KR102400114B1 - Composition for enhancing skin elasticity comprising retinoids derivative as active ingredient - Google Patents

Abstract

The present invention provides a composition for enhancing skin elasticity containing a retinoid derivative as an active ingredient. The retinoid derivative of the present invention can be usefully used as an active ingredient in a pharmaceutical composition or cosmetic composition for promoting elastin synthesis and enhancing skin elasticity by lifting the skin.

Description

Composition for enhancing skin elasticity containing a retinoid derivative as an active ingredient

The present invention relates to a cosmetic composition or pharmaceutical composition for enhancing skin elasticity containing a retinoid derivative as an active ingredient.

Skin aging can be roughly divided into intrinsic aging or chronological aging and extrinsic aging. Among them, intrinsic aging is histologically a natural decline phenomenon in which elastin decreases in the extracellular matrix and elastin fibers are decomposed. Extrinsic aging refers to a phenomenon in which the appearance or function of the skin is changed due to repeated exposure to sunlight (photo-aging) or environmental pollution and stress.

Elastin is an important protein constituting the connective tissue of the lungs, skin, and blood vessels as a protein fiber that gives cell tissue elasticity. When the skin is pulled, the skin does not stretch to a certain extent. At this time, collagen acts as a non-stretching agent, and collagen plays a role in resisting pressure or external forces applied to the skin. On the other hand, elastin plays a role in maintaining the elasticity of the skin like a spring. In other words, it is because elastin exists that makes the skin return to its original state when the pulled skin is released. So, when the skin is pulled, it quickly returns to its original state, meaning less elastin is damaged.

Elastin is not produced in the human body after puberty and aging begins. This results in skin sagging. Therefore, in order to prevent loss of elasticity that causes skin sagging, it is important to prevent degradation or loss of elastin and to promote elastin production.

In general, moisturizing or anti-wrinkle cosmetics are used to prevent skin aging and improve elasticity. However, cosmetics up to now are only used for the prevention of skin aging, and there is a disadvantage in that it is difficult to obtain a practical improvement effect for elasticity improvement.

Korean Patent Registration No. 10-1503158

An object of the present invention is to promote the synthesis of elastin, which plays an important role in skin elasticity, and to provide a composition for enhancing skin elasticity that can improve skin elasticity by lifting the skin to reduce skin sagging.

To this end, the present invention provides a pharmaceutical composition for enhancing skin elasticity containing a retinoid derivative represented by the following formula (1) as an active ingredient:

[Formula 1]

(In the above formula,

R ₁ and R ₂ are the same as or different from each other and are hydrogen or a C1-C6 straight-chain or branched alkyl group.)

In addition, the present invention provides a cosmetic composition for enhancing skin elasticity containing the retinoid derivative represented by Formula 1 as an active ingredient.

Since the retinoid derivative according to the present invention promotes the synthesis of elastin responsible for skin elasticity and lifts the skin, a composition containing it as an active ingredient is very useful for improving or treating skin elasticity.

1 is a graph showing the elastin synthesis ability test results according to the treatment with the retinoid derivative of Example 1 in fibroblasts.
Figure 2 is a graph showing the clinical trial results using the cream containing the retinoid derivative of Example 1.

Hereinafter, the present invention will be described in detail.

The retinoid derivative contained as an active ingredient in the composition according to the present invention has the structure of Formula 1 below.

[Formula 1]

(In the above formula,

R ₁ and R ₂ are the same as or different from each other and are hydrogen or a C1-C6 straight-chain or branched alkyl group.)

More preferably, in the retinoid derivative, in Formula 1, R ₁ is a methyl group and R ₂ is 1,5-bis retinamido of hydrogen is 2-methyl pentane.

The retinoid derivative of Formula 1 according to the present invention may be prepared by reacting a compound of Formula 2 with a compound of Formula 3 below:

[Formula 2]

[Formula 3]

(In the above formula,

Y is hydroxy or halogen,

R ₁ and R ₂ are the same as or different from each other and are hydrogen or a C1-C6 straight-chain or branched alkyl group.)

When Y is hydroxy, the compound of Formula 2 may be reacted with the compound of Formula 3 in a solvent in the presence of a condensing agent and an organic amine catalyst to obtain a retinoid derivative.

At this time, as a condensing agent, N,N,N',N'-tetramethyl-(benzotriazol-1-yl)-uroniumtetrafluoroborate (TBTU), N-(3-dimethylaminopropyl)-N' -Ethyl-carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), or N,N'-dicyclohexylcarbodiimide (DCC) may be used, but is not limited thereto.

In addition, diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP) may be used as the organic amine catalyst for accelerating the condensation reaction, but is not limited thereto. As the solvent, an anhydrous organic solvent, for example, one or more selected from dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether may be used, but is not limited thereto. The reaction is usually preferably carried out in a state in which light and moisture are blocked under a nitrogen atmosphere, and may be carried out in a cooled or warmed state.

