A composition for application to the skin can stimulate the in vivo synthesis of collagen and proteoglycans and improve the appearance of the skin, increasing its elasticity and fullness. In general, a composition according to the present invention comprises: (1) an antioxidant compound in a quantity sufficient to enhance collagen synthesis in the skin; (2) an organic penetrant in which the antioxidant compound is soluble in a sufficient quantity that a concentration of the antioxidant compound sufficient to enhance collagen synthesis can be applied topically and penetrate the skin; (3) a mixture of essential amino acids; (4) a supplemental source of sulfur; and (5) a topical pharmaceutically acceptable carrier. The antioxidant compound can be lipoic acid, a lipoic acid analogue or derivative, a bioflavonoid, a constituent of ginkgo, or an isoflavone. The organic penetrant is preferably benzyl alcohol. Other ingredients, such as esters of tocopherol and ascorbic acid, can be included.

Description of the Invention

SUMMARY OF THE INVENTION

One embodiment of the invention is a composition for topical application to the skin to enhance collagen synthesis comprising:

(1) an antioxidant compound selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, salts of dihydrolipoic acid, bioflavonoids, constituents of ginkgo, isoflavones, and mixtures thereof, in a quantity sufficient to enhance collagen synthesis in the skin;

(2) an organic penetrant in which the antioxidant compound is soluble in a sufficient quantity that a concentration of the antioxidant compound sufficient to enhance collagen synthesis can be applied topically and penetrate the skin;

(3) a mixture of essential amino acids comprising: (a) from about 5% to about 20% of isoleucine; (b) from about 5% to about 20% of leucine; (c) from about 10% to about 25% of lysine; (d) from about 2% to about 35% of methionine; (e) from about 5% to about 20% of phenylalanine; (f) from about 5% to about 25% of threonine; (g) from about 5% to about 20% of tryptophan; (h) from about 10% to about 25% of valine; (i) from about 5% to about 20% of histidine; and (j) from about 5% to about 20% of arginine; and

(4) a topical pharmaceutically acceptable carrier.

Typically, the antioxidant compound is selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, and salts of dihydrolipoic acid. Preferably, the antioxidant compound is lipoic acid or dihydrolipoic acid.

Alternatively, the antioxidant is a bioflavonoid. Typically, the bioflavonoid is selected from the group consisting of quercetin, quercitrin, kaempferol, kaempferol 3-rutinoside, 3'-methoxy kaempferol 3-rutinoside, 5,8,4'-trihydroxyl-6,7-dimethoxyflavone, catechin, epicachetin, epicachetin gallate, epigallocachetin gallate, hesperidin, naringin, rutin, vixetin, proanthocyanidin, apigenin, myricetin, tricetin, quercetin, naringin, kaempferol, luteolin, biflavonyl, silybin, silydianin, and silychristin, and derivatives and glycosides of these compounds. Preferably, the bioflavonoid is proanthocyanidin.

In another alternative, the antioxidant is a constituent of ginkgo. Typically, the constituent of ginkgo is selected from the group consisting of ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide.

In yet another alternative, the antioxidant is an isoflavone. Typically, the isoflavone is selected from the group consisting of genistein, genistin, 6''-0-malonylgenistin, 6''-0-acetylgenistin, daidzein, daidzin, 6''-0-malonyidaidzin, 6''-0-acetylgenistin, glycitein, glycitin, 6''-0-malonylglycitin, and 6-0-acetylglycitin.

In still another alternative, the antioxidant can be a mixture of: (1) a compound selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, and salts of dihydrolipoic acid; and (2) a bioflavonoid, a constituent of ginkgo, or an isoflavone.

Typically, the organic penetrant is selected from the group consisting of lower alkyl diols, C.sub.10-C.sub.20 fatty acids and esters thereof, and C.sub.4-C.sub.20 optionally substituted aliphatic alcohols. Preferably, the organic penetrant is a C.sub.4-C.sub.20 optionally substituted aliphatic alcohol. More preferably, the C.sub.4-C.sub.20 optionally substituted aliphatic alcohol is substituted with an aromatic substituent. Still more preferably, the C.sub.4-C.sub.20 aliphatic alcohol substituted with an aromatic substituent is selected from the group consisting of benzyl alcohol and phenethyl alcohol. Most preferably, the organic penetrant is benzyl alcohol.

