WO2009093925A1

WO2009093925A1 - COSMETIC COMPOSITIONS COMPRISING 5-AMINO-L-β-D- RIBOFURANOSYL-LH-IMIDAZOLE-4-CARBOXAMIDE OR DERIVATIVES, OR SALTS THEREOF

Info

Publication number: WO2009093925A1
Application number: PCT/RU2008/000030
Authority: WO
Inventors: Tatiana Vyacheslavovna Popkova
Original assignee: United Technologies Ut Ag
Priority date: 2008-01-23
Filing date: 2008-01-23
Publication date: 2009-07-30

Abstract

The present invention relates to cosmetic compositions comprising 5-amino-1- beta-D-ribofuranosyl-imidazole-4-carboxamide or acyl derivatives thereof, or cosmetically acceptable salts thereof and at least one a cosmetically acceptable carrier. Preferably, the composition of the invention further comprises succinic acid or cosmetically acceptable salt thereof, or alpha- glycerylphosphorylcholine. Further, the invention relates to the use of 5-amino-1-beta-D-ribofuranosyl- imidazole-4-carboxamide or acyl derivatives thereof, or cosmetically acceptable salt thereof for the manufacturing a cosmetic formulation. Further, the invention relates to a method for the skin, hair, or nail care comprising applying the compositions of the invention to skin, hair, or nail of a subject in need thereof.

Description

COSMETIC COMPOSITIONS COMPRISING 5-AMINO-l-β-D- RIBOFURANOSYL-lH-IMIDAZOLE-4-CARBOXAMIDE OR DERIVATIVES,

OR SALTS THEREOF

Field of the Invention

The present invention relates to cosmetic compositions containing 5-amino-l- β-D-ribofuranosyl-lH-imidazole-4-carboxamide or derivatives, analogs, or salts thereof for the improvement of skin appearance and health.

Background of the invention 5-Amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide, which is also named AICA riboside, AICAR, and Acadesine, is a naturally occurring intermediate in purine biosynthesis with CAS RN 2627-69-2 and with the following formula.

AICAR 5 '-monophosphate, which is also named AICA ribotide, ZMP, and

Acadesine 5 '-monophosphate, has CAS RN 3031-94-5 and is a natural occurring metabolite of AICAR. It is known as the natural activator of AMP-activated protein kinase (AMPK), a human enzyme that acts as a metabolic master switch regulating cellular energy homeostasis, and several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids, the biogenesis of glucose transporters, and biogenesis of mitochondria, a powerhouse of the cell. Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol. 277: 1-10, 1999. P Kumar and C Peers. AMP-activated protein kinase: function and dysfunction in health and disease. J Physiol 574: 3-6. 2006.

There are patents granted and patent applications published, which relate to the use of AICAR for: preventing tissue damage due to decreased blood flow (US patents 4,912,092 and 5,817,640); treating neurodegenerative conditions (US patent 5,187,162); preventing injury to the central nervous system (US patent 5,236,908); treating obesity (WO 0193873 Al); treating type 2 diabetes (WO

0197816 Al); and treating conditions associated with insulin resistance (WO

0209726). There are patents granted and patent applications published, which relates to the use of AICAR 5 '-monophosphate as flavoring material (US patent 3,355,301); antyhyperlipidemic agent (WO 9303734); antiobesity agent (WO

0193874 Al);, and anti-diabetic agent (WO 0197816 Al). US patent 5,082,829 describes AICAR derivatives, including 2',3'-diacylesters of AICAR. US patent

5,777,100 discloses AICAR analogs. However, nothing is published or disclosed in the art related to the use of AICAR or their 5 '-monophosphate, or their derivatives, analogs, or salts thereof for the use in cosmetic compositions.

Surprisingly, it has been found that the use of AICAR or AICAR 5'- monophosphate in cosmetic compositions is useful for the improvement of skin, hair, and nail health and appearance, especially under aging.