When Y is halogen, it can be prepared by reacting the compound of Formula 2 with the compound of Formula 3 in a solvent in the presence of an organic amine.

In this case, pyridine or triethylamine may be used as the organic amine acting as a base, but the present invention is not limited thereto. As the solvent, an anhydrous organic solvent, for example, one or more selected from dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether may be used, but is not limited thereto. In this case, the organic amine is preferably used in an equivalent ratio of 1.0 to 2.0 based on the compound of Formula 3. The reaction is usually preferably carried out in a state in which light and moisture are blocked under a nitrogen atmosphere, and may be carried out in a cooled or warmed state.

The compound of Formula 2 in which Y is halogen, used as a starting material, can be prepared by reacting retinoic acid with a halogenating agent such as phosphorus trichloride, thionyl chloride and oxalyl chloride.

The compound of Formula 1 prepared by the above method may be separated and purified using a conventional separation and purification method, for example, recrystallization or column chromatography.

The compound of Formula 1 promotes the synthesis of elastin, which plays an important role in the skin having elasticity, and lifts the sagging skin by losing elasticity.

Accordingly, the composition comprising the compound of Formula 1 as an active ingredient may be formulated as a pharmaceutical composition or a cosmetic composition for enhancing skin elasticity.

When formulated as a pharmaceutical composition, the composition of the present invention may be formulated by a method known in the pharmaceutical field, and is mixed with a pharmaceutically acceptable carrier, excipient, etc., and mixed with a conventional pharmaceutical preparation, for example, a solution, a syrup, It can be formulated in capsules, granules, powders, ointments, emulsions, gels, creams, etc., and it can be administered by various routes. Preferably, it may be formulated in a liquid, cream, paste or solid form for transdermal administration, such as an external solution, an emulsion, or an ointment.

The pharmaceutical composition of the present invention contains 0.001 to 10% by weight of the retinoid derivative of Formula 1 in the total pharmaceutical composition. The pharmaceutical composition thus prepared is used in an effective amount of 0.00001 mg/kg to 400 mg/kg per one time, and the actual dosage of the active ingredient depends on the severity of symptoms, the route of administration selected, the age, sex, weight and health status of the subject. It should be understood that the determination should be made in light of several relevant factors, such as Accordingly, the above dosage does not limit the scope of the present invention in any way. Administration may be administered once to several times a day.

When formulated as a cosmetic composition, the content of the retinoid derivative of Formula 1 is 0.0001 to 10% by weight, preferably 0.01 to 5.0% by weight, based on the total weight of the cosmetic composition. In order to achieve the minimum skin elasticity improvement effect, the content of the retinoid derivative is preferably equal to or higher than the above minimum value, and the content of the retinoid derivative is preferably less than or equal to the maximum in consideration of the decrease in feeling of use due to excessive addition and the possibility of application to various formulations. . In this case, the content of the retinoid derivative is preferably adjusted within the above range according to the content of the ingredients contained in the formulation or cosmetic composition.

The ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions in addition to the retinoid derivative as an active ingredient, for example, conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and carrier.

The composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, softening lotion, astringent lotion, nutrient lotion, nourishing cream, massage cream, essence, eye cream, eye essence, cleansing cream, It can be formulated into cosmetics such as cleansing foam, cleansing water, pack, gel, powder, spray, gel, foam, body lotion, body cream, body oil, and body essence.

When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component. can

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additional chlorofluorohydrocarbon, propane /may contain propellants such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylglycol oil, glycerol fatty esters, fatty acid esters of polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Adult cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used.

When the formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide as carrier components Ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester may be used.

Hereinafter, preferred embodiments of the present invention will be described. The following examples are only described for the purpose of more clearly expressing the present invention, but the content of the present invention is not limited to the following examples.

Example 1: 1,5- bis Retinamido 2- methyl pentane synthesis

After retinoic acid 35 g (0.0116 mol) was dissolved in 150 ml of anhydrous toluene, 16.3 g (0.0116 mol) of phosphorus trichloride (PCl ₃ ) was added dropwise thereto, and the mixture was stirred at room temperature under nitrogen while blocking light and moisture for 15 hours. . The obtained retinoic acid chloride solution was added dropwise to a solution in which 6.77 g (0.058 mol) of 2-methyl-1,5-diaminopentane and 11.8 g (0.117 mol) of triethylamine were dissolved in 100 ml of anhydrous dichloromethane under ice cooling for 30 minutes. After that, stirring was continued at room temperature for 5 hours. The reaction solution was added to 250 ml of a saturated aqueous sodium chloride solution, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (SiO ₂ , 200-400 mesh, ethal acetate/hexane=1:3, v/v) to obtain 56.1 g (yield: 71%) of the title compound.

