KR20200002409A - Wet granulation composition comprising polaprezinc and method for preparing tablet using the same - Google Patents

Abstract

The present invention relates to: a wet granulation composition manufactured by a wet granulation method by mixing various additives and a binder with polaprezinc; a method for manufacturing a tablet using the same; and a tablet manufactured from the same. When the tablet is manufactured by using a wet composition, it is possible to provide a tablet formulation which exhibits a high dissolution rate despite low solubility of polaprezinc, regardless of a particle size of polaprezinc, thereby being able to increase bioavailability. In addition, the tablet formulation can exhibit smooth productivity and stable medicinal efficacy by maintaining high stability.

Description

WET GRANULATION COMPOSITION COMPRISING POLAPREZINC AND METHOD FOR PREPARING TABLET USING THE SAME}

The present invention relates to a wet granule composition comprising a polar presink, a method for preparing a tablet using the same, and a tablet prepared therefrom. More specifically, the present invention relates to a wet granules by mixing various additives and a binder with a polar presink. To a wet granulated composition and a tablet prepared therefrom.

Polaprezinc is a complex compound of zinc and L-carnosine, which shows the therapeutic action of peptic ulcer, and granular and oral disintegrating tablets containing Polarpresink have been released and marketed as a medicine for treating gastritis and gastric ulcer. . However, granules and orally disintegrating tablets are expensive to manufacture, and in particular, in the case of granules, not only is it inconvenient to take, but also some of the active ingredients may be lost during taking.

Accordingly, as a medicament containing Polar Presink, various methods have been attempted to reduce the manufacturing cost and prepare a dosage form that is convenient to take. For example, Korean Patent No. 10-1399514 provides a tablet including Polar Presink having a specific particle size, and it is confirmed that Polar Presink shows excellent dissolution rate, bioavailability, and storage stability when the particle size is described. However, if the particle size of Polar Presink is too large, it is difficult to expect sufficient expression of the drug due to the slow dissolution rate after taking it, and the change of dissolution rate due to curing of Polar Presink particles in a compressed form such as tablets. May appear. In addition, when the particle size of the polar presink is too small or large, there is a disadvantage that problems may occur in mass production, such as mixing unevenness, poor fluidity, and sticking. In addition, Korean Patent Registration No. 10-1788268 discloses a method for manufacturing a raw material of Polar Presink, but does not set a separate standard for the particle size of Polar Presink.

In fact, in the production of the polar presink raw material, it is not easy to produce a product by uniformly standardizing the particle size of the polar presink according to various reaction conditions, production methods, and post-treatment used. Accordingly, there is an urgent need to develop a tablet formulation that can exhibit high dissolution rate and express high stability and good efficacy regardless of the polar solubility of polar presink.

Patent Document 1: Korea Patent Registration 10-1399514 Patent Document 2: Korea Patent Registration 10-1788268

Thus, the present inventors show a high dissolution rate despite the low solubility of the polar pre-jinks, regardless of the particle size of the polar pre-jinks through the polar granules of the wet granules prepared by the wet granules method, the smooth productivity and high stability The present invention has been completed by preparing a maintaining tablet formulation.

Accordingly, it is an object of the present invention to provide a wet granulation composition comprising polar presink, a pharmaceutically acceptable additive and a binder.

Another object of the present invention is to provide a method for preparing a tablet using the wet granule composition.

Another object of the present invention is to provide a tablet prepared by the wet granulation method from the composition.

In order to achieve the above object, the present invention provides a wet granulation composition comprising polar presink, a pharmaceutically acceptable first additive and a binder.

In addition, the present invention comprises the steps of: a) preparing a mixture by mixing polar presink and a pharmaceutically acceptable first additive; b) preparing a wet granulated composition using a binder solution including a binder and purified water; c) drying the composition to obtain granules; d) adding a pharmaceutically acceptable second additive to the granules; And e) tableting the resultant of step d) to form a tablet.

The present invention also provides a tablet prepared by the wet granulation method from the wet granulation composition.

The present invention can increase the bioavailability by showing a high dissolution rate in spite of the low solubility of Polar Presink, regardless of the particle size of Polar Presink, tablet formulation that can express a stable drug by maintaining a smooth productivity and high stability Can be provided. In particular, the present invention provides a polar prejink wet type which exhibits a high dissolution rate by preparing a wet granule composition of the polar prejink even when the particle size of the polar prejink is too high (D90 500 μm or more) or too low (D90 30 μm or less). It is to provide a tablet formulation of the granular composition.

Unless otherwise defined, all terms (including technical and scientific terms) used in the present specification may be used in a sense that can be commonly understood by those skilled in the art. In addition, the terms defined in the commonly used dictionaries are not ideally or excessively interpreted unless they are specifically defined clearly.

As used herein, the singular forms "a", "an" and "the" may include the plural forms as well, unless the context clearly indicates otherwise.

In the present specification, when a part "includes" a certain component, this means that the component may further include other components, except for the case where there is no description to the contrary.

In addition, all numbers and expressions indicating amounts of components, reaction conditions, and the like described herein are to be understood as being modified in all instances by the term "about" unless otherwise specified.

As used herein, "pharmaceutically acceptable" means that it can be approved by the government or equivalent regulatory body for use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional pharmaceutical dosages. , As listed in the Pharmacopoeia, or as recognized by other general pharmacopeias.

When describing the particle size of an active ingredient herein, it is referred to as "D90" which is commonly used in the art. For example, “D90 100 μm” means that at least 90% of the active ingredient particles have an equivalent spherical volume diameter of 100 μm or less. Such equivalent spherical volume diameter can be measured using, for example, Mastersizer (Malvern Instruments), HELOS Particle Size Analysis (Sympatec), but is not limited to such particle size measuring instruments.

One aspect of the invention provides a wet granulation composition comprising polar presink, a pharmaceutically acceptable first additive and a binder.

In one embodiment of the present invention, the binder is carboxymethyl cellulose sodium, carboxymethyl cellulose, cellulose (powder), copovidone, croscarmellose sodium, dextrose anhydride, dextrose hydrate, ethyl cellulose, hydroxyethyl cellulose, Hydroxypropyl cellulose, hydroxypropyl cellulose-L, hydroxypropyl methyl cellulose, isomalt, anhydrous lactose, lactose hydrate, low substituted hydroxypropyl cellulose, maltodextrin, methyl cellulose, methyl hydroxyethyl cellulose, poly (ethylene) One or more selected from glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (povidone), pregelatinized starch, prosolve, sodium alginate, starch, sucrose, talc and xanthan gum can be used, but not limited thereto. It doesn't happen.

