the examples and comparative examples of the present invention. FIG.

Hereinafter, the present invention will be described in detail.

According to one aspect of the present invention, there is provided a stabilized improved polypregnix wet granule tablet comprising a polarizing agent and an alcohol-binding liquid, and further an excipient, a disintegrant and a lubricant.

The alcohol may be at least one alcohol selected from the group consisting of ethanol, methanol, butanol, propanol and isopropanol.

As used herein, the term "granule " is also referred to as" granulate ", including the wet granulation immediately before tableting, and the wet granule immediately before tableting is the same as the wet granule in the preparation method according to the present invention, And the like.

In the above-mentioned tablet, the granules containing the polar prinks have a particle size (d90) corresponding to 90% of the maximum particle size in a cumulative particle size distribution of 250 m or less, preferably 80 to 100% in the particle size distribution, Mu m.

The granules in the tablets according to the present invention were found to be highly desirable in terms of fluidity, particle size distribution, content uniformity, storage stability and mass production easiness as well as high therapeutic effect and dissolution rate when having the above range of particle size. Specifically, when the particle size of the granules containing the polyphenzquio is in the range of 100 to 250 μm in particle size distribution, it accounts for about 80% of the entire granules, which is preferable because the fluidity is excellent and the tableting can proceed smoothly.

When the particle size of the granules is too large, the rate of dissolution after taking is slow, so that it is difficult to expect sufficient expression of the drug efficacy. Also, in a compressed form such as tablets, a change in dissolution rate due to curing of granular particles may occur over time . Also, when the particle size of the granules is too small or large, problems may arise in mass production such as uneven mixing, poor fluidity, and sticking.

In describing the particle size of the active ingredient in the present specification, it is described as "d90" For example, "d90 of 200 [mu] m" means that at least 90% of the active ingredient particles have an equivalent spherical volume diameter of 200 [mu] m or less. Such an equivalent spherical volume diameter can be measured using, for example, a Mastersizer (Malvern Instruments), a HELOS Particle Size Analysis (Sympatec) or the like, but the present invention is not limited to such a particle size measuring instrument.

The polar pharmaceutical preparations according to the present invention further comprise additives such as pharmaceutically acceptable excipients, binders, disintegrants, lubricants and the like for preparing tablets.

As the excipient, at least one selected from sugar, mannitol, starch, and microcrystalline cellulose may be used, and further, pharmaceutically acceptable ingredients may be further included.

As the disintegrant, at least one selected from the group consisting of starch, starch derivatives, carboxymethylcellulose calcium, carboxymethylcellulose derivatives, microcrystalline cellulose and crospovidone may be used, and further, pharmaceutically acceptable ingredients may be further included .

As the lubricant, at least one selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG) and talc may be used. In addition, Components. ≪ / RTI >

The tablet may further contain at least one binder selected from methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, starch, gelatin, povidone and gum arabic.

The above excipients and disintegrants may be included in a ratio of 60 to 80:20 to 40. When the excipient and the disintegrant are included in the above ratio, the flowability is improved, so that the productivity can be further improved in mass production, and the uniformity of content is further improved.

In addition, the tablets exhibit a Carr's compressibility value of 10 to 20% before tableting, and thus exhibit excellent fluidity.

The Karl index is an index used to evaluate the fluidity of the powder during the constraint. If the Karl index is greater than 25%, the fluidity of the powder is considered to be poor.

In addition, when the tablets were stored in an extreme environment at 40 DEG C and 75% humidity for 3 months, the residual amount of the polarized zinc was 90% by weight or more and the total amount of the flexible substances was less than 0.22% by weight, .

The present invention also relates to a method of preparing a pharmaceutical composition comprising the steps of: (1) mixing an excipient into a polar prink; (2) mixing the mixture of step (1) with an alcohol-binding solution or an alcohol-binding solution containing a binder to prepare granules; (3) drying and granulating the granules to prepare a sized product; (4) mixing the disintegrant with a disintegrant and a lubricant; And (5) tableting the mixture of step (4). The present invention also provides a method for preparing the purified Porphyrazine wet granule tablets.