Experimental example 1: elastin ( Elastin ) synthetic effect

Normal human fibroblasts were cultured in a 24-well microplate for 24 hours, treated with the retinoid derivative of Example 1 at 1 ug/mL, and cultured for 1 or 2 days. The amount of elastin newly synthesized and secreted by fibroblasts was measured for each time using an elastin kit (fastin elastin assay kit), and the results are shown in FIG. 1 .

As shown in Figure 1, the retinoid-treated group increased the elastin synthesis effect 2-3 times compared to the control group.

Experimental example 2: Clinical trial

2-1. Example 1 of retinoid Preparation of creams containing derivatives

A cream containing a retinoid derivative having the ingredients and contents shown in Table 1 was prepared. Specifically, the aqueous phase purified water, triethanolamine, and propylene glycol were heated to 70° C. and dissolved, and then the oil phase fatty acid, oily component, emulsifier and preservative were heated to 70° C. and dissolved to emulsify. After the emulsification was completed, the solution was cooled to 45°C, retinoid derivatives were added and dispersed, and then cooled to 30°C.

ingredient content (wt%) retinoid derivatives 3 lipophilic monostearate glycerin 2 cetearyl alcohol 2 stearic acid 1.5 Polysorbate 60 1.5 Sorbitan Stearate 0.6 Hydrogenated polyisobutene One squalane 3 mineral oil 5 cyclomethicone 5 dimethicone One tocopherol acetate 0.5 glycerin 5 betaine 3 triethanolamine One Xanthan Gum 0.05 incense appropriate amount antiseptic appropriate amount pigment appropriate amount Distilled water remaining amount Sum 100

2-2. Example 1 of retinoid Measurement of skin elasticity improvement effect of cream containing derivatives

The average age of the cream prepared by the method 2-1 above was 43.05 years. Twenty-two healthy women were instructed to use the product twice a day for 3 months on each subject's face.

2-3. Evaluation site and measurement method

For the instrumental evaluation, the test subject was allowed to adjust the skin surface temperature and humidity to the environment of the measurement space by taking a rest for 30 minutes in a waiting room under constant temperature and humidity conditions with an indoor temperature of 20~25℃ and a humidity of 40~60%. During this time, water intake was limited. For objective measurement, one researcher measured, and the same area was measured for each measurement.

2-4. skin elasticity measurement

Skin elasticity was measured using a Cutometer CM580. The measurement was carried out once, and the R2 (skin re-strain force) value was used as the skin elasticity evaluation data. The R2 value is the overall elasticity, and a value closer to 1 means more elastic.

2-5. face lifting Measure

Facial lifting measurement was performed by analyzing images taken using F-ray, which is a device that expresses the appearance of the skin as contour lines, with Image-pro plus. Measurements were taken of the same site before, 3, and 6 weeks after using the test product, and was measured based on a curve formed near the test site. Measurement was evaluated by drawing a straight line from the center of the circle based on the circle formed near the cheekbones and measuring the angle with the straight line across the mouth. The smaller the angle of the two straight lines, the greater the lifting effect.

2-6. skin swelling measurement

For skin swelling measurement, facial images were analyzed using PRIMOS Bodyscan 3D, which can measure skin 3D volume, and used as skin swelling evaluation data. For data analysis, the reference image (left) and the image to be compared (right) were used. The facial volume (ml) value of the stored image was analyzed, and as the volume (ml) decreased, the skin swelling was improved.

2-7. statistical analysis

SPSS 19.0, a statistical analysis program, was used to examine the significance of skin measurements compared to before using the test product. Significance was confirmed when the probability of significance was p<0.05 in the 95% confidence interval, and the probability of significance was rounded to three decimal places. Continuous variables were summarized as mean and standard deviation, and categorical variables were summarized as frequencies and percentages. Comparison before and after normality was tested by repeated measures ANOVA (post-hoc test: Bonferroni correction), a parametric method, and Friedman test (post-hoc test: Wilcoxon signed rank test with Bonferroni correction), a non-parametric method.

The clinical test results are shown in FIG. 2 . Referring to FIG. 2 , after 3 weeks of using the cream containing the retinoid derivative of Example 1, skin elasticity was improved, the skin was lifted, and skin swelling was reduced.

Hereinafter, skin ointment, softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, essence and pack are exemplified as formulation examples of the present invention, but the formulation of the composition of the present invention is not limited thereto.