In one embodiment of the present invention, the binder may be included in 1% to 20% by weight, more preferably 1% to 10% by weight, most preferably 1.5% by weight based on the total weight of solids of the composition % To 8% by weight. When included in less than 1% by weight, the mixture may not be uniformly mixed, tableting may not be performed well when preparing tablets, and when it is more than 20% by weight, it may show a low dissolution rate.

In one embodiment of the present invention, the first additive is one or more excipients selected from microcrystalline cellulose, starch, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose-L, dextrose, lactose, mannitol and crospovidone are used. But it is not limited thereto. The excipient may be included in 20 to 50% by weight, more preferably 30 to 40% by weight, most preferably 35 to 40% by weight based on the total weight of solids of the composition.

In one embodiment of the present invention, the polar presink is 30% to 70% by weight, more preferably 40% to 60% by weight, most preferably 45% by weight, based on the total weight of solids of the composition It may be included in the 55% by weight, if less than 30% by weight of the active ingredient is less effective because the drug is not effectively expressed, if it exceeds 70% by weight may cause a problem of poor fluidity after taking.

In one embodiment of the present invention, the wet granulation composition may further include one or more second additives selected from adsorbents, stabilizers, disintegrants, sustained release agents, sweeteners and lubricants.

The adsorbent may include, but is not limited to, one or more selected from colloidal silicon dioxide, hydrous silicon dioxide, hard silicic anhydride, and magnesium metasilicate aluminate.

The stabilizer is beta-carotene, riboflavin, butyric riboflavin, rocotriboflavin, riboflavin sodium phosphate, ascorbic acid, ascorbyl palmitate, ascorbic acid calcium, ascorbic acid nicotinamide, sodium ascorbate, dehydroascorbic acid, glutathione, Glutathione disulfide, selenium, selenium sulfide, sodium selenite, sodium selenite, silymarin, resveratrol, pyridoxamine hydrochloride, pyridoxine phosphate, pyridoxalate, agaro oligosaccharides, melatonin, ubidecarenone, ornithine, aspartic acid ornichin Or at least one selected from ornithine hydrochloride, arginine, arginine hydrochloride, arginine sodium, arginine glutamate, protoporphyrindisodium, hamatopolpyrin, cyclosilic acid, cytilon, urazamide, azintamide and hismecromon It may, but is not limited to.

The disintegrant may include, but is not limited to, one or more selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate.

The sustained-release agent is a cellulose derivative such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, or sodium carboxymethyl cellulose, polyethylene oxide, polyvinylpyrrolidone, guar gum, locust bean gum , Polyvinylacetate, polyvinylacetate phthalate, polymethacrylate, polyacrylic acid, glycerol monostearate and poloxamer, but may include, but are not limited to.

The sweetener may include, but is not limited to, one or more selected from glucose, sucrose, saccharin, sorbitol, aspartame, acesulfame salt and neotime.

The glidant may include one or more selected from magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc, stearyl fumarate sodium, aluminum magnesium silicate, stearic acid and sucrose fatty acid esters, It is not limited to this.

In addition, an aspect of the present invention comprises the steps of: a) mixing the polar presink and the pharmaceutically acceptable first additive to prepare a mixture; b) preparing a wet granulated composition using a binder solution including a binder and purified water; c) drying the composition to obtain granules; d) adding a pharmaceutically acceptable second additive to the dried granules; And e) tableting the resultant of step d) to form a tablet.

In one embodiment of the present invention, the first additive is one or more excipients selected from microcrystalline cellulose, starch, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose-L, dextrose, lactose, mannitol and crospovidone are used. However, it is not limited thereto. The excipient may be included in 20 to 50% by weight, more preferably 30 to 40% by weight, most preferably 35 to 40% by weight based on the total weight of the tablet.

In one embodiment of the present invention, the binder is carboxymethyl cellulose sodium, carboxymethyl cellulose, cellulose (powder), copovidone, croscarmellose sodium, dextrose anhydride, dextrose hydrate, ethyl cellulose, hydroxyethyl cellulose, Hydroxypropyl cellulose, hydroxypropyl cellulose-L, hydroxypropyl methyl cellulose, isomalt, anhydrous lactose, lactose hydrate, low substituted hydroxypropyl cellulose, maltodextrin, methyl cellulose, methyl hydroxyethyl cellulose, poly (ethylene) One or more selected from glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (povidone), pregelatinized starch, prosolve, sodium alginate, starch, sucrose, talc and xanthan gum can be used, but not limited thereto. It doesn't happen.

In one embodiment of the present invention, the binder may be included in an amount of 1 wt% to 20 wt%, more preferably 1 wt% to 10 wt%, and most preferably 1.5 wt%, based on the total weight of the tablet. To 8 wt%. When included in less than 1% by weight, the mixture may not be uniformly mixed, tableting may not be performed well when preparing tablets, and when it is more than 20% by weight, it may show a low dissolution rate.

In one embodiment of the present invention, the drying may be performed such that the weight of the prepared granules is reduced by 10% by weight, more preferably 5% by weight, most preferably 3% by weight or less, based on the weight before drying. have. When the reduced weight exceeds 10% by weight, problems such as quality issues due to sticking or decreasing content may be caused.

In one embodiment of the present invention, the second additive may further include, but is not limited to, at least one selected from adsorbents, stabilizers, disintegrants, sustained release agents, sweeteners, and glidants. The adsorbents, stabilizers, disintegrants, sustained release agents, sweeteners and lubricants are as defined above. The second additive may be included in an amount of 1 wt% to 20 wt%, more preferably 5 wt% to 15 wt%, and most preferably 3 wt% to 7 wt%, based on the total weight of the tablet. Can

In addition, an aspect of the present invention provides a tablet prepared by the wet granulation method from the wet granulation composition.

In one embodiment of the invention, the tablets do not suffer from sticking, mixing irregularities, and poor fluidity during manufacture by wet granulation.

In one embodiment of the present invention, the tablets use 900 mL of pH 4.0 buffer as the elution medium, the elution rate at 15 minutes when using a paddle with a rotational speed of 50 rpm is more than 80% (Q), the tablet is high density The dissolution rate may be maintained for 6 months when packaged in a polyethylene container and stored at a temperature of 40 ° C. and a relative humidity of 75%.

