CN1375290A - Method and composition for releasing L-ascorbic acid substances to skin dermis - Google Patents

Abstract

A method and composition for treating and preventing skin aging or related skin disorders by topical application to the skin is provided. A method for delivering L-ascorbic acid (vitamin C), an L-ascorbic acid derivative and/or an L-ascorbic acid-containing extract to the dermal layer of the skin, characterized in that a composition comprising from about 1% to about 20% of L-ascorbic acid, an L-ascorbic acid derivative and/or an L-ascorbic acid-containing extract in a pharmaceutically acceptable carrier containing a hygroscopic, hydrophilic and water-soluble liquid is applied.

Description

Method for releasing L-ascorbic acid substances to the dermis of skin and its composition

The present invention relates to methods and compositions for delivering L-ascorbic acid (vitamin C), L-ascorbic acid derivatives and/or L-ascorbic acid-containing extracts to the dermis of the skin. And by topically applying the composition to the skin, it can be used to treat and/or prevent, for example, sunburn, wrinkles, poor skin tone, skin discoloration, and the like.

The beneficial effect of L-ascorbic acid on the blood flow of the dermis of the skin and the effect on the production of collagen or elastin are both well known. The most recent documents related to the present invention are listed below.

S.R. Pinnell, "Regulation of collagen biosynthesis by L-ascorbic acid," Yale J. Biol. Med. 58:554-559 (1985).

Dumas et al., "In vitro biosynthesis of collagen types I and III by human dermal fibroblasts from aged donors," Mechanism of Aging and Development, vol. 73 (1994) pp. 179-187.

Phillips et al., "Effect of L-ascorbic acid on age-related proliferation and collagen synthesis of human dermal fibroblasts and donors," Journal of Investigative Dermatology, vol.103, No.2, Aug.1994, pp.228-232.

Sephel et al., "Elastin production and age-related decrease in human dermal fibroblast cultures," Journal of Investigative Dermatology, vol.86, No.3, Mar.1986, pp, 279-285.

Takema et al., "Age-dependent changes in the properties and thickness of elastin in human facial skin", British Journal of Dermatology, vol.131, 1994, pp.641-648.

A major obstacle to the use of L-ascorbic acid in therapy has been the actual release of L-ascorbic acid at concentrations high enough to exert the beneficial effects described above into the dermis. We punctured tiny electrodes into the dermis to measure the oxidation-reduction potential, and demonstrated that the concentration of L-ascorbic acid in the dermis hardly increased when L-ascorbic acid was administered orally. If L-ascorbic acid is added to the medium to support the transfer of L-ascorbic acid to the dermis of the skin, there is a possibility of topical application to the skin. In the patent literature, many systems or formulations (compositions) related to the topical application of ascorbic acid are described.

These patent documents include following several: U.S. Patent No.4938969 (Schinitsky), U.S. Patent No.5140043 (Darr), U.S. Patent No.5281196 (Sultenfuss), U.S. Patent No.5801192 (Dumas), U.S. Patent No.5843411 ( Hernandez), U.S. Patent No. 5,853,741, and literature described therein.

It is said that these prescriptions actually released L-ascorbic acid to the dermis layer in the past, which is a conclusion deduced from experiments on the effect of these prescriptions on fine wrinkles. In these experiments, the concentration of L-ascorbic acid in the dermis was not directly determined, and the observed results may also be due to various other components contained in the tested components, sometimes in large quantities. It is therefore an object of the present invention to provide (in a demonstrable way) a method that supports the penetration of L-ascorbic acid, L-ascorbic acid derivatives and/or L-ascorbic acid-containing extracts into human skin (but avoids irritation) release methods and compositions.

Another object of the present invention is to provide a formulation of L-ascorbic acid, L-ascorbic acid derivatives and/or L-ascorbic acid-containing extracts that also reduce epidermal wrinkles through excessive exposure to sunlight or natural aging processes. Release methods and compositions.

In order to achieve the purpose of the present invention, the method of item 1 is a method for releasing L-ascorbic acid, L-ascorbic acid derivatives and/or extracts containing L-ascorbic acid to the dermis of the skin, characterized in that the hygroscopic A composition containing about 1% to about 20% of L-ascorbic acid, L-ascorbic acid derivatives and/or L-ascorbic acid-containing extracts in a pharmaceutically acceptable carrier of a hydrophilic and water-soluble liquid is applied.

In addition, the invention of claim 2 is the invention according to claim 1, characterized in that as the hygroscopic, hydrophilic and water-soluble liquid, a compound having 3 to 4 hydroxyl groups and 3 to 10 carbon atoms is used. of polyols.

The invention according to claim 3 is the invention according to claim 1, wherein a mixture of two or more types of carriers is used as the hygroscopic, hydrophilic, and water-soluble liquid.