Formulation example 1: Ointment for external use on the skin

As shown in Table 2 below, an external skin ointment containing the retinoid derivative of Example 1 was prepared according to a conventional method.

ingredient content (wt%) retinoid derivatives 10 diethyl sebacate 8 brazing 5 Polyoxyethylene oleyl ether phosphate 6 sodium benzoate appropriate amount vaseline remaining amount Sum 100

Formulation example 2: Softening lotion ( skin )

As shown in Table 3 below, a softening lotion containing the retinoid derivative of Example 1 was prepared according to a conventional method.

ingredient content (wt%) retinoid derivatives One glycerin 5 1,3-butylene glycol 3 betaine One allantoin 0.1 DL-Panthenol 0.3 EDTA-2Na 0.02 Sodium Hyaluronate Powder 0.05 ethanol 5 Octyldodeces-16 0.2 Polyoxyethylene hydrogenated castor oil 0.2 incense appropriate amount antiseptic appropriate amount pigment appropriate amount Purified water remaining amount Sum 100

Formulation example 3: Nutrient lotion (lotion)

Nutrient lotion containing the retinoid derivative of Example 1 was prepared according to a conventional method as shown in Table 4 below.

ingredient content (wt%) retinoid derivatives 3 Glyceryl Stearate SE 1.5 cetearyl alcohol 1.0 shea butter 1.5 Polysorbate 60 1.3 Sorbitan Stearate 0.5 hydrogenated vegetable oil One mineral oil 5 squalane 3 cyclomethicone 2 dimethicone 0.8 tocopherol acetate 0.5 Carbomer 0.12 glycerin 5 1,3-butylene glycol 3 Sodium Hyaluronate Powder 0.05 triethanolamine 0.12 incense appropriate amount antiseptic appropriate amount pigment appropriate amount Distilled water remaining amount Sum 100

Formulation example 4 : massage cream

As shown in Table 5 below, a massage cream containing the retinoid derivative of Example 1 was prepared according to a conventional method.

ingredient content (wt%) retinoid derivatives 3 lipophilic monostearate glycerin 1.5 cetearyl alcohol 1.5 stearic acid One Polysorbate 60 1.5 Sorbitan Stearate 0.6 isostearyl isosterate 5 squalane 5 mineral oil 35 dimethicone 0.5 Hydroxyethyl Cellulose 0.12 glycerin 6 1,3-butylene glycol 3 triethanolamine 0.3 incense appropriate amount antiseptic appropriate amount pigment appropriate amount Distilled water remaining amount Sum 100

Formulation example 5: Essence

As shown in Table 6 below, an essence containing the retinoid derivative of Example 1 was prepared according to a conventional method.

ingredient content (wt%) retinoid derivatives 3 glycerin 6 betaine 5 PEG 1500 2 allantoin 0.1 DL-Panthenol 0.3 EDTA-2Na 0.02 Hydrogenated Lecithin 0.6 Hydroxyethyl Cellulose 0.1 Sodium Hyaluronate Powder 0.08 Carboxyvinyl Polymer 0.2 triethanolamine 0.2 ceramide 0.2 Octyldodecanol 3 squalane 3 Polysorbate 60 0.4 Glyceryl Stearate SE 1.5 incense appropriate amount antiseptic appropriate amount pigment appropriate amount Distilled water remaining amount Sum 100

Formulation example 6: Pack

As shown in Table 7 below, a pack containing the retinoid derivative of Example 1 was prepared according to a conventional method.

ingredient content (wt%) retinoid derivatives One polyvinyl alcohol 15 Cellulose Gum 0.15 glycerin 3 PEG 1500 2 betaine 2 DL-Panthenol 0.4 allantoin 0.1 triethanolamine 0.2 nicotinamide 0.5 ethanol 6 PEG 40 hydrogenated castor oil 0.3 incense appropriate amount antiseptic appropriate amount pigment appropriate amount Distilled water remaining amount Sum 100

Claims (8)

delete delete delete delete A cosmetic composition for skin swelling relief and lifting containing a retinoid derivative represented by the following formula (1) as an active ingredient:
[Formula 1]

(In the above formula,
R ₁ and R ₂ are the same as or different from each other and are hydrogen or a C1-C6 straight-chain or branched alkyl group.) 6. The method of claim 5,
Wherein R ₁ is a methyl group and R ₂ is A cosmetic composition for skin swelling relief and lifting, characterized in that it is hydrogen. 6. The method of claim 5,
The content of the retinoid derivative is a cosmetic composition for skin swelling relief and lifting, characterized in that it is contained in an amount of 0.001 to 10% by weight based on the total weight of the cosmetic composition. 7. The method of claim 6,
The cosmetic composition is a softening lotion, astringent lotion, nutritional lotion, nourishing cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, gel, powder, spray, gel, foam, body lotion , body cream, body oil, and a cosmetic composition for skin swelling relief and lifting, characterized in that any one formulation selected from the group consisting of body essence.

Images