When the antioxidant is lipoic acid, typically it is present in a concentration of from about 0.3% (w/w) to about 2.0% (w/w). Preferably, it is present in a concentration of from about 0.5% (w/w) to about 1.5% (w/w). More preferably, it is present in a concentration of about 1.0% (w/w).

When the organic penetrant is benzyl alcohol, typically it is present in a concentration of from about 1.0% (w/w) to about 15.0% (w/w). Preferably, it is present in a concentration of from about 1.5% (w/w) to about 2.5% (w/w). More preferably, it is present in a concentration of about 2.0% (w/w).

In the mixture of essential amino acids, the methionine typically comprises from about 2% to about 5% of the mixture. The mixture of essential amino acids can further comprise cysteine. When the mixture includes cysteine, typically, the cysteine comprises from about 2% to about 75% of the mixture, preferably about 40% of the mixture. Although cysteine is not an essential amino acid for human nutrition, it is an additional source of organic sulfur. When cysteine comprises about 40% of the mixture, a composition according to the present invention typically comprises about 0.3% of essential amino acids (excluding cysteine) and about 0.2% of cysteine.

Preferably, the mixture of essential amino acids comprises: (a) about 8.20% of isoleucine; (b) about 10.92% of leucine; (c) about 14.20% of lysine; (d) about 3.28% of methionine; (e) about 8.20% of phenylalanine; (f) about 12.02% of threonine; (g) about 7.65% of tryptophan; (h) about 16.39% of valine; (i) about 8.20% of histidine; and (j) about 10.92% of arginine.

Typically, the mixture of essential amino acids comprises from about 0.005% (w/v) to about 0.5% (w/w) of the composition. Preferably, the mixture of essential amino acids comprises from about 0.1% (w/w) to about 0.4% (w/w) of the composition. More preferably, the mixture of essential amino acids comprises about 0.3% (w/w) of the composition.

Typically, the composition further comprises a long-chain fatty acid ester of tocopherol. Preferably, the long-chain fatty acid ester of tocopherol is selected from the group consisting of tocopheryl palmitate, tocopheryl myristate, and tocopheryl stearate. More preferably, the long-chain fatty acid ester of tocopherol is tocopheryl palmitate.

Typically, the composition also further comprises a long-chain fatty acid ester of ascorbic acid. Preferably, the long-chain fatty acid ester of ascorbic acid is selected from the group consisting of ascorbyl palmitate, ascorbyl myristate, and ascorbyl stearate. More preferably, the long-chain fatty acid ester of ascorbic acid is ascorbyl palmitate.

Typically, the topical pharmaceutically acceptable carrier comprises: (a) water; (b) propylene glycol; (c) carbopol; (d) an octyl ester of a long-chain fatty acid selected from the group consisting of octyl palmitate, octyl stearate, and octyl myristate. (e) silicone fluid; (f) cetearyl alcohol; (g) triethanolamine; and (h) at least one non-sensitizing preservative.

Typically, the octyl ester of the long-chain fatty acid is octyl palmitate. Typically, the at least one non-sensitizing preservative comprises at least one of methylparaben, ethylparaben, propylparaben, butylparaben, and diazolidinyl urea. Preferably, the at least one non-sensitizing preservative comprises methylparaben, propylparaben, and diazolidinyl urea.

The topical pharmaceutically acceptable carrier can comprise other ingredients, such as: (1) a surface-coated starch polymer; (2) a long-chain fatty acid isopropyl ester selected from the group consisting of isopropyl palmitate, isopropyl myristate, and isopropyl stearate, which is typically isopropyl palmitate; (3) a mixture of glyceryl stearate and PEG-100 stearate; (4) a long-chain fatty acid selected from the group consisting of palmitic acid, stearic acid, and myristic acid, which is typically stearic acid; (5) caprylic/capric triglyceride; (6) cetearyl alcohol; (7) caprylic/capric stearyl triglyceride; and (8) fragrance, which typically comprises natural lavender and chamomile oils.

Typically, the composition enhances the synthesis of at least one sulfur-containing antioxidant in vivo when applied to the skin of a user. Preferably, the at least one sulfur-containing antioxidant whose synthesis is enhanced in vivo is glutathione.