Tablets prepared by the conventional direct tableting method has a disadvantage in that when the particle size of the polar presink is too large (D90 is greater than about 550 μm), the dissolution rate after taking is slow. A change in dissolution rate may occur over time due to curing of the zinc particles. In addition, when the particle size of the polar presink is too small (D90 is less than about 30 μm), problems may occur in mass production such as mixing unevenness, poor fluidity, and sticking.

On the other hand, tablets prepared by the wet granulation method according to an embodiment of the present invention may exhibit a high dissolution rate despite the low solubility of the polar presink regardless of the particle size of the polar presink can further increase the bioavailability. In addition, it is possible to exhibit very desirable effects in storage stability, mass production ease, and the like.

In addition, the formulation uniformity and content uniformity appeared to be suitable, it can ensure excellent stability for the intermediate and tablets can express a stable drug efficacy.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

EXAMPLES Preparation of Tablets Containing Polar Presink

Example 1 Preparation of Tablets Containing Polar Presink Wet Granule Composition of Medium Particle Size (D90 of about 250 μm)

75.0 g of Polar Presink and 53.0 g of microcrystalline cellulose having a particle size of D90 of about 250 μm were mixed with apples to prepare a mixture. Meanwhile, a binder solution including 10.0 g of hydroxypropyl cellulose-L (HPC-L) and 72.0 g of purified water was prepared, and then combined with the mixture to prepare granules. The granules were dried in a forced circulation dryer so that the drying loss was 3% or less. After the granules were established, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed with a tablet press to make a tablet containing 75 mg of wet granules of Polar Presink.

Example 2 Preparation of Tablets Containing Wet Granule Composition of Polar Presink with Large Particle Size (D90 is about 550 μm)

A tablet containing 75 mg of wet granules was prepared in substantially the same manner as in Example 1, except that Polar Presink having a particle size of D90 of about 550 μm was used.

Example 3 Preparation of Tablets Containing Wet Granule Composition of Polar Presink with Small Particle Size (D90 is about 20 μm)

Tablets containing 75 mg of wet granules were prepared in the same manner as in Example 1, except that Polar Presink, which had a particle size of D90 of about 20 μm, was used.

Examples 4 to 44 Preparation of Tablets Containing Wet Granule Compositions of Polar Presink with Medium Particle Size (D90 of about 250 μm) Containing Various Binders

Except for using hydroxypropylcellulose-L (HPC-L) as a binder, as shown in Table 1, was carried out substantially the same as in Example 1 to contain 75 mg of wet granules of Polar Presink A tablet was prepared.

Comparative Example 1: Preparation of Tablet containing Polar Presink

75.0 g of polar presink having a particle size of D90 of about 250 μm, microcrystalline cellulose 63.0 g, crospovidone 10.0 g, and magnesium stearate 2.0 g were mixed homogeneously. The mixture was compressed with a tablet press to make a tablet containing 75 mg of Polar Presink.

Comparative Example 2: Preparation of Tablet Containing Polar Presink

A tablet containing 75 mg of Polar Presink was prepared in the same manner as in Comparative Example 1, except that Polar Presink having a particle size of D90 of about 550 μm was used.

Comparative Example 3: Preparation of Tablet containing Polar Presink

A tablet containing 75 mg of Polar Presink was prepared in the same manner as in Comparative Example 1, except that Polar Presink having a particle size of D90 of about 20 μm was used.

Table 1 below shows the composition of the tablets containing Polar Presink.

Test Example 1: Tablet Physical Property Test

Test Example 1-1: Formulation Uniformity and Content Uniformity Test

Formulation uniformity of the tablet formulation containing the wet granule composition of the polar prejink prepared in Examples 1 to 44 and the tablet formulation containing the polar prejink prepared by the direct tableting method in Comparative Examples 1 to 3 and Content uniformity test was performed. The formulation uniformity test was conducted according to the mass deviation test of the formulation uniformity test method, which is a general test method of the University Pharmacopoeia, and the content uniformity test was performed as follows.

1) Preparation of Test Solution

Take 20 tablets or more of the above-prepared tablets and weigh them precisely to make a powder, precisely weigh the amount corresponding to 100 mg, add 20 ml of 0.2 mol / L hydrochloric acid solution, shake vigorously for 10 minutes, and then centrifuge. Separated. Take 2 mL of the supernatant, add 2 mL of the internal standard solution, and add a mobile phase to make 20 mL.

2) Preparation of Standard Solution

15 mg of Polar Presink standard was precisely weighed and dissolved in 2 mL of 0.2 mol / L hydrochloric acid solution. Then, 2 mL of internal standard solution was added and the mobile phase was added to make 20 mL.

3) Preparation of internal standard solution

5 mL of acetonitrile was dissolved in 0.25 g of acetenone p-amino acid to make 100 mL of the mobile phase.

4) Liquid chromatograph conditions

4-1) Preparation of Mobile Phase

Mobile Phase A: 1.4 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, and then adjusted to pH 3.5 using diluted phosphoric acid (1/100). 2 g of 1-octane sulfonate was dissolved in 900 mL of the prepared solution, and then 100 mL of acetonitrile was added thereto. Filtration was performed with a 0.45 μm membrane filter.

4-2) Operation condition

UV detector: 210 nm

Column: Capcell Pak UG 120, 4.6 x 150 mm, 5 μm

Column temperature: 45 ° C

Sample temperature: 5 ℃

Flow rate: 0.9 mL / min

Injection volume: 5 μL

Analysis time: 20 minutes

5) System suitability

In the chromatogram obtained using 5 μL of the standard solution, the degree of separation between the p-aminoacephenone peak and the L-caronosine peak was 5 or more, the L-carnosine symmetry was 0.5 to 1.5, and the theoretical number was 2000 or more.

6) operation and detection

By using a sample solution and the standard solution 5 μL test according to the Pharmacopoeia performance liquid chromatography for the following conditions to obtain L- Caro didanosine the peak area ratio Q _R and Q _S of the peak area of the internal standard.

