KR20200002486A - Wet granulation composition, tablet comprising same, and method for preparing the tablet - Google Patents

Abstract

The present invention relates to a wet granulation composition, a tablet containing the same, and a method for manufacturing the tablet. More particularly, the present invention relates to: a wet granulation composition manufactured by a binder having excellent compatibility with polaprezinc, which has polaprezinc a main raw material; a tablet containing the same; and a method for manufacturing the tablet. When the tablet is manufactured by using a wet composition, it is possible to provide the tablet 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, it is possible to maintain high stability against heat, moisture, UV, VIS, etc. thereby being able to exhibit smooth productivity and stable medicinal efficacy.

Description

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

The present invention relates to a wet granulation composition, a tablet containing the same, and a method for preparing the tablet, and more particularly, to a wet granulation composition prepared by a binder having excellent compatibility with Polar Presink as a main raw material, It relates to a safe tablet containing and a method for producing the tablet.

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. 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 polar presink raw material, it is difficult to produce a product by uniformly standardizing the particle size of the polar presink according to various reaction conditions, production methods, and post-treatment. Accordingly, tablets have been developed using the wet granulation method, which exhibit high dissolution rate and high stability and excellent drug efficacy regardless of the polar solubility of polar presink regardless of particle size. However, tablets prepared by the wet granulation method may have a disadvantage in that they do not maintain high stability in content, soft substances, elution, color, etc. when left in a long-term high temperature to high humidity conditions or long term UV to VIS conditions during the stability test. . Accordingly, there is an urgent need to develop stable tablets capable of expressing excellent efficacy regardless of the particle size of polar presink and maintaining high stability against heat, moisture, UV, VIS, and the like.

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

Accordingly, the present inventors found that the wet granulation composition of Polar Presink prepared by the wet granulation method using a binder having excellent compatibility with Polar Presink is high despite the low solubility of Polar Presink regardless of the particle size of Polar Presink. It was found that not only showed dissolution rate but also high stability against heat, moisture, UV, VIS and the like, and completed the present invention by preparing a stable tablet containing the wet granule composition.

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

In addition, the present invention comprises the steps of a) preparing a wet granulation composition by mixing polar presink, excipient and binder; b) drying the composition to obtain granules; c) adding disintegrants, glidants or both to the granules; And d) tableting the resultant of step c) 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 exhibiting a high dissolution rate despite the low solubility of the Polar Presink regardless of the particle size of the Polar Presink, and provides a tablet that can express a stable drug by maintaining a smooth productivity and high stability can do.

In particular, the present invention provides a tablet by wet granulation method with a binder having excellent compounding compatibility with polar presink, microcrystalline cellulose, crospovidone, magnesium stearate, and polar presink, thereby providing heat, moisture, UV, VIS It is possible to provide a tablet of the polar granules wet granule composition that can maintain high stability and excellent manufacturing processability and tablet properties.

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 present invention provides a wet granulation composition comprising polar presink, an excipient 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, lactose monohydrate, isomalt, anhydrous lactose, lactose hydrate, low substituted hydroxypropyl cellulose, maltodextrin, methyl cellulose, methyl hydroxyethyl cellulose, One or more selected from poly (ethylene) glycol, polyethylene glycol, polyvinyl alcohol, povidone, gelatinized starch, prosolve, sodium alginate, corn starch, sucrose, talc and xanthan gum can be used, cellulose, croscarmellose Os sodium, hydroxy More preferably, but not limited to, one or more selected from peel cellulose, hydroxypropylmethyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose LH-11 and LH-12, gelatinized starch, corn starch and talc .

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 excipient may be one or more excipients selected from microcrystalline cellulose, starch, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose-L, dextrose, starch, lactose and mannitol, It is not limited to this. 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 disintegrants selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate, but It is not limited.

The wet granulation composition may further include one or more additives selected from adsorbents, stabilizers, sustained release agents, sweeteners and glidants.

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 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) preparing a wet granulation composition by mixing polar presink, excipient and binder; b) drying the composition to obtain granules; c) adding disintegrants, glidants or both to the granules; And d) tableting the resultant of step c) to form a tablet.