Typically, the composition enhances the synthesis of proteoglycans when applied to the skin of a user.

Typically, the composition provides organic sulfate to act as a precursor of proteoglycans when applied to the skin of a user.

Typically, the composition enhances the thickness of the dermis and epidermis when applied to the skin of a user.

Typically, the composition generates sustainable hydration of the epidermis when applied to the skin of a user.

Another aspect of the invention is a method of stimulating collagen synthesis in skin in vivo comprising applying a composition of the present invention, as described above, to skin in a quantity effective to stimulate collagen synthesis in the skin.

Similarly, another aspect of the invention is a method of enhancing the synthesis of at least one sulfur-containing antioxidant in vivo comprising applying a composition of the present invention to skin in a quantity effective to enhance the synthesis of at least one sulfur-containing antioxidant in vivo. Typically, the at least one sulfur-containing antioxidant is glutathione.

Yet another aspect of the invention is a method of enhancing the synthesis of a proteoglycan in vivo comprising applying a composition of the present invention to skin in a quantity effective to enhance the synthesis of a proteoglycan in vivo.

Yet another aspect of the invention is a method of providing organic sulfate to act as a precursor of proteoglycans in vivo comprising applying a composition of the present invention to skin in a quantity effective to provide organic sulfate to act as a precursor of proteoglycans.

Still another aspect of the present invention is a method of enhancing the thickness of epidermis and dermis comprising applying a composition of the present invention to skin in a quantity effective to enhance the thickness of epidermis and dermis.

Yet another aspect of the present invention is a method of generating sustainable hydration of epidermis comprising applying a composition of the present invention to skin in a quantity effective to generate sustainable hydration of the epidermis.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is of the best currently contemplated modes of carrying out the invention. The description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention, since the scope of the invention is best defined by the appended claims.

The ability to stimulate collagen production by the transdermal delivery of compounds included in the formulation of the present invention makes it possible to reverse some of the age-related changes described above. In addition the presence of an essential sulfur-amino acid in our mixture, a precursor of glycosaminoglycans present in proteoglycans, is likely to enhance the synthesis of these water retaining molecules, by making available inorganic sulfate to the organism as shown during oral supplementation of sulfur containing supplements (F. Cordoba & M. Nimni, "Chondroitin Sulfate and Other Sulfate Containing Chondroprotective Agents May Exhibit Their Effects by Overcoming a Deficiency of Sulfur Amino Acids," Osteoarthritis & Cartilage 11: 228-230 (2003)).

Accordingly, one aspect of the invention is a composition for topical application to the skin to enhance collagen synthesis. The composition is applied directly to the skin.

In general, a composition according to the present invention for topical application to the skin to enhance collagen synthesis comprises:

(1) an antioxidant compound selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, salts of dihydrolipoic acid, bioflavonoids, constituents of ginkgo, isoflavones, and mixtures thereof, in a quantity sufficient to enhance collagen synthesis in the skin;

(2) an organic penetrant in which the antioxidant compound is soluble in a sufficient quantity that a concentration of the antioxidant compound sufficient to enhance collagen synthesis can be applied topically and penetrate the skin;

(3) a mixture of essential amino acids comprising: (a) from about 5% to about 20% of isoleucine; (b) from about 5% to about 20% of leucine; (c) from about 10% to about 25% of lysine; (d) from about 2% to about 35% of methionine; (e) from about 5% to about 20% of phenylalanine; (f) from about 5% to about 25% of threonine; (g) from about 5% to about 20% of tryptophan; (h) from about 10% to about 25% of valine; (i) from about 5% to about 20% of histidine; and (j) from about 5% to about 20% of arginine; and

(4) a topical pharmaceutically acceptable carrier.

In one embodiment, the antioxidant is selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, and salts of dihydrolipoic acid. Lipoic acid, also known as .alpha.-lipoic acid, thioctic acid, 1,2-dithiolane-3-pentanoic acid, and 1,2-dithiolane-3-valeric acid, has the following structural formula -- see Original Patent.

The disulfide (S--S) bond of lipoic acid is subject to reduction by chemical or biological reducing agents, leading to dihydrolipoic acid, in which the disulfide bond is replaced with two sulfhydryl (SH) groups. Because the two forms are readily interchangeable in vivo, both lipoic acid and dihydrolipoic acid, as well as their derivatives such as esters, amides, and salts, can be used in compositions according to the present invention.

