KR101237498B1 - Pharmaceutical composition containing ascorbic acid and tranexamic acid having enhanced stability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for skin whitening containing ascorbic acid and tranexamic acid, wherein the stability is reduced by mutual reaction.
Stabilized composition containing ascorbic acid and tranexamic acid of the present invention can solve the problems of content degradation and drug efficacy caused by the mutual reaction between the active ingredients to improve the stability of the drug, the content stability Not only can it reduce the side effects caused by impurities.

Description

Pharmaceutical composition containing ascorbic acid and tranexamic acid having enhanced stability

The present invention relates to a pharmaceutical composition for skin whitening containing ascorbic acid and tranexamic acid, wherein the stability is reduced by mutual reaction.

Human skin color is determined by the concentration and distribution of melanin in the skin. In addition to genetic factors, it is also influenced by environmental or physiological conditions such as ultraviolet light, fatigue and stress.

Melanin pigment is produced in melanocytes, and it is a phenolic polymer material having a complex form of black pigment and protein, and plays an important role in inhibiting skin damage by ultraviolet rays.

Melanin is produced by the action of an enzyme called tyrosinase present in pigmented cells. Tyrosinase is found exclusively in melanocytes, which are pigment cells. Melanosite is located in the basal layer and hair root of the epidermis. Melanin pigments are produced and deposited in melanosite-specific organs called melanosomes, which are then transported from melanocytes to surrounding keratinocytes and spread widely through the skin epidermis or pores.

Several other enzymes are known that are involved in melanin biosynthesis, such as tyrosinase related protein 1 (TRP 1) and tyrosinase related protein 2 (TRP 2) (Cohen, T., et al. Nucleic Acids Res. 18: 2807-2808 (1990)); Jackson, I. J., et al., EMBO J., 11: 327-535 (1992). Recent studies have shown that tyrosinase, TRP 1 and TRP 2 interact to form complexes and reduce the activity of tyrosinase in these complexes, thus suggesting that the TRPs will act as inhibitors of tyrosinase activity. Orlow, SJ, et al., J. Invest. Dermatol., 103: 196-201 (1994).

Melanin is converted from tyrosine, a type of amino acid, to dopa (DOPA) and dopaquinone by tyrosinase, TRP 1 and TRP 2, and then biosynthesized through non-enzymatic oxidation. The produced melanin is transferred to keratinocytes through melanosomes, and the keratinocytes are released to the skin surface after 28 days of keratinization. However, in the keratinization process, the melanin is excessively produced by some factor, and the pigmentation occurs if the melanin pigment is not completely removed by the keratinization.

On the other hand, the action of the whitening agent used in the whitening cosmetics appears in various ways. First, as a method of removing the cause of melanin by blocking ultraviolet rays, this method uses a light scattering agent or a light blocking agent. Second, as a method of inhibiting the biosynthesis of tyrosinase, this method uses a substance that blocks signal transduction or inhibits gene expression. Third, as a method of inhibiting the function of tyrosinase, this method uses a substance which competitively binds to the substrate of the enzyme or a substance which loses the activity of the enzyme by binding to the enzyme and changing its structure. Fourth, it is a method of using a substance having a specific toxicity to melanocytes.

Meanwhile, Korean Patent Laid-Open Publication No. 2004-60157 discloses that tranexamic acid may exhibit a whitening effect by inhibiting melanin production by inhibiting the proliferation of melanocytes, which are skin pigment cells. The transnexamic acid is a trans-4- (aminomethyl) cyclohexane carboxylic acid, and has a molecular formula of C ₈ H ₁₅ NO ₂ , and has a conventional antifibrinolytic effect. It was known to have) and was used as a hemostatic agent or a thrombolytic agent.

In addition, ascorbic acid is a substance that inhibits tyrosinase activity by reducing quinones to phenols, and shows a high inhibitory effect on tyrosinase activity, but the formulation is unstable, and is easily oxidized by air, moisture, etc., causing skin irritation. There is this. In particular, when mixed with the tranxamic acid, impurities are generated to show side effects, and there is a problem in that the amount of the active ingredient is reduced.

Accordingly, the present inventors have studied and tried to solve the problem of degeneration when mixing ascorbic acid and tranexamic acid. As a result, the granules are respectively granulated in order to prevent ascorbic acid and tranexamic acid from contacting each other as much as possible. The present invention was completed by discovering that after preparing with water, mixing and tableting the same, a drug having excellent stability can be prepared.