In one embodiment of the invention, the binder is a cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose LH-11 and LH-12 One or more selected from gelatinized starch, corn starch and talc may be used, but is not limited thereto.

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 excipient may be one or more excipients selected from microcrystalline cellulose, starch, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose-L, dextrose, starch, lactose and mannitol, It is not limited to this. 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 invention, in step a) One or more disintegrants selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate can be further mixed, but is not limited thereto.

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 invention, the disintegrant is at least one selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate, and the state lubricant is magnesium stearate, stearyl Sodium fumarate, colloidal silicon dioxide, talc, stearyl fumarate sodium, aluminum magnesium silicate, stearic acid and sucrose fatty acid esters, but are not limited thereto.

The disintegrant 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% to 8 wt%, based on the total weight of the tablet. have. The glidant may be included in 0.1 to 5% by weight, more preferably 0.5 to 3% by weight, most preferably 1 to 3% by weight based on the total weight of the tablet.

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 12 months when packaged in a polyethylene container and stored at a temperature of 40 ° C. and a relative humidity of 75%.

In one embodiment of the present invention, the tablet does not have a color change over time under a temperature of at least 80 ℃, a relative humidity of at least 75%, UV and VIS conditions have excellent stability.

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 can overcome the drawbacks of the direct tableting method, but the content, softening material, elution, color when left in a long-term high temperature to high humidity conditions or long-term UV to VIS conditions during stability tests It may be difficult to maintain high stability on the back.

However, tablets prepared by the wet granulation method using a binder having excellent compatibility with Polar Presink are excellent in manufacturing due to the advantages of less scattering, good fluidity, and uniform weighing due to their uniform particle size. Fairness. In addition, it exhibits excellent formulation uniformity and content uniformity without being limited to the particle size, and shows high dissolution rate in spite of the low solubility of Polar Presink regardless of the particle size of Polar Presink. have. Furthermore, it has excellent non-hygroscopicity and stability, and can exhibit high stability without color change over time even when exposed to UV to VIS for a long time, and thus, there is an advantage in that a stable drug can be expressed.

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.

Comparative Example 1 Preparation of Tablets Containing Polar Presink Wet Granule Composition Comprising Hydroxypropylcellulose-L (HPC-L) as Binder (Particle Size (D90) About 250 μm)

A mixture was prepared by mixing apples with 75.0 g of Polar Presink and 53.0 g of microcrystalline cellulose having a particle size of D90 of about 250 μm. Thereafter, a binder solution containing 10.0 g of HPC-L and 90.0 g of purified water was prepared as a binder to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules comprising 75 mg of Polar Presink.

Comparative Example 2: Preparation of Tablet Containing Polar Presink Wet Granule Composition Comprising Polyvinylpyrrolidone (PVP K30) as Binder (Particle Size (D90) about 250 μm)

Except for using polyvinylpyrrolidone (PVP K30) as a binder, a tablet containing 75 mg of wet granules was prepared in the same manner as in Comparative Example 1 above.

EXAMPLES Preparation of Tablets Containing Polar Presink Wet Granule Compositions Comprising a Binder with Good Compatibility with Polar Presink

Examples 1 to 10 Preparation of Tablets Containing Polarpresink Wet Granule Composition Without Crospovidone As Disintegrant (Particle Size (D90) About 250 μm)

A mixture was prepared by mixing apples with 75.0 g of Polar Presink and 53.0 g of microcrystalline cellulose having a particle size of D90 of about 250 μm. Thereafter, a binder solution containing 10.0 g of binder and 90.0 g of purified water was prepared to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. After the granulation was established, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The compositions of the tablets prepared in Examples 1 to 10 are shown in Table 1 below.

Examples 11-20: Preparation of Tablets Containing Polarpresink Wet Granule Composition Comprising Crospovidone as Disintegrant (Particle Size (D90) About 250 μm)

75.0 g of Polar Presink, 53.0 g of microcrystalline cellulose, and 10.0 g of crospovidone having a particle size of D90 of about 250 μm were mixed with apples to prepare a mixture. Thereafter, a binder solution containing 10.0 g of binder and 90.0 g of purified water was prepared to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 2.0 g of magnesium stearate was mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The compositions of the tablets prepared in Examples 11 to 20 are shown in Table 1 below.