In another embodiment, the antioxidant is a bioflavonoid. Typically, the bioflavonoid is selected from the group consisting of quercetin, quercitrin, kaempferol, kaempferol 3-rutinoside, 3'-methoxy kaempferol 3-rutinoside, 5,8,4'-trihydroxyl-6,7-dimethoxyflavone, catechin, epicachetin, epicachetin gallate, epigallocachetin gallate, hesperidin, naringin, rutin, vixetin, proanthocyanidin, apigenin, myricetin, tricetin, quercetin, naringin, kaempferol, luteolin, biflavonyl, silybin, silydianin, and silychristin, and derivatives and glycosides of these compounds. Bioflavonoids are described, for example, in U.S. Pat. No. 6,576,271 to Nair et al., incorporated herein by this reference. Typically, the bioflavonoid is proanthocyanidin.

In yet another embodiment, the antioxidant is a constituent of ginkgo. Typically, the constituent of ginkgo is selected from the group consisting of ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide.

In yet another embodiment, the antioxidant is an isoflavone. Typically, the isoflavone is selected from the group consisting of genistein, genistin, 6''-0-malonylgenistin, 6''-0-acetylgenistin, daidzein, daidzin, 6''-0-malonyldaidzin, 6''-0-acetylgenistin, glycitein, glycitin, 6''-0-malonylglycitin, and 6-0-acetylglycitin. Preferably, the isoflavone is genistein or daidzein. Isoflavones can be isolated from soy or other phytochemical sources. One isolation process is disclosed in U.S. Pat. No. 6,565,912 to Gugger et al., incorporated herein by this reference.

In still another alternative, the antioxidant can be a mixture of: (1) a compound selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, and salts of dihydrolipoic acid; and (2) a bioflavonoid, a constituent of ginkgo, or an isoflavone. Various mixtures of lipoic acid and other biological antioxidants can be used.

Mixtures of antioxidants can alternatively be used. For example, the antioxidant can be a mixture of: (1) a compound selected from the group consisting of lipoic acid, dihydrolipoic acid, lipoic acid esters, dihydrolipoic acid esters, lipoic acid amides, dihydrolipoic acid amides, salts of lipoic acid, and salts of dihydrolipoic acid; and (2) a bioflavonoid, a constituent of ginkgo, or an isoflavone. The mixture of antioxidants can be chosen by one of ordinary skill in the art to achieve a particularly desirable result, taking into account skin type, age of the expected user, conditions affecting the elasticity or firmness of the skin, or other factors affecting skin condition.

Typically, the organic penetrant is selected from the group consisting of lower alkyl diols, C.sub.10-C.sub.20 fatty acids and esters thereof, and C.sub.4-C.sub.20 optionally substituted aliphatic alcohols. Preferably, the organic penetrant is a C.sub.4-C.sub.20 optionally substituted aliphatic alcohol. More preferably, the C.sub.4-C.sub.20 optionally substituted aliphatic alcohol is substituted with an aromatic substituent. Still more preferably, the C.sub.4-C.sub.20 optionally substituted aliphatic alcohol is benzyl alcohol or phenethyl alcohol. Most preferably, the C.sub.4-C.sub.20 optionally substituted aliphatic alcohol is benzyl alcohol. However, other alcohols substituted with an aromatic substituent can alternatively be used.

When the antioxidant is lipoic acid, it is typically present in the composition in a concentration of from about 0.3% (w/w) to about 2.0% (w/w). Preferably, the lipoic acid is present in the composition in a concentration of from about 0.5% (w/w) to about 1.5% (w/w). More preferably, the lipoic acid is present in a concentration of about 1.0% (w/w). Unless stated otherwise, all other percentages of ingredients specified herein are (w/w).

When the antioxidant is proanthocyanidin, it is typically present in the composition in a concentration of from about 0.3% (w/w) to about 2.0% (w/w). Preferably, the proanthocyanidin is present in the composition in a concentration of from about 0.5% (w/w) to about 1.5% (w/w). More preferably, the proanthocyanidin is present in a concentration of about 1.0% (w/w).

