WO1991007167A1 - Activateurs de la kinase de proteine comme promoteurs de la production de melamine - Google Patents

Activateurs de la kinase de proteine comme promoteurs de la production de melamine Download PDF

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Publication number
WO1991007167A1
WO1991007167A1 PCT/US1990/006327 US9006327W WO9107167A1 WO 1991007167 A1 WO1991007167 A1 WO 1991007167A1 US 9006327 W US9006327 W US 9006327W WO 9107167 A1 WO9107167 A1 WO 9107167A1
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composition
glycerol
agents
activator
cis
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PCT/US1990/006327
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English (en)
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Patricia A. Agin
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Schering-Plough Healthcare Products, Inc.
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Publication of WO1991007167A1 publication Critical patent/WO1991007167A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Definitions

  • This invention relates to the enhancement of melanin production by the topical application to the skin of at least on Protein Kinase C activator.
  • Melanin pigmentation is largely responsible for norma skin color and protection against ultraviolet damage, including photocarcinogenesis.
  • Melanin is produced in melanocytes, neural crest derived cells situated in the basal layer of the epidermis, a is transferred via dendrites to surrounding keratinocytes, the mo abundant cell in the epidermis.
  • Gordon et al. disclose that this anatomical relationship, termed the epidermal melanin unit, is envisioned as one melanocyte in contact with an estimated 36 keratinocytes in the basal and suprabasal layers.
  • IT may persist for 36-48 hours after prolonged exposure, at which stage it blends with delayed tanning (DT). See Regan, editor, The Science of Photomedicine. pp. 241-242, 1982. According to Fitzpatrick et al., IT occurs within minutes of exposure to UVA (320-400 nm) and to visible light. Fitzpatrick et al. disclose that IT becomes most prominent within 1 hour of exposure and almost completely disappears within 4 hours.
  • Fitzpatrick et al. further disclose that studies with electron spin resonance have shown that IT reaction is probably an oxidation reaction that involves the generation of unstable semi-quinone-like free radicals in melanin.
  • DT develops 48-72 hours after exposure to UV light, and DT involves new production of melanosomes and therefore appears slowly over a period of days. See Fitzpatrick et al., editors, Sunlight and Man, p. 175, 1974.
  • Fitzpatrick et al. editors, Sunlight and Man, p. 175, 1974.
  • Farooqui et al. disclose that the activity of protein kinase C is altered by several lipids such as diacylglycerol, free fatty acids, lipoxins, gangliosides, lipopolysaccharides (diacylglucosamine 1 -phosphate) and sulfatides. According to Farooqui et al., these lipids may interact with protein kinase C either directly or through calcium ions and produce their regulatory effect (activation or inhibition) on the activities of the enzymes phosphorylated by this kinase. It is disclosed that the activity of tyrosine hydroxylase is increased by the phosphorylation by Protein Kinase C.
  • Kishimoto et al. studied the structural requirement of diacylglycerol for the activation of protein kinase C and found that the activation required the presence of an unsaturated fatty acid within the diacylglycerol molecule.
  • 1 ,2-diacylglycerols containing two long-chain saturated fatty acids were less effective than diolein.
  • dopachrome conversion factor increases the conversion of dopachrome to 5,6-dihydroxyindole
  • 5,6-dihydroxyindole conversion factor increases the conversion of 5,6-dihydroxyindole to the quino and subsequently to melanin.
  • the desir for a deep, dark tan has generated the proliferation of cosmetic products claiming to enhance or accelerate the tanning process- e.g., Germaine Monteil's Pre Tan Starter (1981), Estee Lauder's Golden Pre-Tan Accelerator with a Bio-Tan complex (1985), and Plough's Coppertone Natural Tan Accelerator (1986).
  • Duggan et al. further disclose that these products contain tyrosine, tyrosine derivatives, tyrosine/riboflavin complex and/or amino acid blends.
  • tyrosine is used to increase the substrate available for tyrosinase, and tyrosine was complexed with riboflavin in order to accelerate tyrosine's oxidation. See Duggan, M., et al., "Tyrosinase... The Enzyme Behind the Tan", Cosmetics & Toiletries, pp. 97-101 , March 1987.
  • melanin is produced in melanocytes and transferred to keratinocytes.
  • cultured human melanocytes and keratinocytes were studied by P.R. Gordon al. According to the study, the dendricity-inducing activity in keratinocyte cultured medium passed through filters with molecular weight exclusions as low as 500 daltons; while growth promoting activity was found in both retentate and ultra filtrate using 10,000, 2,000, and 500 molecular weight exclusion filters.
  • Wren et al. report their examination of the possibility that activation of melanocytes (MC) by ultraviolet radiation (UVR) is mediated by diacylglycerol.
  • UVR ultraviolet radiation
  • OAG 1 -oleyl-2-acetyl glycerol
  • DOG dioctanoyl glycerol
  • TPA 12-0 tetradecanoyl phorbol 13-acetate
  • OAG known to activate protein kinase C, caused a significant dose-related augmentation of melanogenesis in both human MC and S91 cells: at 100 mM OAG, basal melanin content was increased by 7.2 fold in HuMC and 3.1 fold in S91 ceils, while in UV-irradiated cells, OAG caused increases of 10.2 and 6.1 respectively.
  • DOG another diacylglycerol that activates kinase C, caused only a 70% increase in basal melanin content and a 2 fold increase in UV-induced melanogenesis in HuMC. Wren et al.
  • TPA a potent activator of protein - kinase C
  • TPA a potent activator of protein - kinase C
  • PK-C Protein Kinase C
  • the absorbed Protein Kinase C (hereinafter "PK-C”) Activator enhances, potentiates or increases the growth and replication- of tyrosinase and melanosomal protein without exposure to UV radiation by delaying cells in G2 phase of the cell cycle causing increased protein synthesis, particularly tyrosinase.
  • melanin precursors i.e., tyrosinase and melanosomes- is enhanced, potentiated or increased when a PK-C Activator is used in combination with exposure to UV radiation (UVA 320-400 nm and/or UVB 290-320 nm).
  • UVA 320-400 nm and/or UVB 290-320 nm UVA 320-400 nm and/or UVB 290-320 nm.
  • this invention provides a method of enhancing melanin production comprising applying topically to the skin a composition comprising an effective amount of at least one Protein Kinase C Activator.
  • the PK-C Activator is applied in an amount effective to stimulate the enhanced production of melanin.
  • the PK-C Activator is combined with a suitable solvent and other optional ingredients.
  • the composition will also contain an effective amount of a suitable antioxidant.
  • the composition can optionally contain at least one other ingredient selected from the group consisting of: riboflavin, riboflavin phosphate, a mixture of riboflavin and riboflavin phosphate, DOPA phosphates, sunscreening agents, emollients, emulsifiers, solvents for sunscreening agents, waxes, thickeners, film formers, humectants, antioxidants, preservatives, surfactants, perfumes, biological additives, buffering agents, chelating agents, emulsion stabilizers, opacifying agents, pH adjusters, propellants, and coloring agents.