A _T : L-carnosine peak area in the sample solution

A _S : L-carnosine peak area in the standard solution

I _T : p-aminoacephenone peak area in the sample solution

I _S : p-aminoacephenone peak area in standard solution

W _S : Standard sample amount (mg)

W _T : Sample collection amount (mg)

W _M : 20 tablets average weight

LC: display amount (75 mg)

10: dilution drainage

Formulation uniformity (standard: 10 tablets, within 15.0% of weight deviation) Content uniformity (standard: 95.0 to 105.0%) Fit Comparative Example 1 Determination value 1.71% 103.2 ± 1.0% fitness Comparative Example 2 Judgment value 1.96% 98.0 ± 1.4% fitness Comparative Example 3 Judgment value 3.40% 98.1 ± 3.4% fitness Example 1 Decision value 1.68% 101.2 ± 1.5% fitness Example 2 Decision value 1.26% 98.6 ± 1.6% fitness Example 3 Judgment value 2.68% 99.9 ± 3.1% fitness Example 4 Judgment value 1.85% 101.0 ± 2.1% fitness Example 5 Judgment value 2.55% 101.4 ± 2.3% fitness Example 6 Judgment value 3.25% 98.4 ± 1.8% fitness Example 7 Judgment value 2.00% 99.5 ± 0.7% fitness Example 8 Judgment value 2.45% 98.1 ± 1.9% fitness Example 9 Decision value 1.88% 97.5 ± 1.2% fitness Example 10 Determination value 2.54% 96.9 ± 0.8% fitness Example 11 Determination value 3.02% 100.1 ± 1.8% fitness Example 12 Judgment value 3.00% 100.8 ± 1.8% fitness Example 13 Determination value 2.50% 100.8 ± 2.0% fitness Example 14 Judgment value 2.25% 100.4 ± 1.3% fitness Example 15 Determination value 3.01% 101.1 ± 2.2% fitness Example 16 Judgment value 1.85% 102.1 ± 1.2% fitness Example 17 Decision value 1.95% 99.1 ± 0.8% fitness Example 18 Judgment value 1.25% 97.8 ± 0.8% fitness Example 19 Judgment value 3.85% 99.8 ± 2.1% fitness Example 20 Judgment value 3.54% 99.8 ± 2.0% fitness Example 21 Determination value 4.01% 99.5 ± 1.4% fitness Example 22 Judgment value 2.25% 102.0 ± 0.7% fitness Example 23 Judgment value 2.66% 101.5 ± 1.4% fitness Example 24 Judgment value 3.00% 103.1 ± 1.1% fitness Example 25 Judgment value 1.85% 102.5 ± 1.0% fitness Example 26 Judgment value 1.96% 99.0 ± 1.8% fitness Example 27 Judgment value 2.64% 98.5 ± 0.8% fitness Example 28 Determination value 3.46% 96.9 ± 1.1% fitness Example 29 Judgment value 3.24% 100.0 ± 2.0% fitness Example 30 Judgment value 2.48% 101.5 ± 1.2% fitness Example 31 Judgment value 2.16% 99.9 ± 2.8% fitness Example 32 Determination value 2.58% 98.9 ± 2.0% fitness Example 33 Determination value 3.02% 99.0 ± 1.5% fitness Example 34 Determination value 1.58% 97.5 ± 1.5% fitness Example 35 Judgment value 2.55% 101.4 ± 2.3% fitness Example 36 Judgment value 3.45% 100.8 ± 1.9% fitness Example 37 Decision value 1.08% 99.8 ± 3.1% fitness Example 38 Judgment value 2.85% 102.1 ± 1.4% fitness Example 39 Judgment value 3.85% 100.4 ± 2.8% fitness Example 40 Judgment value 2.11% 99.5 ± 2.7% fitness Example 41 Decision value 1.89% 96.9 ± 1.0% fitness Example 42 Judgment value 2.85% 98.5 ± 1.9% fitness Example 43 Determination value 3.01% 102.1 ± 2.1% fitness Example 44 Judgment value 2.55% 101.8 ± 1.8% fitness

As shown in Table 2 above, Tablet formulations of the wet granulation composition of Polar Presink prepared by the wet granulation method (Examples 1 to 44) are equivalent to those of the Polar Presink containing tablet formulations prepared by the direct tableting method (Comparative Examples 1 to 3). It can be seen that uniformity and content uniformity are shown.

Test Example 1-2: Dissolution Rate Test

The dissolution rate of the tablet formulation containing the wet granule composition of the polar presink prepared in Examples 1 to 44 and the tablet formulation containing the polar presink prepared by the direct tableting method prepared in Comparative Examples 1 to 3 For comparison, the following experiment was conducted.

The tablet formulations of Examples 1 to 44 and Comparative Examples 1 to 3 were added to 900 mL of acetate buffer solution of pH 4.0, respectively, and maintained at 37 ± 0.5 ° C., followed by the second method of the dissolution test method of the Korean Pharmacopoeia General Test Method (paddle method). Elution test was conducted for 15 minutes at 50 revolutions per minute. Analysis of the eluted sample is shown in Table 3 by analyzing the test solution taken using HPLC.

Dissolution rate (reference: 15 minutes, 80% (Q) or more) Fit Comparative Example 1 93.0 ± 2.1% fitness Comparative Example 2 92.3 ± 1.2% fitness Comparative Example 3 94.0 ± 3.7% fitness Example 1 87.4 ± 4.1% fitness Example 2 90.4 ± 0.7% fitness Example 3 87.2 ± 2.5% fitness Example 4 93.5 ± 1.9% fitness Example 5 88.4 ± 4.1% fitness Example 6 92.2 ± 2.1% fitness Example 7 89.3 ± 1.8% fitness Example 8 91.2 ± 1.8% fitness Example 9 91.8 ± 2.8% fitness Example 10 88.5 ± 3.0% fitness Example 11 87.9 ± 2.1% fitness Example 12 94.2 ± 1.9% fitness Example 13 90.5 ± 1.7% fitness Example 14 92.4 ± 2.2% fitness Example 15 94.1 ± 2.8% fitness Example 16 93.8 ± 3.0% fitness Example 17 89.9 ± 2.1% fitness Example 18 89.1 ± 1.8% fitness Example 19 94.5 ± 0.9% fitness Example 20 92.5 ± 1.7% fitness Example 21 90.4 ± 2.4% fitness Example 22 88.9 ± 3.3% fitness Example 23 84.1 ± 1.2% fitness Example 24 81.9 ± 0.8% fitness Example 25 89.8 ± 4.2% fitness Example 26 94.3 ± 1.2% fitness Example 27 93.7 ± 1.1% fitness Example 28 97.0 ± 1.4% fitness Example 29 95.8 ± 0.9% fitness Example 30 88.4 ± 2.8% fitness Example 31 89.4 ± 2.7% fitness Example 32 88.9 ± 1.0% fitness Example 33 89.5 ± 1.8% fitness Example 34 91.8 ± 2.1% fitness Example 35 88.4 ± 4.1% fitness Example 36 89.5 ± 2.9% fitness Example 37 94.2 ± 1.1% fitness Example 38 90.5 ± 1.8% fitness Example 39 89.9 ± 2.5% fitness Example 40 85.4 ± 3.2% fitness Example 41 94.8 ± 2.8% fitness Example 42 96.1 ± 1.1% fitness Example 43 82.8 ± 1.9% fitness Example 44 88.5 ± 1.5% fitness