The AICAR effect can be synergistically increased by combined action with succinic acid, a well known naturally occurring respiratory substrate, which plays a role in energy metabolism, has CAS RN 110-15-6.

The AICAR effect can be synergistically increased by combined action with alpha-glycerylphosphorylcholine, which is also named Alpha-GPC, has CAS RN 28319-77-9, and is a naturally occurring phospholipid precursor and metabolite. It is an object of the present invention to provide cosmetic compositions comprising 5-amino-l-β-D-ribofuranosyl- 1 H-imidazole-4-carboxamide, acetyl derivatives thereof, or cosmetically acceptable salts thereof, for the improvement skin health and appearance.

It is an object of the present invention to provide methods for the skin care, hair care, or nail care comprising applying said cosmetic composition to skin, hair, or nail of a subject in need thereof.

Detailed Description of the Invention

The present invention provides a cosmetic composition comprising an effective amount of a compound of general formula (I)

wherein

R₁ is independently selected from the group consisting of H₅ PO₃H, and C_2- sacyl; R₂ is independently selected from the group consisting of H and C₂. sacyl;

R₃ is independently selected from the group consisting of H and C_2-sacyl; or a cosmetically acceptable salt thereof and at least one a cosmetically acceptable carrier.

The term "C₂-₈acyl" as used herein at all occurrences means a straight or branched chain acyl C_nH_2n+! CO- radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, including, but not limited to acetyl, propionyl, butyryl, isobutyryl.

The term «cosmetically acceptable salt" refers to non-toxic acid addition salts. The cosmetically acceptable salts of the invention are prepared by a reaction of compound of formula (I) with a cosmetically acceptable acid by methods well- known from the art. Such salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, succinate, fumarate, malate, ketoglutarate, citrate, and acetate salt. Preferably, the cosmetically acceptable salt of the invention is hydrochloride salt. Preferred compounds of the present invention include 5-amino-l-β-D- ribofuranosyl-lH-imidazole-4-carboxamide, 5-amino-l-β-D-ribofuranosyl-lH- imidazole-4-carboxamide 5 ' -monophosphate, 5 -amino-1-β-D-ribofuranosyl- 1 H- imidazole-4-carboxamide 2',3'-diacetyl ester, and 5-amino-l-β-D-ribofuranosyl- lH-irnidazole-4-carboxamide 2',3',5'-triacetyl ester. The content of compound of formula (I) or a cosmetically acceptable salt thereof is in the range from 0.0001 to 10 %, preferably 0.01 to 1 % by the weight of the composition.

The term «cosmetically acceptable carrier" refers to one or more compatible solid or liquid filler diluents, which are suitable for administration to any portion of the human skin, hair, and nail. Examples of such carriers include, but are not limited to, distilled or deionized water, propyleneglycol, and glycerol.

Preferably, the composition of present invention further comprises an effective amount of succinic acid or a cosmetically acceptable salt thereof. The term ((cosmetically acceptable salt" refers to non-toxic base addition salts. The cosmetically acceptable salts of the invention are prepared by a reaction of succinic acid with a cosmetically acceptable organic or inorganic base by methods well-known from the art. Such bases include, but are not limited to, sodium hydroxide and potassium hydroxide, ethanolamine, and choline base. The content of succinic acid or a cosmetically acceptable salt thereof is in the range from 0.0001 to 10 %, preferably 0.01 to 1 % by the weight of the composition.

Preferably, the composition of present invention further comprises an effective amount of alpha-glycerylphosphorylcholine. The content of alpha-glycerylphosphorylcholine is in the range from 0.0001 to

10 %, preferably 0.01 to 1 % by the weight of the composition.

More preferably, the composition of the invention comprises an effective amount of the compound of general formula (I) in combination with effective amounts of succinic acid or a cosmetically acceptable salt thereof and alpha- glycerylphosphorylcholine.

