KR20190098945A - 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. Since a granule containing polaprezinc according to the present invention has excellent fluidity, tableting can be progressed smoothly, thereby being easy for 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 able to be usefully used.

Description

Wet granulation tablets with improved stability and method for preparing the same}

The present invention relates to Paula Presink wet granule tablets and a method for preparing the same having improved stability.

Polaprezinc is a complex compound of zinc and L-carnosine, and is used as a gastritis and gastric ulcer treatment agent for promoting ulcer healing, promoting cell regeneration, immunomodulation, and anti-inflammatory action.

Korean Patent No. 10-1399514 relates to a Polar Presink tablet manufactured by a direct stroke method, and the particle size (d90) of Polar Presink, a main component, is limited to 500 µm or less, preferably 30 to 300 µm. Such conventional Polar Presink tablets have a problem in that the fluidity is not good and the particle size distribution is not uniform, so that tableting disturbance occurs in the mass production process or the content uniformity is not good.

JP 1984-033270 A KR 10-1399514 B

SUMMARY OF THE INVENTION An object of the present invention is to provide a Paula Presink wet granule tablet with improved fluidity and stability, characterized in that it comprises a Polar Presink and an alcohol binder and an excipient, a disintegrant and a lubricant.

In addition, another object of the present invention is to provide a method for producing the polar pre-ink granules wet tablets.

In order to achieve the above object, the present invention provides a Paula Presink wet granule tablet with improved stability, characterized in that it comprises a polar presink and alcohol binder and additionally, an excipient, a disintegrant and a lubricant.

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

According to one embodiment of the present invention, the granules may have a particle size of 100 to 250 ㎛ corresponding to 80% in 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 invention, the disintegrant may be one or more selected from starch, starch derivatives, carboxymethyl cellulose calcium, carboxymethyl cellulose derivatives, microcrystalline cellulose and crospovidone.

According to an 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 one embodiment of the invention, the tablet is a binder of at least one selected from methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, starch, gelatin, povidone and gum arabic. It may further include.

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

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

According to one embodiment of the present invention, the tablet may be less than 0.22% by weight of the total amount of the flexible material when stored for 3 months at 40 ℃, 75% humidity environment.

The present invention also comprises the steps of (1) mixing excipients and disintegrants into Polar Presink; (2) preparing granules by mixing the alcohol binder liquid or the alcohol binder liquid containing the binder with the mixture of step (1); (3) drying and granulating the granules to produce a sieved material; (4) mixing a lubricant with the formulation; And (5) tableting the mixture of step (4).

According to one embodiment of the present invention, in step (4), at least one selected from excipients and disintegrants may be further mixed with the formulation.

The present invention also comprises the steps of (1) mixing excipients in Polar Presink; (2) mixing granules of (1) with an alcohol binder or an alcohol binder containing a binder to prepare granules; (3) drying and granulating the granules to produce a sieved material; (4) mixing a disintegrant and a lubricant with the formulation; And (5) compressing the mixture of step (4). The method provides a method of preparing polar pre-packed wet granule tablets having improved stability.

Since the granules containing the polar presink according to the present invention has excellent fluidity, the tableting proceeds smoothly and is easy for mass production, and the content uniformity is excellent. Therefore, it can be usefully used.

1 is a graph showing the particle size distribution of the mixture before tableting according to the Examples and Comparative Examples of the present invention.
Figure 2 is a graph showing the result of measuring the amount of lead substances generated after the initial and three months of storage of the tablets prepared according to Examples and Comparative Examples of the present invention.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

According to one aspect of the present invention, there is provided a polar pre-jink wet granule tablet with improved stability, including a polar pre-jink and alcohol binder, and additionally excipients, disintegrants and lubricants.

The alcohol may be one or more alcohols selected from the group consisting of ethanol, methanol, butanol, propanol and isopropanol.

As used herein, the term "granule" is also referred to as "granule", and includes the wet granules immediately before the tableting, the wet granules just before the tableting, the lubricant of step (4) in the manufacturing method according to the present invention It means the sintered material which mixed etc.

