JP2006514047A - Promotion of skin cell regeneration by water-soluble vitamin E - Google Patents

Abstract

The present invention relates to a method for increasing the rate of skin peeling by including a water-soluble vitamin E derivative in a cosmetic composition containing water and suitable for application to mammalian skin. The pH of the composition is about 4.5 to 9 and can increase the natural skin release rate by at least 10%.

Description

References to Related Applications This application is filed in US Patent No. 6,645,514 filed on December 19, 2002 and US filed on October 10, 2003, each titled “Increasing Skin Cell Renewal With Water-Soluble Vitamin E.” Claim priority of proxy number 3086/1421.

BACKGROUND OF THE INVENTION Human skin is constantly being attacked by environmental conditions such as the sun, wind, and pollution. These attacks by the environment age the visible skin layer and reduce the ability of the skin to function as an effective barrier layer to the environment. This weathering causes undesirable conditions such as wrinkles, aging spots, roughening, scaling, flaking, uneven appearance, and uneven color. In addition, the skin is wrinkled by the effects of natural aging.
These undesirable effects can be prevented or at least ameliorated by applying a skin care cosmetic comprising a skin conditioner that enhances exfoliation of the present invention.

Human skin can be divided into two main parts, the outer layer or epidermis and the lower layer or dermis. The dermis, along with others, contains blood vessels, nerves, collagen, elastin, and fibroblasts that are responsible for the biosynthesis of collagen and elastin.
The epidermis can be considered to consist of two main regions, the inner layer or Malpiggy layer and the outer layer or stratum corneum. The living Malpiggy layer, a living tissue, can be further classified into a basal layer, a spiny layer, and a granular layer. The outer horny layer, the dead tissue, is also called the stratum corneum.

In the natural skin regeneration process, basal cells move outward from the basal layer, pass through the spinous layer and the granular layer, and become dead cells called keratinocytes in the stratum corneum. This process of forming keratinocytes is called keratinization. The stratum corneum consists of approximately 14 dead cell layers, which are skin tissues that sense when touching the surface of the skin.
In normal skin, it takes about 14 days for the basal cells to move from the basal layer to the end of the granule layer to become keratinocytes, and the horny cells reach the outermost layer of the stratum corneum and naturally It takes another 14 days to peel off or peel off. Therefore, in the process of skin regeneration, it takes about 28 days for the cells of the basal layer to move outward to the surface.

  Based on this knowledge of skin properties, two well-known methods have been used to improve the appearance of the skin through the application of a topical composition. In the first method, a composition that protects the live part of the skin from damage is applied. In the second method, a composition is applied that increases the rate of natural detachment of the skin (cell regeneration rate), thereby increasing the rate of replacing the outer layer of dead cells (the stratum corneum).

One conventional method for protecting living skin cells from oxidative damage is by applying a composition comprising α-tocopherol (natural vitamin E) to the skin surface. Natural vitamin E is oil soluble and improves skin appearance through continuous use by permeating through the outer layers of the skin and protecting living skin cells from oxidative attack such as radicals and peroxides. Can be made. In addition, ester-derived vitamin E, tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate / oleate, tocopheryl nicotinate, and oil-soluble vitamin E derivatives such as tocopherol (vitamin E alcohol) also attack living skin cells. Can play a role in protecting against. It is believed that natural vitamin E and its oil-soluble derivatives can improve the appearance of the skin by reducing oxidative damage to living cells. These oil-soluble preparations are not known to increase the rate of detachment (skin cell regeneration).
Unlike oil-soluble vitamin E derivatives, water-soluble vitamin E derivatives are known to prevent organ damage when administered in the body. US Pat. No. 6,022,867 describes DL-α-tocopherol phosphate (VEP), a water-soluble vitamin E derivative. This derivative can be prepared by reacting vitamin E with sodium phosphate. The '867 patent discloses how VEP can improve animal health when administered internally. Similarly, WO 93/15731 discloses how liver damage can be prevented by in vivo administration of phosphate-derived vitamin E to mice. Unlike previous oil-soluble vitamin E preparations, VEP is water soluble.