The compositions of the present invention are useful for topical application. Because of acceleration skin metabolism, the compositions of the invention are particularly advantageous for regulating skin conditions associated with factors slowing metabolism such as metabolic disorders, obesity, and aging. Also, the compositions of the present invention are particularly advantageous for regeneration of damaged hair and stimulating hair growth in subjects in need thereof. Also, the compositions of the present invention are particularly advantageous to improve nail health and appearance, accelerate nail growth and regeneration, to make nails more strength and flexible, and eliminate nail problems such as changes in the shape and texture of nails, thickened nails, nail fragility, and brittle nails.

The compositions of the present invention are useful for regulating the skin condition, visible and/or tactile discontinuities in skin (especially the skin surface; such discontinuities are generally undesirable). Such discontinuities may be induced or caused by internal and/or external factors, and include the signs of skin aging described herein. The term "regulating skin condition" includes prophylactically regulating and/or therapeutically regulating skin condition, including visible and/or tactile discontinuities in skin. As used herein, prophylactically regulating skin condition includes delaying, minimizing and/or preventing visible and/or tactile discontinuities in skin. As used herein, therapeutically regulating skin condition includes ameliorating, e.g., diminishing, minimizing and/or effacing, discontinuities in skin. Regulating skin condition involves improving skin appearance and/or feel.

The compositions of the present invention are particularly advantageous for regulating signs of skin aging, more especially visible and/or tactile discontinuities in skin texture associated with aging. "Regulating the signs of skin aging" includes prophylactically regulating and/or therapeutically regulating one or more of such signs (similarly, regulating a given sign of skin aging, e.g., lines, wrinkles or pores, includes prophylactically regulating and/or therapeutically regulating that sign). As used herein, prophylactically regulating such signs includes delaying, minimizing and/or preventing signs of skin aging. As used herein, therapeutically regulating such signs includes ameliorating, e.g., diminishing, minimizing and/or effacing signs of skin aging.

"Signs of skin aging" include, but are not limited to, all outward visibly and tactilely perceptible manifestations as well as any other macro or micro effects due to skin aging. Such signs may be induced or caused by intrinsic factors or extrinsic factors, e.g., chronological aging and/or environmental damage. These signs may result from processes which include, but are not limited to, the development of textural discontinuities such as wrinkles, including both fine superficial wrinkles and coarse deep wrinkles, skin lines, crevices, bumps, large pores (e.g., associated with adnexal structures such as sweat gland ducts, sebaceous glands, or hair follicles), scaliness, flakiness and/or other forms of skin unevenness or roughness, loss of skin elasticity (loss and/or inactivation of functional skin elastin), sagging (including puffmess in the eye area and jowls), loss of skin firmness, loss of skin tightness, loss of skin recoil from deformation, discoloration (including undereye circles), blotching, sallowness, hyperpigmented skin regions such as age spots and freckles, keratoses, abnormal differentiation, hyperkeratinization, elastosis, collagen breakdown, and other histological changes in the stratum corneum, dermis, epidermis, the skin vascular system (e.g., telangiectasia or spider vessels), and underlying tissues, especially those proximate to the skin. The compositions of the invention are prepared by known procedures using well-known ingredients. The composition of the invention can comprise optional ingredients. Such optional ingredients generally are used individually at levels from about 0.0005% to about 10.0%, preferably from about 0.005% to about 1.0% by weight of the composition. Examples of suitable optional ingredients include, but are not limited to, depigmentation agents; reflectants; humectants; antimicrobial (e.g., antibacterial) agents; UV absorbers; anti-acne agents; anti-aging agents; anti-wrinkling agents, antiseptics; local anesthetics; wound healing promoters; deodorants and antiper spirants; skin emollients and skin moisturizers; tanning agents; skin lightening agents; antifungals; depilating agents; external analgesics; counterirritants; anti-diaper rash agents; make-up preparations; vitamins and nutrients such as thiamin, riboflavin, niacin, pantothenates, pyridoxine, folic acid, cobalamin, biotin, choline, inositol, ascorbic acid, lipoic acid, carnitine, and etc.; amino acids and their derivatives such as alanine, arginine, asparagine, aspartic acid, carnitine, citrulline, cysteine, dimethylglycine, gamma-aminobutyric acid, glutamic acid, glutamine, glutathione, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, praline, serine, taurine, threonine, tryptophan, tyrosine, valine; minerals such as boron, calcium, chromium, cobalt, copper, fluoride, germanium, iodine, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, vanadium, zinc; herbal extracts; retinoids; bioflavonoids; anti-oxidants; skin conditioners; hair lighteners; chelating agents; cell turnover enhancers; coloring agents; sunscreens and the like, and mixtures thereof.