As another specific example of the method for producing the polar prink zinc tablet of the present invention, the following method can be mentioned. First, 60 to 80 parts by weight of microcrystalline cellulose as an excipient is mixed in a high-speed mixer under the conditions of an agitator of 200 to 300 rpm and a chopper of 3000 to 3500 rpm based on 100 parts by weight of the polar prepreg. (2) 0.05 to 0.15 parts by weight of an alcohol-binding liquid, preferably an anhydrous ethanol alcohol-binding liquid, selected from anhydrous ethanol, methanol and isopropanol is added to the mixture, or 0.05 to 0.15 parts by weight of anhydrous ethanol is added to povidone or HPMC 1 to 3 parts by weight of hydroxypropyl methylcellulose (hydroxypropyl methylcellulose) is added, and the mixture is homogenized by mixing in a homogenizer at 3000 to 4000 rpm for 5 to 15 minutes to dissolve or uniformly suspend the mixture, Agitator 200-300 rpm, chopper 3000-3500 rpm in a mixer to form granules. (3) The granules are placed in a hot-air dryer at 50 to 60 ° C and then tray-dried to form granules having an LOD of 3% or less, and the dried granules are formulated into granules using a granulator. (4) 5 to 25 parts by weight of crospovidone is mixed with the above-mentioned sieved product, and 1 to 5 parts by weight of magnesium stearate is added to the mixture to form a final granule. (5) tableting with a circular punch having a diameter of about 5 to 10 mm using a rotary tablet machine to produce tablets having a total weight of 100 to 200 mg

Hereinafter, the stability of the Porphyrazine wet granule tablets of the present invention will be described in detail with reference to examples.

Example

EXAMPLES 1 TO 3: Production of polar prepreg according to the present invention

Paula prezink tablets were prepared with the compositions shown in Table 1 below.

Composition (mg) Example 1 Example 2 Example 3 Alcohol
Binding liquid Anhydrous ethanol 0.08 Methanol 0.08 Isopropanol (IPA) 0.08 Paula Prezink 75.0 75.0 75.0 Microcrystalline cellulose 53.0 53.0 53.0 Crospovidone 20.0 20.0 20.0 Magnesium stearate 2.0 2.0 2.0 Total mass 150.0 150.0 150.0 Manufacturing method Wet granule Wet granule Wet granule

First, 33 mg of microcrystalline cellulose and 10 mg of crospovidone The mixture was agitator 250 rpm and chopper 3200 rpm in a high speed mixer (Hi Speed Mixer KMLC, Geosungsangi). An alcohol-bound liquid was added to the mixture in the amounts shown in Table 1, and granules were formed in a high-speed mixer (Hi Speed Mixer KMLC, manufactured by Kumseongsan) under the conditions of agitator 250 rpm and chopper 3200 rpm.

The granules were placed in a 55 ° C hot air drier and tray-dried to form granules having an LOD of 3% or less. The granules were dried using QUADRO COMIL.

Magnesium stearate was added to the mixture obtained by mixing the sieves with the balance of each of microcrystalline cellulose and crospovidone, and the mixture was subjected to filtration to form final granules.

Next, the tablets were tableted with a circular punch having a diameter of about 7.5 mm using a rotary tablet machine (VANTIXP130S, Sejong) to prepare tablets having a total weight of about 150.0 mg.

Examples 4 to 5: Preparation of Polar Frescian Tablets According to the Present Invention

A polar repinque tablet was prepared with the composition shown in Table 2 below

Composition (mg) Example 4 Example 5 Binding liquid Anhydrous ethanol 0.08 0.08 Povidone 1.5 HPMC 1.5 Paula Prezink 75.0 75.0 Microcrystalline cellulose 53.0 53.0 Crospovidone 18.5 18.5 Magnesium stearate 2.0 2.0 Total mass 150.0 150.0 Manufacturing method Wet granule Wet granule

In the same manner as the composition shown in Table 2, the polarized zinc and microcrystalline cellulose were mixed in a high-speed mixer (Hi Speed Mixer KMLC, Kumseongsan) under the conditions of agitator 250 rpm and chopper 3200 rpm. To the mixture, povidone or HPMC (hydroxypropyl methylcellulose) was added to anhydrous ethanol, and the mixture was mixed by homogenizer (Homo Mixer, Tokushu Kiku) at 3500 rpm for 10 minutes to dissolve or uniformly suspend the mixture. , And granules were formed in a high speed mixer (Hi Speed Mixer KMLC, Geosungsan) with agitator 250 rpm and chopper 3200 rpm.