  • the PK-C Activators useful in this invention are those Activators which are physiologically compatible with the skin, are reae.ily absorbable through or into the skin, and penetrate through the stratum corneum and the epidermis to reach the melanocytes.
  • the PK-C Activators may be used individually or in combination.
  • Suitable PK-C Activators are those physiologically acceptable substances which activate protein kinase C by their direct action, or are substances which are metabolized to other substances which activate protein kinase C, or are substances which act upon other substances to produce a resulitng substance that activates protein kinase C and may include substances selected from the group consisting of: diacylglycerols; triacylglycerols; lipopoiysaccharides; unsaturated free fatty acids; short chain saturated free fatty acids; glycophospholipids; enzymes which hydrolyze glycophospholipids (phosphoglycerides) to diacylglycerols such as Phospholipase C which hydrolyzes the phosphodiester bond linking the phosphorylated inositol unit to the acylated glycerol moiety to form diacylglycerol in the phosphoinositide cascade; and naturally occurring substances such as bryostatins which are naturally occurring macrocylic
  • the acyl groups of the diacylglycerols and triacylglycerols can be unsaturated, saturated or a combination of unsaturated and saturated.
  • Each acyl chain (group) contains at least 1 carbon atom (including the carbonyl carbon) and usually contains from about 1 to about 30 carbon atoms (including the carbonyl carbon) with about 2 to about 24 carbon atoms being preferred and about 6 to about 20 carbon atoms being most preferred.
  • the acyl group is derived from a naturally occurring fatty acid and the fatty acid usually contains an even number of carbon atoms and is unbranched.
  • the diacylglycerols are preferably 1 ,2- diacylglycerols, and most preferably 1 ,2-diacyl-sn-gIycols.
  • saturated free fatty acids (fatty acids) from which the acyl groups may be derived from include, but are not limited to: methanoic (formic); ethanoic (acetic); propanoic (propionic); butanoic (butyric); pentanoic (valeric); hexanoic (caproic); heptanoic (enanthic); octanoic (caprylic); nonanoic (pelargonic); decanoic (capric); undecanoic (undecylic); dodecanoic (lauric); tridecanoic (tridecylic); tetradecanoic (myristic); pentadecanoic (pentadecylic); hexadecanoic (palmitic); heptadecanoic (margaric); octadecanoic (stearic); nonadecanoic (nonadecylic); eicosanoic (arachidic);
  • Preferred saturated acyl groups are derived from fatty acids selected from the group consisting of: acetic, hexanoic, octanoic, decanoic, hexadecanoic, octadecanoic, and eicosanoic. Most preferred saturated fatty acids are selected from the group consisting of: acetic, hexanoic, octanoic and octadecanoic.
  • Representative unsaturated free fatty acids (fatty acids) from which the acyl groups may be derived from include, but are not limited to:
  • trans-11 -octadecenoic (trans-vaccenic); 1 1. cis-12 hydroxy-9-octadecenoic (ricinoleic) ;
  • Preferred unsaturated fatty acids are selected from the group consisting of: cis-9-octadecenoic; and cis-5,8,11,14- eicosatetraenoic.
  • diacylglycerols include, but are not limited to: 1. diarachidin (dieicosanoyl-glycerol, reported to be approximately 50% 1,3- and 50% 1,2-isomer);
  • dicaprin (didecanoylglycerol, reported to be 50% 1,3- and 50% 1,2-isomer); 4. 1,3-dicaprin (1,3-didecanoylglycerol);
  • dicaproin dihexanoylglycerol, reported to be 50% 1,3- and 50% 1,2-isomers
  • dilaurin didodecanoylglycerol, reported to be approximately 50% 1,3- and 50% 1,2-isomer
  • dimyristin (ditetradecanoylglycerol, reported to be approximately 50% 1,3- and 50% 1,2-isomer); 18. 1,3-dimyristin (1,3-ditetradecanoylglycerol);
  • diolein di-[(cis)-9-octc ⁇ decenoyl]glycerol, reported to be approximately 85% 1,3- and 15% 1,2-isomer
  • dipalmitin dihexadecanoylglycerol, renorted to be approximately 50% 1,2- and 50% 1,3-isomer
  • 35 1 -oleoyl-2-acetyl-rac-glycerol (1 -[(cis)-9- octadecenoyl]-2-acetyl-rac-glycerol); 36. 1 -oleoyl-2-acetyl-sn-glycerol (1 -[(cis)-9- octadecenoyl]-2-acetyl-sn-glycerol);
  • diacylglycerol is selected from the group consisting of:
  • the diacylglycerol is selected from the group consisting of: 1 ,2-dihexanoyl-sn-glycerol; 1 ,2-dioctanoyl- rac-glycerol; 1 ,2-dioctanoyl-sn-glycerol; 1 -oleoyl-2-acetyl-rac- glycerol; 1 -oleoyl-2-acetyl-sn-glycerol, or 1 -stearoyl-2- arachidonoyl-sn-glycerol. Most preferably 1 ,2-dioctanoyl- ac- glycerol or 1 ,2-dioctanoyl-sn-glycerol is used.
  • Diacylglycerols are available commercially from, for example: (1) Sigma Chemical Company, St. Louis, MO. --see Sigma's 1989 catalogue of Biochemicals Organic Compounds for Research and Diagnostic Reagents; (2) Serdary Research Laboratories, Port Huron, Ml; (3) Molecular Probes Inc., Junction City, OR; and (4) Avanti Polar Lipids, Birmingham, AL.
  • Diacylgycerols may also be prepared in accordance with procedures well known in the art, for example see: (1) Gunstone et al., editors, The Lipid Handbook pp. 295, et seq., ⁇ 1986; (2) Ebeling et al., Proc. Natl. Acad. Sci. USA, Vol. 82, pp 815-819, at page 816, February 1985; and (3) Ganong et al., Proc. Natl. Acad. Sci. USA, Vol. 83, pp. 1184-1188, March 1986.
  • triacylglycerols may include but are not limited to:
  • trimyristin (1 ,2,3-tritetradecanoylglycerol)
  • trimyristolein (1 ,2,3-tri-[(cis)-9-tetradecenoyl]- glycerol) ;
  • triolein (1 ,2,3-tri-[(cis)-9-octadecenoyl]glycerol ; glyceryl trioleate); 40. tripalmitin (1 ,2,3-trihexadecanoylglycerol);
  • tripentadecanoin (1 ,2,3-tripentadecanoylglycerol);
  • tristearin (1 ,2,3-trioctadecanoylglycerol);
  • Triacylglycerols are commercially available from Sigma Chemical Company (same address and catalogue as cited above). Triacylglycerols may also be prepared in accordance with procedures well known in the art, for example see Gunstone et al., editors, The Lipid Handbook, p. 295 et seq., ⁇ 1986.
  • Lipopolysaccharides may also be useful in this invention as PK-C Activators.
  • the active lipid moiety. of LPS of Gram-negative bacteria is diacylglucosamine 1 -phosphate. Thus, either a diacylglucosamine 1 -phosphate or the LPS containing it may be used.