Examples of suitable reflectants include, but not limited to, mica, alumina, calcium silicate, glycol dioleate, glycol distearate, silica, sodium magnesium fluorosilicate, and mixtures thereof.

Examples of suitable UV absorbers include, but not limited to, benzophenone, bomelone, butyl paba, cinnamidopropyl trimethyl ammonium chloride, disodium distyrylbiphenyl disulfonate, paba, potassium methoxycinnamate, and mixtures thereof.

Examples of suitable humectants include, but not limited to, water soluble liquid polyols selected from the group comprising glycerine, propylene glycol, hexylene glycol, butylene glycol, pentylene glycol, dipropylene glycol, and mixtures thereof. The humectant is preferably present in an amount of from about 0 percent to about percent, more preferably from about 0.5 percent to about 5 percent, based on the overall weight of the composition.

Suitable amino acid agents include amino acids derived from the hydrolysis of various proteins as well as the salts, esters, and acyl derivatives thereof. Examples of such amino acid agents nonexclusively include amphoteric amino acids such as alkylamido alkylamines, i.e. stearyl acetyl glutamate, capryloyl silk amino acid, caprylol collagen amino acids; capryloyl kertain amino acids; capryloyl pea amino acids; cocodimonium hydroxypropyl silk amino acids; corn gluten amino acids; cysteine; glutamic acid; glycine; hair keratin amino acids; hair amino acids such as aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, half- cystine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, cysteic acid, lysine, histidine, arginine, cysteine, tryptophan, citrulline; lysine; silk amino acids, wheat amino acids; and mixtures thereof Examples of suitable proteins include, but not limited to, collagen, deoxyribonuclease, iodized corn protein; keratin; milk protein; protease; serum protein; silk; sweet almond protein; wheat germ protein; wheat protein; wheat protein, alpha and beta helix of keratin proteins; hair proteins, such as intermediate filament proteins, high-sulfur proteins, ultrahigh-sulfur proteins, intermediate filament-associated proteins, high-tyrosine proteins, high-glycine tyrosine proteins, tricohyalin, and mixtures thereof.

Examples of suitable antiperspirants and deodorants include, but not limited to, aluminium chlorohydrates, aluminium zirconium chlorohydrates, and mixtures thereof. Examples of sunscreen agents include, but not limited to, titanium dioxide and zinc oxide. δ

Examples of suitable counterirritants include, but not limited to, camphor, menthol, methyl salicylate, peppermint and clove oils, ichtammol, and mixtures thereof.

Examples of suitable anti-aging agents include, but are not limited to, inorganic sunscreens such as tianium dioxide and zinc oxide; organic sunscreens such as octyl-methyl cinnamates and derivatives thereof; retinoids; vitamins such as vitamin C, vitamin B, and derivatives thereof; antioxidants including alpha hydroxy acid such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic acid, atrrolactic acid, alpha-hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid, glucopehtonic acid, glucopheptono 1,4-lactone, gluconic acid, gluconolactone, glucuronic acid, glucurronolactone, glycolic acid, isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvia acid, saccharic acid, saccaric acid 1,4-lactone, tartaric acid, and tartronic acid; succinic acid or salts thereof; beta hydroxy acids such as beta-hydroxybutyric acid, beta-phenyl-lactic acid, beta-phenylpyruvic acid; botanical extracts such as green tea, soy, milk thistle, algae, aloe, angelica, bitter orange, coffee, goldthread, grapefruit, hoellen, honeysuckle, Job's tears, lithospermum, mulberry, peony, puerarua, rice, safflower, and mixtures thereof. Suitable amounts of anti-aging agents include, based upon the total weight of the composition, from about 0.01 percent to about 10 percent, and preferably from about 0.04 percent to about 5 percent.

