WO1988008695A1 - Methods for stimulating hair growth - Google Patents

Methods for stimulating hair growth Download PDF

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Publication number
WO1988008695A1
WO1988008695A1 PCT/US1988/001555 US8801555W WO8808695A1 WO 1988008695 A1 WO1988008695 A1 WO 1988008695A1 US 8801555 W US8801555 W US 8801555W WO 8808695 A1 WO8808695 A1 WO 8808695A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
moieties containing
phenylalanyl
valyl
valine
Prior art date
Application number
PCT/US1988/001555
Other languages
English (en)
French (fr)
Inventor
Loren Ralph Pickart
Original Assignee
Procyte Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Procyte Corporation filed Critical Procyte Corporation
Priority to DE3851203T priority Critical patent/DE3851203T2/de
Priority to EP88904835A priority patent/EP0314755B1/en
Publication of WO1988008695A1 publication Critical patent/WO1988008695A1/en
Priority to NO890089A priority patent/NO175616C/no
Priority to DK010389A priority patent/DK10389A/da
Priority to KR89700033A priority patent/KR960014776B1/ko

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Classifications

    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • 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
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/58—Metal complex; Coordination compounds

Definitions

  • the present invention relates to cosmetic compositions and the stimulation of hair growth in general, and more specifically, to the use of derivatives of glycyl-L- histidyl-L-lysine: copper(II) (GHL-Cu) as cosmetic compositions and in the stimulation of hair growth in warm-blooded animals.
  • compositions and methods for stimulating the growth of hair include compositions of vitamins E, B 2 , and B 6 , crude drug extracts, karotin-solubilizing agents, germacides, and scalp-stimulating agents, all alleged to stimulate the growth of hair.
  • the present invention discloses pharmaceutical and cosmetic compositions for use, in part, within a method for stimulating the growth of hair in warm-blooded animals.
  • the method generally comprises administering to the animal a stimulatory amount of a derivative of GHL-Cu having the general formulas wherein R is selected from the group consisting of alkyl moieties containing from one to eighteen carbon atoms, aryl moieties containing from six to twelve carbon atoms, alkoxy moieties containing from one to twelve carbon atoms, and aryloxy moieties containing from six to twelve carbon atoms, or where R is L-prolyl-L-valyl-L-phenylalanyl-L-valine or L-valyl-L-phenylalanyl-L-valine.
  • the alkyl moiety is an unbranched chain, such as an N-octyl moiety. Further, the alkyl moiety may be an N-stearyl moiety or an N-palmityl moiety. Another aspect of the present invention, a method for increasing subcutaneous fat in warm-blooded animals, is disclosed.
  • the method comprises administering to the animal an effective amount of a composition including a derivative of GHL-Cu having the general formula: wherein R is selected from the group consisting of alkyl moieties containing from one to eighteen carbon atoms, aryl moieties containing from six to twelve carbon atoms, alkoxy moieties containing from one to twelve carbon atoms, and aryloxy moieties containing from six to twelve carbon atoms, or where R is L-prolyl-L-valyl-L-phenylalanyl-L- valine or L-valyl-L-phenylalanyl-L-valine.
  • a method for increasing the density of hair follicles in warm-blooded animals comprises administering to the animal an effective amount of a composition comprising a derivative of GHL-Cu having the general formula: wherein R is selected from the group consisting of alkyl moieties containing from one to eighteen carbon atoms, aryl moieties containing from six to twelve carbon atoms, alkoxy moieties containing from one to twelve carbon atoms, and aryloxy moieties containing from six to twelve carbon atoms, or where R is L-prolyl-L-valyl-L-phenylalanyl-L-valine or L-valyl-L-phenylalanyl-L-valine.
  • glycine may be replaced by a variety of other small amino acids, including alanine, serine and valine.
  • the copper (II) binding affinity of the molecule could be increased by addition of an N-terminal amino acid such as glycine to convert glycyl-L-histidyl-L-lysine to glycyl-L-glycyl-L-histidyl-L-lysine.
  • glycine cou.ld be added to a derivative as described above to create the corresponding tetrapeptide.