  • the acyl groups of the diacylglucosamine 1- phosphates from LPS are usually from predominantly Ci 4 to Ci 8 fatty acids which may be saturated or monosaturated, but not polyunsaturated.
  • LPS and bacterial fatty acids see, for example, Davis et al., editors, Microbiology. Third Edition, pp 82 to 91 , ⁇ 1980, the disclosure of which is incorporated herein by reference thereto.
  • bacteria from which LPS can be derived from for use in this invention include, but are not limited to: Escherichia coli (E. coli), Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella abortus equi, Salmonella enteritidis, Salmonella minnesota, Salmonella typhimurium, Salmonella typhosa, Serratia marcescens, Shigella flexneri, Vibrio cholerae, and the like.
  • Bacterial Lipid A and Lipid X may also prove useful. Lipid A aind Lipid X are well known to those skilled in the art. See for example: (1) Wightman et al., The Journal of Biological Chemistry. Vol.
  • Lipid A is commercially available from, for example, Sigma Chemical Company.
  • Lipid X is available from Lipidex, Inc., Middleton, Wl.
  • LPS are available commercially, for example, form Sigma Chemical Co. (already cited above).
  • Examples of LPS available commercially include those derived from: E. coli Serotype 026:B6; E. coli Serotype 055:B5; E. coli Serotype 0111 :B4; E. coli Serotype 0127:B8; E. coli Serotype 01 8:B12; E. coli EH-100 (Ra mutant); E. coli F-583 (Rd mutant); E. coli Strain J5 (Re mutant); E.
  • LPS may be derived from bacteria by techniques well known to those skilled in the art.
  • lyophilized powders are available as phenol, trichloroacetic acid (TCA), butanol or phenol-chloroform-petroleum ether extracts.
  • TCA trichloroacetic acid
  • BCA phenol-chloroform-petroleum ether extracts.
  • TCA trichloroacetic acid
  • TCA trichloroacetic acid
  • butanol phenol-chloroform-petroleum ether extracts.
  • Such procedures are referenced in Sigma Chemical Company's 1989 Biochemicals Organic Compounds catalogue (cited above) as: Westphal et al., Methods in Carbohydrate Chem., 5., 83 (1965) for a phenol extraction procedure; Staub, Methods in Carbohydrate Chem., 5., 92 (1965) for a TCA extraction procedure; Lieve et al., Methods in Enzymology
  • Unsaturated free fatty acids may also be useful in this invention as PK-C Activators. It is believed that unsaturated free fatty acids having 1 to about 4 double bonds and ⁇ about 14 to about 20 carbon atoms are preferred PK-C Activators. Cis- and trans-unsaturated free fatty acids are suitable with the proviso that trans-elaidic acid may not be as useful as other unsaturated free fatty acids.
  • Suitable unsaturated free fatty acids may be selected from amongst those unsaturated fatty • acids already described above for the acyl groups of the diacylglycerols and triacylglycerols.
  • Preferred unsaturated free fatty acids include linoleic acid, arachidonic acid and oleic acid.
  • Short chain saturated free fatty acids may also prove useful.
  • Suitable saturated free fatty acids may be selected from amongst those saturated fatty acids, having 4 to 10 carbon atoms, described above for the acyl groups of the diacylglycerols and the triacylglycerols.
  • Saturated fatty acids having more than 10 carbon atoms --e.g., 11 -20- may also prove useful.
  • lauric, myristic, palmitic, stearic, and arachidic may be suitable.
  • Phosphoglycerides consist of a glycerol background, two acyl groups derived from fatty acids (usually bound to the C-1 and C-2 glycerol carbons) and a phosphorylated alcohol.
  • the major phosphoglycerides are derivatives of phosphatidate (diacylglycerol 3-phosphate). The phosphate group of phosphatidate becomes esterified to the hydroxyl group of one of several alcohols.
  • alcohols include serine, threonine, ethanolamine, choline, glycerol, inositol, and the like.
  • the disclosure above pertaining to the acyl groups of the di- and triacylglycerols pertain equally as well to the acyl groups of the phosphoglycerides.
  • phosphoglycerides include, but are not limited to:
  • L- ⁇ -phosphatidylcholine such as that obtained from bovine brain, bovine heart, bovine liver, egg yolk (diced, fresh, frozen or fresh frozen), turkey egg yolk (fresh), and soybean;
  • L- ⁇ -phosphatidylcholine dilinoleoyl
  • 22 L- ⁇ -phosphatidycholine, dimyristoyl
  • L- ⁇ -phosphatidylcholine dipentadecanoyl (1 ,2- dipentadecanoyl-sn-glycero-3-phosphocholine); 31 . L- ⁇ -phosphatidylcholine, distearoyl;
  • L- ⁇ -phosphatidylethanolamine such as that obtained from bovine brain, sheep brain, egg yolk, soybean, Escherichia coli, dog brain, bovine liver, or porcine liver;
  • L- ⁇ -phosphatidylethanolamine dilauroyl (1 ,2- didodecanoyl-sn-glycero-3-phosphoethanolamine); 53. L- ⁇ -phosphatidylethanolamine, dimyristoyl (1 ,2- ditetradecanoyl-sn-glycero-3-phosphoethanolamine) ;
  • L- ⁇ -phosphatidylethanolamine dipalmitoyl-N- dansyl (1 ,2-dihexadecanoyl-sn-glycero-3-phospho-[N- dansyljethanolamine);
  • L- ⁇ -phosphatidyl-DL-glycerol (1 -[3-sn- phosphatidyl]-rac-glyceroI) [prepared by reaction of cabbage phospholipase D with egg yolk L- ⁇ -phosphatidylcholine in the presence of glycerol], including the ammonium salt from egg yolk lecithin and the sodium salt from egg yolk lecithin;.
  • L- ⁇ -phosphatidyl-DL-glycerol dipalmitoyl (1 ,2- dihexadecanoyl-sn-glycero-3-[phospho-rac-(1 -glycerol)]), including the ammonium and sodium salts
  • 71 L- ⁇ -phosphatidyl-DL-glycerol, distearoyl (1 ,2- distearoyl-sn-glycero-3-[phospho-rac-(1 -glycerol)]) ammonium salt;
  • L- ⁇ -phosphatidylinositol e.g. from soybean (including the ammonium and sodium salts), and from bovine liver (ammonium salt), as well as TYPE 1 : Folch Fraction 1 from bovine brain reported to contain 10-20% phosphatidyl inositides, 50-60% phosphatidyl serine as well as several other brain lipids; '
  • phosphoinositide sodium salt from bovine brain
  • 75 phosphoinositides, sodium salt, from bovine brain, Extract Type 1 , reported to contain approximately 15-20% phosphatidylinositol 4-monophosphate and phosphatidylinositol 4,5-biphosphate with the remainder being a mixture of phosphatidylinositol and phosphatidylserine;
  • L- ⁇ -phosphatidyl-L-serine e.g., from bovine brain (including the sodium salt), as well as TYPE III: Folch Fraction III from bovine brain reported to contain 80-85% phosphatidylserine with the balance being other brain lipids; 79. L- ⁇ -phosphatidylserine, dansyl; and
  • the liquid PK-C Activators may be applied neat to the skin, it is generally more convenient to form a composition by combining, such as by mixing, blending or dissolving, the PK-C Activators with a suitable solvent.