When the organic penetrant is benzyl alcohol, it is typically present in the composition in a concentration of from about 1.0% (w/w) to about 15.0% (w/w). Preferably, the benzyl alcohol is present in the composition in a concentration of from about 1.5% (w/w) to about 2.5% (w/w). More preferably, the benzyl alcohol is present in the composition at a concentration of about 2.0% (w/w).

Typically, the methionine comprises from about 2% to about 5% by weight of the mixture of essential amino acids. However, as indicated above, it can be incorporated in the mixture in a greater proportion, i.e., up to about 35% by weight of the mixture of essential amino acids.

In another alternative, the mixture of essential amino acids can further comprise cysteine. Although cysteine is nutritionally not an essential human acid in the human diet, it can be included as a source of organic sulfur. When the mixture of essential amino acids further comprises cysteine, typically, the cysteine comprises from about 2% to about 75% of all amino acids in the mixture by weight; more typically, the cysteine comprises from about 25% to about 75% of all amino acids in the mixture by weight. Preferably, the cysteine comprises about 40% of all amino acids in the mixture by weight. As used herein, recitation of cysteine and other amino acids refers to the naturally-occurring L optical isomer of these amino acids, as that is the isomer that is incorporated into proteins.

Typically, the mixture of essential amino acids (not including cysteine) comprises: (1) about 8.20% of isoleucine; (2) about 10.92% of leucine; (3) about 14.20% of lysine; (4) about 3.28% of methionine; (5) about 8.20% of phenylalanine; (6) about 12.02% of threonine; (7) about 7.65% of tryptophan; (8) about 16.39% of valine; (9) about 8.20% of histidine; and (10) about 10.92% of arginine.

Typically, the mixture of essential amino acids (including methionine, but not including cysteine) comprises from about 0.005% (w/w) to about 0.5% (w/w) of the composition. Preferably, the mixture of essential amino acids (including methionine, but not including cysteine) comprises from about 0.1% (w/w) to about 0.4% (w/w) of the composition. More preferably, the mixture of essential amino acids (including methionine, but not including cysteine) comprises about 0.3% (w/w) of the composition. As indicated above, this does not include cysteine, which is preferred. Cysteine typically comprises from about 0.01% (w/w) to about 0.4% (w/w) of the composition. Preferably, cysteine comprises about 0.2% (w/w) of the composition.

Other ingredients can also be used. For example, the composition can further comprise a long-chain fatty acid ester of tocopherol. Typically, the long-chain fatty acid ester of tocopherol is selected from the group consisting of tocopheryl palmitate, tocopheryl myristate, and tocopheryl stearate. Preferably, the long-chain fatty acid ester of tocopherol is tocopheryl palmitate. Typically, the long-chain fatty acid ester of tocopherol is present in the composition at a concentration of from about 0.01% (w/w) to about 3.0% (w/w). Preferably, the long-chain fatty acid ester of tocopherol, such as tocopheryl palmitate, is present in the composition at a concentration of about 0.3% (w/w).

Similarly, the composition can further comprise a long-chain fatty acid ester of ascorbic acid. Typically, the long-chain fatty acid ester of ascorbic acid is selected from the group consisting of ascorbyl palmitate, ascorbyl myristate, and ascorbyl stearate. Preferably, the long-chain fatty acid ester of ascorbic acid is ascorbyl palmitate. Typically, the long-chain fatty acid ester of ascorbic acid is present in the composition at a concentration of from about 0.1% (w/w) to about 0.6% (w/w). Preferably, the long-chain fatty acid ester of ascorbic acid, such as ascorbyl palmitate, is present in the composition at a concentration of about 0.3% (w/w).

Suitable topical pharmaceutically acceptable carriers are disclosed in U.S. Pat. No. 5,935,994, incorporated herein by this reference. The carrier is typically in the form of a cream base that is compatible with all of the ingredients as far as stability is concerned.

Typically, the topical pharmaceutically acceptable carrier comprises: (1) water; (2) propylene glycol; (3) carbopol; (4) an octyl ester of a long-chain fatty acid selected from the group consisting of octyl palmitate, octyl stearate, and octyl myristate. (5) silicone fluid; (6) cetearyl alcohol; (7) triethanolamine; and (8) at least one non-sensitizing preservative.