  Another conventional method for improving the appearance of the skin is through the application of exfoliating acids, increasing the outermost natural exfoliation rate (cell regeneration rate) of the stratum corneum, thereby lowering the layer below the stratum corneum. To expose. Unlike the previous method of protecting living skin cells with oil-soluble vitamin E and its oil-soluble derivatives, exfoliating acid here accelerates the process of natural exfoliation by acting on a layer of dead skin cells . Many exfoliating acids are known to increase the rate of natural exfoliation. Exfoliating acids include glycolic acid, lactic acid, citric acid, malic acid, tartaric acid, salicylic acid, acetic acid, pyruvic acid, polyhydroxy acids (including gluconolactone and derivatives), and alpha and beta that have recently gained attention A hydroxycarboxylic acid is mentioned. Low molecular weight short chain acids such as lactic acid and glycolic acid are the most widely used exfoliating acids in cosmetics.

A major drawback in the use of acids as release agents, including hydroxycarboxylic acids, is that they are most effective at low pH of about 4.0 or lower. Yu, RJ, et al. “Bioavailability of Alpha-Hydroxy Acids in Topical Formulations,” Cosmetic Dermatology, Vol. 9, No. 6 (June 1996). It is believed to protonate and thus lose its beneficial activity at high pH due to lack of bioavailability. The inability of exfoliating acid to maintain its effect in the high pH region is described by Smith, WP, “Hydroxy Acids and Skin Aging,” Soap / Cosmetics / Chemical Specialties, pp. 54-58, 76 (September 1993) Also shown by
Another drawback in the use of exfoliating acid is that there is a strong correlation between its ability to exfoliate (increase cell regeneration rate) and thereby the degree of skin irritation. This increased stimulation is likely due to the acidity of the active substance. Therefore, in compositions that rely on exfoliated acid for increased cell regeneration rate, the extent of exfoliation increases with increasing acidity and irritation. Thus, in actual use, the amount of beneficial skin release that the exfoliating acid can achieve can be applied to the skin without undue irritation, not by the acid's ability to exfoliate. Limited by frequency.

  As stated earlier, at pH of about 4.0 or lower, exfoliating acids including hydroxycarboxylic acids show significant cell regeneration promoting effects with an undesirable degree of skin irritation. However, as the pH of the acidic composition is raised to approach neutral (7.0), cell regeneration decreases rapidly with skin irritation. Accordingly, it may be beneficial to provide an exfoliating composition that increases the rate of natural skin exfoliation without the skin irritation associated with exfoliating acids. It is most desirable to provide an enhanced skin release action at a pH closer to neutral to reduce skin irritation. The compositions of the present invention provide less irritating and improved skin release compared to conventional exfoliating acids, thereby overcoming the major drawbacks of acidic release agents.

SUMMARY OF THE INVENTION In certain embodiments, the present invention provides a topical cosmetic or dermopharmaceutical composition comprising a water soluble vitamin E derivative and a hydrous carrier. The water-soluble vitamin E derivative is preferably a water-soluble salt of vitamin E and is present in the aqueous phase.

In another embodiment, the water soluble vitamin E derivative is present in the composition in an amount that has the effect of increasing the rate of natural skin exfoliation at a pH that significantly reduces skin irritation compared to conventional exfoliating acids. To do. Water-soluble vitamin E derivatives increase the rate of skin peeling without undue irritation.
According to this aspect of the invention, there is provided a composition comprising a water-soluble vitamin E derivative present in a therapeutically effective amount in an externally acceptable carrier, wherein the composition is applied to human skin. (apply) to increase the rate of natural skin peeling. Preferably, the composition comprises from about 0.05% to about 30% water soluble vitamin E derivative and has a pH value in the range of about 4.5 to 9.