Examples 21 and 25: Preparation of Tablets Containing Polarpresink Wet Granule Composition Without Disintegrating Crospovidone (Particle Size (D90) About 550 μm)

A mixture was prepared by mixing apples with 75.0 g of Polar Presink and 53.0 g of microcrystalline cellulose having a particle size of D90 of about 550 μm. Thereafter, a binder solution containing 10.0 g of binder and 90.0 g of purified water was prepared to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed using a suitable tabletting machine to prepare tablets containing wet granules containing 75 mg of Polar Presink. The compositions of the tablets prepared in Examples 21 and 25 are shown in Table 2 below.

Examples 22 and 26 Preparation of Tablets Containing Polarpresink Wet Granule Composition Without Crospovidone As Disintegrant (Granular Size (D90) About 30 μm)

A mixture was prepared by mixing apples with 75.0 g of Polar Presink and 53.0 g of microcrystalline cellulose having a particle size of D90 of about 30 μm. Thereafter, a binder solution containing 10.0 g of binder and 90.0 g of purified water was prepared to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The compositions of the tablets prepared in Examples 21 and 25 are shown in Table 2 below.

Examples 23 and 27: Preparation of Tablets Containing Polarpresink Wet Granule Composition Comprising Crospovidone as Disintegrant (Granular Size (D90) About 550 μm)

75.0 g of Polar Presink, 53.0 g of microcrystalline cellulose, and 10.0 g of crospovidone having a particle size of D90 of about 550 µm were mixed with apples to prepare a mixture. Thereafter, a binder solution containing 10.0 g of binder and 90.0 g of purified water was prepared to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 2.0 g of magnesium stearate was mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The compositions of the tablets prepared in Examples 23 and 27 are shown in Table 2 below.

Examples 24 and 28: Preparation of tablets containing Polarpresink wet granule composition comprising crospovidone as disintegrant (particle size (D90) about 20 μm)

75.0 g of Polar Presink, 53.0 g of microcrystalline cellulose, and 10.0 g of crospovidone having a particle size of D90 of about 20 μm were mixed with apples to prepare a mixture. Thereafter, a binder solution containing 10.0 g of binder and 90.0 g of purified water was prepared to associate with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 2.0 g of magnesium stearate was mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The compositions of the tablets prepared in Examples 24 and 28 are shown in Table 2 below.

Example 29 Preparation of a Tablet Containing a Polar Presink Wet Granule Composition Comprising No Crospovidone as Disintegrant (Particle Size (D90) About 250 μm)

A mixture was prepared by mixing apples with 75.0 g of Polar Presink and 58.0 g of microcrystalline cellulose having a particle size of D90 of about 250 μm. Thereafter, a binder solution containing 5.0 g of a binder and 90.0 g of purified water was prepared, and then combined with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. After the granulation was established, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The composition of the tablet prepared in Example 29 is shown in Table 2 below.

Example 30 Preparation of a Tablet Containing a Polar Presink Wet Granule Composition Comprising Crospovidone as a Disintegrant (particle size (D90) about 250 μm)

75.0 g of Polar Presink, 58.0 g of microcrystalline cellulose and 10.0 g of crospovidone having a particle size of D90 of about 250 μm were mixed with apples to prepare a mixture. Thereafter, a binder solution containing 5.0 g of a binder and 90.0 g of purified water was prepared, and then combined with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 2.0 g of magnesium stearate was mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The composition of the tablet prepared in Example 29 is shown in Table 2 below.

Example 31 Preparation of Tablets Containing Polarpresink Wet Granule Composition Without Crospovidone as Disintegrant (Granular Size (D90) About 250 μm)

75.0 g of Polar Presink and 48.0 g of microcrystalline cellulose having a particle size of D90 of about 250 μm were mixed with apples to prepare a mixture. Thereafter, a binder solution containing 15.0 g of binder and 90.0 g of purified water was prepared, and then combined with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. After the granulation was established, 10.0 g of crospovidone and 2.0 g of magnesium stearate were mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The composition of the tablet prepared in Example 31 is shown in Table 2 below.