The granules were placed in a 55 ° C hot air drier and tray-dried to form granules with an LOD of 3% or less. The granules were dried using a quadrifuge (QUADRO COMIL).

Crospovidone and magnesium stearate were added to the sized product, followed by post mixing and filtration to form final granules.

Next, the tablets were tableted with a circular punch having a diameter of about 7.5 mm using a rotary tablet machine (VANTIXP130S, Sejong) to prepare tablets having a total weight of about 150.0 mg.

Comparative Examples 1 to 2

Polar fragile tablets were prepared with the compositions shown in Table 3 below.

Composition (mg) Comparative Example 1 Comparative Example 2  Paula Prezink 75.0 75.0 Microcrystalline cellulose 53.0 53.0 Crospovidone 20.0 20.0 Magnesium stearate 2.0 2.0 Total mass 150.0 150.0 Manufacturing method Direct method Dry granule

Comparative Example  3

(Japanese Patent Registration No. 5420321, Sawai Pharmaceutical Co., Ltd., refer to the production method in "Oral disintegrating tablet containing polyprepink").

Composition (mg) Comparative Example 3 Purified water 0.12 Paula Prezink 75.0 Microcrystalline cellulose 37.0 D-mannitol 23.0 Crospovidone 10 Polyvinylpyrrolidone 3.0 Magnesium stearate 2.0 Total mass 150.0 Manufacturing method Wet granule

Experimental Example

Experimental Example 1. Measurement of fluidity

The bulk density and the tap density were measured on the premixed mixture (the granules prepared in each step (4)) of the above-mentioned Examples and Comparative Examples, and the results are shown in Table 5 below. The bulk density was measured according to the bulk density test of USP 35 / NF30, and the tap density was measured according to the tap density test method of USPK 35 / NF30.

The results of calculation of Carr's compressibility and Hausner ratio are shown in the following Table 5, and the fluidity was evaluated according to the indexes shown in Table 6. The Karl index and the Hauser ratio were evaluated in accordance with the contents disclosed in USPK 35 / NF30 bulk density and tap density, respectively.

division Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Bulk density
(g / mL) 0.42 0.42 0.40 0.43 0.33 0.40 0.41 Tap density
(g / mL) 0.49 0.50 0.48 0.50 0.53 0.51 0.48 Black index 14.58% 16.67% 16.00% 13.04% 36.67% 22.00% 14.29% Houseboar 1.17 1.20 1.19 1.15 1.58 1.28 1.17

division Black index Houseboar Exceelent below 10 1.00-1.11 Good 11-15 1.12-1.18 Fair 16-20 1.19-1.25 Passable 21-25 1.26-1.34 Poor 26-31 1.35-1.45 Very poor 32-37 1.46-1.59 Very very poor Above 38 Greater than 1.60

As shown in Tables 5 and 6, in the case of Comparative Example 1, the carbon index is very poor, which is 36.7%, while in Examples 1 to 4 and Comparative Example 3, the flowability of "excellent" or "good" . ≪ / RTI > In the case of the housing ratio, the granules obtained by the direct method were evaluated to be very poor, whereas the granules of Examples 1 to 4 and Comparative Example 3 were found to be excellent or good and the fluidity was greatly improved.

Experimental Example  2. Disintegration  Measure

The disintegration time in purified water was measured according to the Disintegration Test of Kagaku Kogaku Co., Ltd. The results are shown in Table 7 below.

division Tablet thickness (mm) Purification hardness (kp) Disintegration time Example 1 3.45 8-10 Within 2 minutes Example 2 3.45 8-10 Within 3 minutes Example 3 3.48 8-10 Within 2 minutes Example 4 3.45 8-10 Within 2 minutes Comparative Example 1 3.55 8 ~ 11 Within 2 minutes Comparative Example 2 3.53 8-12 Within 4 minutes Comparative Example 3 3.46 8-13 Within 5 minutes

As shown in Table 7, the disintegration time of each of Examples 1 to 4 and Comparative Examples 1 to 3 was less than 5 minutes. In the case of the dry granule refining of Comparative Example 2 and the wet granule refining using the purified water of Comparative Example 3 as the binding liquid, the disintegration power decreased. The polarizing force of the tablet is an important factor for judging the quality of the tablet since the polarophazen is applied to the gastric mucosa to show the therapeutic effect. From this point of view, Comparative Example 2 and Comparative Example 3 would be disadvantageous for exhibiting a high therapeutic effect.

