KR20000073077A - Composition for skin depigmentation, containing hydroquinone, tretinoin and hydrocortisone - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for treating melasma is provided to comprise the necessary components, such as some known hydroquinone, tretinoin and hydrocortisone in their appropriate combination ratios, to stabilize its formulation effectively, and give a good protection from contamination, discoloration, or deformation of the formulation. CONSTITUTION: The pharmaceutical composition for treating melasma is characterized by comprising 2 to 6 wt% of hydroquinone, 0.001 to 0.1 wt% of tretinoin and 0.001 to 1.0 wt% of acetic acid hydrocortisone in major components; and 1 to 50 wt% of oil phase substance, 1 to 15 wt% of an emulsifier, 0.001 to 1.0 wt% of an oil phase stabilizer, 0.001 to 1.0 wt% of an aqueous phase stabilizer, 10 to 40 wt% of an aqueous phase substance and water in minor components.

Description

Composition for skin depigmentation, containing hydroquinone, tretinoin and hydrocortisone, including hydroquinone, tretinoin, and hydrocortisone

The present invention relates to a stable pharmaceutical formulation of a complex composition containing hydroquinone, tretinoin and hydrocortisone, and more particularly, to unstable hydroquinone, tretinoin and hydrocortisone, which are used for the treatment of melanin overdeposition and melanoma of the skin, respectively. The present invention also relates to a composition for treating melanoma, in which the pharmacological effect is also increased by adding the additives which can be mixed at an appropriate ratio and stabilize the above ingredients to increase the stability of the preparation.

Dermal pigment is associated with carotinoids, hemoglobin and melanin, of which melanin is brown by melanocytes secreted from melanocytes and in melanocytes It is made based on tyrosine for the enzyme tyrosinase.

Pigmentation occurs in the epidermal melanin unit of melanocytes surrounded by endothelial cells, and abnormalities in such pigmentation can lead to the destruction and property change of melanocytes, disrupting melanin and its precursor biosynthesis, tyrosine It is caused by mechanisms such as inhibition of phagocytosis of inactive, melanogenic cell dendrities, disruption of melanocyte granules into endothelial cells due to intercellular edema, and changes in melanin in melanosomes.

One of such representative pigmentations, melanoma and freckle (melasma) are common acquired diseases of Asians. 0.25-4% of patients seeking dermatology have spots, especially among middle-aged women aged 30-44. Sunlight, genetic predisposition, changes in hormonal status associated with pregnancy, and oral contraceptives are known as causes or worsening symptoms, but removing the cause alone is not a treatment. The treatment for melanosis known as skin depigmentation so far is Hydroquinone, Retinoic acid, Albutin, Kojic acid, Salicylic acid, Glycolic acid, N- Acetyl-4-s-cysteminylphenol (N-acetyl-4-s-cysteminylphenol), azelaic acid, isopropyl catechol, resorcinol, etc. In the case of treatment for melanoma by using a combination of tretinoin, hydroquinone, steroids, etc., rather than a single agent is excellent in the therapeutic effect (US Patent No. 3,856,934).

Hydroquinone (1,4-benzenediol) is a component that inhibits the synthesis of melanin pigments by inhibiting tyrosinase, an enzyme involved in the process of tyrosine metabolism into melanin and consequently prevents skin deposition of melanin pigments. It is easy to change and oxidize to quinone by, and alkali, and the oxidized quinone becomes brown and loses its value as an agent.

In addition, tretinoin (all-trans-tretinoic acid) reduces the adhesion of keratinized cells and increases the division and alteration of epithelial cells, which not only has the effect of removing acne from epithelial cells but also disperse pigment granules of keratinocytes and transport pigments. To prevent epidermal turnover, resulting in loss of pigment. However, this tretinoin is easily decomposed by oxidation reaction, photochemical reaction and fruit opening reaction, and is decomposed into isomers such as isotretinoin by light irradiation, and by-products can be generated by reacting with excipients in the blend. This by-product also shows side effects such as irritating side effects and irritable side effects. In other words, tretinoin blemish treatment effect is widely recognized, but there are side effects such as erythema, itching, keratin, it is important to select the appropriate concentration.