  • the PK-C Activator in the composition is in a concentration which is effective to provide the desired level of activity.
  • the PK-C Activator is present in an amount of about 0.01% to about 20% by weight of the ' total composition with about 0.05% to about 10% being preferred and about 0.05% to about .1.0% being most preferred.
  • Combinations of PK-C Activators may be used such that their total amount is within these specified ranges.
  • the PK-C Activator composition is applied in a sufficient amount to uniformly coat the skin.
  • the composition is applied in an amount sufficient to provide about 0.01 to about 120 micromoles of PK-C Activator to an area of skin about 10 to about 12 cm 2 with about 2 to about 25 micromoles of PK-C Activator being preferred and about 1 to about 10 micromoles being most preferred.
  • the PK-C Activator is applied at least 1 to about 6 times with about 1 to about 3 times being preferred over a time period of about 24 hours.
  • Suitable solvents are those which effectively dissolve or disperse the PK-C Activator, or form a stable emulsion therewith, and are inert to the Activator and physiologically acceptable to the skin. Mixtures of solvents may also be used.
  • the solvent may conveniently be a solvent for sunscreening agents. Those skilled in the art will appreciate that the solvents are used in amounts which will provide the desired concentration of PK-C Activator and other ingredients in the composition. Thus, an amount of solvent can be used which would bring the total amount of all ingredients in the composition to 100% by weight.
  • Suitable solvents may be selected from amongst those solvents well known to those skilled in the art for their use in the cosmetics industry. Examples include, but are not limted to: liposomes; ketones such as acetone and the like; alcohols such as benzyl alcohol, ethanol, t-butyl alcohol, cetyl alcohol, glycol
  • Fats and oils such as avocado oil, cocoa butter, coconut oil, corn oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated vegetable oil, lanolin oil, mink oil, palm oil, peanut oil, safflower oil, soybean oil, sunflower seed oil, sweet almond oil, vegetable oil (expressed oil of vegetable origin consisting primarily of triglycerides of fatty acids), walnut oil, wheat germ oil and the like; hydrocarbons such as mineral oil and the like; alkoxylated alcohols or polymeric ethers such as PEG-8, PEG-14M and the like; lanolin and lanolin derivatives such as hydrogenated lanolin and the like; glyceryl esters and derivatives such as hydrogenated palm kernel oil and the like; esters such as isopropyl myristate, isopropyl palmitate and the like; water
  • the PK-C Activators are lipophilic. Therefore, if it is desirable to use water as a solvent it may be desirable to add components to the water to improve the solubility of the PK-C Activator in the water. For example, solvents such as alcohols and ketones, discussed above, which are water miscible may be added to improve the solubility of the PK-C Activator.
  • Liposomes may also prove useful as a solvent for the PK-C Activators, or as a means of encapsulating the PK-C Activators, or as a means of complexing with the PK-C Activators.
  • Liposomes are aqueous compartments enclosed by a lipid bilayer. They are produced by techniques well known to those skilled in the art. For example, liposomes can be produced by suspending a suitable lipid, such as phosphatidyl choline, in an aqueous medium. This mixture is then sonicated to give a dispersion of closed vesicles that are quite uniform in size. See, for example, Stryer, Biochemistry. Third Edition, pp. 290-292,
  • Liposome Kit L-4262 contains L- alpha-phosphatidylcholine (egg yolk), dicetyl phosphate and cholesterol.
  • Suitable negatively charged liposome mixture available from Sigma Chemcial Company is L-4012 which contains L-alpha- phosphatidylcholine, dicetyl phosphate and cholesterol.
  • Suitable positively charged liposome mixtures available from Sigma Chemical Company contains L-alpha-phosphatidylcholine, stearylamine and cholesterol (catalog numbers L-4137 and L-3887).
  • lipids in suitable liposomes are phospholipids, glycosphingolipids, ceramides, cholesterol sulfate and neutral lipids. Various combinations of these lipids are found in neonatal mouse, pig and human stratum granulosum and stratum corneum. Other categories of lipids which can be used to make the liposomes are straight chain fatty acids, glycerol esters, glycerides, phosphoglycerides, sphingolipids, waxes, terpenes and steroids. Specific preferred lipids suitable for use are phosphatidyl choline, dicetyl phosphate and cholesterol.
  • the liposomes may simply be used as the solvent for the PK-C Activators -i.e., after the liposomes are produced and isolated the PK-C Activator is added to the liposomes.
  • the PK-C Activators may also be encapsulated in (or trapped in) the compartment portion of the liposome. This can be done by adding an aqueous solution of PK-C Activator to a suitable lipid and mixing (e.g., sonicating) to produce the liposomes containing the PK-C Activator.
  • To make the aqueous solution of the PK-C Activator it may be desirable, as discussed above, to add additional water soluble components (e.g. alcohols, acetone, and the like) to increase the solubility of the PK-C Activator in the aqueous solution or to help maintain the PK-C Activator in the aqueous solution.
  • the PK-C Activators may also be added directly to a suitable lipid and mixed therewith so that there is a blend of PK-C Activators and lipid. Then when an aqueous solution is added to this blend and sonicated to produce the liposomes, the PK-C Activators will be in the lipid layer of the liposome and not the compartment of the liposome.
  • the liposome (as solvent) and PK-C Activator composition or the liposomes (PK-C Activator in compartment or lipid layer) can then be combined with a suitable topical vehicle, e.g. a lotion, gel or cream vehicle.
  • a suitable topical vehicle e.g. a lotion, gel or cream vehicle.
  • the lipid mixture which forms the liposome can be any of the conventional mixtures available or discussed in the literature which are pharmaceutically and cosmetically acceptable.
  • Preferred lipid mixtures contain a phosphatidyl choline, dicetyl phosphate and cholesterol.
  • the lipid mixtures which form the liposomes are commercially available in a solvent such as ethanol or chloroform.
  • a typical mixture contains on a weight basis, seven parts phosphatidylcholine, 2 parts dicetyl phosphate and one part cholesterol.
  • the PK-C Activator composition is not used immediately after made up, or frozen at about -20°C until use, then it is necessary to add an effective amount of at least one antioxidant to the composition to protect the PK-C Activator from degradation. Thus, if a PK-C Activator is used which will not degrade over time the antioxidant is no longer necessary, but its use is still preferred. Generally, about 0.05 to about 0.10% by weight of the composition of an antioxidant is sufficient. Any of the antioxidants known for use in the cosmetics industry may be used.