In the tablet, the granules containing polar presink has a particle size (d90) of 90% to the maximum particle size in the cumulative particle size distribution of 250 μm or less, preferably of 100 to 250 of 80% of the particle size distribution. It is characterized by a micrometer.

The granules in the tablet according to the present invention were not only preferable to have a high therapeutic effect, dissolution rate, etc. when they had the above particle size range, but also showed very desirable effects on fluidity, particle size distribution, content uniformity, storage stability, mass production ease, and the like. Specifically, when the particle size of the granules containing the polar presink is between 100 and 250 μm in the particle size distribution, it accounts for about 80% of the whole, and thus, the tableting may proceed smoothly.

If the particle size of the granules is too large, it is difficult to expect sufficient expression of the drug due to the slow dissolution rate after taking the tablet, and also the change in dissolution rate due to hardening of the granule particles may occur in a compressed form such as a tablet. . In addition, when the particle size of the granules is too small or too large, problems may occur in mass production, such as uneven mixing, poor fluidity, and sticking.

When describing the particle size of the active ingredient herein, it is described as "d90" commonly used in the industry. For example, “d90 is 200 μm” means that at least 90% of the active ingredient particles have an equivalent spherical volume diameter of 200 μm or less. Such equivalent spherical volume diameters can be measured using, for example, Mastersizer (Malvern Instruments), HELOS Particle Size Analysis (Sympatec), but the present invention is not limited to such particle size measuring instruments.

Polarpresink-containing tablets according to the invention further comprise additives such as pharmaceutically acceptable excipients, binders, disintegrants, glidants and the like for preparing tablets.

As the excipient, one or more selected from sugars, mannitol, starch, and microcrystalline cellulose may be used, and in addition, it may further include pharmaceutically acceptable ingredients.

As the disintegrant, one or more selected from starch, starch derivative, carboxymethyl cellulose calcium, carboxymethyl cellulose derivative, microcrystalline cellulose and crospovidone may be used, and may further include pharmaceutically acceptable ingredients. .

As the lubricant, one or more selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG), and talc may be used. It may further comprise components.

In addition, the tablet may further include a binder which is at least one selected from methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch, gelatin, povidone and gum arabic.

The excipient and disintegrant may be included in a ratio of 60 to 80:20 to 40. In the case where the excipient and the disintegrant are included in the above ratio, the fluidity is improved, so that the productivity can be improved at the time of mass production, and the content uniformity is also improved.

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

The Carr's Index is an index used to evaluate the fluidity of a powder in pharmaceuticals. If the Carr's index is greater than 25%, the fluidity of the powder is considered poor.

In addition, the tablet has a residual amount of Polar Presink 90% or more when stored for 3 months in an extreme environment of 40 ℃, 75% humidity, the total amount of the flexible material is less than 0.22% by weight, so excellent storage stability. .

The present invention also comprises the steps of (1) mixing excipients in Polar Presink; (2) preparing granules by mixing the alcohol binder liquid or the alcohol binder liquid containing the binder with the mixture of step (1); (3) drying and granulating the granules to produce a sieved material; (4) mixing a disintegrant and a lubricant with the formulation; And (5) compressing the mixture of step (4). The method provides a method of preparing polar pre-packed wet granule tablets having improved stability.