Hydrocortisone and acetic acid hydrocortisone are saccharide steroids isolated from the adrenal cortex. The effect of steroids on the treatment of melanoma is not constant, but it can be effective in some patients. Ideally, 0.5-1.0% by weight of hydrocortisone with the least amount of side effects may be applied, but long-term application can lead to steroid side effects such as capillary dilation and acne outbreaks.

As described above, it has been reported in US Pat. No. 3,856,934 that combination treatment rather than hydroquinone, tretinoin and hydrocortisone alone can treat skin deposition more synergistically. Tretinoin emulsified cream formulations have also been filed by Bristol-Myers Company (Korean Patent Application No. 90-10586), and hydroquinone stabilized compositions are described in US Pat. No. 2,376,884. However, the method prepared by mixing each composition in the above-described existing patent is difficult to disperse the raw material drugs, the skin penetration is poor, the roughness and malleability is poor, it may feel a foreign body when the drug coating. In addition, the existing formulations are poor in stability may be contaminated by microorganisms, rapidly discoloration and deterioration may appear, so the shelf life is shortened.

Recently, as women's interest in beauty increases, efforts have been made to remove spots and freckles. In addition to treatment with drugs, plastic surgery and dermatology are using peeling or laser treatment. However, agents such as creams, ointments and liquids that are easily applied are preferred. Therefore, there is a need for drugs that are easy to use, inexpensive, and have good patient compliance. However, the above-mentioned drugs have problems in stability, and especially in the case of a complex of components having a lot of stability problems, it is more difficult to control stability and safety, and attention is also required to adjust the concentration of each component. Therefore, it is very important to ensure the stability of these composite formulations that have good effects but stability is a problem.

Accordingly, the present inventors have tried to prepare a stable composition of a combination of hydroquinone, tretinoin, and hydrocortisone (or hydrocortisone acetate) for the treatment of melanoma, while appropriately adjusting the content of these three components and stabilizing the preparation. By selecting the additives and adjusting the content thereof, a stable composite composition containing hydroquinone, tretinoin and hydrocortisone was prepared to complete the present invention.

It is an object of the present invention to provide a stable pharmaceutical formulation of a composite composition containing hydroquinone, tretinoin and hydrocortisone.

1 is a graph showing the thermal stability test results of the composition of the present invention,

Figure 2 is a graph showing the light stability test results of the composition of the present invention.

In order to achieve the above object, in the present invention, hydroquinone, tretinoin, and hydrocortisone, which are used for the purpose of treating melanin overdeposition and melanoma, respectively, but having stability problems, are mixed in an appropriate ratio, and an additive capable of stabilizing the components therein. It is added to increase the stability of the formulation and its pharmacological effect also provides a composition for the treatment of melanoma.

Hereinafter, the present invention will be described in detail.

The present invention contains 2 to 6% by weight of hydroquinone, 0.001 to 0.1% by weight of tretinoin, and 0 to 2% by weight of hydrocortisone or hydrocortisone acetate; 1 to 50% by weight of oily material, 1 to 15% by weight of emulsifier, 0.001 to 1.0% by weight of oil phase stabilizer, 0.001 to 1.0% by weight of water phase stabilizer, and 10 to 40% by weight of water phase material; And it provides a composition for treating melanoma, characterized in that it contains water.

At this time, the oily base material is a fatty acid having 12 to 20 carbon atoms, fatty acid ester having 6 to 20 carbon atoms, fatty alcohol having 12 to 20 carbon atoms, or used alone or in combination. Preference is given to using 1-30% by weight of alcohol, cetyl alcohol and stearyl alcohol alone or in combination.

In addition, in the composition of the present invention, an emulsifier may be used as a nonionic, cationic, anionic emulsifier, or a mixture thereof. As the nonionic emulsifier, monostearate sorbitan, glycerol monostearate, polyethylenecetyl ether, polyoxyethylene ste Aryl ether and polyoxyethylene hydrogenated castor oil may be used alone or in combination, sodium lauryl sulfate or sodium seryl sulfate as the anionic emulsifier, and cetyl trimethylammonium bromide as the cationic emulsifier.

In the composition of the present invention, the oil phase stabilizer may be used alone or in combination of 0.0075 to 0.1% by weight of butylhydroxytoluene, 0.005 to 0.02% by weight of butylhydroxyanisole and 0.001 to 0.1% by weight of tocopherol.