Example 32 Preparation of a Tablet Containing a Polar Presink Wet Granule Composition Comprising Crospovidone as a Disintegrant (particle size (D90) about 250 μm)

75.0 g of Polar Presink, 48.0 g of microcrystalline cellulose and 10.0 g of crospovidone having a particle size of D90 of about 250 μm were mixed with apples to prepare a mixture. Thereafter, a binder solution containing 15.0 g of binder and 90.0 g of purified water was prepared, and then combined with the mixture to prepare a wet granule composition. The composition was dried with a forced circulation dryer to achieve a drying loss of 3% or less. Thereafter, 2.0 g of magnesium stearate was mixed homogeneously. The mixture was compressed using a suitable tabletting machine to make tablets containing wet granules containing 75 mg of Polar Presink. The composition of the tablet prepared in Example 29 is shown in Table 2 below.

Test Example 1: Tablet Physical Property Test

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

Formulation uniformity and content uniformity tests of the tablets containing the wet granule composition of the Polar Presink prepared in Examples 1 to 32 and the tablets containing the Polar Presink prepared in Comparative Examples 1 and 2 were 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 Example 1 Judgment value 3.70% 102.0% ± 1.8% fitness Example 2 Judgment value 3.95% 102.1% ± 2.2% fitness Example 3 Determination value 4.23% 97.8% ± 3.4% fitness Example 4 Judgment value 2.95% 99.0% ± 3.1% fitness Example 5 Judgment value 2.99% 102.6% ± 1.7% fitness Example 6 Decision value 1.79% 99.5% ± 2.2% fitness Example 7 Decision value 1.98% 97.2% ± 1.9% fitness Example 8 Determination value 2.32% 102.1% ± 0.8% fitness Example 9 Determination value 4.38% 99.5% ± 1.7% fitness Example 10 Determination value 2.24% 100.7% ± 2.9% fitness Example 11 Determination value 4.09% 99.6% ± 2.6% fitness Example 12 Determination value 4.24% 98.8% ± 3.1% fitness Example 13 Determination value 3.36% 98.2% ± 1.5% fitness Example 14 Judgment value 3.59% 101.1% ± 0.9% fitness Example 15 Decision value 1.55% 102.5% ± 1.7% fitness Example 16 Decision value 1.17% 97.3% ± 2.8% fitness Example 17 Determination value 3.04% 97.2% ± 2.2% fitness Example 18 Judgment value 2.60% 97.5% ± 1.8% fitness Example 19 Determination value 2.54% 98.4% ± 3.1% fitness Example 20 Decision value 1.06% 100.1% ± 2.7% fitness Example 21 Determination value 2.86% 97.3% ± 1.9% fitness Example 22 Determination value 3.33% 99.4% ± 2.8% fitness Example 23 Decision value 1.55% 102.0% ± 2.1% fitness Example 24 Judgment value 2.19% 101.3% ± 1.1% fitness Example 25 Determination value 1.62% 98.0% ± 1.0% fitness Example 26 Judgment value 3.19% 101.0% ± 1.3% fitness Example 27 Determination value 4.44% 102.1% ± 1.8% fitness Example 28 Decision value 4.90% 99.7% ± 2.0% fitness Example 29 Determination value 3.86% 99.2% ± 1.1% fitness Example 30 Determination value 3.73% 101.9% ± 2.0% fitness Example 31 Judgment value 2.48% 100.7% ± 1.9% fitness Example 32 Judgment value 2.66% 98.0% ± 2.3% fitness

As shown in Table 3 above, It can be seen that the tablets containing the wet granule composition of Polar Presink prepared in Examples 1 to 32 exhibited formulation uniformity and content uniformity at the same level as Comparative Examples 1 and 2.

Test Example 1-2: Dissolution Rate Test

Dissolution rate tests were performed on the tablets containing the wet granule composition of Polar Presink prepared in Examples 1 to 32 and the tablets containing Polar Presink prepared in Comparative Examples 1 and 2.