As another specific example of the manufacturing method of the polar preink tablet of this invention, the following method is mentioned. First, 60 to 80 parts by weight of microcrystalline cellulose as an excipient based on 100 parts by weight of the polar presink is mixed in a polar mixer under conditions of agitator 200 to 300 rpm and chopper 3000 to 3500 rpm. (2) 0.05 to 0.15 parts by weight of one alcohol binding liquid selected from anhydrous ethanol, methanol and isopropanol, preferably anhydrous ethanol alcohol binding liquid, or 0.05 to 0.15 parts by weight of anhydrous ethanol or povidone or HPMC After adding 1 to 3 parts by weight of (hydroxypropyl methylcellulose), mixed with homogenizer at 3000 to 4000 rpm for 5 to 15 minutes to add dissolved or uniformly suspended binder solution, and Granules are formed in a mixer under conditions of agitator 200 to 300 rpm and chopper 3000 to 3500 rpm. (3) The granules are put in a hot air dryer at 50 to 60 ° C. and dried in a tray to form granules having an LOD of 3% or less, and the dried granules are formed using a sizing machine. (4) After mixing 5 to 25 parts by weight of crospovidone to the sieved material, 1 to 5 parts by weight of magnesium stearate is added to the mixture to perform lubrication to form a final granule. (5) Tableting tablets with a total weight of 100 to 200 mg by compression using a rotary tablet machine with a circular punch having a diameter of about 5 to 10 mm.

Hereinafter, the polar prejinx wet granule tablets having improved stability of the present invention will be described in detail with reference to Examples.

Example

Examples 1 to 3: Preparation of polar presink tablet according to the present invention

To prepare a polar prejink tablet in the composition of Table 1.

Composition (mg) Example 1 Example 2 Example 3 Alcohol
Binder Anhydrous ethanol 0.08 Methanol 0.08 Isopropanol (IPA) 0.08 Paula Presink 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 Gross mass 150.0 150.0 150.0 Manufacturing method Wet granules Wet granules Wet granules

First, to Polar Presink 33 mg of microcrystalline cellulose and 10 mg of crospovidone The mixture was mixed in a high speed mixer (Hi Speed Mixer KMLC, Geumseongsan group) under agitator 250 rpm and chopper 3200 rpm. The alcohol binding solution was added to the mixture in the amount shown in Table 1, and granules were formed under agitator 250 rpm and chopper 3200 rpm in a high speed mixer (Hi Speed Mixer KMLC, Venus acid).

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

Magnesium stearate was added to the mixture in which the remaining amounts of microcrystalline cellulose and crospovidone, respectively, were mixed with the sieved to form a final granule.

Next, using a rotary tableting machine (VANTIXP130S, Sejong) was compressed into a circular punch having a diameter of about 7.5 mm to prepare an uncoated tablet having a total weight of about 150.0 mg.

Examples 4-5: Preparation of polar preink tablets according to the present invention

To prepare a polar prejink tablet in the composition of Table 2.

Composition (mg) Example 4 Example 5 Binder Anhydrous ethanol 0.08 0.08 Povidone 1.5 HPMC 1.5 Paula Presink 75.0 75.0 Microcrystalline cellulose 53.0 53.0 Crospovidone 18.5 18.5 Magnesium stearate 2.0 2.0 Gross mass 150.0 150.0 Manufacturing method Wet granules Wet granules

In the same manner as in the composition of Table 2, Polar Presink and microcrystalline cellulose were mixed in agitator 250 rpm, chopper 3200 rpm conditions in a high speed mixer (Hi Speed Mixer KMLC, Venus acid group). Pobindon or HPMC (hydroxypropyl methylcellulose) was added to anhydrous ethanol, and the mixture was dissolved or uniformly suspended at 3500 rpm for 10 minutes in a homogenizer (Homo Mixer, Tokushu Kiku). The granules were added under agitator 250 rpm and chopper 3200 rpm in a high speed mixer (Hi Speed Mixer KMLC, Venus acid).

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

Crospovidone and magnesium stearate were added to the sieved material, followed by post-mixing and lubrication to form final granules.

Next, using a rotary tableting machine (VANTIXP130S, Sejong) was compressed into a circular punch having a diameter of about 7.5 mm to prepare an uncoated tablet having a total weight of about 150.0 mg.

Comparative Examples 1 and 2

To prepare a polar prejink tablet in the composition of Table 3.