Examples of suitable depigmentation agents include, but are not limited to, hydroquinone and it derivatives; vitamins such as niacin, vitamin C and its derivatives; extracts such as chamomile and green tea, and mixtures thereof. Examples of skin lightening agents include, but not limited to, hydroquinone, catechol and its derivatives, ascorbic acid and its derivatives, and mixtures thereof.

The compositions of the present invention are usually formulated to have a pH of 9.5 or below and in general have a pH in the range from about 4.5 to about

9, more preferably from about 5 to about 8.5. The compositions of the present invention are formulated in a variety of forms including, but are not limited to, lotions, gels, creams, sprays, and solutions. The compositions of the invention are prepared by methods well-known from the art in accordance with accepted procedures in a variety of forms. Such forms include, but are not limited to, solution, lotion, gel, emulsion, spray, and cream.

Further, the present invention provides a method for the skin, hair, or nail care comprising the step of applying the composition of the invention to skin, hair, or nail of a subject in need thereof. In the method of the invention, an effective amount of the composition of the invention is topically applied to the skin, and is preferably left on the skin for a period of at least about 15 minutes, more preferably at least about 30 minutes, even more preferably at least about 1 hour, most preferably for at least several hours, e.g., up to about 12 hours. This method can be reapplied from 1 to about 5, preferably from 1 to 3 times per day.

Typically, the effective amount of the composition is from about 1 gram to about

100 grams, preferably from about 1 gram to about 20 grams.

Further, the present invention provides the use of a compound of general formula (I)

wherein

R₁ is independently selected from the group consisting of H, PO₃H, and C_2- ₈acyl; R₂ is independently selected from the group consisting of H and C_2- ₈acyl; R₃ is independently selected from the group consisting of H and C_2- gacyl; for the manufacturing a cosmetic composition.

The 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide or 5'- monophosphate thereof could be prepared by methods well-known from the art.

Acyl derivatives of 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide could be prepared by reaction of AICAR with carboxylic acid anhydrides in the presence of a catalyst, preferably phosphoric acid.

Because of the use of the compounds of general formula (I) in cosmetic compositions, it is now possible to improve skin, hair, and nail health and appearance, especially under aging. The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1. This example demonstrates cosmetic gel comprising compound of formula (I).

Ingredient Content

5 -amino-1-β-D-ribofuranosy 1- 1 H- 100 mg imidazole-4-carboxamide

Disodium phosphate qs to pH 5.5

Ethylcellulose 60 mg

Distilled water to 10.0 ml

The gel preparation: 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4- carboxamide is mixed with above-mentioned ingredients in the conventional manner to prepare the cosmetic gel.

The method of skin care with the use of the gel: 1 g of above-mentioned gel is topically applied to the skin, and is preferably left on the skin for a period of at least about 15 minutes.

Example 2.

This example demonstrates cosmetic gel comprising compound of formula (I).

Ingredient Content

5-amino-l-β-D-ribofuranosyl-lH- 100 mg imidazole-4-carboxamide, 5'- monophosphate

Disodium phosphate qs to pH 5.5

Ethylcellulose 60 mg

Distilled water to 10.0 ml

The gel preparation: 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4- carboxamide 5 '-monophosphate is mixed with above-mentioned ingredients in the conventional manner to prepare the cosmetic gel. The method of hair care with the use of the gel: 1 g of above-mentioned gel is topically applied to the hair and skin surrounding the hair, and is preferably left on the skin for a period of at least about 15 minutes.

Example 3.

This example demonstrates cosmetic gel comprising compound of formula (I).