The tablets of Examples 1 to 32 and Comparative Examples 1 and 2 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). The dissolution 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 Example 1 90.4 ± 2.5% fitness Example 2 93.6 ± 3.7% fitness Example 3 96.9 ± 2.2% fitness Example 4 86.6 ± 1.9% fitness Example 5 91.7 ± 2.5% fitness Example 6 95.3 ± 3.4% fitness Example 7 83.6 ± 1.9% fitness Example 8 87.4 ± 2.7% fitness Example 9 89.2 ± 3.0% fitness Example 10 83.4 ± 2.4% fitness Example 11 84.7 ± 2.9% fitness Example 12 81.4 ± 1.3% fitness Example 13 93.6 ± 1.2% fitness Example 14 94.1 ± 0.9% fitness Example 15 86.3 ± 0.8% fitness Example 16 95.9 ± 1.2% fitness Example 17 91.6 ± 3.0% fitness Example 18 89.8 ± 1.8% fitness Example 19 88.5 ± 1.1% fitness Example 20 91.6 ± 2.7% fitness Example 21 93.4 ± 2.0% fitness Example 22 90.1 ± 1.8% fitness Example 23 95.1 ± 1.6% fitness Example 24 84.3 ± 1.8% fitness Example 25 83.2 ± 2.8% fitness Example 26 94.5 ± 1.7% fitness Example 27 96.9 ± 3.0% fitness Example 28 85.1 ± 2.9% fitness Example 29 95.8 ± 2.0% fitness Example 30 88.8 ± 3.1% fitness Example 31 89.9% ± 2.1 fitness Example 32 86.8 ± 0.7% fitness

As shown in Table 4 above, It can be seen that the tablets containing the wet granules composition of Polar Presink prepared in Examples 1 to 32 exhibit a higher level of dissolution rate than Comparative Examples 1 and 2. This, when using the binder used in Examples 1 to 32, was found to show a high dissolution rate despite the low solubility of Polar Presink, regardless of the particle size of Polar Presink compared to Comparative Examples 1 and 2, It is expected that bioavailability can be further increased.

Test Example 2: Stability Test

Test Example 2-1: Nonhygroscopic Test

Non-hygroscopicity tests were performed on the tablets containing the wet granule composition of the polar presink prepared in Examples 1 to 32 and the tablets containing the polar presink prepared in Comparative Examples 1 and 2.

The tablets of Examples 1 to 32 and Comparative Examples 1 and 2 were measured by Karl-Fischer moisture meter under time of 40 ° C. and 75% relative humidity, respectively, and are shown in Table 5 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% Example 1 0.29% 0.51% 0.58% 0.30% Example 2 0.25% 0.46% 0.65% 0.40% Example 3 0.21% 0.52% 0.51% 0.30% Example 4 0.34% 0.21% 0.45% 0.11% Example 5 0.18% 0.58% 0.76% 0.59% Example 6 0.24% 0.65% 0.70% 0.47% Example 7 0.31% 0.64% 0.72% 0.41% Example 8 0.24% 0.64% 0.64% 0.40% Example 9 0.21% 0.26% 0.57% 0.36% Example 10 0.20% 0.57% 0.54% 0.33% Example 11 0.13% 0.29% 0.51% 0.38% Example 12 0.36% 0.66% 0.58% 0.22% Example 13 0.15% 0.53% 0.71% 0.55% Example 14 0.18% 0.63% 0.61% 0.44% Example 15 0.14% 0.52% 0.48% 0.33% Example 16 0.36% 0.25% 0.83% 0.46% Example 17 0.15% 0.40% 0.43% 0.28% Example 18 0.36% 0.61% 0.79% 0.42% Example 19 0.12% 0.38% 0.51% 0.39% Example 20 0.23% 0.29% 0.36% 0.13% Example 21 0.30% 0.55% 0.81% 0.50% Example 22 0.15% 0.29% 0.87% 0.72% Example 23 0.19% 0.28% 0.56% 0.36% Example 24 0.21% 0.39% 0.35% 0.14% Example 25 0.11% 0.56% 0.58% 0.47% Example 26 0.27% 0.31% 0.74% 0.47% Example 27 0.24% 0.68% 0.79% 0.56% Example 28 0.30% 0.63% 0.75% 0.45% Example 29 0.19% 0.58% 0.69% 0.50% Example 30 0.28% 0.46% 0.80% 0.53% Example 31 0.30% 0.64% 0.68% 0.38% Example 32 0.19% 0.54% 0.80% 0.61%

As shown in Table 5, the tablets containing the wet granule composition of Polar Presink prepared in Examples 1 to 32 compared with the hygroscopicity for Comparative Examples 1 and 2, all showed a suitable result.