Meanwhile, in the composition of the present invention, an aqueous phase material that is a base of an aqueous phase may be used alone or in combination of polyethylene glycol 200, 400, 600, 1500, 2000, 4000, and polypropylene glycol, and as a stabilizer of the aqueous phase, 0.01 to ascorbic acid may be used. 1.0 weight%, sodium edetate 0.005 to 0.1 weight%, and sodium hydrogen sulfite 0.01 to 1.0 weight% can be used alone or in combination.

In addition, the composition of the present invention is 0.05 to 0.2% by weight in addition to the above components; 0.1 to 1.0 wt% thickening and stabilizer; Or 0.1 to 2.0% by weight of an antifoaming agent, wherein the preservative is sorbic acid; Parabens including methyl paraben, propyl paraben or ethyl paraben; Benzoic acid; Benzyl alcohol; Imidazolidinyl urea; And diazolidinyl urea, the increasing and stabilizing agent is selected from xanthan gum, poloxamer and cobopol, and the antifoaming agent is preferably selected from dimethicone, cyclomethicone and silicone oil.

Preferred examples of the components of the compositions of the present invention and their contents are shown in Table 1 below.

Award ingredient Parts by weight Active ingredient Hydroquinone 2.0-6.0 antiseptic Sorbic acid 0.05-0.2 Incremental and Stabilizers Xanthan gum 0.1-0.5 Emulsifier Sodium Lauryl Sulfate 0.2-0.5 Substance (Base) Polyethylene Glycol 1500 1-5 Polyethylene Glycol 4000 1-5 stabilizator Ascorbic acid 0.1-1.0 Purified water Quantity The upper part ingredient Parts by weight Active ingredient Tretinoin 0.001-0.1 Active ingredient Hydrocortisone 0.01-2 Oily substance (base) Isopropyl myristate 1-10 Oily substance Cetostearyl alcohol 2-10 Emulsifier Glycerol monostearate 1-10 Oily substance (base) Floating paraffin 2-10 Emulsifier Sorbitan monosulfate 1-10 Emulsifier Seto Macrogol 1000 1-10 stabilizator Butylated hydroxytoluene 0.0075-0.1

In the present invention, the composition for treating the melanoma is preferably prepared by a melting method. As described above, the conventional patents are prepared by simply mixing the components of the preparation, which makes it difficult to disperse the raw drug and lower the skin penetration, as well as roughness. And there was a problem of poor ductility, there was also a problem that the effective period is shortened by discoloration and deterioration occurs. Therefore, as in the present invention, it is preferable to design the formulation by selecting an appropriate excipient and additives such as stabilizers, and preferably by melting in consideration of the properties of each component.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are merely to illustrate the invention and the present invention is not limited by the examples.

Examples 1-3.

Using the composition of Table 2 to prepare a composition of Examples 1-3 as follows.

1. Separately prepared water mixture tube was put purified water, heated to 80-85 ℃ and completely dissolved sorbic acid, and then mixed xanthan gum as a thickener and stabilizer.

2. When completely dissolved and showing viscosity, Polyethyleneglycol 1500 and Polyethyleneglycol 4000 were added and dissolved, and sodium lauryl sulfate and ascorbic acid were added rapidly.

3. When 2 completely dissolved, hydroquinone, the main component, was added to dissolve and compensated for the amount of water lost during heating of the aqueous phase.

4. Separately prepared isopropyl myristate, cetostearyl alcohol, polyethylene cetyl ether, monostearic acid, sorbitan and liquid paraffin were added separately, and the mixture was warmed to 85 ° C., completely dissolved under stirring, and butylhydroxytoluene was added thereto.

5. To this, tretinoin, the main component, was added to dissolve rapidly, hydrocortisone was added, and the mixture was sufficiently stirred using a homomixer to disperse without lumps.