  • compositions described herein may be injected intradermally or applied topically, and are rendered suitable for administration to warm-blooded animals for the purposes of the present invention by combining the deriva tive with a vehicle which adapts the composition for either intradermal injection or topical application to a warmblooded animal.
  • Suitable vehicles include physiological saline.
  • Figures 1 and 2 are photographs illustrating the stimulation of hair growth through the use of a representative derivative of the present invention.
  • Figure 3 is a microphotograph of a biopsy section taken through an area of enhanced hair growth. The photograph illustrates an increase in the density of hair follicles embedded in a heavy field of large, subcutaneous fat cells, as shown toward the right side of the figure.
  • Figure 4A is a photograph illustrating the stimulation of hair growth through the use of another representative derivative of the present invention.
  • Figure 4B is a microphotograph of a biopsy section taken through an area of enhanced hair growth, generated by the derivative of Figure 4A. The photograph illustrates an increase in the density of hair follicles within the subcutaneous fat cell layer in the area near the injection site.
  • Figure 5 is a microphotograph of a control area (bottom) and an area of increased subcutaneous fat cells and hair follicle density (top) generated through use of a representative derivative of the present invention.
  • Figure 6 is a photograph illustrating the stimulation of hair growth around a surgical defect utilizing a derivative of the present invention.
  • Figure 7 is a photograph illustrating enhanced hair growth surrounding a healing wound in a horse. Best Mode for Carrying Out the Invention
  • GHL-Cu various derivatives of GHL-Cu may be used to stimulate the growth of hair in warmblooded animals.
  • these derivatives can be tailored to increase their fat solubility, resulting in a form of the molecule which is more useful in a formulation of pharmaceutical and cosmetic creams and gels.
  • the derivatives of the present invention are described in detail in pending U.S. Patent Application No. 040,460 and U.S. Patent No. 4,665,054, which documents are hereby incorporated by reference.
  • the derivatives of the present invention may be prepared by esterification, by the removal of a water molecule, or by the addition of a group (either an alcohol such as octanol, methanol, benzol alcohol or NH 3 ) to the carboxylic acid terminus of GHL, resulting in the formation of the more lipophilic derivative.
  • a group either an alcohol such as octanol, methanol, benzol alcohol or NH 3
  • reaction is most readily carried out by adding the R group to the amino acid lysine prior to the combination of lysine with the other two amino acids to GHL.
  • the copper (II) is chelated to the molecule to form the bioactive complex.
  • the overall reaction to form the more lipophilic derivatives of GHL-Cu may be characterized:
  • L-histidine-L-lysine-R 3 blocked L-histidine-L-lysine-R + blocked-glycine -----> blocked glycyl-L-histidine-L-lysine-R 4) blocked glycyl-L-histidine-L-lysine-R -----> glycyl-L-histidine-L-lysine-R
  • GHL and copper are present in a 1:1 or 2:1 ratio.
  • the derivatives of the present invention are useful in stimulating the growth of hair in warm-blooded animals. While one of the characteristics associated with male pattern baldness is the severe diminution of hair follicles, use of the derivatives as described herein results in increased adipocyte formation, which is spatially and temporally linked with hair follicle formation, and is an integral phase of hair follicle formation (Hausman- et al., Am. J. Anat. 161: 85-100, 1981). The results of the use of the derivatives as described herein are illustrated, in part, in Figures 3, 4B and 5, which, are microphotographs of areas of enhanced hair growth.
  • the derivatives of the present invention have clinical use in at least four primary areas: (1) the direct stimulation of hair growth in persons with hair loss, (2) the stimulation of hair transplants, (3) increasing the subcutaneous fat content, and (4) in general cosmetic applications.