The composition of item 4 is characterized in that it contains about 1% to about 20% of L-ascorbic acid, L-ascorbic acid derivatives and /or extracts containing L-ascorbic acid.

The invention according to claim 5 is the invention according to claim 4, wherein the hygroscopic, hydrophilic and water-soluble liquid is a linear polymer of ethylene and propylene oxide represented by the following general formula.

RO-[CH ₂ CH(CH ₃ )O] _n -[CH ₂ CH ₂ O] _m -H

In the formula, R is hydrogen or an alkyl group having 1 to 18 carbon atoms, and 1≤n+m≤40.

The invention according to claim 6 is the invention according to claim 4, wherein the hygroscopic, hydrophilic and water-soluble liquid is a mixture of two or more carriers.

Embodiments of the present invention

The present invention is based on the following insights: organic solvents with the highest polarity and hygroscopic molecular weight below 2000 can dissolve an appropriate amount of L-ascorbic acid, and are suitable as a carrier for L-ascorbic acid passing through the epithelium. Examples of suitable carriers are not limited, and the carriers are listed below.

1. A linear polymer of ethylene and ethylene oxide represented by the general formula RO-[CH ₂ CH(CH ₃ )O] _n -[CH ₂ CH ₂ O] _m -H Formula (1).

In the general formula, R is hydrogen or an alkyl group having 1 to 18 carbon atoms, provided that 1≤n+m≤40. As specific examples of such compounds, propylene glycol, dipropylene glycol, tetrapropylene glycol, and polyethers (one or two hydroxyl groups) can be selected.

2. Mixtures of linear polymers of ethylene having the above general formula and propylene oxide. As a specific example of such a compound, a mixture of polypropylene glycols having an average molecular weight of 1000 (R=H, m=0 in the above general formula), that is, Lyondell's Acclaim ^™ (hereinafter ^TM is represented as a trade name), and Acclaim™ having an average A mixture of poly(alkylene oxide) copolymers with a molecular weight of 270 (R=butyl, n=m in the above general formula) is Union Carbide's UCON ^™ 50-HB-55.

3. Polyols having 3-hydroxyl groups and 3-10 carbon atoms.

As a specific example of such a compound, there is glycerin.

Example

The effect of the carrier matrix was measured using the voltameter technique described below.

Insert an ultramicro electrode (anode) formed by a 5-micron platinum thin wire pierced into the glass, and two ultramicro electrodes of another electrode (the reference electrode is the cathode), and insert them laterally under the skin of the shoulder or upper chest, pay attention The tip of the electrode should enter the dermis. The distance between the front ends of the two electrodes was kept about 1mm. The above-mentioned ultramicroelectrodes are recorded in the following documents: [R.Mark Wightman and Davicl O.Wipf, "Voltammetry at Ultramicrodes Electrodes" in Electroanalytical Chemistry, "Voltammetry at Ultrmicrodes Electrodes" in Electroanalytical Chemistry, Vol 15, pp267～253 , eds., Allan J. Bard, Marcel Dekker, 1989].

Comparative Test

(for the standard calomel electrode) at a scan rate of 550 volts per second, make 25 scan curves between -0.2 and +0.2 volts, record the integral value of the anode cycle part of the voltage-current curve, and store it in the computer. The average of the 25 scans was used as the background value for the unit of measure where oxidation was found in the anodic cycle.

Penetration:

The solution containing 3% L-ascorbic acid in the test carrier matrix is applied at 0.05ml/cm ² to the skin part on the electrode (the total coating area is about 5cm ² ), and the above-mentioned periodic wave is caused after 20 seconds. A unit of measure for measuring where total oxidation is found. The difference between this value and the oxidation background value obtained in the reference test is used as the oxidation measurement unit of L-ascorbic acid. This is the unit of measure for L-ascorbic acid concentration (osmolarity) in the dermis.

The values obtained cannot be simply interpreted as the true concentration of L-ascorbic acid, and the accuracy of the determination is not high (±10%).

In order to have a certain correlation between the measured value in vivo and the dermal concentration of L-ascorbic acid, the same electrode was immersed in 0.5ml of human blood kept at 37°C, and the current measurement was performed as described above, and L-ascorbic acid was added to the blood sample. (1ml blood 7.5mg), and then conduct current measurement. The difference between these two oxidation values is arbitrarily enlarged and expressed by 100 times. Table 1 shows the results of several measurements performed with this scale. For the samples in the table, L-ascorbic acid is directly dissolved in the carrier solvent. In order to speed up the dissolution process, the operation is performed with heating if necessary.