  Another aspect of the present invention includes a method of increasing the rate of skin detachment, wherein the method is an amount of aqueous solution that has the effect of increasing the rate of skin cell detachment over the rate of naturally occurring skin cell detachment. Applying a cosmetic composition comprising a sexual vitamin E derivative for external use. In this embodiment, the method comprises applying the composition comprising a water soluble vitamin E derivative to the skin externally in an amount sufficient to increase the rate of natural skin exfoliation and for a sufficient period of time.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions that increase the rate of skin cell regeneration or detachment, and methods for increasing the rate of skin cell regeneration. This composition is believed to act by promoting the detachment of dead cells, or "dissociation", rather than by repair of live skin cells or protection from disorders such as oxidative damage from radicals and peroxides. Thus, the compositions of the invention increase the rate at which dead keratinocytes dissociate; that is, the compounds are not believed to protect live cells from damage.

  Many benefits can be obtained by increasing the rate of exfoliation of mammalian skin. In certain embodiments, visible skin layers can be regenerated to reduce uneven appearance and color unevenness. When the regenerated skin is exposed to light, the skin appears “brighter” and healthier. In another embodiment, increasing the peel rate improves skin texture, for example, by reducing wrinkles, roughening, scaling, and flaking. Thus, the appearance of the skin can be improved by smoothing the texture of the skin.

In particular, the present invention relates to a composition comprising a skin conditioning agent comprising a water-soluble vitamin E derivative that promotes cell regeneration but does not unduly stimulate at a desired pH. In a particularly preferred embodiment, the present invention comprises a composition comprising vitamin E (VEP) derived from sodium phosphate. The present invention further relates to a method for increasing the rate of skin cell detachment by applying the composition to the skin, the composition comprising an effective amount of a water-soluble vitamin E derivative and a carrier.
According to one embodiment of the present invention, a composition acceptable for topical application to the skin comprises a water-soluble vitamin E salt and a carrier.

  Water-soluble vitamin E salts useful in the present invention include all enantiomers, whether alone or in combination. With respect to salts, preferred salts include phosphate and sulfate, where phosphate is presently preferred. The cation portion of the salt includes, but is not limited to, alkali metals and alkaline earth metals such as sodium, potassium, calcium, and magnesium. The cations may be used alone or in a mixture of two or more. The preferred cation for this salt is sodium.

  Suitable water-soluble vitamin E derivatives include, for example, vitamin E sodium phosphate (VEP), Lauryl Imino Dipropionic Acid Tocopheryl Phosphate, tocopheryl glycoside, tocopheryl oxalate, tocofersolan ( Tocopheryl succinate polyethylene glycol 1000), disodium lauriminodipropionate Tocopheryl Phosphates, Tocophereth-5, 10, 12, 18, and 50 (polyethylene glycol (PEG) tocopheryl ether) ). Laurumiminodipropionate disodium tocopheryl phosphate can be considered to be vitamin E phosphate and its derivatives with beta-alanine functionality. With respect to PEG vitamin E derivatives, an increase in the number represents an increase in the number of PEG molecules attached to vitamin E. Therefore, as the number increases, solubilities increase, tocopheres-5 has the lowest water solubility, and tocopheres-50 has the highest water solubility. Preferred water-soluble vitamin E derivatives include sodium vitamin E phosphate (VEP), tocopheryl lauryliminodipropionate phosphate, and disodium laurimidinodipropionate tocopheryl phosphate.

To prepare the composition of the present invention, at least one water-soluble vitamin E salt may be mixed with a pharmaceutically or cosmetically acceptable water-containing carrier. Desirably, from about 0.05% to about 30%, more preferably from about 0.1% to about 15% of the composition is a water-soluble vitamin E derivative. At present, compositions comprising about 0.4% to about 5% water-soluble vitamin E derivative are particularly preferred. Unless otherwise noted, all percentages are given on a weight / weight basis.
Desirably, the carrier can help maintain the desired pH of the composition. The pH value for the composition of the present invention is about 4.5 to about 9, preferably 4.8 to 8.2, and more preferably 5.6 to 7.9.
Since the relationship between the pH value and the acidity is logarithmic, the difference in acidity is large despite the small difference between these pH values. Therefore, pH 5 is significantly less acidic than pH 4.