  • antioxidants include but are not limited to beta- carotene, BHA, BHT, ⁇ -tocopherol, propyl gallate " , sodium bisulfate, sodium metabisulfate, ascorbyl dipalmitate, TENOX (trademark for food grade antioxidants containing one or more of the following ingredients: butylated hydroxyanisole, butylated hydroxytoluene, and/or propyl gallate with or without citric acid; some formulas are supplied in solvents such as propylene glycol); and the like. See, for example, the CTFA Cosmetic Ingredient Handbook cited above.
  • the PK-C Activator or PK-C Activator composition can be combined with a penetration enhancer to enhance the absorption of the Activator into the skin.
  • the enhancer can be used in amounts of about 0.5% to about 99% by weight of the total composition with about 1% to about 25% being preferred and about 2% to about 10% being most preferred.
  • penetration enhancers include, but are not limited to: DMSO (dimethyl sulfoxide), Azone (laurocapram, 1 -dodecylazacycloheptan-2-one, from Nelson Research, Irving, CA), N-methylpyrrolidone, alcohols such as panthenol, the SD alcohols and oleic alcohol, fatty acids such as oleic acid and linoleic acid, liposomes, and the like. Preferably, fatty acids are used.
  • Other ingredients or components can be added to or combined (blended) with the PK-C Activator, or with the PK-C Activator composition formed from the PK-C Activator and solvents and/or penetration enhancers mentioned above.
  • These other ingredients include, for example riboflavin, riboflavin phosphate, mixtures of riboflavin and riboflavin phosphate, DOPA phosphates (such as a mixture of monophosphorylated isomers of DOPA -see U.S. Patent No.
  • sunscreening agents emollients, emulsifiers, solvents for sunscreening agents, waxes, thickeners, film formers, humectants, preservatives, surfactants, perfumes, biological additives, .buffering agents, chelating agents, emulsion stabilizers, opacifying agents, pH adjusters, propellants, coloring agents, and the like.
  • the compositions can be formed into formulations, such as lotions, creams, gels, aerosols and sticks, in accordance with procedures well known in the art.
  • the PK-C Activators may conveniently be added to known vehicles (formulations) for sunscreening agents.
  • the inclusion of the sunscreening agent would be optional.
  • Riboflavin, riboflavin phosphate or mixtures thereof may be used in amounts of at least about 0.05% by weight of the total composition. Generally riboflavin, riboflavin phosphate or mixtures thereof are used in an amount of about 0.1% to about 2% by weight of the total composition with about 0.1% to abut 0.3% being preferred and about 0.15% to about 0.3% being most preferred and about 0.2% to about 0.3% being even more preferred.
  • the riboflavin, riboflavin phosphate or mixtures thereof may be combined, along with the PK-C activators, with a known formulation (vehicle) for a sunscreening agent.
  • a known formulation for a sunscreening agent.
  • the inclusion of the sunscreening agent would be optional.
  • a formulation contains effective amounts of water and a humectant (such as sorbitol as well as the other humectants discussed below).
  • the humectant is usually present in amounts of about 1 to about 7% by weight of the total composition with about 4 to 5% being preferred.
  • the water can be present in amounts such that the total amount of ingredients equals 100% by weight.
  • the water may be present in amounts of about 40 to about 86% by weight of the total composition.
  • the riboflavin, riboflavin phosphate or mixtures thereof may also be encapsulated in liposomes.
  • DOPA phosphates can be used in amounts of about 0.005 to about 1.0% by weight of the total composition with about 0.015 to about 0.5 being preferred and about 0.05 to about 0.29 being most preferred.
  • the DOPA phosphates (phosphodopas) are O- phosphorylated derivatives of DOPA.
  • the DOPA phosphates are represented by Formulas I-V:
  • R 1 and R 2 each represent hydrogen or
  • R 4 and R 3 each represent hydrogen or a pharmaceutically acceptable cation; with the provisos that R 1 and R 2 cannot both be hydrogen.
  • the sunscreening agents used can be of the UVA type, UVB type, or a combination of both. Generally, the sunscreening agents are used in amounts effective to provide the desired level of protection against UVA and/or UVB radiation. Usually, the sunscreening agents are used in amounts of about 2% to about 20% by weight of the total composition with about 5% to about 18% being preferred and about 2% to about 15% being most preferred.
  • Typical UVB type sunscreening agents include substituted para-aminobenzoates, alkyl esters of para- methoxycinnamate and certain esters of salicylic acid.
  • Typical UVA type sunscreening agents include certain benz ⁇ phenones and dibenzoyl methanes.
  • UVB type sunscreening agents include but are not limited to:
  • Ethyl Dihydroxypropyl PABA ethyl dihydroxypropyl p-aminobenzoate
  • AMERSCREEN P from Amerchol Corp.
  • Glyceryl PABA glyceryl-p-aminobenzoate
  • NIPA G.M.P.A. tradename NIPA G.M.P.A. from NIPA Laboratories
  • Homosalate Homomenthyl salicylate
  • KEMESTER HMS from Humko Chemical
  • Octocrylene (2-ethylhexyl-2-cyano-3,3- diphenylacrylate) e.g., tradename UVINUL N-539 from BASF Chemical Co.
  • Octyl Salicylate (2-ethylhexy salicylate), e.g., tradename SUNAROME WMO from Felton Worldwide, Inc.;
  • NIPA PABA from NIPA Laboratories Inc.
  • Novantisol e.g., tradename EUSOLEX 232 and NEO-HELIOPAN HYDRO from EM Industries, Inc. and Haarmann & Reimer Corp., respectively;
  • TEA Salicylate triethanolamine salicylate
  • SUNAROME W and SUNAROME G from Felton Worldwide, Inc.
  • L 3-(4-methylbenzlidene)camphor or 3-(4- methylbenzyIidene)boran-2-one, e.g., tradename EUSOLEX 6300 from EM Industries, Inc.; and
  • UVA type sunscreening agents include but are not limited to:
  • Benzophenone-3 (2-hydroxy-4-methoxy- benzophenone), e.g., tradename SPECTRA-SORB UV- 9 and UVINUL M-40 from American Cyanamid Co. and BASF Chemical Co., respectively;
  • Benzophenone-4 (sulisobenzone), e.g., tradename UVINUL MS-40 from BASF Chemical Co.;
  • Benzophenone-8 (dioxybenzone), e.g., tradename SPECTRA-SORB UV-24 from American Cyanamid Co.;
  • Menthyl Anthranilate (Menthyl-O-aminobenzoate), e.g., tradename SUNAROME UVA from Felton Worldwide, Inc.;
  • UVINOL 408 from BASF Chemical Co.
  • Physical sunscreening agents may also be used.
  • red petrolatum in amounts of about 30 to about 99% by weight of the total composition, or titanium dioxide in amounts of about 2 to about 25% by weight of the total composition may be - used.
  • Talc, kaolin, chalk, and precipitated silica may also be used in effective amounts, e.g., about 1% to about 10% by weight of the total composition.
  • Additional sunscreening agents include lawsone (hydroxynaphthoquinone, C10H6O3, the coloring matter of henna leaves) with dihydroxy acetone.
  • At least one UVB type and at least one UVA type sunscreening agent is used.