6. The water phase part and the oil phase part were emulsified rapidly at 80-85 degreeC.

7. Dimethicone was added to the antifoaming agent with rapid cooling, followed by rapid cooling with stirring.

8. The above composition was filled into jars, tubes, and airless pump type containers.

ingredient Parts by weight Example 1 Example 2 Example 3 Award Active ingredient Hydroquinone 4.0 5.0 6.0 antiseptic Sorbic acid - 0.2 0.2 antiseptic Methylparaben 0.1 - - antiseptic Propylparaben 0.05 - - Thickener Xanthan gum - 0.1 0.1 Thickener Cabopol - - - Emulsifier Sodium lauryl sulfate - 0.2 0.2 Mechanism Polyethylene Glycol 1500 1.5 3 3 Mechanism Polyethylene Glycol 4000 1.5 3 3 stabilizator Ascorbic acid - - 0.5 stabilizator Sodium Edetate 0.5 - - stabilizator Sodium sulfite - 0.5 - menstruum Purified water Quantity Quantity Quantity The upper part Active ingredient Tretinoin 0.01 0.1 0.003 Active ingredient Hydrocortisone - 1.0 2.0 Mechanism Isopropyl myristate 5.0 7.0 - Mechanism Cetostearyl alcohol 3.0 3.0 - Mechanism Glycerol monostearate 3.0 5.0 - Mechanism Floating paraffin 3.0 5.0 - Mechanism Sorbitan monosulfate 1.5 1.5 6.0 Mechanism Seto Macrogol 1000 1.5 1.5 1.5 Mechanism vaseline 5 - 8.0 Mechanism Propylene glycol 0.5 - - Mechanism Cetanol - - 8.0 Mechanism lanolin - - 2.0 stabilizator Tocopherol 0.1 - 0.1 stabilizator Butylhydroxytoluene 0.1 0.1 0.1

Experimental Example 1. Sensory experiment of the composite composition

Table 3 shows the state of the composition prepared in Example 1 visually and under a microscope.

Sensory test results of the composition Item pH Constellation color smell Complex 3.5-4.5 Homogeneous cream Light yellow to yellow Odorless

As shown in Table 3, the state after manufacture of the composite composition prepared in the present invention was very good.

Example 2 Thermal Stability Experiment of Composite Composition

As a result of the thermal stability test of the composition prepared in Example 1 of the present invention, the composition was put into a vial, nitrogen-substituted at the top, stored at 40 ° C. for 90 days, taken on a designated date, and the content of each component was analyzed by HPLC. Shown in At this time, the control group is a composition prepared by mixing hydroquinone, tretinoin and hydrocortisone, which are active ingredients of the present invention, in a hydrophilic ointment base.

As shown in FIG. 1, the control group exhibited a chemically good stability for 90 days at 40 ° C in severe conditions compared to about 50% of the content of the composition of the present invention.

Meanwhile, Table 4 below shows the percentage of each ingredient remaining after storage at the designated time and temperature relative to the initial amount, showing the residual amount of each ingredient in the cream formulation of the example at room temperature and 40 ° C. measured at different time intervals. will be.

Thermal stability test results of composite composition (40 degrees, room temperature) Result time / temperature Hydroquinone Tretinoin Hydrocortisone Control Example Control Example Control Example 10 days / 40 degrees 99 101 98 98 97 98 20 days / 40 degrees 95 100 92 100 92 100 30 days / 40 degrees 86 99 90 96 90 100 40 days / 40 degrees 80 96 83 95 83 98 50 days / 40 degrees 72 96 72 92 72 96 60 days / 40 degrees 65 95 66 95 66 95 70 days / 40 degrees 62 96 60 93 60 95 80 days / 40 degrees 55 95 52 94 52 93 90 days / 40 degrees 48 95 50 94 50 94 12 weeks / room temperature 98 100 98 99 98 98 24 weeks / room temperature 92 98 93 94 91 100 40 weeks / room temperature 88 99 87 98 87 97 1 year / room temperature 85 95 82 97 81 96 60 weeks / room temperature 80 96 79 97 73 96 80 weeks / room temperature 75 94 74 94 74 95 90 weeks / room temperature 68 95 63 95 72 93 2 years / room temperature 65 95 62 95 65 93

As can be seen in Table 4, it can be seen that the composition of the present invention is stable when stored at 40 ° C. for 90 days and at room temperature for 2 years.

Experimental Example 3. Light Stability Experiment of Composite Composition

2 and Table 5 show the results of comparing the composition prepared in Example 1 with the same control as Experimental Example 2 into an optical tester under the harsh conditions of light amount of 150,000 lx, and the residual amount in percent. Represented by.

Light stability test results of the composition Light exposure time (hours) Hydroquinone Tretinoin Control Example Control Example 0.5 99 99 98 100 One 95 96 83 98 1.5 92 97 77 96 2 88 95 66 95 4 75 95 60 95 8 70 95 59 95 10 62 93 51 94 12 50 92 42 94 14 44 93 35 92

As can be seen in Table 5, when compared with the control of Experimental Example 2 in the harsh conditions, the control group became unstable in about 2 hours of light exposure time, but in the case of Example showed stable results up to about 15 hours.