  Desirably, the water soluble vitamin E derivative is not combined to form a composition comprising exfoliating acid, squalene, or squalane. “Squalane” is a saturated hydrocarbon formed by reducing squalene, an unsaturated hydrocarbon present in fish and vegetable oils. In another embodiment, the composition does not include a stripping acid at a concentration sufficient to provide an increase in strip rate. In another embodiment, the composition does not contain more than 2% exfoliating acid. In yet another embodiment, the composition does not comprise exfoliating acid with a bioavailability greater than 4%, more preferably greater than 1%.

The compositions of the present invention may be formulated as aqueous solutions, gels, lotions, creams, ointments, oil-in-water emulsions, water-in-oil emulsions, or other pharmaceutically acceptable forms. However, when the aqueous composition includes an oil, the water-soluble vitamin E salt is substantially in the aqueous phase.
A cosmetically acceptable carrier comprises water and preferably functions as a carrier for diluents, dispersants, or other cosmetic ingredients present in the composition, when the composition is applied to the skin. Promote distribution. Preferably the composition comprises 5 to 98% water, more preferably 80 to 98% water.

  The composition of the present invention may further contain various conventional cosmetic ingredients as long as they do not adversely affect the desired skin peeling enhancing effect or composition pH. Suitable cosmetic ingredients include liquid or solid emollients, organic or inorganic sunscreens, preservatives, buffers, solvents, wetting agents, viscosity modifiers, alcohols, fats, oils, surfactants Fatty acids, silicone oils, humectants, emulsifiers, stabilizers, colorants, and fragrances. The composition of the present invention may further comprise a propellant such as propane, isobutane, dimethyl ether, carbon dioxide, and nitrous oxide.

As used herein, “emollient” means a substance used to prevent or reduce skin dryness, as well as to protect the skin. A wide range of suitable emollients are known and are used in the present invention, as described in Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972). obtain.
The composition may optionally include inorganic and organic sunscreens as cosmetic ingredients that provide protection from harmful effects from excessive exposure to sunlight during use. In certain embodiments, preferred compositions comprise 0.1 to 10%, more preferably 1 to 5% organic sunscreen.
Examples of suitable organic sunscreens include those listed in Table 1 below, and mixtures thereof.

The composition of the present invention may further contain an inorganic sunscreen, for example, titanium dioxide; zinc oxide having an average particle size of 1 to 300 nm; iron oxide having an average particle size of 1 to 300 nm; and average particle size Includes, but is not limited to, 1 to 100 nm silica, such as fumed silica. The total amount of titanium dioxide that may be included in the composition is 1 to 25%, preferably 2 to 10%, and ideally 3 to 7%.
Furthermore, it may be desirable to include anti-inflammatory and / or anti-irritant agents in the compositions of the present invention. Natural anti-inflammatory and / or anti-irritant agents are preferred. For example, extracted from licorice and its extract, dipotassium glycyrrhizinate, oat and oat extracts, candelilla wax, alfa bisabolol, aloe vera, mandista (Rubia cordifolia L) ), As well as Guggal (extracted from plants of the genus Comifola, in particular Commiphora Mukul)).

  Additional skin conditioning agents such as ceramide, glycoceramide, pseudoceramide, sphingolipids (e.g. sphingomyelin, cerebroside, sulfatide, and ganglioside), sphingosine, dihydrosphingosine, phytosphingosine, and phospholipids, either individually or as a mixture However, it may be included in the composition of the present invention. Fatty acids may be combined with these skin conditioners. Examples of ceramide and glycoceramide include those described in US Pat. Nos. 5,589,178, 5,661,118, and 5,688,752. Examples of pseudoceramides include those described in US Pat. Nos. 5,198,210; 5,206,020; and 5,415,855.