Ingredient Content

5-amino-l-β-D-ribofuranosyl- IH- 100 mg imidazole-4-carboxamide 2 ' ,3 ' -diacetyl

Disodium phosphate qs to pH 5.5

Ethylcellulose 60 mg

Distilled water to 10.0 ml

The method of nail care with the use of the gel: 1 g of above-mentioned gel is topically applied to the skin surrounding a nail plate, and is preferably left on the skin for a period of at least about 15 minutes.

Example 4.

This example demonstrates cosmetic gel comprising compound of formula (I).

Ingredient Content

5-amino-l-β-D-ribofuranosyl-lH- 100 mg imidazole-4-carboxamide

Succinic acid 200 mg

Sodium hydroxide qs to pH 5.5

Alpha- glycerylphosphorylcholine 200 mg

Ethylcellulose 100 mg

Distilled water to 10.0 ml

The gel preparation: 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4- carboxamide is mixed with above-mentioned ingredients in the conventional manner to prepare the cosmetic gel. The method of skin, hair, and nail care with the use of the gel: 1 g of above- mentioned gel is topically applied to the skin, and is preferably left on the skin for a period of at least about 15 minutes.

Example 5. This example demonstrates that the compound of formula (I) of the invention significantly accelerate skin cell metabolism.

Glucose uptake by mammalian cells was used as an index of metabolic activity of the cells. The uptake has been monitored by fluorescent D-glucose derivative, 2-[N-(7-nitrobenz-2-oxa- 1 ,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2- NBDG) as described. Yoshioka K, et al., Biochim Biophvs Acta 1996, 1289(1^*): 5-

9. A431 human keratinocytes were treated for 24 hours with 100 μM of 5-amino-l- β-D-ribofuranosyl-lH-imidazole-4-carboxamide in combination with none, 10 μM succinic acid, or 50 μM alpha-glycerylphosphorylcholine. Then, cells were treated for 5 min with 50 μg/ml 2-NBDG dissolved in deionized water. 2-NBDG uptake was measured. Data are presented as mean ± SEM (n=8) in % of 2-NBDG uptake in control cells.

Treatment Glucose uptake, in % of control

Control 100 ± 9

5-amino-l-β-D-ribofuranosyl-lH- 136 U P imidazole-4-carboxamide (AICAR)

AICAR + succinic acid 151 ± 13 *

AICAR + α-glycerylphosphorylcholine 146 ±9*

*Denotes statistically significant difference of the control (p<0.05).

Claims

What is claimed is:

1. A cosmetic composition comprising an effective amount of a compound of general formula (I)

wherein

R₁ is independently selected from the group consisting of H, PO₃H₅ and C_2- ₈acyl; R₂ is independently selected from the group consisting of H and C_2- ₈acyl; R₃ is independently selected from the group consisting of H and C₂-_SaCyI; or a cosmetically acceptable salt thereof and at least one a cosmetically acceptable carrier.

2. The composition of claim 1, wherein said compound is selected from the group consisting of 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide, 5- amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide 5 '-monophosphate, 5- amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide 2',3'-diacetyl ester, and 5-amino-l-β-D-ribofuranosyl-lH-imidazole-4-carboxamide 2',3 ',5'-triacetyl ester.

3. The composition of claim 1, further comprising an effective amount of succinic acid or a cosmetically acceptable salt thereof.

4. The composition of claim 1, further comprising an effective amount of alpha- glycerylphosphorylcholine.

5. The composition of claim 1, further comprising combination of effective amounts of succinic acid or a cosmetically acceptable salt thereof and alpha- glycerylphosphorylcholine.

6. A method for the skin, hair, or nail care comprising the step of applying a composition of claim 1 to skin, hair, or nail of a subject in need thereof.

7. The use of a compound of general formula (I)

wherein

R₁ is independently selected from the group consisting of H, PO₃H, and C_2- ₈acyl; R₂ is independently selected from the group consisting of H and C_2- ₈acyl; R₃ is independently selected from the group consisting of H and C_2- sacyl; for the manufacturing a cosmetic composition.