A suitable silicone fluid is a silicone fluid with a viscosity of 200 cs.

A suitable preparation of carbopol is Carbopol 940. Other carboxypolymethylene polymers are known in the art, such as Carbomer polymers, and can be used.

Triethanolamine is a buffer and can be replaced by other buffers that can buffer the topical pharmaceutically acceptable carrier to a physiological pH.

Typically, the octyl ester of a long-chain fatty acid is selected from the group consisting of octyl palmitate, octyl stearate, and octyl myristate is octyl palmitate.

The topical pharmaceutically acceptable carrier can further comprise other, optional, ingredients.

For example, the topical pharmaceutically acceptable carrier can further comprise a surface-coated starch polymer. A suitable surface-coated starch polymer is Dryflo PC, marketed by National Starch.

The topical pharmaceutically acceptable carrier can also further comprise a long-chain fatty acid isopropyl ester selected from the group consisting of isopropyl palmitate, isopropyl myristate, and isopropyl stearate. Typically, the long-chain fatty acid isopropyl ester is isopropyl palmitate.

The topical pharmaceutically acceptable carrier can also further comprise a mixture of glyceryl stearate and PEG-100 stearate. A suitable mixture of glyceryl stearate and PEG-100 stearate is Arlacel 165.

The topical pharmaceutically acceptable carrier can also further comprise a long-chain fatty acid selected from the group consisting of palmitic acid, stearic acid, and myristic acid. Typically, the long-chain fatty acid is stearic acid.

The topical pharmaceutically acceptable carrier can also further comprise caprylic/capric triglyceride. A suitable caprylic/capric triglyceride is Miglyol 812.

The topical pharmaceutically acceptable carrier can also further comprise cetearyl alcohol.

The topical pharmaceutically acceptable carrier can also further comprise caprylic/capric stearyl triglyceride. A suitable caprylic/capric stearyl triglyceride is Softisan 378.

The topical pharmaceutically acceptable carrier can also further comprise fragrance. Typically, the fragrance comprises natural lavender and chamomile oils. However, other fragrances are well known in the art of preparing products suitable for application to the skin, and can be used as alternatives.

Typically, the non-sensitizing preservative of the topical pharmaceutically acceptable carrier comprises at least one of methylparaben, ethylparaben, propylparaben, butylparaben, and diazolidinyl urea. Preferably, the non-sensitizing preservative comprises methylparaben, propylparaben, and diazolidinyl urea. A suitable preparation of diazolidinyl urea is Germall 2.

Other ingredients are well known in the art of preparing cosmetics and other products suitable for application for the skin, and can be used in the topical pharmaceutically acceptable carrier. For example, other lipid-soluble components can be used in addition to or in place of the caprylic/capric triglycerides. Such components can include but are not limited to: steareth-2; steareth-21; polyglyceryl-3 beeswax; a branched-chain carboxylic acid ester of a branched-chain alcohol selected from the group consisting of isononyl isononanoate, isodecyl isononanoate, isooctyl isononanoate, isononyl isooctanoate, isodecyl isooctanoate, isooctyl isooctanoate, isononyl isodecanoate, isooctyl isodecanoate, and isodecyl isodecanoate; acrylates/C.sub.10-C.sub.30 alkyl acrylates cross-polymers; methylgluceth-20; a glyceryl ester of a long-chain fatty acid selected from the group consisting of glyceryl monostearate, glyceryl monopalmitate, and glyceryl monoarachidate; hydrogenated vegetable oil; squalane; C.sub.12-C.sub.15 alkylbenzoates; di-C.sub.12-C.sub.15 alkylfumarate; cholesterol; lanolin alcohol; octyldodecanol; isostearic acid; a branched-chain neopentanoate selected from the group consisting of octyldodecyl neopentanoate, heptyldodecyl neopentanoate, nonyldodecyl neopentanoate, octylundecyl neopentanoate, heptylundecyl neopentanoate, nonylundecyl neopentanoate, octyltridecyl neopentanoate, heptyltridecyl neopentanoate, and nonyltridecyl neopentanoate; an arachidyl ester of a short-chain carboxylic acid selected from the group consisting of arachidyl propionate, arachidyl acetate, arachidyl butyrate, and arachidyl isobutyrate; jojoba oil; a myristyl ester of a long-chain fatty acid selected from the group consisting of myristyl myristate, myristyl laurate, and myristyl palmitate; bisabolol; hydrogenated jojoba oil; jojoba esters; methylgluceth-20 sesquistearate; PPG-14 butyl ether; PPG-15 stearyl ether; PPG-1-isoceteth-3-acetate; laureth-2-benzoate; diisostearyl dimer dilinoleate; a long-chain cis-monounsaturated fatty acid ester of a medium-chain alcohol; a medium-chain saturated carboxylic acid ester of a long-chain alcohol; hydrogenated soy glycerides; a long-chain fatty acid ester of cetyl alcohol selected from the group consisting of cetyl palmitate, cetyl stearate, and cetyl myristate; palm kernel oil; and palm oil.