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

In order to compare the dissolution rates of the tablets containing the wet granule composition of the polar presink prepared in Examples 1 to 32 and the tablets containing the polar presink prepared in Comparative Examples 1 and 2 as follows. .

The tablets of Examples 1 to 32 and Comparative Examples 1 and 2 were respectively packaged together with silica gel in a high-density polyethylene container and stored at 40 ° C. and 75% relative humidity, and then partially removed after 6 months and 12 months. The dissolution rate test was performed and shown in Table 6 below.

Dissolution rate (reference: 15 minutes, 80% (Q) or more) /
Storage condition (40 ℃, relative humidity 75%) Early 6 months 12 months Fit Comparative Example 1 89.7% 91.7% 79.2% incongruity Comparative Example 2 89.2% 82.5% 72.7% incongruity Example 1 89.3% 89.8% 93.2% fitness Example 2 91.8% 99.2% 82.9% fitness Example 3 94.2% 85.7% 91.4% fitness Example 4 86.1% 85.7% 87.8% fitness Example 5 90.4% 95.9% 84.3% fitness Example 6 89.7% 91.6% 83.7% fitness Example 7 88.9% 91.8% 92.2% fitness Example 8 94.2% 89.5% 96.6% fitness Example 9 94.8% 88.1% 97.9% fitness Example 10 82.8% 85.9% 90.7% fitness Example 11 93.9% 91.5% 93.1% fitness Example 12 90.7% 96.0% 84.5% fitness Example 13 84.9% 99.1% 83.6% fitness Example 14 95.0% 84.8% 82.0% fitness Example 15 95.2% 89.0% 90.6% fitness Example 16 91.1% 91.6% 81.7% fitness Example 17 94.7% 94.4% 84.8% fitness Example 18 93.5% 93.9% 82.6% fitness Example 19 92.2% 85.1% 96.4% fitness Example 20 83.7% 92.4% 90.9% fitness Example 21 83.8% 86.7% 82.5% fitness Example 22 92.7% 94.5% 90.7% fitness Example 23 83.4% 87.5% 88.3% fitness Example 24 97.5% 94.9% 97.1% fitness Example 25 88.8% 87.1% 85.9% fitness Example 26 95.7% 97.4% 93.4% fitness Example 27 86.0% 85.9% 84.3% fitness Example 28 94.0% 91.4% 97.2% fitness Example 29 95.0% 96.5% 96.4% fitness Example 30 82.3% 81.5% 83.4% fitness Example 31 94.6% 90.2% 94.5% fitness Example 32 85.0% 81.9% 84.8% fitness

As shown in Table 6 above, the tablets containing the wet granule composition of Polar Presink prepared in Examples 1 to 32 and Comparative Examples 1 and 2 were compared with time-dependent change test for dissolution rate under accelerated conditions. As a result, the tablets containing the wet granule composition using the binders used in Examples 1 to 32 all showed suitable dissolution rate results. On the other hand, in Comparative Examples 1 and 2, the dissolution rate was decreased over time, indicating an inadequate dissolution rate result. Through this, it can be confirmed that excellent stability for the tablet containing the wet granules composition using the binders used in Examples 1 to 32 can be ensured to express a stable drug efficacy.

Test Example 2-3: Lead Material Test

In order to compare the stability of the tablets containing the wet granules composition of the polar prepreg prepared in Examples 1 to 32 and the tablets containing the polar pre-jink prepared in Comparative Examples 1 and 2 as follows. .

The tablets of Examples 1 to 32 and Comparative Examples 1 and 2 were stored for a period of time according to the respective storage conditions, and analyzed using HPLC according to the flexible material test method.