Experimental Example 4. Physical Stability Test of Composite Composition

Table 6 shows the results of observing the physical state, that is, the separation of phases and the smell of decay, while storing the composition prepared in Example 1 of the present invention at 40 ° C in severe conditions.

Physical stability test results of the composition Elapsed days 10 20 30 40 50 60 Appearance (phase separation) stability stability stability stability stability stability color stability stability stability stability stability stability smell stability stability stability stability stability stability Stability: The compositions of the examples observed with the naked eye show no phase separation into the water phase and the oil phase, and the color and odor also show no change in the state immediately after preparation as shown in Table 3.

When the phase separation of the composition of the present invention and the color and appearance of the composition were observed for 60 days at 40 ° C., no phase separation occurred and no discoloration due to oxidation.

As described above, the composition of the present invention contains hydroquinone, tretinoin, and hydrocortisone having low stability at an appropriate concentration, and stabilizes the preparation by selecting appropriate excipients and additives such as stabilizers and containing them in an appropriate amount, and contamination by microorganisms. Discoloration and deterioration can be prevented. In addition, securing the stability of the preparation may not only increase the pharmacological effect of the preparation but also reduce side effects.

Claims (10)

2 to 6% by weight of hydroquinone, 0.001 to 0.1% by weight of tretinoin, and 0 to 2% by weight of hydrocortisone or acetic acid hydrocortisone as main components; 1 to 50% by weight of oily material, 1 to 15% by weight of emulsifier, 0.001 to 1.0% by weight of oil phase stabilizer, 0.001 to 1.0% by weight of water phase stabilizer, and 10 to 40% by weight of water phase material; And a composition for treating melanoma, comprising water According to claim 1, The oily base material is a fatty acid having 12 to 20 carbon atoms, fatty acid ester having 6 to 20 carbon atoms, fatty alcohol having 12 to 20 carbon atoms alone or in combination Composition for the treatment of melanoma The composition for treating melanoma according to claim 1 or 2, wherein the oily substance contains 1 to 30% by weight of cetostearyl alcohol, cetyl alcohol and stearyl alcohol alone or in combination. The composition of claim 1, wherein the emulsifier is a nonionic, cationic, anionic emulsifier or a mixture thereof. The nonionic emulsifier is used alone or in combination with monostearate sorbitan, glycerol monostearate, polyethylenecetylether, polyoxyethylene stearylether and polyoxyethylene hydrogenated castor oil; Anionic emulsifiers are sodium lauryl sulfate or sodium cetyl sulfate; Cationic emulsifier is cetyl trimethylammonium bromide The black skin according to claim 1, wherein the oil-based stabilizer is used alone or in combination of 0.0075 to 0.1% by weight of butylhydroxytoluene, 0.005 to 0.02% by weight of butylhydroxyanisole and 0.001 to 0.1% by weight of tocopherol. Composition for the Treatment of Symptoms The method of claim 1, wherein the aqueous phase material of the aqueous phase is a composition for treatment of melanoma, characterized in that the use of polyethylene glycol 200, 400, 600, 1500, 2000, 4000 and polypropylene glycol alone or in combination. The method of claim 1, wherein the stabilizing agent of the aqueous phase is characterized by the use of ascorbic acid 0.01 to 1.0% by weight, sodium edetate 0.005 to 0.1% by weight and sodium bisulfite 0.01 to 1.0% by weight alone or in combination Therapeutic Composition 2. The method of claim 1, further comprising 0.05 to 0.2% by weight of a preservative in addition to the above components; 0.1 to 1.0 wt% thickening and stabilizer; Or 0.1 to 2.0 wt% of an antifoaming agent. The method of claim 9, wherein the preservative is sorbic acid; Parabens including methyl paraben, propyl paraben or ethyl paraben; Benzoic acid; Benzyl alcohol; Imidazolidinyl urea; And diazolidinyl urea, the thickening and stabilizing agent is selected from xanthan gum, poloxamer, and carbopol, and the antifoaming agent is a composition for treating melanoma, characterized in that selected from dimethicone, cyclomethicone and silicone oil.