  • at least one of the following UVB type sunscreening agents can be used: from about 1.5 to about 8.0% by weight of the total composition of octyl dimethyl PABA; octyl para- methoxycinnamate in amounts of about 1.5 to about 7.5% by weight of the total composition; homomenthyl salicylate in amounts of about 4.0 to about 15% by weight of the total composition; and octyl salicylate in amounts of about 3 to about 5% by weight of the total composition.
  • UVA type sunscreening agents can be used: ben ophenone-3 in amounts of about 0.5 to about 6% by weight of the total composition; benzophenone-8 in amounts of about 0.5 to about 3% by weight of the total composition; and menthyl anthran ⁇ ate in amounts of about 3.5 to about 5.0% by weight of the total composition.
  • ben ophenone-3 in amounts of about 0.5 to about 6% by weight of the total composition
  • benzophenone-8 in amounts of about 0.5 to about 3% by weight of the total composition
  • menthyl anthran ⁇ ate in amounts of about 3.5 to about 5.0% by weight of the total composition.
  • Activators or PK-C Activator compositions can be incorporated into formulations such as lotions, creams, gels mousses, waxed based sticks, aerosols, alcohol sticks and the like. These formulations are well known in the art, for example see Balsam, M.S., and Sagrin, E. (Editors) Cosmetics Science and Technology. Second Edition, Volumes 1 and 2, Wiley-lnterscience, a division of John Wiley & Sons, Inc., New York, copyright 1972; and Flick, E.W., Cosmetic and Toiletry Formulations, Noyes Publications, 1984.
  • Emollients may be used in amounts which are effective to prevent or relieve dryness.
  • Useful emollients may include: hydrocarbon oils and waxes; silicone oils; triglyceride esters; acetoglyceride esters; ethoxylated glyceride; alkyl esters; alkenyl esters; fatty acids; fatty alcohols; fatty alcohol ethers; ether- esters; lanolin and derivatives; polyhydric alcohols (polyols) and polyether derivatives; polyhydric alcohol (polyol) esters; wax esters; beeswax derivatives; vegetable waxes; phospholipids; sterols; and amides.
  • typical emollients include mineral oil, especially mineral oils having a viscosity in the range of 50 to 500 SUS, lanolin oil, mink oil, coconut oil, cocoa butter, olive oil, almond oil, macadamia nut oil, aloe extract, jojoba oil, safflower oil, corn oil, liquid lanolin, cottonseed oil, peanut oil, purcellin oil, perhydrosqualene (squalene), caster oil, polybutene, odorless mineral spirits, sweet almond oil, avocado oil, calophyllum oil, ricin oil, vitamin E acetate, olive oil, mineral spirits, cetearyl alcohol (mixture of fatty alcohols consisting predominantly of cetyl and stearyl alcohols), linolenic alcohol, oleyl alcohol, octyl dodecanol, the oil of cereal germs such as the oil of wheat germ cetearyl octanoate (ester of cetearyl alcohol and 2-
  • Fatty acid soaps e.g., potassium stearate, sodium stearate, ammonium stearate, and triethanolamine stearate
  • Polyol fatty acid monoesters containing fatty acid soaps e.g., glycerol monostearate containing either potassium or sodium salt
  • Sulfuric esters sodium salts
  • sodium lauryl sulfate e.g., sodium lauryl sulfate, and sodium cetyl sulfate
  • Polyol fatty acid monoesters containing sulfuric esters e.g., glyceryl monostearate containing sodium lauryl sulfate;
  • polyoxyethylene fatty alcohol ethers e.g., polyoxyethylene lauryl alcohol
  • polyoxypropylene fatty alcohol ethers e.g., propoxylated oleyl alcohol
  • polyoxyethylene fatty acid esters e.g., polyoxyethylene stearate
  • polyoxyethylene sorbitan fatty acid esters e.g , polyoxyethylene sorbitan monostearate
  • sorbitan fatty acid esters e.g., sorbitan monostearate
  • polyoxyethylene glycol fatty acid esters e.g., polyoxyethylene glycol monostearate
  • polyol fatty acid esters e.g., glyceryl monostearate and propylene glycol monostearate
  • ethoxylated lanolin derivatives e.g., ethoxylated lanolins, ethoxylated lanolin alcohols and ethoxylated cholesterol.
  • Surfactants may also be used in the compositions of this invention. Suitable surfactants may include those generally grouped as cleansing agents, emulsifying agents, foam boosters, hydrotropes, solubilizing agents, suspending agents and nonsurfactants (facilitates the dispersion of solids in liquids). The surfactants are usually classified as amphoteric, anionic, cationic and nonionic surfactants. Amphoteric surfactants include acylamino acids and derivatives and N-alkylamino acids.
  • Anionic surfactants include: acylamino acids and salts, such as, acylglutamates, acylpeptides, acylsarcosinates, and acyltaurates; carboxylic acids and salts, such as, alkanoic acids, ester carboxylic acids, and ether carboxylic acids; sulfonic acids and salts, such as, acyl isethionates, alkylaryl sulfonates, alkyl sulfonates, and sulfosuccinates; sulfuric acid esters, such as, alkyl ether sulfates and alkyl sulfates.
  • acylamino acids and salts such as, acylglutamates, acylpeptides, acylsarcosinates, and acyltaurates
  • carboxylic acids and salts such as, alkanoic acids, ester carboxylic acids, and ether carboxylic acids
  • Cationic surfactants include: alkylamines, alkyl imidazolines, ethoxylated amines, and quaternaries (such as, alkylbenzyldimethylammonium salts, alkyl betaines, heterocyclic ammonium salts, and tetra alkylammonium salts).
  • Nonionic surfactants include: alcohols, such as primary alcohols containing 8 to 18 carbon atoms; alkanolamides such as alkanolamine derived amides and ethoxylated amides; amine oxides; esters such as ethoxylated carboxylic acids, ethoxylated glycerides, glycol esters and derivatives, monoglycerides, polyglyceryl.
  • esters polyhydric alcohol esters and ethers, sorbitan/sorbitol esters, and triesters of phosphoric acid; and ethers such as ethoxylated alcohols, ethoxylated lanolin, ethoxylated polysiloxanes, and propoxylated polyoxyethylene ethers.
  • Useful solvents for sunscreening agents include those solvents already disclosed as being useful solvents for the PK-C Activators.
  • Suitable waxes which may prove useful include: animal waxes, such as beeswax, spermaceti, or wool wax (lanolin); plant waxes, such as carnauba or candelilla; mineral waxes, such as montan wax or ozokerite; and petroleum waxes, such as paraffin wax and microcrystalline wax (a high molecular weight petroleum wax).
  • animal waxes such as beeswax, spermaceti, or wool wax (lanolin); plant waxes, such as carnauba or candelilla; mineral waxes, such as montan wax or ozokerite; and petroleum waxes, such as paraffin wax and microcrystalline wax (a high molecular weight petroleum wax).