As shown in Table 3 above, Tablet formulations of the wet granulation composition of Polar Presink prepared by the wet granulation method (Examples 1 to 44) have a dissolution rate equivalent to that of the Polar Presink containing tablet formulations prepared by the direct tableting method (Comparative Examples 1 to 3). It can be seen that indicates. Furthermore, the tablet formulation of the polar granules wet granule composition prepared by the wet granulation method Compared to the polar pre-zinc containing tablet formulation prepared by the direct tableting method, it has been confirmed that it shows a high dissolution rate despite the low solubility of the polar pre-ink regardless of the particle size of the polar pre-jink, which can further increase the bioavailability. It is expected to be.

Test Example 2: Stability Test

Test Example 2-1: Nonhygroscopic Test

Hygroscopic properties of the tablet formulation containing the wet granule composition of polar presink prepared in Examples 1 to 44 and the tablet formulation containing polar presink prepared by the direct tableting method prepared in Comparative Examples 1 to 3 above. For comparison, the following experiment was conducted.

The tablet formulations of Examples 1 to 44 and Comparative Examples 1 to 3, respectively, were measured by Karl-Fischer moisture meter under the condition of 40 ° C. and 75% relative humidity, and are shown in Table 4 below.

Storage humidity (relative humidity 75%)
Standard: Information only Water content change (final-initial) Early After 72 hours 120 hours later Comparative Example 1 1.10% 1.23% 1.45% 0.35% Comparative Example 2 1.00% 1.10% 1.18% 0.18% Comparative Example 3 0.81% 1.20% 1.51% 0.70% Example 1 1.11% 1.17% 1.59% 0.48% Example 2 0.96% 1.18% 2.00% 1.04% Example 3 1.19% 1.73% 1.82% 0.63% Example 4 0.89% 1.64% 1.97% 1.08% Example 5 0.99% 2.01% 2.74% 1.75% Example 6 1.12% 1.54% 2.32% 1.20% Example 7 1.20% 1.18% 1.78% 0.58% Example 8 1.19% 1.42% 1.51% 0.32% Example 9 0.88% 1.20% 1.79% 0.91% Example 10 1.14% 1.73% 2.93% 2.79% Example 11 1.00% 1.82% 1.52% 0.52% Example 12 1.16% 1.15% 1.79% 0.63% Example 13 0.93% 1.80% 1.92% 0.99% Example 14 0.89% 1.69% 1.86% 0.97% Example 15 1.07% 1.57% 1.82% 0.85% Example 16 0.99% 1.27% 1.59% 0.60% Example 17 1.20% 1.56% 1.68% 0.48% Example 18 0.96% 1.43% 1.63% 0.67% Example 19 0.86% 1.37% 1.54% 0.68% Example 20 1.04% 1.94% 1.91% 0.87% Example 21 1.17% 1.55% 1.73% 0.56% Example 22 0.82% 1.70% 1.82% 1.00% Example 23 1.00% 1.69% 1.50% 0.50% Example 24 1.16% 1.96% 1.67% 0.51% Example 25 0.89% 1.52% 1.96% 1.07% Example 26 0.95% 1.17% 1.63% 0.68% Example 27 1.05% 1.84% 1.72% 0.67% Example 28 0.94% 1.13% 1.80% 0.86% Example 29 0.80% 1.55% 1.50% 0.70% Example 30 1.08% 1.80% 1.69% 0.61% Example 31 0.84% 1.57% 1.83% 0.99% Example 32 1.09% 1.12% 1.67% 0.58% Example 33 1.15% 1.14% 2.91% 1.76% Example 34 0.81% 1.44% 3.11% 2.30% Example 35 0.99% 2.01% 2.74% 1.75% Example 36 1.24% 1.94% 2.75% 1.55% Example 37 1.01% 1.90% 1.50% 0.49% Example 38 0.88% 1.88% 1.93% 1.05% Example 39 0.64% 1.87% 1.72% 1.08% Example 40 0.91% 2.01% 1.63% 0.72% Example 41 0.81% 1.22% 1.68% 0.87% Example 42 0.88% 1.94% 1.79% 0.91% Example 43 1.17% 1.58% 1.90% 0.73% Example 44 0.94% 1.17% 1.77% 0.83%

As shown in Table 4, the tablet formulation (Examples 1 to 44) of the polar granules wet granules composition prepared by the wet granulation method is a polar presink containing tablet formulation prepared by the direct tableting method (Comparative Example 1 It can be seen that the results show a non-hygroscopic result equivalent to 3).

Test Example 2-2: Test for confirming the change of tablet dissolution rate over time during accelerated storage

The dissolution rate of the tablet formulation containing the wet granule composition of the polar presink prepared in Examples 1 to 44 and the tablet formulation containing the polar presink prepared by the direct tableting method prepared in Comparative Examples 1 to 3 For comparison, the following experiment was conducted.

The tablet formulations of Examples 1 to 44, and Comparative Examples 1 to 3, respectively, were packed together with silica gel in a high-density polyethylene container and stored at 40 ° C. and 75% relative humidity, and then stored for 1 month, 2 months, and 3 months. After six months and six months, a part was taken out and the dissolution rate test was performed.