In addition, the topical pharmaceutically acceptable carrier can further comprise other ingredients that are generally used in the cosmetic art and in the art of over-the-counter skin preparations. These ingredients include, but are not limited to:

(1) plant extracts, such as horsetail extract, horse chestnut extract, rose extract, or lavender extract;

(2) a long-chain fatty acid ester of retinol or a retinol derivative or analogue wherein the acyl moiety of the ester is selected from the group consisting of myristic acid, palmitic acid, and stearic acid; and

(3) a sunscreen, which can be at least one compound selected from the group consisting of octyl methoxycinnamate, p-aminobenzoic acid, ethyl p-aminobenzoate, isobutyl p-aminobenzoate, glyceryl p-aminobenzoate, p-dimethylaminobenzoic acid, methyl anthranilate, menthyl anthranilate, phenyl anthranilate, benzyl anthranilate, phenylethyl anthranilate, linalyl anthranilate, terpinyl anthranilate, cyclohexenyl anthranilate, amyl salicylate, phenyl salicylate, benzyl salicylate, menthyl salicylate, glyceryl salicylate, dipropyleneglycol salicylate, methyl cinnamate, benzyl cinnamate, .alpha.-phenyl cinnamonitrile, butyl cinnamoylpyruvate, umbelliferone, methylacetoumbelliferone, esculetin, methylesculetin, daphnetin, esculin, daphnin, diphenylbutadiene, stilbene, dibenzalacetone, benzalacetophenone, sodium 2-naphthol-3,6-disulfonate, sodium 2-naphthol-6,8-disulfonate, dihydroxynaphthoic acid, salts of dihydroxynaphthoic acid, o-hydroxybiphenyldisulfonates, p-hydroxybiphenyldisulfonates, 7-hydroxycoumarin, 7-methylcoumarin, 3-phenylcoumarin, 2-acetyl-3-bromoindazole, phenylbenzoxazole, methylnaphthoxazole, arylbenzothiazoles, quinine bisulfate, quinine sulfate, quinine chloride, quinine oleate, quinine tannate, 8-hydroxyquinoline salts, 2-phenylquinoline, hydroxy-substituted benzophenones, methoxy-substituted benzophenones, uric acid, vilouric acid, tannic acid, tannic acid hexaethylether, hydroquinone, oxybenzone, sulisobenzone, dioxybenzone, benzoresorcinol, 2,2',4,4'-tetrahydroxybenzo-phenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone, 4-isopropyldibenzoylmethane, butylmethoxydibenzoylmethane, etocrylene, and 4-isopropyldibenzoylmethane.

Other ingredients can optionally be included in the topical pharmaceutically acceptable carrier.

Compositions according to the present invention can be prepared by standard procedures, such as those typically used for cosmetic preparations and pharmaceutical compositions intended for topical application to the skin. These procedures include mixing techniques, including both manual and mechanical mixing, and including homogenization mixing and sweep mixing. The mixing techniques to be used can be chosen by one of ordinary skill in the art based on variables such as the viscosity of the components to be mixed and the volume of those components, as well as the relative proportion of lipid-soluble and water-soluble ingredients. Typically, the individual active ingredients are added sequentially, and benzyl alcohol or the other organic penetrant is added to the desired final concentration. Water and oil phases are heated separately to 70.degree. C., blended, and cooled with normal mixing.

One preferred formulation of the topical pharmaceutically acceptable carrier is shown in Table 1 (see Original Patent).