Table 1

Oxidation value when the therapeutic prescription composition of L-ascorbic acid is applied to the skin in vivo carrier base % of L-Ascorbic Acid oxidation value Propylene Glycol 0 0 Propylene Glycol 3 50 glycerin 0 0 glycerin 3 20 tetrapropylene glycol 0 0 tetrapropylene glycol 3 40 Propylene Glycol 400 ¹ 0 0 Propylene Glycol 400 ¹ 3 15 Acclaim ^™ 1000 ² 0 0 Acclaim ^™ 1000 ² 3 10 UCON ^TM 50-HB-55 ³ 0 0 UCON ^TM 50-HB-55 ³ 3 60 ^UCONTM 50-HB-100 ⁴ 0 0 ^UCONTM 50-HB-100 ⁴ 3 25 UCON ^TM 50-HB-2000 ⁵ 0 0 UCON ^TM 50-HB-2000 ⁵ 3 20 ^UCONTM 50-LB-65 ⁶ 0 0 ^UCONTM 50-LB-65 ⁶ 3 20

In Table 1, polypropylene glycol 400 ¹ is a mixture of polypropylene glycols with an average molecular weight of 400 derived from the polymerization of propylene oxide.

Acclaim ^™ 1000 ² is a mixture of polypropylene glycols with an average molecular weight of 1000 derived from the polymerization of propylene oxide (supplier: Lyondell Corporation).

UCON ^™ 50-HB-55 ³ is a mixture of polyethers of the aforementioned formula (1), R = butyl, n = m, and an average molecular weight of 270 (supplier: Union Carbide Corporation).

UCOM ^™ 50-HB-100 ⁴ is a mixture of polyethers of formula (1) above, R = butyl, n = m and an average molecular weight of 520 (supplier: Union Carbide Corporation).

UCOM ^™ 50-HB-2000 ⁵ is a mixture of polyethers of formula (1) above, R = butyl, n = m and an average molecular weight of 2660 (supplier: Union Carbide Corporation).

UCOM ^™ 50-LB-65 ⁶ is a mixture of polyethers of the above formula (1), R = butyl, n = 0, and an average molecular weight of 340 (supplier: Union Carbide Corporation).

The transepithelial penetration of solutions applied topically using a hygroscopic carrier was also demonstrated in the same way as ascorbyl palmitate.

In addition, it has been found that in the method and composition of the present invention, L-ascorbic acid, L-ascorbic acid derivatives and/or L-ascorbic acid derivatives and/or L- The amount of the extract of ascorbic acid is in the range of 1%-20%, and the expected effect can be obtained, and the most suitable range is 3%-10%.

The effect of the invention

The present invention is a method for releasing L-ascorbic acid (vitamin C), L-ascorbic acid derivatives and/or extracts containing L-ascorbic acid to the dermis of the skin. The pharmaceutically acceptable carrier contains the composition of effective portion of L-ascorbic acid, L-ascorbic acid derivatives and/or extracts containing L-ascorbic acid. The hygroscopic base makes possible a suitable sustained diffusion of L-ascorbic acid through the epidermis of the skin to the dermis. By topical application of such compositions to the skin, they can be used to treat and/or prevent actinic skin aging or related skin disorders such as sunburn, wrinkles, poor skin tone, skin discoloration, and the like.

Claims (6)

1. A method for releasing L-ascorbic acid, L-ascorbic acid derivatives and/or extracts containing L-ascorbic acid to the dermis of the skin, wherein the medicament containing a hygroscopic, hydrophilic and water-soluble liquid A composition containing about 1% to about 20% of L-ascorbic acid, L-ascorbic acid derivatives and/or L-ascorbic acid-containing extracts in a pharmaceutically acceptable carrier is applied. 2. The method for releasing L-ascorbic acid, L-ascorbic acid derivatives and/or extracts containing L-ascorbic acid to the skin dermis according to claim 1, characterized in that, as the above-mentioned hygroscopicity, hydrophilicity and water-soluble As a permanent liquid, polyhydric alcohols with 3 to 4 hydroxyl groups and 3 to 10 carbon atoms are used. 3. The method for releasing L-ascorbic acid, L-ascorbic acid derivatives and/or extracts containing L-ascorbic acid to the skin dermis according to claim 1, characterized in that, as the above-mentioned hygroscopicity, hydrophilicity and water-soluble For a specific carrier, use a mixture of two or more carriers. 4. A composition characterized in that it contains about 1% to about 20% of L-ascorbic acid, L-ascorbic acid derivatives and/or Or extracts containing L-ascorbic acid. 5. The composition according to claim 4, wherein the above-mentioned hygroscopic, hydrophilic and water-soluble liquid is a linear polymer of ethylene and propylene oxide represented by the following general formula, RO-[CH ₂ CH(CH ₃ )O] _n -[CH ₂ CH ₂ O] _m -H In the general formula, R is hydrogen or an alkyl group with 1 to 18 carbon atoms, 1≤n+m≤ 40. 6. The composition according to claim 4, wherein the hygroscopic, hydrophilic and water-soluble liquid is a mixture of two or more carriers.