Accordingly, an object of the present invention is to provide a composition for skin whitening containing ascorbic acid and tranexamic acid having excellent stability, and a method for preparing oral medicament using the same.

The present invention is characterized by a pharmaceutical composition for skin whitening comprising ascorbic acid granules and tranexamic acid granules.

Further, according to the present invention,

Granular compounds and ascorrosion selected from polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters and C ₆ to C ₃₀ higher alcohols Mixing asnic acid to produce ascorbic acid granules;

Mixing the ascorbic acid granules and tranexamic acid granules with at least one carrier selected from a disintegrant and a lubricant; And

Tableting the mixture

Characterized by another method for the preparation of a pharmaceutical for oral administration for skin whitening comprising a.

Stabilized composition containing ascorbic acid and tranexamic acid of the present invention can solve the problems of content degradation and drug efficacy caused by the mutual reaction between the active ingredients to improve the stability of the drug, the content stability Not only can it reduce the side effects caused by impurities. Accordingly, the present invention makes it possible to provide useful pharmaceutical formulations in stable formulations, and to enable long-term preservation or safe distribution, which can be applied industrially usefully.

1 is a photograph confirming the change in appearance by storing the tablets of Examples and Comparative Examples at 40 ℃, 70% RH conditions for 5 days.

Hereinafter, the pharmaceutical composition for skin whitening of the present invention will be described in detail.

In order to provide stability of the formulation comprising ascorbic acid and tranexamic acid, the present invention is to prepare each component into granules and then mix with each other to obtain a pharmaceutical composition for skin whitening.

Ascorbic acid granules are granules selected from polysaccharide polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters and C ₆ to C ₃₀ higher alcohols. It can be prepared by conventional granulation method by the compounding compound.

The tranexamic acid granules are also selected from polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, fatty acids of C ₈ to C ₂₆ , fatty acid esters of C ₈ to C ₅₀ , and higher alcohols of C ₆ to C ₃₀ . The granulated compound is granulated in a conventional manner by the granulation compound, and mixing with the ascorbic acid granules in the granulated state is advantageous to block the mutual reaction between the two components.

Examples of the polysaccharide-based polymer include starch, gelatinized starch, hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, alginic acid, alginic acid alkali metal salt, guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum. One or two or more compounds selected from gellan gum, carrageenan, casein, tara gum, tamarind gum, tragacanth gum, gati gum, gelatin, collagen, protamine and zein can be used.

In addition, the cellulose derivative is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, butyl One or two or more compounds selected from cellulose, benzyl cellulose and cyanoethyl cellulose can be used.

In addition, the vinyl derivative may be used at least one compound selected from polyvinylpyrrolidone and polyvinyl alcohol, as the acrylic acid copolymer Of Eudragit RS, Eudragit RS30D, Eudragit RL, Eudragit RL30D, Eudragit NE30D, Eudragit E, Eudragit E100, Eudragit L, Eudragit S, and Eudragit 4135F One or two or more compounds selected can be used.

In addition, the fatty acid of C ₈ ~ C ₂₆ is preferably used one or two or more compounds selected from stearic acid, lauric acid, myristic acid and palmitic acid, the fatty acid ester of C ₈ ~ C ₅₀ is acetyl It is preferable to use one or two or more compounds selected from glycerin fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters and glycerin monostearate, and higher alcohols of C ₆ to C ₃₀ include cetyl alcohol, stearyl alcohol and It is preferable to use one or two or more compounds selected from cetostearyl alcohol.

Granulating compounds for granulation of ascorbic acid are more preferably starch, alginic acid, guar gum, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, ethyl cellulose, Eudragit RS Ascorbic acid granules may be prepared by wet or dry granulation of a compound selected from stearic acid, glyceryl behenate, and stearyl alcohol with ascorbic acid. The prepared ascorbic acid granules may be present in the form in which the polymer is coated on the surface of ascorbic acid particles, thereby preventing a chemical reaction with an external material.

The granulation compound for granulation of ascorbic acid is preferably used in an amount of 0.5 to 100 parts by weight, preferably 1 to 50 parts by weight, based on 100 parts by weight of ascorbic acid. If the polymer is used in less than 0.5 parts by weight can not completely block the contact of ascorbic acid and tranexamic acid there is a problem that the stability of the formulation is inferior, when used in excess of 100 parts by weight of the granulation process time There is a problem.

In addition, as a granulation compound for granulation of trinexamic acid, starch, alginic acid, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, ethyl cellulose, stearic acid and glyceryl behenate And granulation by wet or dry granulation with a compound selected from stearyl alcohol.