Total Flexible Material Storage condition (40 ℃, 75% relative humidity) Fit Early 1 month 3 months 6 months Comparative Example 1 0.23% 0.38% 0.40% 0.23% fitness Comparative Example 2 0.17% 0.23% 0.28% 0.17% fitness Example 1 0.31% 0.22% 0.21% 0.31% fitness Example 2 0.30% 0.21% 0.23% 0.30% fitness Example 3 0.22% 0.34% 0.40% 0.22% fitness Example 4 0.16% 0.32% 0.36% 0.46% fitness Example 5 0.17% 0.29% 0.22% 0.17% fitness Example 6 0.23% 0.26% 0.27% 0.23% fitness Example 7 0.13% 0.36% 0.30% 0.13% fitness Example 8 0.12% 0.17% 0.22% 0.28% fitness Example 9 0.19% 0.22% 0.28% 0.29% fitness Example 10 0.45% 0.12% 0.30% 0.29% fitness Example 11 0.23% 0.27% 0.49% 0.48% fitness Example 12 0.21% 0.24% 0.37% 0.53% fitness Example 13 0.21% 0.44% 0.37% 0.33% fitness Example 14 0.15% 0.24% 0.38% 0.44% fitness Example 15 0.27% 0.30% 0.33% 0.40% fitness Example 16 0.29% 0.35% 0.30% 0.46% fitness Example 17 0.19% 0.20% 0.39% 0.45% fitness Example 18 0.14% 0.29% 0.39% 0.35% fitness Example 19 0.18% 0.31% 0.36% 0.47% fitness Example 20 0.21% 0.42% 0.38% 0.44% fitness Example 21 0.27% 0.37% 0.35% 0.40% fitness Example 22 0.22% 0.39% 0.34% 0.40% fitness Example 23 0.24% 0.27% 0.42% 0.49% fitness Example 24 0.29% 0.36% 0.37% 0.45% fitness Example 25 0.21% 0.26% 0.34% 0.29% fitness Example 26 0.15% 0.14% 0.33% 0.23% fitness Example 27 0.22% 0.20% 0.31% 0.28% fitness Example 28 0.19% 0.40% 0.46% 0.38% fitness Example 29 0.28% 0.35% 0.41% 0.49% fitness Example 30 0.20% 0.21% 0.34% 0.21% fitness Example 31 0.30% 0.43% 0.33% 0.33% fitness Example 32 0.19% 0.31% 0.40% 0.39% fitness

As shown in Table 7, the tablets containing the wet granule composition of Polar Presink prepared in Examples 1 to 32 and Comparative Examples 1 and 2 show that the stability results for the equivalent level of tablets. have. Through this, it can be confirmed that excellent stability for the purification of the wet granules composition of Polar Presink can express a stable drug efficacy.

Test Example 2-4: Change in Color over Tablet

In order to compare the color change with respect to the tablet containing the wet granules composition of the Polar Presink prepared in Examples 1 to 32 and the tablet containing the Polar Presink prepared in Comparative Examples 1 and 2 as follows. Was done.

The tablets of Examples 1 to 32 and Comparative Examples 1 and 2 were stored for a period of time according to their respective storage conditions, and the color changes of the tablets were visually analyzed.

Color change 80 ℃, 3 weeks 40 ℃ RH75% 3 weeks UV 1 week VIS 1 week Comparative Example 1 White White Slightly yellow White Comparative Example 2 White White Slightly yellow White Example 1 White White White White Example 2 White White White White Example 3 White White White White Example 4 White White White White Example 5 White White White White Example 6 White White White White Example 7 White White White White Example 8 White White White White Example 9 White White White White Example 10 White White White White Example 11 White White White White Example 12 White White White White Example 13 White White White White Example 14 White White White White Example 15 White White White White Example 16 White White White White Example 17 White White White White Example 18 White White White White Example 19 White White White White Example 20 White White White White Example 21 White White White White Example 22 White White White White Example 23 White White White White Example 24 White White White White Example 25 White White White White Example 26 White White White White Example 27 White White White White Example 28 White White White White Example 29 White White White White Example 30 White White White White Example 31 White White White White Example 32 White White White White

As shown in Table 8, in the case of tablets containing the wet granule composition of Polar Presink prepared in Examples 1 to 32, it appears that the color does not change under high temperature to high humidity conditions, or UV to VIS conditions, It was confirmed that high stability can be maintained during storage. On the other hand, in Comparative Examples 1 and 2 it was observed that the color changes under the UV conditions over time. Through this, it can be seen that the tablet containing the wet granules composition using the binders used in Examples 1 to 32 has excellent stability during storage and thereby can express stable drug efficacy.