Dissolution rate (reference: 15 minutes, 80% (Q) or more) /
Storage condition (40 ℃, relative humidity 75%) Dissolution test result (six months) Early 1 month 3 months 6 months Comparative Example 1 93.0 ± 2.1% 92.8% 91.5% 93.2% fitness Comparative Example 2 92.3 ± 1.2% 92.1% 81.3% 70.4% incongruity Comparative Example 3 94.0 ± 3.7% 94.5% 84.5% 79.4% incongruity Example 1 87.4 ± 4.1% 91.7% 99.6% 92.2% fitness Example 2 90.4 ± 0.7% 89.4% 94.6% 96.9% fitness Example 3 87.2 ± 2.5% 91.7% 93.4% 95.2% fitness Example 4 93.5 ± 1.9% 94.1% 88.0% 86.2% fitness Example 5 88.4 ± 4.1% 82.5% 82.7% 84.2% fitness Example 6 93.2 ± 1.2% 84.5% 81.5% 80.8% fitness Example 7 89.3 ± 1.8% 98.5% 89.0% 89.8% fitness Example 8 91.2 ± 1.8% 94.1% 91.7% 87.2% fitness Example 9 91.8 ± 2.8% 98.0% 99.8% 99.2% fitness Example 10 88.5 ± 3.0% 92.0% 86.2% 82.2% fitness Example 11 87.9 ± 2.1% 89.2% 97.4% 95.4% fitness Example 12 94.2 ± 1.9% 88.7% 89.9% 85.7% fitness Example 13 90.5 ± 1.7% 90.7% 98.8% 91.3% fitness Example 14 92.4 ± 2.2% 87.8% 96.0% 95.7% fitness Example 15 94.1 ± 2.8% 88.0% 88.1% 82.7% fitness Example 16 93.8 ± 3.0% 95.8% 98.3% 90.9% fitness Example 17 89.9 ± 2.1% 92.2% 87.1% 95.3% fitness Example 18 89.1 ± 1.8% 90.7% 84.9% 95.6% fitness Example 19 94.5 ± 0.9% 84.5% 91.9% 87.6% fitness Example 20 92.5 ± 1.7% 86.6% 97.8% 88.8% fitness Example 21 90.4 ± 2.4% 97.3% 93.7% 95.9% fitness Example 22 88.9 ± 3.3% 99.7% 97.5% 93.9% fitness Example 23 84.1 ± 1.2% 84.0% 90.5% 91.6% fitness Example 24 81.9 ± 0.8% 99.4% 94.6% 91.8% fitness Example 25 89.8 ± 4.2% 87.6% 87.5% 97.0% fitness Example 26 94.3 ± 1.2% 85.3% 82.6% 81.1% fitness Example 27 93.7 ± 1.1% 87.1% 89.5% 85.3% fitness Example 28 97.0 ± 1.4% 92.4% 98.9% 97.7% fitness Example 29 95.8 ± 0.9% 98.8% 86.7% 85.4% fitness Example 30 88.4 ± 2.8% 87.5% 85.3% 96.9% fitness Example 31 89.4 ± 2.7% 90.3% 88.4% 84.4% fitness Example 32 88.9 ± 1.0% 93.9% 93.6% 94.1% fitness Example 33 89.5 ± 1.8% 85.0% 86.4% 82.0% fitness Example 34 91.8 ± 2.1% 84.5% 83.2% 87.0% fitness Example 35 88.4 ± 4.1% 82.5% 82.7% 84.2% fitness Example 36 89.5 ± 2.9% 89.0% 84.5% 86.6% fitness Example 37 94.2 ± 1.1% 88.9% 86.6% 89.5% fitness Example 38 90.5 ± 1.8% 90.8% 90.2% 94.3% fitness Example 39 89.9 ± 2.5% 92.1% 89.5% 94.8% fitness Example 40 85.4 ± 3.2% 86.5% 82.8% 84.8% fitness Example 41 94.8 ± 2.8% 86.9% 91.5% 88.1% fitness Example 42 96.1 ± 1.1% 86.1% 91.5% 87.3% fitness Example 43 82.8 ± 1.9% 90.9% 91.0% 85.9% fitness Example 44 88.5 ± 1.5% 84.5% 86.5% 81.8% fitness

As shown in Table 5, the tablet formulation (Examples 1 to 44) of the polar granules wet granule composition prepared by the wet granulation method is a polar presink containing tablet formulation prepared by direct tableting method (Comparative Example 1 To 3) and the change over time for dissolution rate under accelerated conditions was compared. As a result, all tablet formulations prepared by the wet granulation method showed the dissolution rate results of the suitable level. On the other hand, in Comparative Examples 2 and 3, which are tablet formulations prepared by direct tableting, the dissolution rate decreased over time, indicating an inadequate dissolution rate result. Through this, it can be confirmed that excellent stability for the tablet formulation of the wet granule composition of Polar Presink can express a stable drug efficacy.

Test Example 2-3: Flexible Material Test (Intermediate)

Stability of the tablet formulations containing the wet granule composition of the polar presink prepared in Examples 1 to 44 and the polar formulations prepared by the direct compression method prepared in Comparative Examples 1 to 3 For comparison, the following experiment was conducted.

The intermediates immediately before the preparation of tablets in the tablet formulation preparation process of Examples 1 to 44, and Comparative Examples 1 to 3 were stored for a period of time according to the respective storage conditions, and then analyzed using HPLC according to a flexible material test method. 6 is shown.

1) Preparation of Test Solution

Take 3.00 g (corresponding to about 20 tablets) of the intermediate just before the preparation of tablets, and accurately weigh 50 mg (25 mg as polar preze) and add 5 mL of 0.1 mol / L hydrochloric acid solution. After melting, mobile phase was added to make 50 mL. After ultrasonic extraction for 10 minutes, it was filtered through a 0.2 μm membrane filter to obtain a sample solution.

2) Preparation of Standard Solution

25 mg of Polar Presink standard was precisely weighed and dissolved in 5 mL of 0.1 mol / L hydrochloric acid solution, and then the mobile phase was added to make 50 mL. After ultrasonic extraction for 10 minutes, 1 mL of the supernatant was taken into a 100 mL volumetric flask, and a mobile phase was added to make 100 mL. Filtration with a 0.2 μm membrane filter gave a standard solution.

3) System compatibility solution preparation

7.5 mg of L-histidine was placed in a 100 mL volumetric flask, followed by ultrasonic extraction for 10 minutes (100 μg / mL concentration of L-histidine solution) by adding a mobile phase to 100 mL. Separately, weigh 25 mg of Polar Presink standard and add 5 mL of 0.1 mol / L hydrochloric acid solution to dissolve it, add 1 mL of 75 μg / mL concentration of L-histidine solution, and add a mobile phase to make 50 mL. After ultrasonic extraction for 10 minutes, it was filtered through a 0.2 μm membrane filter to obtain a system compatibility solution.

4) Liquid chromatograph conditions

4-1) Preparation of Mobile Phase

Mobile Phase A: 1.4 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, and then adjusted to pH 3.5 using diluted phosphoric acid (1/100). 2 g of 1-octane sulfonate was dissolved in 900 mL of the prepared solution, and then 100 mL of acetonitrile was added thereto. It is used by filtration with 0.45 micrometer membrane filter.