The granulation compound for granulation of tranexamic acid is preferably used in an amount of 0.5 to 200 parts by weight, more preferably 1 to 150 parts by weight, based on 100 parts by weight of tranexamic acid. If the polymer is used in less than 0.5 parts by weight can not completely block the contact of the tranexamic acid and ascorbic acid, the stability of the formulation is lowered, if used in excess of 200 parts by weight of the long time of the granexamine acid granulation process There is a problem of increasing the size of the formulation.

Ascorbic acid granules and tranexamic acid granules whose surface of the ascorbic acid is blocked by the granulation compound may be mixed to obtain a pharmaceutical composition for skin whitening.

The ascorbic acid granules and tranexamic acid granules may be prepared as a medicament for oral administration by mixing with one or more carriers selected from disintegrants and lubricants, and then tableting or capsule filling.

As the disintegrant, a low-substituted hydroxypropyl cellulose, carboxymethyl cellulose sodium, sodium starch glyconate, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, starch, microcrystalline cellulose, etc. which can be generally orally administered can be used. It is preferable to use low-substituted hydroxypropyl cellulose.

In addition, the lubricant may generally be used orally administered magnesium stearate, glyceryl behenate, colloidal silicon oxide, talc, stearic acid, sodium stearyl fumarate and the like.

 The oral dosage form of the medicament for administration is not limited, but preferably may be prepared in tablets, hard capsules, granules, most preferably in tablets.

Further, according to the present invention,

Granular compounds and ascorrosion selected from polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters and C ₆ to C ₃₀ higher alcohols Mixing asnic acid to produce ascorbic acid granules;

Mixing the ascorbic acid granules and tranexamic acid granules with at least one carrier selected from a disintegrant and a lubricant; And

Tableting the mixture;

Includes as a right to the manufacturing method of the drug for oral administration for skin whitening comprising a.

At this time, the transnexamic acid is selected from polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, fatty acids of C ₈ ~ C ₂₆ , fatty acid esters of C ₈ ~ C ₅₀ and higher alcohols of C ₆ ~ C ₃₀ It is preferred that the granules be prepared together with the granulating compound.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples, but the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

Examples 1-2: Tablets Containing Ascorbic Acid Granules and Tranexamic Acid Granules

Starch was swelled in water at a concentration of 5% by weight and continuous spray coating on ascorbic acid by a wet spray method to obtain ascorbic acid granules. The wet spraying was carried out by supplying ascorbic acid to the fluidized bed granulation apparatus and spraying 50 ml of the starch aqueous solution with a 0.5 mm nozzle per hour while maintaining the fluid state and the internal temperature of 50 ° C.

On the other hand, after trannexamic acid was homogeneously mixed with low-substituted hydroxypropyl cellulose and microcrystalline cellulose for 5 minutes, hydroxypropyl cellulose was dissolved in 0.06 g of purified water, and stirred for 5 minutes to associate. The association was dried at 50 ° C. for 1 hour to establish 20 mesh. The ascorbic acid granules were mixed with the low-substituted hydroxypropyl cellulose for 5 minutes in the sieved material, and then magnesium stearate, glyceryl behenate, and colloidal silicon oxide were mixed for 5 minutes, followed by 295 mg of circular tablets. Tableting.

The components and compositions used in the preparation of the tablets are shown in Table 1 below.

Raw material name (mg) Example 1 Example 2 Ascorbic acid 50.5 50.5 Starch 1.6 20.2 Tranexamic acid 125 125 Hydroxypropyl Cellulose (HPC-L) 15 15 Low Substituted Hydroxypropyl Cellulose
(L-HPC) 30 30 Microcrystalline cellulose (Avicel 101) 54.9 36.3 Magnesium stearate 8 8 Glyceryl Behenate (Compritol) 6 6 Colloidal silicon dioxide 4 4

Example  3 to 7: ascorbic acid granules and Tranexamic acid  Tablets containing granules

Tablets were prepared in the same manner as in Example 1 except for preparing ascorbic acid granules using alginic acid, xanthan gum, polyvinylpyrrolidone, ethylcellulose or Eudragit RS instead of starch. However, when ethyl cellulose or Eudragit RS was used, wet spraying with ethanol as a solvent instead of water was performed. The components and compositions used in the preparation of the tablets are shown in Table 2 below.