Test Example 3: Manufacturing Process

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

In order to compare the occurrence of sticking of the tablets containing the wet granule composition of the polar presink prepared in Examples 1 to 32 and the tablets containing the polar presink prepared in Comparative Examples 1 and 2 as follows: Was done.

As a result of checking whether the tablets of Examples 1 to 32 and Comparative Examples 1 and 2 were produced during the production of 1,000 tablets, respectively, the Comparative Examples and Examples did not cause problems due to sticking.

Test Example 3-2: Test on Fluidity

In order to compare the fluidity of the tablets containing the wet granule composition of the polar presink prepared in Examples 1 to 32 and the tablets containing the polar presink prepared in Comparative Examples 1 and 2 as follows. .

As a result of checking whether the tablets of Examples 1 to 32 and Comparative Examples 1 and 2 had problems during the preparation of 1,000 tablets, respectively, the Comparative Examples and Examples did not cause problems due to poor fluidity.

As a result, the purification of the wet granule composition of Polar Presink using a binder having excellent compatibility with Polar Presink has the advantage of relatively accurate weighing due to its low scattering property, good fluidity, and uniform particle size. It was confirmed to have excellent manufacturing processability. In addition, it showed excellent formulation uniformity and content uniformity without being limited to the particle size, and showed high dissolution rate in spite of the low solubility of Polar Presink regardless of the particle size of Polar Presink. It can be confirmed.

Furthermore, tablets made from wet granule compositions containing binders selected through a compatibility test with Polar Presink showed excellent non-hygroscopicity and stability results, and long-term accelerated conditions in the results of changes over time for dissolution rates under accelerated conditions. Under the conditions of exposure, the dissolution rate results were met. In addition, it was confirmed that even long-term exposure to UV to VIS shows a high stability without color change over time. It is expected to be able to express a stable drug through this.

Claims (18)

Wet granules composition comprising polaprezinc, excipient and binder. The method of claim 1,
The binder is cellulose, croscarmellose sodium, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC 2910), lactose monohydrate, low-substituted hydroxypropyl cellulose (L- HPC) Wet granules composition, at least one selected from LH-11 and LH-12, pregelatinized starch (PGS), corn starch and talc. 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 excipient is at least one selected from microcrystalline cellulose, starch, low substituted hydroxypropylcellulose, dextrose, lactose and mannitol. 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 granulation composition further comprises one or more disintegrants selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate. a) mixing the polar presink, excipient and binder to produce a wet granule composition;
b) drying the composition to obtain granules;
c) adding disintegrants, glidants or both to the granules; And
d) tableting the resultant of step c) to form a tablet. The method of claim 7, wherein
The binder is selected from cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, lactose monohydrate, low substituted hydroxypropyl cellulose LH-11 and LH-12, gelatinized starch, corn starch and talc Which is one or more, a method for producing a tablet. 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 excipient is at least one selected from microcrystalline cellulose, starch, low-substituted hydroxypropyl cellulose, dextrose, lactose and mannitol. The method of claim 7, wherein
And further mixing at least one disintegrant selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate in step a). 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 disintegrant is at least one selected from crospovidone, sodium starch glycolate, sodium croscarmellose, polysorbate and sodium lauryl sulfate, and the lubricant is magnesium stearate, sodium stearyl fumarate, colloidal dioxide And at least one selected from silicon, talc, sodium stearyl fumarate, aluminum magnesium silicate, stearic acid and sucrose fatty acid ester. A tablet prepared by the wet granulation method from the wet granulation composition of claim 1. The method of claim 14,
Wherein the tablet does not suffer from sticking, mixing irregularities, and poor fluidity during manufacture by wet granulation. The method of claim 14,
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 16,
Wherein the tablet is packaged in a high density polyethylene container to maintain the dissolution rate for 12 months when stored at 40 ° C. and 75% relative humidity conditions. The method of claim 14,
Wherein the tablet has no color change over time under a temperature of at least 80 ° C., a relative humidity of at least 75%, and under UV and VIS conditions.