  • animal waxes such as beeswax, spermaceti, or wool wax (lanolin)
  • plant waxes such as carnauba or candelilla
  • mineral waxes such as montan wax or ozokerite
  • petroleum waxes such as
  • Suitable waxes which may be useful also include the synthetic waxes including polyethylene polyoxyethylene and hydrocarbon waxes derived from carbon monoxide and hydrogen (Fischer-Tropsch synthesis).
  • Representative waxes also include: ceresin; cetyl esters; hydrogenated jojoba oil; hydrogenated jojoba wax; hydrogenated rice bran wax; Japan wax; jojoba butter; jojoba oil; jojoba wax; munk wax; montan acid wax; ouricury wax; rice bran wax; shellac wax; sufurized jojoba oil; synthetic beeswax; synthetic jojoba oils; trihydroxystearin; cetyl alcohol; stearyl alcohol; cocoa butter; fatty acids of lanolin; mono-, di- and triglycerides which are solid at 25°C, e.g., glyceyl tribehenate (a triester of behenic acid and glycerine) and C18-C36 acid triglyceride (a mixture of triesters of C18-C36 carboxylic acids and glycerine) available from Croda, Inc., New York, NY under the tradenames Syncrowax HRC
  • Thickeners which may be used in effective amounts in aqueous systems include: algin; carbomers such as carbomer 934, 934P, 940 and 941 ; cellulose gum; cetearyl alcohol, cocamide DEA, dextrin; gelatin; hydroxyethylcellulose; hydroxypropylcellulose; hydroxypropyl methylcellulose; magnesium aluminum silicate; myristyl alcohol; oat flour; oleamide DEA; oleyl alcohol; PEG-7M; PEG-14M; PEG-90M; stearamide DEA; Stearamide MEA; stearyl alcohol; tragacanth gum; wheat starch; xanthan gum; and the like.
  • carbomers such as carbomer 934, 934P, 940 and 941
  • cellulose gum cetearyl alcohol, cocamide DEA, dextrin
  • gelatin hydroxyethylcellulose; hydroxypropylcellulose; hydroxypropyl methylcellulose
  • magnesium aluminum silicate
  • thickeners which may be used in effective amounts in nonaqueous systems include, aluminum stearates; beeswax; candelilla wax; carnauba; ceresin; cetearyl alcohol; cetyl alcohol; cholesterol; hydrated silica; hydrogenated castor oil; hydrogenated cottonseed oil; hydrogenated soybean oil; hydrogenated tallow glyceride; hydrogenated vegetable oil; hydroxypropyl cellulose; lanolin alcohol; myristyl alcohol; octyldodecyl stearoyl sulfate; oleyl alcohol; ozokerite; microcystalline wax; paraffin; pentaerythrityl tetraoctanoate; polyacrylamide; polybutene; polyethylene; propylene glycol dicaprylate; propylene glycol dipelargonate; stearalkonium
  • Suitable film formers which may be used include: acrylamide/sodium acrylate copolymer; ammonium acrylates copolymer; Balsam Peru; cellulose gum; ethylene/maleic anhydride copolymer; hydroxyethylcellulose; hydroxypropylcellulose; polyacrylamide; polyethylene; polyvinyl alcohol; pvm/MA copolymer (polyvinyl methylether/ maleic anhydride); PVP
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • maleic anhydride copolymer such as PA-18 available from Gulf Science and Technology
  • PVP/hexadecene copolymer such as Ganex V-216 available from GAF Corporation
  • acrylic/acryiate copolymer and the like.
  • film formers can be used in amounts of about
  • Humectants which may be used in effective amounts include: fructose; glucose; glulamic acid; glycerin; honey; maltitol; methyl gluceth-10; methyl gluceth-20; propylene glycol; sodium lactate; sucrose; and the like.
  • Preservatives which may be used in effective amounts include: butylparaben; ethylparaben; imidazolidinyl urea; methylparaben; O-phenylphenol; propylparaben; quatemium-14; quaternium-15; sodium dehydroacetate; zinc pyrithione; and the like.
  • the preservatives are used in amounts effective to prevent or retard microbial growth. Generally, the preservatives are used in amounts of about 0.1% to about 1 % by weight of the total composition with about 0.1% to about 0.8% being preferred and about 0.1% to about 0.5% being most preferred.
  • Perfumes fragment components
  • colorants coloring agents
  • ingredients which may by added or used in amounts effective for their intended use include: biological additives to enhance performance or consumer appeal such as amino acids, proteins, vanilla, aloe extract, bioflavinoids, and the like; buffering agents; chelating agents such as EDTA; emulsion stabilizers; pH adjusters; opacifying agents; and propellants such as butane carbon dioxide, ethane, hydrochlorofluorocarbons 22 and 142b, hydrofluorocarbon 152a, isobutane, isopentane, nitrogen, nitrous oxide, pentane, propane, and the like.
  • biological additives to enhance performance or consumer appeal such as amino acids, proteins, vanilla, aloe extract, bioflavinoids, and the like
  • buffering agents such as chelating agents such as EDTA; emulsion stabilizers; pH adjusters; opacifying agents
  • propellants such as butane carbon dioxide, ethane, hydrochlorofluorocarbons 22 and 142b, hydro
  • ingredients -sunscreening agents, emollients, emulsifiers, surfactants, solvents for sunscreening agents, waxes, thickeners, film formers, humectants, preservatives, surfactants, perfumes, coloring agents, biological additives, buffering agents, chelating agents, emulsion stabilizers, opacifying agents, pH adjusters, and propellants- are all well known to those skilled in the art, and the determination of which ingredients to use to obtain the intended formulations, and the determination of the amounts which may be used to achieve the intended functions and effects of these ingredients are well within the capabilities of those skilled in the art without the need for undue experimentation. Further information may be obtained on these ingredients by reference to:
  • PK-C Activators should not be heated and the PK-C Activators should not be ' subjected to high alkaline conditions. If riboflavin, riboflavin phosphate or mixtures thereof are used it is preferred that these ingredients not be heated nor subjected to high alkaline conditions.
  • Table 1 a typical lotion formulation is listed in Table 1.
  • Emcol RHT (Glyceryl Stearate) 1
  • parts 1 and 2 are heated separately to 180°F. Part 1 is then added to Part 2. The resultant blend is cooled to 120°F and Part 3 is then added.
  • formulations which may prove useful which are oil-in-water creams, oil-in-water lotions, - water-in-oil lotions, oil-in-water resistant creams and lotions, sticks, gels, oils and mousses may be found in, for example, Cosmetics & Toiletries, Vol. 102, pp 117-130, March 1987, the disclosure of which is incorporated herein by reference thereto.
  • formulations which may prove useful which are hand and body lotions, oii-in-water emollient creams, moisturizing lotions, after sun emollient stick, facial spray mist,- skin mousse and moisturizing gel may be found, for example, in Cosmetics & Toiletries, Vol.
  • UV irradiation 3 times weekly (Monday, Wednesday and Friday) from a bank of Kodacel 401 -filtered FS20 lamps.- A total of 9 irradiations was given at approximately 0.8 MED/dose (MED is an abbreviation for "minimal erythermal dose" which is that amount of radiation needed to produce a barely perceptible response).