Raw material name (mg) Example 3 Example 4 Example 5 Example 6 Example 7 Ascorbic acid 50.5 50.5 50.5 50.5 50.5 Alginic acid 1.6 - - - - Xanthan gum - 1.6 - - - Polyvinylpyrrolidone - - 1.6 - - Ethyl cellulose - - - 1.6 - Eudragit RS - - - - 1.6 Tranexamic acid 125 125 125 125 125 Hydroxypropyl Cellulose (HPC-L) 15 15 15 15 15 Low Substituted Hydroxypropyl Cellulose
(L-HPC) 30 30 30 30 30 Microcrystalline cellulose (Avicel 101) 54.9 54.9 54.9 54.9 54.9 Magnesium stearate 8 8 8 8 8 Glyceryl Behenate (Compritol) 6 6 6 6 6 Colloidal silicon dioxide 4 4 4 4 4

Example  8-15: ascorbic acid granules and Tranexamic acid  Tablets containing granules

Except for adjusting the content of hydroxypropyl cellulose in Example 1, using alginic acid, xanthan gum, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, ethyl cellulose or Eudragit RS instead of hydroxypropyl cellulose Prepared tablets in the same manner. The components and compositions used in the preparation of the tablets are shown in Table 3 below.

Raw material name (mg) Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Ascorbic acid 50.5 50.5 50.5 50.5 50.5 50.5 50.5 50.5 Starch 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 Low Substituted Hydroxypropyl Cellulose (L-HPC) 30 30 30 30 30 30 30 30 Microcrystalline cellulose (Avicel 101) 39.9 19.9 64.9 64.9 54.9 54.9 64.9 64.9 Tranexamic acid 125 125 125 125 125 125 125 125 Hydroxypropyl cellulose
(HPC-L) 30 50 - - - - - - Alginic acid - - 5 - - - - - Xanthan gum - - - 5 - - - - Hydroxypropylmethylcellulose - - - - 15 - - - Polyvinylpyrrolidone - - - - - 15 - - Ethyl cellulose - - - - - - 5 - Eudragit RS - - - - - - - 5 Magnesium stearate 8 8 8 8 8 8 8 8 Glyceryl Behenate (Compritol) 6 6 6 6 6 6 6 6 Colloidal silicon dioxide 4 4 4 4 4 4 4 4

Example 16 Double Tablets Containing Ascorbic Acid Granules and Tranexamic Acid Granules

Starch was swelled in water at a concentration of 5% by weight and continuous spray coating on ascorbic acid by a wet spray method to obtain ascorbic acid granules. The wet spraying was performed by supplying ascorbic acid to the fluidized bed granulation apparatus and spraying 50 ml of the starch aqueous solution with a 0.5 mm nozzle per hour while maintaining the fluid state and the internal temperature of 50 ° C.

After homogeneously mixing microcrystalline cellulose and low-substituted hydroxypropyl cellulose for 5 minutes, the ascorbic acid granules and magnesium stearate were added and mixed to prepare an ascorbic acid granule mixture layer composition.

On the other hand, after trannexamic acid was homogeneously mixed with low-substituted hydroxypropyl cellulose and microcrystalline cellulose for 5 minutes, hydroxypropyl cellulose was dissolved in 0.06 g of purified water, and stirred for 5 minutes to associate. The association was dried at 50 ° C. for 1 hour to establish 20 mesh. After mixing the sieved material, glyceryl behenate, and colloidal silicon oxide for 5 minutes to prepare a tranexamic acid layer composition, the ascorbic acid granule mixture layer composition and the tranexamic acid layer composition using a double tableting machine Tableting. The composition of the components used was the same as in Example 1.

Comparative Example 1: Simple Mixed Tablets

Ascorbic acid 52.1 mg

Tranexamic Acid 125 mg

Low Substituted Hydroxypropyl Cellulose (L-HPC) 30 mg

Microcrystalline cellulose (Avicel 101) 54.9 mg

Hydroxypropyl cellulose (HPC-L) 15 mg

Magnesium Stearate 8 mg

Glyceryl Behenate (Compritol) 6 mg

Colloidal Silicon Oxide 4 mg

Ascorbic acid, tranexamic acid, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose (Avicel 102) and hydroxypropyl cellulose (HPC-L) are mixed homogeneously for 5 minutes, and then magnesium stearate , Glyceryl behenate (Compritol), and colloidal silicon oxide was added and mixed again for 5 minutes was compressed into tablets of 295 mg.