  • the derivatives described herein intradermally in the center of the area to be treated, along with a suitable vehicle in a concentration of approximately 50 micrograms of derivative per .1 ml of vehicle. It is preferable to use a dosage of approximately 9 micro grams per cm 2 of area to be treated, although dosages greater than 9 micrograms/cm 2 , up to approximately 40 micrograms/cm 2 , may be used.
  • Suitable vehicles in this regard include saline.
  • a suitable penetrating agent such as DMSO
  • the composition may further contain a moistening agent, softening agent, perfume or colorant.
  • Example I illustrates the synthesis of glycyl-L-histidyl-L-lysine benzyl ester: copper(II).
  • Example II demonstrates the syunthesis of glycyl-L-histidyl-L-lysine n-octyl ester: copper(II).
  • Example III illustrates (A) the synthesis of glycyl-L-histidyl-L-lysine n-stearyl ester: copper(II), and (B) its synthesis by an alternative procedure.
  • Example IV illustrates the synthesis of glycyl-L-histidyl-L-lysyl-L-prolyl-L-valyl-L-phenylalanyl-L-valine: copper (II) and glycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine: copper (II).
  • Examples V, VI and VII illustrate the hair growth stimulating activity of preferred derivatives of the present invention.
  • Example VIII demonstrates the stimulation of hair growth around healing wounds in warm-blooded animals.
  • Chemicals and peptide intermediates utilized in the following examples may be purchased from the following suppliers: Sigma Chemical Co.
  • N a -t-butyloxycarbonyl-N im -benzyloxycarbonyl-L-histidyl-N e -benzyloxycarbony1-L-lysine benzyl ester was crystallized from solution.
  • the N-terminal group of the blocked dipeptide was removed by stirring in 50% trifluoroacetic acid in dichloromethane for 30 minutes, then vacuum evaporated.
  • N im -benzyloxycarbony1-L-histidyl-N e -benzoylcarbony1-L-lysine benzyl ester was coupled to benzyloxycarbonylglycine with dicyclohexylcarbodiimide as a coupling agent.
  • Blocking groups were removed by catalytic hydrogenation using 10% palladium on carbon in glacial acetic acid.
  • the glycyl-L-histidyl-L-lysine benzyl ester was dissolved in water with equimolar copper acetate added. The pH was raised to neutrality with sodium hydroxide. The solution was centrifuged at 20,000 ⁇ g for 1 hour at 3°C to remove poorly water-soluble material. The supernatant was lyophilized to obtain glycyl-L-histidyl-L-lysine benzyl ester: copper (II).
  • n-octyl N im -benzyloxycarbonyl-L-histidyl-N e -benzyloxycarbonyl-L-lysinate was dissolved in tetrahydrofuran, and isobutyl chloroformate, N-methylmorpholine and benzyloxycarbonylglycine were added to form n-octyl benzyloxycarbonylglycyl-N im -benzyloxycarbony1-L-histidyl-N e -benzyloxycarbonyl-L-lysinate.
  • the product was dissolved in 50% trifluoroacetic acid in dichloromethane for 30 minutes, then evaporated, forming n-stearyl N im -benzyloxycarbonyl-L-histidyl-N e -benzyloxycarbonyl-L-lysinate, which was dissolved in tetrahydrofuran, isobutyl chloroformate, N-methylmorpholine and benzyloxycarbonylglycine to form n-stearyl benzyloxycarbonylglycyl-N im -benzyloxycarbonyl-L-histidyl-N e -benzyloxycarbonyl-L-lysinate.
  • the product was dissolved in 50% trifluoroacetic acid in dichloromethane for 30 minutes, then evaporated, forming n-stearyl ester glycyl-L-histidyl- L-lysine.
  • the resultant molecule glycyl-L-histidyl-L-lysine n-stearyl ester, was converted to the copper complex by the addition of an equimolar quantity of copper diacetate.
  • the pH was raised to neutrality with sodium hydroxide to obtain a product useful for animal studies.
  • n-palmityl alcohol for the n-stearyl alcohol, glycyl-L-histidyl-L-lysine n-palmityl ester may be similarly synthesized.
  • N( ⁇ )-benzyloxycarbonyl-L-lysine, n-stearyl alcohol, p-toluenesulfonic acid monohydrate, and benzene are refluxed together using a Dean-Stark trap to azeotropically remove the evolved water.
  • n-stearyl N( ⁇ )-benzyloxycarbonyl-L-lysinate p-toluenesulfonate salt is collected by filtration, treated with 2 M aqueous potassium bicarbonate solution, and extracted into dichloromethane.
  • Evaporation gives the partially deblocked dipeptide, which is redissolved in dry THF and added to a stirring solution of benzyloxycarbonyl glycine, N-methylmorpholine and isobutyl chloroformate in dry THF at -15°C.
  • the formed, fully protected tripeptide fester is totally deblocked by treatment with hydrogen gas in glacial acetic acid at room temperature in the presence of Pd-C catalyst. Filtration, evaporation and purification on a microcrystalline cellulose column followed by lyophilization give the desired tripeptide ester as its triacetate salt.