  According to one aspect of the present invention, the rate of natural skin peeling can be increased by applying the composition of the present invention to the skin externally. In this regard, the present invention encompasses a method for increasing the rate of natural skin peeling, which is a water soluble vitamin in an amount sufficient to increase the rate of natural skin peeling and for a sufficient period of time. Applying to the skin a composition comprising an E derivative (salt). In another embodiment, the vitamin E salt is provided in a carrier that includes water and can help maintain the desired pH of the composition.

  Generally, the topical composition is applied at least daily and can be applied over any suitable period. Compared to conventional acidic (pH ≦ 4.0) compositions, the compositions of the present invention can be applied more regularly, thereby substantially reducing irritation to the skin. While not wishing to be bound by any particular theory, the reduced skin irritation achieved when promoting exfoliation that the compositions of the present invention can provide is that the pH of the composition is It is thought to be due to being closer and higher than that of the skin (pH˜5). By routinely applying the composition of the present invention to the skin, the user can recognize improvements in skin texture and smoothness with low irritation within a few days.

  Table 3 shows a comparative test between the cell regeneration rates of water-soluble vitamin E derivative (VEP; sodium phosphate) and conventional exfoliated acid (lactic acid). Skin irritation (expressed as “Sting” degree) was also measured. The increase in skin cell regeneration rate and stimulation level was measured substantially according to the procedure described on pages 54-58 and 76 of Soap / Cosmetics / Chemical Specialties for September 1993.

  As is apparent from the table, when VEP is compared to a lactic acid control, a beneficial cell regeneration rate is achieved with a surprisingly low degree of stimulation. This result clearly demonstrates that skin detachment (% cell regeneration rate) increases with increasing VEP concentration and pH. Thus, the ability of conventional acidic strippers to strip water-soluble vitamin E at pH levels above 4.0 at which it loses its activity has been demonstrated. Although the aforementioned exfoliating acids such as lactic acid, salicylic acid, and alpha and beta hydroxy carboxylic acids are generally considered to be effective exfoliants, effective exfoliation at high pH where water-soluble vitamin E derivatives exceed 4.5 The discovery that it can function as an agent was very surprising.

  From this data it is clear that the compositions of the present invention can provide beneficial strip rates at pH above 4.5. On the contrary, desirable cell regeneration rates are observed at pH values above about 5.6 and pH values above about 7.2. This is very surprising because conventional stripping agents not only lose their effect above pH 4.0, but also increase the stripping rate as pH decreases. In contrast to conventional release agents, the composition of the present invention provides a beneficial release action in the region above pH 4.5, and its release ability continues to improve with increasing pH. This is the opposite of the result obtained with the acidic composition and is completely unpredictable from the result.

  Although the stimulation results are somewhat subjective as evidenced by the difference between the 2.0 (wt%) VEP results in Table 3, this result shows that VEP is slightly slower compared to lactic acid in terms of cell regeneration. However, it clearly shows that its irritation to the skin is at least 4.5 times less. On the contrary, at pH 7.21, for example, the irritation to the skin of the composition of the invention is about 1/20. In relation to the results obtained for exfoliating acids with a pKa of 4.0 or less, preferably the composition of the present invention reduces the skin irritation (% irritation) felt by consumers by at least 25%, and more preferably by at least 50%. be able to.

Because the skin irritation caused by water-soluble vitamin E derivatives is significantly reduced compared to exfoliating acids, the compositions of the present invention are more frequently compared to conventional acid-based exfoliating compositions. , And more constantly used to improve the skin. Therefore, since the composition of the present invention can be applied more frequently with less irritation, in actual use, the composition of the present invention is capable of regenerating skin cells compared to a composition containing exfoliating acid. An overall increase in speed can be provided.
The following are illustrative examples of formulations of the present invention. While this example uses only some compounds and formulations, it should be understood that the following examples are illustrative and not limiting.