Experimental Example 3. Identification of particle size distribution

The particle size distribution was confirmed on the premixed mixture (granules produced in the step (4)) of the above Examples and Comparative Examples.

In order to check the particle size distribution, we used 20 pieces (850 ㎛), 30 (600 ㎛), 40 (425 ㎛), 60 (250 ㎛), 80 (180 ㎛) and 100 20 g of the mixture was precisely weighed into the upper (150 ㎛), 140 (106 ㎛) and 200 (75 ㎛) sieves and placed in the upper body of the container and handwoven stack specified above. The results are shown in FIG. 1, which shows the result of measuring the mass of the residue in each sieve and handpiece after shaking or occasionally tapping lightly.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the particle size distribution of pre-tablet granules according to Examples 1 to 4 and Comparative Examples 1 and 2 of the present invention. FIG.

Referring to FIG. 1, in Examples 1 to 4, particle sizes between 100 and 250 .mu.m were found to account for about 80% of the total particle size. Thus, the fluidity was excellent and the tableting process was smooth.

In the case of Comparative Example 1, the particle size distribution showed that the particle size of 106 탆 or less accounted for about 42% of the total particle size, which may result in the occurrence of the tableting disorder due to the differentiation and the mass deviation. As a result of the particle size distribution of Comparative Example 2, it was confirmed that the particle size of 425 占 퐉 or more occupied about 20% of the whole, and the granules of large particles were distributed. This can cause problems of mixing unevenness.

Experimental Example 4: Dissolution test

In order to confirm the dissolution profile according to the production method, a dissolution test was carried out on 6 tablets of Examples 1 to 3 and Comparative Examples 1 to 3, and the results are shown in Table 8. The test conditions are as follows.

[Dissolution condition]

Elution tester (DST-810, LABFINE.INC.), PH 4.0 acetic acid buffer solution 900 mL, Method 2, 50 rpm

[Analysis conditions]

Analytical instrument: HPLC 1260 serise

Detector: Ultraviolet absorptiometer (210 nm)

Column: A column packed with 5 占 퐉 octadecyl silica gel for liquid chromatogram on a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 150 mm

Column temperature: Approved temperature near 45 캜

Flow rate: Main peak hold time adjusted to about 11 minutes

Injection volume: 10 μl

Mobile phase: Dissolve 1.4 g of potassium dihydrogenphosphate in 1000 mL of water. Adjust the pH to 3.5 using diluted phosphoric acid (1 → 10). Dissolve 2 g of sodium 1-octanesulfonate in 900 mL of this solution and add 100 mL of acetonitrile.

division Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 (%) Average SD Average SD Average SD Average SD Average SD Average SD Average SD 5 minutes 86.8 0.5 86.4 1.2 86.2 0.8 92.1 0.9 83.4 1.2 68.2 4.3 60.3 3.8 10 minutes 98.9 0.6 94.7 1.0 97.5 0.8 99.3 0.4 94.7 1.0 79.8 3.2 81.4 2.2 15 minutes 99.6 0.5 98.6 1.8 99.7 0.6 99.8 0.4 96.6 1.8 87.1 2.4 92.1 1.5

As shown in Table 8, in Examples 1 to 4 and Comparative Examples 1 and 3, the dissolution rate was 85% or more for 15 minutes, but the initial dissolution rate was different. The initial dissolution rate of Example 4 was the highest, and it was judged that the effect of the binding solution in which povidone was dissolved improved not only the role of the binder but also the initial dissolution rate as a disintegrant. In the case of the wet granule purification using the dry granule tablet of Comparative Example 2 and the purified water of Comparative Example 3 as the binding agent, the initial dissolution rate was about 20% or lower. This is in agreement with the results of the determination of the degree of slippage in Experimental Example 2 above.