Composition (mg) Comparative Example 1 Comparative Example 2  Paula Presink 75.0 75.0 Microcrystalline cellulose 53.0 53.0 Crospovidone 20.0 20.0 Magnesium stearate 2.0 2.0 Gross mass 150.0 150.0 Manufacturing method Direct stroke Dry granules

Comparative Example 3

To prepare a Polar Presink tablet with the composition shown in Table 4 (see Japanese Patent No. 5420321, Sawai Pharmaceutical Co., Ltd., "Preparation method in oral disintegrating tablet containing Polar Presink").

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

Experimental Example

Experimental Example 1. Measurement of fluidity

The bulk density and the tapped density of the mixtures (the granules prepared in step (4)) of the Examples and Comparative Examples were measured, and the results are shown in Table 5 below. At this time, the bulk density was measured according to the USP 35 / NF30 bulk density test method, the tap density was measured according to the USP 35 / NF30 tap density test method.

In addition, the results of calculating the Carr's compressibility and the Hausner ratio are shown in Table 5 below, and the fluidity was evaluated according to the indicators shown in Table 6 below. Carr's index and Hausner's ratio were evaluated according to the disclosures in US Pharmacopoeia 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 Kar indicators 14.58% 16.67% 16.00% 13.04% 36.67% 22.00% 14.29% Hausner Bee 1.17 1.20 1.19 1.15 1.58 1.28 1.17

division Kar indicators Hausner Bee Very good (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 Over 38 Greater than 1.60

As shown in Tables 5 and 6, the Carr indicator was very bad at 36.7% in Comparative Example 1, while the fluidity of 'excellent' or 'good' at 13% to 17% in Examples 1-4 and Comparative Example 3 It can be seen that. In the Hausner ratio, the granules obtained by the direct hit method were evaluated to be very poor, while the granules of Examples 1 to 4 and Comparative Example 3 were 'excellent' or good, indicating that the fluidity was greatly improved.

Experimental Example 2. Measurement of disintegration

The results of measuring the disintegration time in purified water according to the disintegration test method of the Korean Pharmacopoeia are shown in Table 7 below.

division Tablet thickness (mm) Tablet 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, Examples 1 to 4 and Comparative Examples 1 to 3 each showed disintegration time within 5 minutes. In the case of the dry granule tablet of Comparative Example 2 and the wet granule tablet using the purified water of Comparative Example 3 as a binding solution, the disintegration power was reduced. Since polar presink is applied to the gastric mucosa and has a therapeutic effect, the disintegration power of the tablet is an important factor for determining the quality of the tablet. In view of this aspect, Comparative Example 2 and Comparative Example 3 is considered to be disadvantageous to exhibit a high therapeutic effect.

Experimental Example 3. Confirmation of Particle Size Distribution

The particle size distribution was confirmed for the mixture (the granules prepared in step (4)) immediately before the tableting of the Examples and Comparative Examples.

20 (850 ㎛), 30 (600 ㎛), 40 (425 ㎛), 60 (250 ㎛), 80 (180 ㎛) and 100 Accurately weigh 20 g of the mixture into (150 μm), 140 (106 μm), and 200 (75 μm) sieves, place it in the top sieve of the container with the previously specified sieve and handset, cover, and then horizontally for 3 minutes. After shaking or sometimes tapping lightly, the result of weighing the residues in each sieve and hand is shown in FIG. 1.

1 is a graph showing the particle size distribution of the granules before tableting according to Examples 1 to 4 and Comparative Examples 1 to 2 of the present invention.

Referring to Figure 1, in the case of Examples 1 to 4 was found that the particle size between 100 ~ 250 ㎛ occupies about 80% of the total, it is determined that the tableting proceeds smoothly because of excellent fluidity.

In Comparative Example 1, as a result of the particle size distribution, the particle size of 106 μm or less occupies about 42% of the total particle size, which may cause tableting disorders and mass deviations due to differentiation. As a result of the particle size distribution of Comparative Example 2, it was confirmed that the particle size of 425 μm or more occupies about 20% of the whole, and that granules of large particles are distributed. This can cause the problem of mixing unevenness.