  • the resultant molecule glycyl-L-histidyl-L-lysine n-stearyl ester, was converted to the copper-complex by the addition of an equimolar quantity of copper diacetate.
  • the pH was raised to neutrality with sodium hydroxide to obtain a product useful for animal studies.
  • n-palmityl alcohol for the n-stearyl alcohol, glycyl-L-histidyl-L-lysine n-palmityl ester may be similarly synthesized.
  • peptides are synthesized by standard solid- phase methods common to the peptide field (J. Stewart and J. Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., 1984). Briefly stated, Boc-Val-O-Resin was sequentially coupled with other blocked amino acids using dicyclohexylcarbodiimide as a reaction agent. Protected amino acids, resins for solid-phase synthesis, and coupling agents were obtained from Peninsula Laboratories, San Carlos, California. Blocked amino acids are added in sequential order to obtain the desired peptide. The final peptide is deblocked using hydrogen fluoride. The final peptide is dissolved in 0.5% acetic acid and purified by passage through a Sephadex G-15 column (Pharmacia).
  • A. Stimulation of hair growth in normal skin In order to demonstrate the stimulation of hair growth in warm-blooded animals, the backs of mice were shaved on day 1 using an electric shaver. Subsequently, a single dose of 50 micrograms of glycyl-L-histidyl-L-lysine n-octyl ester: Cu(II) was infiltrated under the skin in eight mice. As shown in Figure 1, by day 7 there was a markedly accelerated growth of hair around the injection area in all of the mice.
  • mice were shaved and injected once with Glycyl-L-Histidyl-L-Lysine Octyl Ester :Copper (II) at a dose of 500 micrograms per mouse.
  • Figure 2 shows that there was a significant acceleration of hair growth within 2-3 weeks following the injection. Mice injected with saline did not show an acceleration.
  • FIG. 4B shows that there was a marked proliferation of hair shaft units which appeared within the subcutaneous fat layer of the area of accelerated hair growth. Examination of the skin distant from the injection site showed a normal histology.
  • the photomicrograph demonstrates the large number of developing hair follicles within the subcutaneous fat layer, similar to that seen following the Glycyl-L-EIistidyl-L-Lysine Decyl Ester: Cu injection.
  • Re-establishment of hair growth is a normal part of healing.
  • the compositions described herein may be used to stimulate the growth of hair around a surgical defect.
  • a 1.2 cm diameter full thickness defect was created on the backs of mice.
  • the defect was treated with a solution containing Glycyl-L-Histidyl-L-Lysine Octyl Ester:Copper (II).
  • II Glycyl-L-Histidyl-L-Lysine Octyl Ester:Copper
  • Treatment of a healing wound with Glycyl-L- Histidyl-L-Lysine:Copper (II) also causes an acceleration of hair growth.
  • a horse with a deep, ulcerating wound was treated with a topical cream containing 0.4% Glycyl-L-Histidyl-L-Lysine:Copper (II) to accelerate the healing process.
  • the hair surrounding the wound was clipped to aid in cleansing the area. Treatment with the cream occurred every day until the wound was closing, followed by less frequent application. After 5 weeks, the wound was almost totally healed with only a small residual scab. As shown in Figure 7, there was a significant acceleration of hair growth surrounding the treated area when compared with the untreated areas.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Cosmetics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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PCT/US1988/001555 1987-05-11 1988-05-11 Methods for stimulating hair growth WO1988008695A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE3851203T DE3851203T2 (de) 1987-05-11 1988-05-11 Gebrauch von GHL-Cu Derivaten für die Herstellung eines Medikaments zur Stimulierung des Haarwachstums.
EP88904835A EP0314755B1 (en) 1987-05-11 1988-05-11 Use of derivatives of GHL-Cu for the manufacture of a medicament for stimulating hair growth
NO890089A NO175616C (no) 1987-05-11 1989-01-10 Blanding for stimulering av hårvekst
DK010389A DK10389A (da) 1987-05-11 1989-01-11 Fremgangsmaade til stimulering af haarvaekst
KR89700033A KR960014776B1 (en) 1987-05-11 1989-01-11 Composition for stimulating hair growth