Comparative Example 2: Simple Wet Granule Tablets

Mix homogeneously with ascorbic acid, tranexamic acid, low-substituted hydroxypropyl cellulose (L-HPC) and microcrystalline cellulose (Avicel 101) for 5 minutes, and add hydroxypropyl cellulose (HPC-L) to purified water 0.06 g / The solution dissolved completely in the tablet was added to the mixture and stirred for 5 minutes to combine. The association was dried at 50 ° C. for 2 hours, sieved to a 20 mesh sieve, magnesium stearate, glyceryl behenate (Compritol), and colloidal silicon oxide, followed by mixing for 5 minutes to be compressed into 295 mg of circular tablets. .

The content of the component used was the same as in Comparative Example 1.

Experimental Example 1 Acceleration Property Change Test

The tablets prepared in Examples and Comparative Examples were placed in polyethylene containers, and stored at 40 ° C. and 70% RH for 5 days to observe changes in color of the tablets. The results are shown in Table 4 and FIG. 1.

Name of sample Example
One Example
2 Example
3 Example
4 Example
5 Example
6 Example
7 Example
8 Example
9 Example
10 Color change - - + + + + + - - - Name of sample Example
11 Example
12 Example
13 Example
14 Example
15 Example
16 Comparative Example
One Comparative Example
2 Color change + + + + + - ++++ ++++ -: Does not change
+: Almost unchanged
++: slightly changed
+++: much changed
++++: very much changed

As shown in Table 4 and Figure 1, the tablet of the comparative example showed a change in color due to the interaction of ascorbic acid and tranexamic acid, but the tablet of the Example showed almost no such change, in particular In Examples 1 to 2 and 8 to 10 it was confirmed that no change in color was observed.

Experimental Example 2: Accelerated Stability Test

In order to evaluate the physicochemical stability of the tablets, the following acceleration stability test was performed.

In the accelerated stability test, the tablets of the above Examples and Comparative Examples were packaged in PE bottles and placed in an accelerated stability tester, and then the content change after 15 days at 40 ° C. and 70% RH was measured.

After 15 days, 20 tablets are crushed and 100 mg of ascorbic acid is taken. Into a 250 mL Erlenmeyer flask, 30 mL of methylene chloride and 100 mL of diluted solution (solution of 30 g of metaphosphoric acid dissolved in 1 L of water) were added.

The solution was ultrasonically shaken for about 5 minutes to completely disperse the sample, mixed with gentle stirring for about 10 minutes with a magnetic stirrer and allowed to stand until the layers were completely separated. About 20 mL of the separated aqueous layer was taken, filtered through paper filter paper, 2 mL of the filtrate was taken and diluted to 100 mL using the dilution solution. The solution which filtered this solution with 0.45 micrometer membrane filter paper was used as the test liquid.

Meanwhile, 10 mg of ascorbic acid standard was precisely weighed and dissolved in the dilution solution to make 100 mL, thereby preparing a standard solution.

10 μL of the sample solution and the standard solution were tested according to the liquid chromatograph method under the following conditions, the peak areas A _T and A _S of each solution were obtained, and the content of ascorbic acid was determined according to the following formula.

[Condition]

Column: Filling a 5 μm octadecylsilylated silica gel into a 4.6 mm × 250 mm stainless tube

Mobile phase: 0.25% (w / v) methaphosphate solution

Flow rate: 1.0 mL / min

Sample injection volume: 10 μL

Column temperature: 30 ℃

Detector: ultraviolet absorption photometer (wavelength 245 nm)

A _T : Peak area of ascorbic acid in the sample solution

A _S : Peak area of ascorbic acid in the standard solution

Ascorbic acid content of each tablet calculated according to Equation 1 is shown in Table 5 below.

content(%) Example
One Example
2 Example
3 Example
4 Example
5 Example
6 Example
7 Example
8 Example
9 Example
10 Early 100 100 100 100 100 100 100 100 100 100 15 days later 100.1 100.2 99.7 99.3 99.7 99.1 99.3 100.3 100.1 99.8 content(%) Example
11 Example
12 Example
13 Example
14 Example
15 Example
16 Comparative Example
One Comparative Example
2 Early 100 100 100 100 100 100 100 100 15 days later 99.5 98.0 98.3 99.4 99.1 99.9 86.8 88.2

As shown in Table 5, the tablet of the present invention can prevent the content decrease by the mutual reaction of ascorbic acid and tranexamic acid, it can be expected to have sufficient efficacy of the active ingredient.