Experimental Example 4. Dissolution Test

In order to confirm the dissolution pattern according to the manufacturing method, dissolution test was carried out on six 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.

[Elution condition]

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

[Analysis condition]

Analyzer: HPLC 1260 serise

Detector: Ultraviolet absorption spectrophotometer (210 nm)

Column: Column filled with octadecyl silica gel for liquid chromatogram of 5 µm in a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 150 mm.

Column temperature: Approved temperature around 45 ℃

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

Injection volume: 10 μl

Mobile phase: Dissolve 1.4 g of potassium dihydrogen phosphate in 1000 mL of water. Adjust to pH 3.5 with diluted phosphoric acid (1 → 10). Dissolve 2 g of 1-octane sulfonate 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, Examples 1 to 4 and Comparative Examples 1 to 3 showed a dissolution rate of more than 85% for 15 minutes, but it was shown that there is a difference in the initial dissolution rate. The initial dissolution rate of Example 4 was the highest, which is believed to improve the initial dissolution rate as a disintegrant as well as the role of the binder under the influence of the binding solution in which povidone is dissolved. In the case of the dry granule tablet of Comparative Example 2 and the wet granule tablet containing the purified water of Comparative Example 3 as a binding solution, the initial dissolution rate was about 20% or lower. This is in accordance with the disintegration measurement results of Experimental Example 2.

Experimental Example 5. Content Uniformity Test

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

[Analysis condition]

Analyzer: HPLC 1260 serise

Detector: Ultraviolet absorption spectrophotometer (210 nm)

Column: Column filled with octadecyl silica gel for liquid chromatogram of 5 µm in a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 150 mm.

Column temperature: Approved temperature around 45 ℃

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

Injection volume: 5 μl

Mobile phase: Dissolve 1.4 g of potassium dihydrogen phosphate in 1000 mL of water. Adjust to pH 3.5 with diluted phosphoric acid (1 → 10). Dissolve 2 g of 1-octane sulfonate 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%. Thus wet granules Examples 1 to 4, Comparative Example 3 was confirmed that the content uniformity. On the other hand, Comparative Examples 1 and 2 showed similar results with the average of Example 1, but the tablets showed a high variation in individual tablets, resulting in a non-uniform tableting content.

As a result, in the case of Comparative Examples 1-2, it is judged that the fluidity | liquidity was not good and it caused the mass deviation.

Experimental Example 6. Measurement of the amount of lead substances generated (stability evaluation)

Comparative Examples 1 and 2 have poor fluidity and are not easy to produce. In Comparative Example 3, since the disintegration power is poor, it is not suitable in terms of bioavailability. Therefore, it is reasonable to prepare the wet granules, and the stability of the tablet of the present invention prepared by the wet granulation method was confirmed. The flexible material generated in the sample stored for 3 months in an acceleration chamber (temperature 40 ℃, humidity 75%, bottle packaging) was measured and the results are shown in Table 10 below. The analysis conditions are as follows.

[Analysis condition]

Analyzer: HPLC 1260 serise

Detector: Ultraviolet absorption spectrophotometer (210 nm)

Column: Column filled with octadecyl silica gel for liquid chromatogram of 5 µm in a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 150 mm.

Column temperature: Approved temperature around 45 ℃

Flow rate: Main peak holding time is adjusted to about 11 minutes

Injection volume: 5 μl

Measuring range: about 3 times the holding time

Mobile phase: Dissolve 1.4 g of potassium dihydrogen phosphate in 1000 mL of water. Adjust to pH 3.5 with diluted phosphoric acid (1 → 10). Dissolve 2 g of 1-octane sulfonate in 900 mL of this solution, and add 100 mL of acetonitrile.

division
Known flexible material (% by weight) Total unknown flexible material (% by weight) Total Lead (wt%) 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 experiment, the criterion of the flexible material is 0.3% or less of the known 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 material varies depending on the type of the binder solution. As in the case of Comparative Example 3, the wet granule tablet to which purified water was added as a binding liquid had a higher incidence of lead substances than other Examples and Comparative Examples from the beginning, and after three months, the upper limit of the base substance and the total lead substance standards was close. The numerical value was confirmed. On the other hand, in the case of Examples 1 to 4 where no purified water was added, it was confirmed that there was no significant change even after 3 months storage. In particular, Example 1 and Example 4 containing anhydrous ethanol also showed good stability in the alcohol-binding solution, in the case of Example 4 it was confirmed that the total flexible material after about three months is lower than about 5%.