Typically, the composition enhances the synthesis of at least one sulfur-containing antioxidant in vivo when applied to the skin of a user. Typically, the at least one sulfur-containing antioxidant is glutathione, which is a biologically significant reducing agent.

Typically, the composition enhances the synthesis of proteoglycans when applied to the skin of a user.

Typically, the composition also provides organic sulfate to act as a precursor of proteoglycans when applied to the skin of a user.

Typically, the composition also enhances the thickness of the dermis and the epidermis when applied to the skin of a user.

Typically, the composition generates sustainable hydration of the epidermis when applied to the skin of a user. This is evidenced by the thickened and more youthful histological appearance of this structure. The composition therefore can overcome some of the age-related changes in skin.

Compositions according to the present invention can be applied by users as they would apply standard cosmetics or other creams, once or more daily, depending on age, skin condition, and other variables readily apparent to the user.

Accordingly, therefore, another aspect of the invention is a method of stimulating collagen synthesis in skin in vivo comprising applying a composition according to the present invention to skin in a quantity effective to stimulate collagen synthesis in the skin.

Yet another aspect of the invention is a method of enhancing the synthesis of at least one sulfur-containing antioxidant in vivo comprising applying a composition according to the present invention to skin in a quantity effective to enhance the synthesis of at least one sulfur-containing antioxidant in vivo. Typically, the at least one sulfur-containing antioxidant is glutathione.

Still another aspect of the invention is a method of enhancing the synthesis of a proteoglycan in vivo comprising applying a composition according to the present invention to skin in a quantity effective to enhance the synthesis of a proteoglycan in vivo. Proteoglycans are complex macromolecules containing protein and carbohydrate components that form part of the ground substance of the skin and contribute greatly to its firmness and elasticity.

Yet another aspect of the invention is a method of providing organic sulfate to act as a precursor of proteoglycans in vivo comprising applying a composition according to the present invention to skin in a quantity effective to provide organic sulfate to act as a precursor of proteoglycans.

Still another aspect of the invention is a method of enhancing the thickness of epidermis and dermis comprising applying a composition according to the present invention to skin in a quantity effective to enhance the thickness of epidermis and dermis.

Still another aspect of the invention is a method of generating sustainable hydration of epidermis comprising applying a composition of claim 1 to skin in a quantity effective to generate sustainable hydration of the epidermis.
 

Claim 1 of 5 Claims

1. A composition for topical application to the skin to enhance collagen synthesis consisting of: proanthocyanidin as an antioxidant compound, in a quantity of from about 0.3% (w/w) to about 2.0% (w/w); (b) an organic penetrant selected from the group consisting of lower alkyl diols, C.sub.10-C.sub.20 fatty acids and esters thereof, and C.sub.4-C.sub.20 optionally substituted aliphatic alcohols in a quantity of from of about 1.0% (w/w) to about 15.0% (w/w); (c) a mixture of essential amino acids consisting of; (i) from about 5% to about 20% of isoleucine; (ii) from about 5% to about 20% of leucine; (iii) from about 10% to about 25% of lysine; (iv) from about 2% to about 35% of methionine; (v) from about 5% to about 20% of phenylalanine; (vi) from about 5% to about 25% of threonine; (vii) from about 5% to about 20% of tryptophan; (viii) from about 10% to about 25% of valine; (ix) from about 5% to about 20% of histidine; and (x) from about 5% to about 20% of arginine, the mixture being present in a quantity sufficient to enhance collagen synthesis in the skin in an individual to which the composition is applied; and (d) a topical pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier consists of: (i) water; (ii) propylene glycol; (iii) carbopol; (iv) a surface coated starch polymer; (v) octyl palmitate; vi) isopropyl palmitate; (vii) silicone fluid; (viii) a mixture of glyceryl stearate and PEG-100 stearate; (ix) cetearyl alcohol; (x) triethanolainine; (xi) caprylic/capric triglyceride; (xii) caprylic/capric stearyl triglyceride; (xiii) natural lavender oils; (xiv) natural chamomile oils; (xv) methylparabern; (xvi) propylparaben; and (xvii) diazolidinyl urea: such that the composition enhances the synthesis of collagen and proteoglycans in skin fibroblasts of an individual to which the composition is applied by the action of the antioxidant compound and the mixture of essential amino acids.

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