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4844487A 1987-05-11 1987-05-11
US048,444 1987-05-11

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WO1988008695A1 true WO1988008695A1 (en) 1988-11-17

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PCT/US1988/001555 WO1988008695A1 (en) 1987-05-11 1988-05-11 Methods for stimulating hair growth

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US (1) US5135913A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
EP (1) EP0314755B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (2) JP2604457B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
KR (1) KR960014776B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AT (1) ATE110255T1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
CA (1) CA1323839C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DE (1) DE3851203T2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DK (1) DK10389A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
MX (1) MX169205B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
NO (1) NO175616C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1988008695A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

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GR890100404A (el) * 1988-06-16 1990-05-11 Procyte Corp Καλλυντικες συνθεσεις και συνθεσεις περιποιησεων του δερματος
WO1991007431A1 (en) * 1989-11-13 1991-05-30 Procyte Corporation Metal-peptide compositions and methods for stimulating hair growth
WO1991014437A3 (en) * 1990-03-26 1991-11-28 Procyte Corp Use of copper(ii) containing compounds to accelerate wound healing
US5118665A (en) * 1990-02-09 1992-06-02 Procyte Corporation Anti-oxidative and anti-inflammatory metal:peptide complexes and uses thereof
US5252559A (en) * 1991-08-20 1993-10-12 The Procter & Gamble Company His-Gly-Gly peptide and derivatives thereof for hair growth
US5382431A (en) * 1992-09-29 1995-01-17 Skin Biology, Inc. Tissue protective and regenerative compositions
WO1995035085A1 (en) * 1994-06-17 1995-12-28 Procyte Corporation Stimulation of hair growth by peptide-copper complexes
FR2733421A1 (fr) * 1995-04-28 1996-10-31 Oreal Utilisation de derives de l'hormone stimulatrice des melanocytes de type alpha pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
US5858993A (en) * 1994-03-28 1999-01-12 Skin Biology, Inc. Starch-metal complexes for skin and hair
US5888522A (en) * 1996-08-23 1999-03-30 Skin Biology, Inc. Tissue protective and regenerative compositions
US6001812A (en) * 1995-04-28 1999-12-14 Societe L'oreal S.A. Modulating body/cranial hair growth with derivatives of the α-type melanocyte-stimulating hormone

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US5425954A (en) * 1993-09-30 1995-06-20 Curafas Incorporated Topical amino acid - vitamin complex compositions for pharmaceutical and cosmetic use
US5735212A (en) * 1994-08-09 1998-04-07 Baldwin-Japan Ltd. Cylinder cleaning apparatus
US5614489A (en) * 1995-05-25 1997-03-25 Mohammadi; Fatemeh Method and composition for treating the skin
US5866142A (en) * 1995-07-20 1999-02-02 Riordan; Neil H. Skin treatment system
US6267957B1 (en) 1998-01-20 2001-07-31 Howard Green Attaching agents to tissue with transglutaminase and a transglutaminase substrate
US6919076B1 (en) 1998-01-20 2005-07-19 Pericor Science, Inc. Conjugates of agents and transglutaminase substrate linking molecules
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EP1220870B1 (en) 1999-10-01 2012-04-11 DMI Biosciences, Inc. Metal-binding compounds and uses therefor
US20030130185A1 (en) * 2000-09-29 2003-07-10 David Bar-Or Metal-binding compounds and uses therefor
US7632803B2 (en) 1999-10-01 2009-12-15 Dmi Life Sciences, Inc. Metal-binding compounds and uses therefor
US7592304B2 (en) 1999-10-01 2009-09-22 Dmi Life Sciences, Inc. Metal-binding compounds and uses therefor
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US20030166510A1 (en) * 2000-10-11 2003-09-04 Pickart Loren R. Methods and compositions for increasing skin remodeling
FR2826580B1 (fr) * 2001-06-29 2005-09-30 Oreal Utilisation du tripeptide lys-pro-val (kpv) pour favoriser le renouvellement epidermique et la micro-cicatrisation cutanee superficielle et/ou ameliorer l'aspect esthetique des plaies et cicatrices
FR2826581B1 (fr) * 2001-06-29 2005-10-07 Oreal Utilisation du tripeptide lys-pro-val (kpv) dans le traitement des melanomes
KR20050033510A (ko) * 2001-10-05 2005-04-12 프로사이트 코포레이션 피부의 색소 과다 침착의 치료방법
WO2003030860A1 (en) * 2001-10-05 2003-04-17 Procyte Corporation Skin care compositions containing peptide copper complexes and retinol, retinol derivatives, or a mixture thereof
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KR20050059003A (ko) * 2002-07-02 2005-06-17 프로사이트 코포레이션 펩티드 구리 착화합물 및 연조직 충전제를 함유하는조성물
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NO890089D0 (no) 1989-01-10
CA1323839C (en) 1993-11-02
JPH09278631A (ja) 1997-10-28
KR960014776B1 (en) 1996-10-19
ATE110255T1 (de) 1994-09-15
DK10389D0 (da) 1989-01-11
AU609819B2 (en) 1991-05-09
US5135913A (en) 1992-08-04
NO175616B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1994-08-01
DK10389A (da) 1989-01-11
DE3851203D1 (de) 1994-09-29
EP0314755B1 (en) 1994-08-24
EP0314755A1 (en) 1989-05-10
KR890701079A (ko) 1989-12-19
DE3851203T2 (de) 1994-12-15
MX169205B (es) 1993-06-24
JPH02500367A (ja) 1990-02-08
JP2604457B2 (ja) 1997-04-30
NO175616C (no) 1994-11-09
JP2988876B2 (ja) 1999-12-13
NO890089L (no) 1989-01-10
AU1729688A (en) 1988-12-06

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