Mobile Phase B: Acetonitrile

Mobile phase A: Mobile phase B = 95: 5 (v / v)

4-2) Operation condition

UV detector: 210 nm

Column: Waters ACQUITY UPLC® BEH C18, 2.1 x 100 mm, 1.7 μm

Column temperature: 45 ° C

Sample temperature: 5 ℃

Flow rate: 0.3 mL / min

Injection volume: 1 μL

Analysis time: 10 minutes

5) System suitability

The separation degree of L-carnosine peak and L-histidine peak in chromatogram obtained using 1 μL of system compatibility solution is 7 or more, and the symmetry of L-caronosine peak in chromatogram obtained using 1 μL of standard solution is 0.5 to 1.5. The theoretical singular number was over 2000.

6) operation and detection

Using 1 μL of the sample solution and the standard solution, the test was performed according to the pharmacopeia liquid chromatography method under the following conditions, and the peak area ratio of each flexible substance to the peak area of the standard solution was determined.

A _S : L-carnosine peak area of the standard solution

A _T : peak area of flexible substance in sample solution

W _S : Polar Pre-Zink Standard Sample Collection (mg)

W _T : Sample collection amount (mg)

LC: display amount (75)

W _M : average weight of 20 tablets (mg)

0.01: dilution factor of the standard

Total Flexible Material Storage condition (40 ℃, relative humidity 75%) /
Standard: Less than 1.0% of total flexible materials Fit Early 1 month 3 months 6 months Comparative Example 1 0.25% 0.25% 0.38% 0.25% fitness Comparative Example 2 0.28% 0.39% 0.42% 0.28% fitness Comparative Example 3 0.30% 0.20% 0.22% 0.30% fitness Example 1 0.23% 0.38% 0.40% 0.23% fitness Example 2 0.30% 0.30% 0.43% 0.30% fitness Example 3 0.21% 0.20% 0.40% 0.21% fitness Example 4 0.35% 0.32% 0.23% 0.35% fitness Example 5 0.68% 0.58% 0.69% 0.90% fitness Example 6 0.24% 0.42% 0.64% 0.68% fitness Example 7 0.31% 0.22% 0.21% 0.31% fitness Example 8 0.18% 0.32% 0.24% 0.18% fitness Example 9 0.30% 0.21% 0.23% 0.30% fitness Example 10 0.16% 0.29% 0.45% 0.66% fitness Example 11 0.25% 0.37% 0.35% 0.25% fitness Example 12 0.22% 0.34% 0.40% 0.22% fitness Example 13 0.26% 0.35% 0.41% 0.26% fitness Example 14 0.17% 0.29% 0.29% 0.17% fitness Example 15 0.16% 0.32% 0.36% 0.46% fitness Example 16 0.27% 0.26% 0.37% 0.27% fitness Example 17 0.19% 0.24% 0.30% 0.19% fitness Example 18 0.33% 0.19% 0.33% 0.33% fitness Example 19 0.23% 0.39% 0.21% 0.23% fitness Example 20 0.14% 0.32% 0.31% 0.14% fitness Example 21 0.17% 0.29% 0.22% 0.17% fitness Example 22 0.23% 0.34% 0.22% 0.23% fitness Example 23 0.23% 0.26% 0.27% 0.23% fitness Example 24 0.13% 0.36% 0.30% 0.13% fitness Example 25 0.18% 0.24% 0.33% 0.18% fitness Example 26 0.15% 0.33% 0.31% 0.49% fitness Example 27 0.25% 0.30% 0.40% 0.25% fitness Example 28 0.13% 0.34% 0.24% 0.13% fitness Example 29 0.34% 0.31% 0.22% 0.34% fitness Example 30 0.17% 0.23% 0.28% 0.17% fitness Example 31 0.20% 0.35% 0.35% 0.20% fitness Example 32 0.25% 0.25% 0.45% 0.25% fitness Example 33 0.47% 0.43% 0.43% 0.87% fitness Example 34 0.62% 0.78% 0.64% 0.72% fitness Example 35 0.68% 0.58% 0.69% 0.90% fitness Example 36 0.43% 0.34% 0.49% 0.64% fitness Example 37 0.12% 0.17% 0.22% 0.28% fitness Example 38 0.06% 0.19% 0.19% 0.28% fitness Example 39 0.17% 0.21% 0.28% 0.17% fitness Example 40 0.15% 0.21% 0.31% 0.33% fitness Example 41 0.19% 0.22% 0.28% 0.29% fitness Example 42 0.33% 0.38% 0.31% 0.24% fitness Example 43 0.45% 0.12% 0.30% 0.29% fitness Example 44 0.34% 0.42% 0.44% 0.58% fitness

Test Example 2-4: Flexible Material Test (Tablet)

Stability of the tablet formulations containing the wet granule composition of the polar presink prepared in Examples 1 to 44 and the polar formulations prepared by the direct compression method prepared in Comparative Examples 1 to 3 For comparison, the following experiment was conducted.

The tablet formulations of Examples 1 to 44 and Comparative Examples 1 to 3 were stored for a period of time according to their respective storage conditions, and analyzed using HPLC according to a flexible material test method.

When preparing the sample solution, take 20 tablets or more tablets and weigh them precisely to make a powder. Mobile phase was added to make 50 mL. After ultrasonic extraction for 10 minutes, it was filtered through a 0.2 μm membrane filter to obtain a sample solution. Except for this, the process was carried out substantially the same as the method conducted in the above test.