In addition, in the case of Comparative Example 1 due to direct prescription and Comparative Example 2 due to dry granulation, it was confirmed that the total amount of generated flexible substances after 3 months was about 20% or more higher than that of Example 1 or Example 4. In particular, in the case of Comparative Example 3, it was confirmed that the total amount of generated flexible material after three months is four times higher than in Example 4.

Although the present invention has been described as the preferred embodiment mentioned above, it is possible to make various modifications or variations without departing from the spirit and scope of the invention. Also, the appended claims cover such modifications and variations as fall within the spirit of the invention.

Claims (14)

Polar pre-jink wet granules tablets with improved stability, characterized in that it comprises a polar pre-ink and alcohol binder, and additionally excipients, disintegrants and lubricants.
The method of claim 1,
Wherein the alcohol is one or more alcohols selected from the group consisting of ethanol, methanol, butanol, propanol and isopropanol stability Paula Presink wet granules tablets with improved stability.
The method of claim 1,
The granules of the granular wettable granular tablets with improved stability, characterized in that the particle size (d90) corresponding to 90% of the maximum particle size in the cumulative particle size distribution is less than 250 ㎛.
The method of claim 1,
The granules of the granular wet granules tablets with improved stability, characterized in that the particle size corresponding to 80% in the particle size distribution of 100 to 250 ㎛.
The method of claim 1,
Wherein the excipient is improved polar stability liquid granules tablets, characterized in that at least one selected from lactose, mannitol, starch and microcrystalline cellulose.
The method of claim 1,
Wherein the disintegrant is starch, starch derivatives, carboxymethyl cellulose calcium, carboxymethyl cellulose derivatives, microcrystalline cellulose and crospovidone, characterized in that the stability stability of the polar prejink granules tablets.
The method of claim 1,
The lubricant is an improved polar presink wet type, characterized in that at least one selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG) and talc Granule tablets.
The method of claim 1,
The tablet further comprises a binder comprising 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 Presink Wet Granule Tablets.
The method of claim 1,
The excipient and the disintegrant is polar presink wet granules tablets, characterized in that it comprises a ratio of 60 to 80: 20 to 40.
The method of claim 1,
The tablets have improved stability of Polar Presink wet granules, characterized in that having a Carr's compressibility value of 10 to 30% before tableting.
The method of claim 1,
Wherein the tablet is stored for 3 months in an environment of 40 ℃, 75% humidity, Paula Presink wet granules tablets with improved stability, characterized in that the total amount of the flexible material is less than 0.22% by weight.
(1) mixing excipients and disintegrants in polar presink;
(2) preparing granules by mixing the alcohol binder liquid or the alcohol binder liquid containing the binder with the mixture of step (1);
(3) drying and granulating the granules to produce a sieved material;
(4) mixing a lubricant with the formulation; And
(5) tableting the mixture of step (4); the method of manufacturing a polar pre-packed wet granules tablets with improved stability comprising a.
The method of claim 12, wherein in step (4)
Method for producing stability of the polar pre-wash granules wet tablets characterized in that the mixture is further mixed with at least one selected from excipients and disintegrants.
(1) mixing excipients in Polar Presink;
(2) mixing granules of (1) with an alcohol binder or an alcohol binder containing a binder to prepare granules;
(3) drying and granulating the granules to produce a sieved material;
(4) mixing a disintegrant and a lubricant with the formulation; And
(5) tableting the mixture of step (4); the method of manufacturing a polar pre-packed wet granules tablets with improved stability comprising a.

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