Experimental Example  5. Content uniformity test

In order to confirm the uniformity of contents according to the production method, the mass and mass deviation of each of the 10 preparations of Examples 1 to 4 and Comparative Examples 1 to 3 were measured, and the results are shown in Table 9 below. The analysis conditions are as follows.

[Analysis conditions]

Analytical instrument: HPLC 1260 serise

Detector: Ultraviolet absorptiometer (210 nm)

Column: A column packed with 5 占 퐉 octadecyl silica gel for liquid chromatogram on a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 150 mm

Column temperature: Approved temperature near 45 캜

Flow rate: Main peak hold time adjusted to about 11 minutes

Injection volume: 5 μl

Mobile phase: Dissolve 1.4 g of potassium dihydrogenphosphate in 1000 mL of water. Adjust the pH to 3.5 using diluted phosphoric acid (1 → 10). Dissolve 2 g of sodium 1-octanesulfonate in 900 mL of this solution and add 100 mL of acetonitrile.

division
(%) One 2 3 4 5 6 7 8 9 10 Average SD Example 1 99.7 99.3 100.2 99.8 99.7 100.2 100.1 99.5 99.2 99.8 99.8 0.3 Example 2 98.8 99.3 100.0 98.8 98.5 101.1 99.9 99.1 98.5 100.7 99.5 0.9 Example 3 100.3 99.5 99.4 101.2 100 100.2 100.3 99.9 98.9 99.8 100.0 0.6 Example 4 99.3 100.1 100.3 100.6 99.8 99.3 99.4 100.8 100.4 100.5 100.1 0.4 Comparative Example 1 99.5 107.8 103.7 94.6 92.3 94.2 108.8 95.5 105.3 93.5 99.5 6.3 Comparative Example 2 106.2 98.3 99.5 97.2 96.7 104.5 96.7 92.5 96.8 103.2 99.2 4.2 Comparative Example 3 99.8 99.5 98.7 100.1 100 98.2 99.3 99.4 97.8 99.1 99.12 0.8

As shown in Table 9, in Example 4, the lowest content was 99.3%, and the highest content was 100.8%. In the wet granules of Examples 1 to 4 and Comparative Example 3, the content uniformity was confirmed. On the other hand, the results of Comparative Examples 1 and 2 were similar to those of Example 1, but the results were not uniform due to high individual variation of tablets.

In the case of Comparative Examples 1 and 2, it was judged that the fluidity was poor and the mass deviation was caused.

EXPERIMENTAL EXAMPLE 6. Measurement of the amount of generated soft materials (stability evaluation)

Comparative Examples 1 and 2 are not easy to produce because of poor fluidity, and in Comparative Example 3, the disintegration force is poor and is not suitable in terms of bioavailability. Therefore, it is appropriate to prepare the wet granules, and the stability of the tablet of the present invention produced by the wet granulation method is confirmed. Flexible materials generated in the samples stored in the acceleration chamber (temperature 40 ° C, humidity 75%, bottle packaging) for 3 months were measured and the results are shown in Table 10 below. The analysis conditions are as follows.

[Analysis conditions]

Analytical instrument: HPLC 1260 serise

Detector: Ultraviolet absorptiometer (210 nm)

Column: A column packed with 5 占 퐉 octadecyl silica gel for liquid chromatogram on a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 150 mm

Column temperature: Approved temperature near 45 캜

Flow rate: Main peak hold time adjusted to about 11 minutes

Injection volume: 5 μl

Measuring range: about three times the holding time

Mobile phase: Dissolve 1.4 g of potassium dihydrogenphosphate in 1000 mL of water. Adjust the pH to 3.5 using diluted phosphoric acid (1 → 10). Dissolve 2 g of sodium 1-octanesulfonate in 900 mL of this solution and add 100 mL of acetonitrile.

division
Base matrix material (% by weight) Total unknowns (wt%) Total flexible material (% by weight) initial 3 months initial 3 months initial 3 months Example 1 0.05 0.07 0.11 0.12 0.16 0.19 Example 2 0.05 0.07 0.12 0.13 0.17 0.20 Example 3 0.05 0.06 0.12 0.14 0.17 0.20 Example 4 0.05 0.06 0.11 0.12 0.16 0.18 Comparative Example 1 0.05 0.11 0.12 0.15 0.17 0.26 Comparative Example 2 0.05 0.09 0.11 0.15 0.16 0.24 Comparative Example 3 0.12 0.26 0.35 0.68 0.47 0.94

In the above test, the standard of the flexible material is 0.3% or less of the base flexible material and 1.0% of the total flexible material.