Total Flexible Material Storage condition (60 ℃)
Standard: Information only Increase in comparison with the beginning of lead material Early 1 week 3 weeks Comparative Example 1 0.19% 0.14% 0.49% 0.31% Comparative Example 2 0.15% 0.12% 0.38% 0.23% Comparative Example 3 0.15% 0.28% 0.42% 0.27% Example 1 0.19% 0.12% 0.38% 0.19% Example 2 0.15% 0.15% 0.38% 0.23% Example 3 0.18% 0.21% 0.36% 0.18% Example 4 0.18% 0.12% 0.38% 0.19% Example 5 0.12% 0.97% 1.37% 1.24% Example 6 0.28% 0.42% 0.88% 0.60% Example 7 0.12% 0.18% 0.42% 0.29% Example 8 0.11% 0.21% 0.31% 0.20% Example 9 0.17% 0.21% 0.37% 0.20% Example 10 0.20% 0.94% 1.55% 1.36% Example 11 0.18% 0.12% 0.36% 0.19% Example 12 0.14% 0.17% 0.32% 0.18% Example 13 0.13% 0.22% 0.31% 0.17% Example 14 0.15% 0.12% 0.39% 0.25% Example 15 0.16% 0.27% 0.47% 0.31% Example 16 0.15% 0.14% 0.48% 0.33% Example 17 0.12% 0.28% 0.47% 0.35% Example 18 0.12% 0.16% 0.49% 0.37% Example 19 0.19% 0.27% 0.39% 0.20% Example 20 0.17% 0.21% 0.37% 0.20% Example 21 0.18% 0.11% 0.40% 0.21% Example 22 0.20% 0.18% 0.42% 0.22% Example 23 0.12% 0.13% 0.39% 0.27% Example 24 0.20% 0.27% 0.30% 0.10% Example 25 0.11% 0.22% 0.31% 0.21% Example 26 0.11% 0.16% 0.34% 0.33% Example 27 0.13% 0.21% 0.49% 0.36% Example 28 0.17% 0.13% 0.35% 0.17% Example 29 0.15% 0.21% 0.40% 0.26% Example 30 0.13% 0.27% 0.46% 0.34% Example 31 0.17% 0.18% 0.35% 0.19% Example 32 0.15% 0.22% 0.48% 0.33% Example 33 0.17% 0.45% 0.97% 0.8% Example 34 0.11% 0.43% 0.81% 0.70% Example 35 0.12% 0.97% 1.37% 1.24% Example 36 0.16% 0.87% 1.41% 1.25% Example 37 0.19% 0.15% 0.39% 0.20% Example 38 0.15% 0.13% 0.47% 0.32% Example 39 0.13% 0.26% 0.46% 0.32% Example 40 0.12% 0.12% 0.44% 0.32% Example 41 0.17% 0.17% 0.43% 0.26% Example 42 0.15% 0.30% 0.34% 0.19% Example 43 0.18% 0.20% 0.43% 0.25% Example 44 0.18% 0.22% 0.73% 0.55%

As shown in Tables 6 and 7, above, the tablet formulation of the wet granule composition of Polar Presink prepared by the wet granulation method (Examples 1 to 44) was prepared by the polar tableting containing tablet formulation (comparatively). It can be seen that the stability results for intermediates and tablets equivalent to Examples 1 to 3) are shown. Through this, it can be confirmed that excellent stability for the tablet formulation of the wet granule composition of Polar Presink can express a stable drug efficacy.

Test Example 3: Manufacturing Process

Test Example 3-1: Test concerning the occurrence of sticking

Sticking to the tablet formulation containing the wet granules composition of the polar presink prepared in Examples 1 to 44 and the tablet formulation containing polar presink prepared by the direct tableting method prepared in Comparative Examples 1 to 3 The following experiments were conducted to compare the occurrences.

As a result of checking whether the tablets of Examples 1 to 44 and Comparative Examples 1 to 3 each had problems during the preparation of 1,000 tablets, the Comparative Examples and Examples did not cause problems due to sticking.

Test Example 3-2: Test on Fluidity

The fluidity of the tablet formulation containing the wet granule composition of the polar prejink prepared in Examples 1 to 44 and the tablet formulation containing the polar presink prepared by the direct tableting method prepared in Comparative Examples 1 to 3 above. For comparison, the following experiment was conducted.

As a result of checking whether the tablets of Examples 1 to 44 and Comparative Examples 1 to 3 had problems while preparing 1,000 tablets, the Comparative Examples and Examples did not cause problems due to poor fluidity.

As a result, compared to the direct tableting method, the tablet formulation of the Paula Presink wet granulation composition prepared by the wet granulation method has the advantage of relatively accurate weighing due to its low scattering property, good fluidity, and uniform particle size. have. In addition, unlike the direct tableting method, it was confirmed that the tablets produced by the wet granulation method exhibited a high dissolution rate in spite of the low solubility of Polar Presink without being limited to the size in the particle size. Through this, it was confirmed that the tablet formulation that can increase the bioavailability, can maintain a stable productivity and high stability to express a stable drug efficacy. In addition, it was confirmed that the storage stability of the intermediate is very good due to the small surface area, it is expected to be able to express a stable drug by maintaining a smooth productivity and high stability.

Claims (16)

Polaprezinc, Wet granules composition comprising a pharmaceutically acceptable first additive and a binder. The method of claim 1,
Wherein said binder is at least one selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose and polyvinylpyrrolidone (povidone). The method of claim 1,
Wherein the binder comprises from 1% to 20% by weight, based on the total weight of solids of the composition. The method of claim 1,
Wherein the first additive is one or more excipients selected from microcrystalline cellulose, starch, low-substituted hydroxypropylcellulose, dextrose, lactose, mannitol and crospovidone. The method of claim 1,
The wet granules composition, wherein the polar prejink is contained in 30% to 70% by weight based on the total weight of solids of the composition. The method of claim 1,
The wet granules composition further comprises at least one second additive selected from adsorbents, stabilizers, disintegrants, sustained release agents, sweeteners and lubricants. a) mixing the polarpresink and the pharmaceutically acceptable first additive to produce a mixture;
b) preparing a wet granulated composition using a binder solution including a binder and purified water;
c) drying the composition to obtain granules;
d) adding a pharmaceutically acceptable second additive to the granules; And
e) tableting the resultant of step d) to form a tablet. The method of claim 7, wherein
Wherein the first additive is one or more excipients selected from microcrystalline cellulose, starch, low substituted hydroxypropyl cellulose, dextrose, lactose, mannitol and crospovidone. The method of claim 7, wherein
The binder is at least one selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone. The method of claim 7, wherein
Wherein the binder comprises from 1% to 20% by weight, based on the total weight of the tablet. The method of claim 7, wherein
The drying is carried out such that the weight of the prepared granules is reduced by 10% by weight or less based on the weight before drying. The method of claim 7, wherein
The second additive further comprises at least one selected from adsorbents, stabilizers, disintegrants, sustained release agents, sweeteners and lubricants. A tablet prepared by the wet granulation method from the wet granulation composition of claim 1. The method of claim 13,
Wherein the tablet does not suffer from sticking, mixing irregularities, and poor fluidity during manufacture by wet granulation. The method of claim 13,
The purification was performed using 900 mL of pH 4.0 buffer as the elution medium, and the elution rate at 15 minutes when using the paddle at a rotational speed of 50 rpm is 80% (Q) or more. The method of claim 15,
Wherein the tablet is packaged in a high density polyethylene container to maintain the dissolution rate for 6 months when stored at 40 ° C. and 75% relative humidity conditions.