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Title:  Method for delivering ascorbic acid and acetone to the dermal layer of the skin

United States Patent:  6,602,906

Issued:  August 5, 2003

Inventors:  Ruhe; Rodney Charles (1122 Halifax Ave., Davis, CA 95616)

Appl. No.:  683994

Filed:  March 9, 2002

Abstract

The present invention provides a more efficient method of delivering therapeutically effective amounts of ascorbic acid and acetone to the dermal layer of the skin via the topical application of 5,6-O-isopropylidene L-ascorbic acid. This invention further provides a stable, cosmetically acceptable vehicle in which the 5,6-O-isopropylidene L-ascorbic acid can be applied to the skin.

SUMMARY OF INVENTION

The object of the present invention is to provide a method of establishing and maintaining levels of ascorbic acid and acetone in the dermal layer of the skin sufficient to produce beneficial effects.

Ascorbic acid prevents oxidative damage and promotes collagen synthesis in the skin, and acetone has anti-inflammatory effects in the skin. However, topically-applied ascorbic acid is not well-absorbed, and direct application of acetone can disrupt the structural integrity of the skin.

The present invention overcomes the aforementioned problems by providing a composition for topical application that incorporates 5,6-O-isopropylidene L-ascorbic acid, a derivative of ascorbic acid that is more lipid soluble that ascorbic acid and thus better absorbed into the dermis with minimal disruption of the structural integrity of the skin. In the dermal layer of the skin, non-specific esterases hydrolyze 5,6-O-isopropylidene L-ascorbic acid to form ascorbic acid and acetone.

Another object of the present invention is to provide a stable, cosmetically-acceptable carrier in which 5,6-O-isopropylidene L-ascorbic acid can be applied topically.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a simple, efficient, and gentle method of increasing the concentration of ascorbic acid in the dermal layer of the skin, which comprises topical application of 5,6-O-isopropylidene-L-ascorbic acid in an amount that will effectively increase ascorbic acid concentration in the dermis.

The present invention also provides a method for enhancing the synthesis of skin collagen, which comprises increasing the ascorbic acid concentration of the dermal layer of the skin via the topical application of 5,6-O-isopropylidene L-ascorbic acid in an amount that will effectively increase ascorbic acid concentration in the dermis.

The present invention further provides a method for increasing the antioxidant potential of the skin, which comprises increasing the ascorbic acid concentration of the dermal layer of the skin via the topical application of 5,6-O-isopropylidene L-ascorbic acid in an amount that will effectively increase ascorbic acid concentration in the dermis.

The present invention provides a method of increasing the concentration of acetone in the dermal layer of the skin, which comprises topical application of 5,6-O-isopropylidene L-ascorbic acid in an amount that will effectively increase the acetone concentration in the dermis.

The present invention also provides a method for decreasing inflammation of the skin, which comprises increasing the acetone concentration of the dermal layer of the skin via the topical application of 5,6-O-isopropylidene L-ascorbic acid in an amount that will effectively increase acetone in the dermis.

As described in "Background of the Invention", increasing the concentration of ascorbic acid in the dermis is desired because this molecule provides numerous benefits which result in enhanced health and appearance of the skin. However, unmodified ascorbic acid is not absorbed well into the skin for several reasons.

Ascorbic acid is a water-soluble molecule. The hydrophilicity of ascorbic acid is attributed to hydroxyl groups at carbons 2, 3, 5, and 6 of the molecule. At a neutral pH, such as in water, these hydroxyl groups, particularly the groups at carbons 2 and 3, are unprotonated and thus carry a negative charge. The negative charges allow ascorbic acid to dissolve quickly and completely in an aqueous solution, but greatly limit the solubility of the molecule in a non-aqueous, organic environment such as the skin. Ascorbic acid at neutral pH also does not dissolve well in organic solvents commonly used in formulations for topical use, such as glycerin, propylene glycol, and various fats, thus limiting the usefulness of organic solvents as a vehicle for carrying ascorbic acid into the skin.

Absorption of ascorbic acid into an organic, non-aqueous material such as the skin requires that all hydroxyl groups be fully protonated, and this state occurs only at a pH of less than 4.2, the pKa of the molecule. The lower the pH, the more likely the hydroxyl groups of ascorbic acid will be protonated, thus making the molecule more lipophilic, or fat soluble. In addition, full protonation of the hydroxyl groups of ascorbic acid at low pH results in greater stability of the molecule.