  • MED is an abbreviation for "minimal erythermal dose" which is that amount of radiation needed to produce a barely perceptible response).
  • Skin samples from the dorsum were stained with either DOPA or Warthin-Starry melanin stains or with Mowry's (acid mucopolysaccharides) or H&E (hematoxylin and eosin) to document irritation in accordance with procedures well known to those skilled in the art (see, for example, Luna, L., Manual of Histologic Staining Methods of the Armed. Forces Institute of Pathology. McGraw-Hill Book Co., New York, 1968).
  • the level of tanning achieved with 1 ,2-Sn- dioctanoylglycerol plus UV was significantly different (i.e., more melanin was measured in the skin sections by image analysis) from that achieved with either UV or 1 ,2-Sn-dioctanoylglycerol alone. H&E and Mowry's staining revealed no irritation to the skin.
  • 1 ,2-sn-Dioctanoylglycerol in acetone was studied at four concentrations, 1.75 ⁇ mole to 3.50 ⁇ mole/dose (0.5, 2.5, 5 and 10 mg/ml), without added UV.
  • Topical applications were made 3 times weekly (Monday, Wednesday and Friday) for 3 weeks to 40 female Skh-2 mice, 10 mice/group, (obtained from Skin and Cancer Hospital, Philadelphia, PA). Evaluation of the histological slides image analysis was followed by statistical analysis of the data. No visible irritation resulted from the 1 ,2-Sn- dioctanoylglycerol applications.
  • the DOPA-stained slides of whole epidermis revealed many highly dendritic melanocytes with nodular areas along the dendrites in the groups treated with the 1 ,2-Sn-dioctanoylglycer
  • the control group epidermis in contrast contained few active melanocytes.
  • the DOPA stain is a sensitive assay of tyrosinase enzyme activity.
  • the Warthin-Stany stain deposits silv on pre-formed melanin. It is, therefore, measuring a different parameter than is measured by the DOPA stain.
  • the treatment w 1 ,2-Sn-dioctanoylglycerol resulted in only minimally enhanced production of melanin, although the treated groups each containe more melanin than did the control group.
  • the Warthin-Starry sta revealed that the increased tyrosinase activity detected by the DOPA stain had not been fully translated into melanin production the time the experiment ended.

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Abstract

Selon un procédé de promotion de la production in vivo de mélamine, on applique topiquement une quantité efficace d'au moins un activateur C de la kinase de protéine à la surface de la peau. Une composition de promotion de la production in vivo de mélamine comprend une quantité efficace d'au moins un activateur C de la kinase de protéine associé à au moins un solvant physiologiquement acceptable. La composition peut contenir facultativement au moins un autre ingrédient sélectionné dans le groupe formé par la riboflavine, le phosphate de riboflavine, des mélanges de riboflavine et de phosphate de riboflavine, des phosphates DOPA, des agents de protection contre la lumière du soleil, des émollients, des émulsifiants, des solvants des agents de protection contre la lumière du soleil, des cires, des épaississants, des agents filmogènes, des humidificateurs, des antioxydants, des agents conservateurs, des agents tensio-actifs, des parfums, des additifs biologiques, des agents de tamponnement, des chélateurs, des stabilisateurs de l'émulsion, des opacifiants, des agents d'ajustement du pH, des propulseurs et des colorants. Les activateurs C de la kinase de protéine présents dans les compositions décrites peuvent être sélectionnés dans le groupe formé des diacylglycérols, des triacylglycérols, des lipopolysaccharides, des acides gras libres insaturés, des acides gras libres saturés à courte chaîne, des glycérolphospholipides, des enzymes qui hydrolysent les glycopholpholipides en diacylglycérols et des bryostatines.
PCT/US1990/006327 1989-11-09 1990-11-07 Activateurs de la kinase de proteine comme promoteurs de la production de melamine WO1991007167A1 (fr)

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EP0533126A1 (fr) * 1991-09-18 1993-03-24 MIVETT NUOVI LABORATORI DI P.G. PAVANI & C. s.n.c. Utilisation de la 1,2-dipalmitoyl-L-alpha phosphatidyl-N,N-diméthyléthanolamine dans des compositions dermatologiques et cosmétiques
WO1994004122A2 (fr) * 1992-08-21 1994-03-03 Trustees Of Boston University Application de diacylglycerols pour accroitre la teneur en melanine des melanocytes
FR2698785A1 (fr) * 1992-12-04 1994-06-10 Thorel Jean Noel Composition régulatrice du système mélanocytaire, préparations pharmaceutiques et cosmétiques incorporant une telle composition.
WO1996009810A1 (fr) * 1994-09-28 1996-04-04 Trustees Of Boston University Procedes permettant d'accroitre la synthese de melanine dans les melanocytes par l'emploi de diacylglycerols, et utilisations de ces procedes

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EP0391431A1 (fr) * 1989-04-07 1990-10-10 Kao Corporation Diacylglycérine et composition cosmétique
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FR2498075A2 (fr) * 1980-01-25 1982-07-23 Oreal Solution stable a l'oxydation d'un acide gras essentiel ou d'un melange de ces acides et compositions cosmetiques la contenant
CA1253807A (fr) * 1985-09-25 1989-05-09 Jacques Valentine Compose topique pour la protection et le traitement de la peau et des cheveux humains
EP0334585A2 (fr) * 1988-03-23 1989-09-27 Unilever Plc Composition cosmétique
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352440A (en) * 1988-03-30 1994-10-04 Trustees Of Boston University Methods for increasing melanin content in melanocytes using diacylglycerols and uses thereof
US5700450A (en) * 1988-03-30 1997-12-23 The Trustees Of Boston University Methods for enhancing melanin synthesis in melanocytes using diacyglycerols and uses thereof
US5750091A (en) * 1988-03-30 1998-05-12 The Trustees Of Boston University Methods for increasing melanin content in melanocytes using diacylglycerols and uses thereof
EP0533126A1 (fr) * 1991-09-18 1993-03-24 MIVETT NUOVI LABORATORI DI P.G. PAVANI & C. s.n.c. Utilisation de la 1,2-dipalmitoyl-L-alpha phosphatidyl-N,N-diméthyléthanolamine dans des compositions dermatologiques et cosmétiques
WO1994004122A2 (fr) * 1992-08-21 1994-03-03 Trustees Of Boston University Application de diacylglycerols pour accroitre la teneur en melanine des melanocytes
WO1994004122A3 (fr) * 1992-08-21 1994-03-31 Univ Boston Application de diacylglycerols pour accroitre la teneur en melanine des melanocytes
FR2698785A1 (fr) * 1992-12-04 1994-06-10 Thorel Jean Noel Composition régulatrice du système mélanocytaire, préparations pharmaceutiques et cosmétiques incorporant une telle composition.
WO1996009810A1 (fr) * 1994-09-28 1996-04-04 Trustees Of Boston University Procedes permettant d'accroitre la synthese de melanine dans les melanocytes par l'emploi de diacylglycerols, et utilisations de ces procedes

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