Experimental Example 3 Hardness and Wear Test

The hardness test was performed using a hardness tester (Pharmatest, Germany) to give a tablet the strength of a certain size. In addition, the tablets were rotated (25 revolutions / minute) for 4 minutes to allow the tablets to repeatedly drop at a constant height, and then weighed to test how much tablets were worn out, and the results are shown in Table 6 below. Shown in

Name of sample Example
One Example
2 Example
3 Example
4 Example
5 Example
6 Example
7 Example
8 Example
9 Example
10 Hardness (Kp) 12 12 11 10 12 10 10 13 13 10 Wear and tear (%) 0.1 0.1 0.2 0.1 0.2 0.1 0.2 0.1 0.1 0.3 Capping radish radish radish radish radish radish radish radish radish radish Name of sample Example
11 Example
12 Example
13 Example
14 Example
15 Example
16 Comparative Example
One Comparative Example
2 Hardness (Kp) 11 11 10 9 11 10 5 4 Wear and tear (%) 0.1 0.1 0.2 0.1 0.1 0.2 0.7 0.6 Capping radish radish radish radish radish radish U U

As shown in Table 6, the tablet of the Example showed lower wear and tear than the comparative example, it was confirmed that the capping phenomenon does not occur, and has excellent physical strength, thereby improving the productivity can be expected. .

Claims (12)

delete Granular compounds selected from polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters and C ₆ to C ₃₀ higher alcohols Ascorbic acid granules coated on the surface of the poor acid particles, the particle surface of which is blocked from the outside; And
Includes tranexamic acid granules,
The granulation compound is a pharmaceutical composition for skin whitening, characterized in that 0.5 to 100 parts by weight based on 100 parts by weight of ascorbic acid.
According to claim 2, wherein the tranexamic acid granules are polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, fatty acids of C ₈ ~ C ₂₆ , fatty acid esters of C ₈ ~ C ₅₀ and C ₆ ~ C A pharmaceutical composition for skin whitening, characterized in that it is prepared in granules with a granulation compound selected from higher alcohols of ₃₀ .
According to claim 2 or 3, wherein the polysaccharide-based polymer is starch, gelatinized starch, hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, alginic acid, alginic acid alkali metal salt, guar gum, locust Skin whitening, characterized in that it is selected from bin gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, carrageenan, casein, taram gum, tamarind gum, tragacanth gum, gati gum, gelatin, collagen, protamine and zein Pharmaceutical compositions.
According to claim 2 or 3, wherein the cellulose derivative is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, ethyl methyl cellulose, ethyl A pharmaceutical composition for skin whitening, characterized in that it is selected from propyl cellulose, isopropyl cellulose, butyl cellulose, benzyl cellulose and cyanoethyl cellulose.
The pharmaceutical composition for skin whitening according to claim 2 or 3, wherein the vinyl derivative is selected from polyvinylpyrrolidone and polyvinyl alcohol.
According to claim 2 or 3, wherein the acrylic acid copolymer is Eudragit RS, Eudragit RS30D, Eudragit RL, Eudragit RL30D, Eudragit NE30D, Eudragit E, Eudragit E100, A pharmaceutical composition for skin whitening, characterized in that it is selected from Eudragit L, Eudragit S, and Eudragit 4135F.
delete The pharmaceutical composition for skin whitening according to claim 3, wherein the granulation compound comprises 0.5 to 200 parts by weight based on 100 parts by weight of tranexamic acid.
The pharmaceutical composition for skin whitening according to claim 2 or 3, which has an effect of alleviating and improving blemishes.
Polysaccharide-based polymer, cellulose derivative, vinyl derivative, acrylic acid copolymer, C ₈ to C ₂₆ fatty acid, C ₈ to C ₅₀ fatty acid ester and C ₆ to C ₃₀ higher alcohol based on 100 parts by weight of ascorbic acid Preparing ascorbic acid granules having a particle surface blocked from the outside by mixing 0.5 to 100 parts by weight of the granulation compound selected from the group;
Mixing the ascorbic acid granules and tranexamic acid granules with at least one carrier selected from a disintegrant and a lubricant; And
Tableting the mixture;
Method for producing a pharmaceutical for oral administration for skin whitening comprising a.
According to claim 11, wherein the tranexamic acid granules are polysaccharide-based polymers, cellulose derivatives, vinyl derivatives, acrylic acid copolymers, C ₈ ~ C ₂₆ fatty acids, C ₈ ~ C ₅₀ fatty acid esters and C ₆ ~ C _30. A method for the preparation of a medicament for oral administration for skin whitening, characterized in that it is prepared in granules with a granulation compound selected from higher alcohols of ₃₀ .

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