As shown in Table 10, it was confirmed that the generation amount of the flexible substance varies depending on the type of bonding liquid. As in the case of Comparative Example 3, in the case of wet granule tablets to which purified water was added as a binding liquid, the incidence rate of the flexible substance from the beginning was higher than those of the other Examples and Comparative Examples, and after 3 months, it was close to the upper limit value It was confirmed that it represents the numerical value. On the other hand, in Examples 1 to 4 in which no purified water was added, it was confirmed that there was no significant change even after storage for 3 months. Particularly, in Example 1, Example 1 and Example 4, which contained anhydrous ethanol, showed good stability, and in Example 4, the total amount of the suppositories after 3 months was lower by about 5% or more.

In addition, it was confirmed that the amount of the total amount of the flexible material produced after 3 months in Comparative Example 1 by the direct line prescription and Comparative Example 2 by the dry granule was about 20% higher than that in Example 1 or Example 4. Particularly, in the case of Comparative Example 3, it was confirmed that the amount of total flexible material generated after 3 months was four times or more higher than that in Example 4.

Although the present invention has been described in terms of the preferred embodiments mentioned above, it is possible to make various modifications and variations without departing from the spirit and scope of the invention. It is also to be understood that the appended claims are intended to cover such modifications and changes as fall within the true spirit of the invention.

Claims (14)

A polyprepinke and an alcohol binding liquid, and further an excipient, a disintegrant, and a glidant. The method according to claim 1,
Wherein the alcohol is at least one alcohol selected from the group consisting of ethanol, methanol, butanol, propanol and isopropanol. The method according to claim 1,
Wherein the granules have a particle size (d90) corresponding to 90% of the maximum particle size in a cumulative particle size distribution of 250 占 퐉 or less. The method according to claim 1,
Wherein the granules have a particle size of 100 to 250 占 퐉 corresponding to 80% of the particle size distribution. The method according to claim 1,
Wherein the excipient is at least one selected from lactose, mannitol, starch and microcrystalline cellulose. The method according to claim 1,
Wherein the disintegrant is at least one selected from starch, starch derivatives, carboxymethylcellulose calcium, carboxymethylcellulose derivatives, microcrystalline cellulose and crospovidone. The method according to claim 1,
The lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG) and talc. Granule refining. The method according to claim 1,
Wherein the tablet further comprises at least one binder selected from methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, starch, gelatin, povidone and gum arabic. Improved Polar Frescene Wet Granule Tablets. The method according to claim 1,
Wherein the excipient and the disintegrant are contained in a ratio of 60 to 80:20 to 40. The method according to claim 1,
Wherein the tablet has a Carr's compressibility value of 10 to 30% before tableting. The method according to claim 1,
Wherein the tablets have a total amount of less than 0.22% by weight of the total amount of the flexible substances when stored for 3 months at 40 DEG C and 75% humidity. (1) mixing the excipient and the disintegrant in a polarized zinc;
(2) mixing the mixture of step (1) with an alcohol-binding solution or an alcohol-binding solution containing a binder to prepare granules;
(3) drying and granulating the granules to prepare a sized product;
(4) mixing the sizing material with a lubricant; And
(5) a step of tableting the mixture of step (4). 13. The method of claim 12, wherein in the step (4)
Characterized in that at least one selected from the group consisting of an excipient and a disintegrant is further mixed into the sized product. (1) mixing an excipient into a polarized zinc;
(2) mixing an alcohol-binding solution or an alcohol-binding solution containing a binder to the mixture of step (1) to prepare granules;
(3) drying and granulating the granules to prepare a sized product;
(4) mixing the disintegrant with a disintegrant and a lubricant; And
(5) a step of tableting the mixture of step (4).

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