Past attempts to increase the stability of ascorbic acid or to enhance the absorption of ascorbic acid into the skin have not been successful (see Background of the Invention). The most successful strategy to date has been to apply unmodified ascorbic acid directly to the skin. However, optimal absorption of unmodified ascorbic acid into the skin requires a relatively high concentration (20 wt %) and a low pH (pH 2.0). Even under these conditions, "optimal absorption" is only about 8% of the ascorbic acid applied to the skin. Also, a 20 wt % concentration of ascorbic acid at pH 2.0 is highly irritating to the skin, so consumer acceptance is limited.

The present invention provides an improved method for increasing vitamin C activity in the dermal layer of the skin via the topical application of ascorbic acid that has been chemically modified to enhance absorption, reduce acidity, and increase stability. In the present invention, said ascorbic acid derivative is 5,6-O-isopropylidene L-ascorbic acid. The chemical structure of 5,6-O-isopropylidene L-ascorbic acid (henceforth referred to as IAA) provides many advantages over the use of unmodified ascorbic acid (henceforth referred to as UAA).

In the UAA molecule, the hydroxyl groups at carbons 5 and 6 tend to withdraw electrons, thereby exerting a weak but significant inductive effect throughout the molecule. This electron-withdrawing inductive effect, acting through the molecular chain, increases the tendency of the hydrogens of hydroxyl groups at carbons 2 and/or 3 to dissociate as protons, leaving a negative charge. Polar repulsive forces resulting from the negative charges at the hydroxyl groups at carbons 2 and/or 3 can decrease stability of the molecule by inducing stereochemical strain, which in turn favors ring disruption. The negative charges also greatly decrease the solubility of UAA in non-aqueous, organic solvents and materials, such as the skin. The greater tendency of the hydroxyl hydrogens to dissociate as protons lowers the pKa and increases the acid strength of the molecule.

In the IAA molecule incorporated into the present invention, the three-carbon substituent bonded to the oxygen atoms at carbons 5 and 6 provide several advantages over the use of UAA:

1. The three-carbon substituent of IAA is much less electronegative than the hydroxyl groups of UAA and therefore does not withdraw electrons. The lack of an electron-withdrawing inductive effect results in an increase in pKa (4.8 for IAA vs. 4.2 for UAA), a decrease in the tendency of the hydroxyl hydrogens at carbons 2 and/or 3 to dissociate as protons, and thus a decrease in the acid strength of the molecule. The IAA molecule can therefore be applied topically at a more neutral pH which is less irritating to the skin.

2. The lack of an electron-withdrawing inductive effect and the subsequent tendency to remain fully protonated at a higher pH provides the IAA molecule with greater stability and thus a longer shelf life.

3. The IAA molecule is much more lipophilic than UAA because of the lipophilic, three-carbon substituent at carbons 5 and 6, and because of the greater tendency of the hydroxyl groups at carbons 2 and 3 to remain protonated. The lipophilic nature and relatively small size of IAA allows it to traverse the stratum corneum and to be absorbed efficiently into the dermal layer of the skin. In the dermis, nonspecific esterases hydrolyze the ester bonds between the three-carbon substituent and the oxygen atoms at carbons 5 and 6. The hydrolysis products are ascorbic acid and acetone.

A fortuitous finding of the present invention was that acetone, previously considered an inactive byproduct of the hydrolysis that liberates ascorbic acid, has anti-inflammatory effect in the skin (see "Background of the Invention"). Although a low concentration of acetone applied directly to the skin can provide an anti-inflammatory effect, this method tends to dehydrate the skin and to disrupt some of the lipid components of the skin. In the present invention, the introduction of small amounts of acetone into the skin via the absorption and hydrolysis of IAA produces the beneficial effects while preserving the structural integrity of the skin.

Claim 1 of 7 Claims

What is claimed is:

1. A method of increasing the concentration of ascorbic acid and acetone in the skin which method comprises hydrolyzing a composition comprising 5,6-O-isopropylidene L-ascorbic acid, propylene glycol, glycerin, 2-phenoxyethanol, zinc sulfate and water by the action of nonspecific esterases located in the dermal layer of the skin upon topical application of said composition wherein the composition hydrolyzed is used in a therapeutically effective amount.




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