Table 4 shows some examples of proposed solution and / or gel formulations that fall within the scope of the present invention, the amounts given being expressed in weight percent.

Table 5 shows some examples of proposed emulsion, cream, and / or lotion formulations that fall within the scope of the present invention, and the amounts given are expressed in weight percent.

  It should be understood that a wide range of changes and modifications can be made to the compositions and methods of the present invention. Accordingly, the foregoing description is not intended to limit the invention but rather to illustrate, and it is the claims that define the invention and are intended to include all equivalents thereof.

Claims (20)

A composition for increasing the rate of mammalian skin exfoliation, comprising:
Vitamin E sodium phosphate, lauryliminodipropionate tocopheryl phosphate, tocopheryl glycoside, tocopheryl oxalate, tocofersolan (tocopheryl polyethylene glycol 1000 oxalate), vitamin E derivative with beta-alanine functional group, tocopheres-5 , 10, 12, 18, and 50, and 0.05% to 30% water soluble vitamin E derivatives selected from the group consisting of mixtures thereof; and
A carrier comprising water;
The composition above, wherein the pH is about 4.5 to 9 and the water soluble vitamin E derivative is substantially present in the water.   The water-soluble vitamin E derivative is selected from the group consisting of vitamin E sodium phosphate, tocopheryl lauryliminodipropionate phosphate, a vitamin E derivative having a beta-alanine functional group, and mixtures thereof. The composition as described.   The composition of claim 1, wherein the composition does not comprise squalene or squalane.   The composition of claim 1, wherein the water-soluble vitamin E derivative comprises sodium vitamin E phosphate.   The composition of claim 1, wherein the water-soluble vitamin E derivative comprises disodium laurimidinodipropionate tocopheryl phosphate.   The composition of claim 1, wherein the composition comprises 0.1% to about 15% of a water soluble vitamin E derivative.   2. The composition of claim 1, wherein the composition comprises from 0.4% to about 5% water soluble vitamin E derivative.   The composition of claim 1, wherein the carrier further comprises a cosmetic ingredient.   The composition of claim 1, wherein the pH of the composition is from 4.8 to 8.2.   The composition of claim 1, wherein the pH of the composition is from 5.6 to 7.9.   11. A composition according to any one of claims 1 to 10 for preparing a pharmaceutical composition, dermatological composition, topical composition or cosmetic composition for increasing the natural exfoliation rate of mammalian skin. Use of things.   12. Use of the composition according to claim 11, wherein the natural peel rate of the mammalian skin is increased by at least 10%.   12. Use of the composition according to claim 11, wherein the natural peel rate of the mammalian skin is increased by at least 15%.   12. Use of a composition according to claim 11 wherein the percent irritation is reduced by at least 25% relative to the percent irritation achieved by the exfoliating acid with a pKa of 4.0 or less.   12. Use of a composition according to claim 11 wherein the percent irritation is reduced by at least 50% relative to the percent irritation achieved by the exfoliating acid of pKa 4.0 or less.   12. The composition of claim 11, wherein the natural exfoliation rate of the skin is increased by at least 10% and the irritation rate is reduced by at least 25% relative to the irritation rate achieved by an exfoliating acid having a pKa of 4.0 or less. Use of things.   12. The natural exfoliation rate of the skin is increased by at least 20% and the irritation rate is reduced by at least 50% relative to the irritation rate achieved by an exfoliating acid with a pKa of 4.0 or less. Use of the composition.   Use of the composition according to claim 11, wherein the pharmaceutical composition, dermatological composition, topical composition or cosmetic composition is prepared as a solution, gel, lotion, cream or ointment.   12. Use of the composition according to claim 11, wherein the increased rate of skin peeling improves the texture of mammalian skin.   12. Use of the composition according to claim 11, wherein the increased rate of skin peeling regenerates mammalian skin.