WO1990006102A1 - Compound and method for the retardation of collagen cross-linking - Google Patents

Compound and method for the retardation of collagen cross-linking Download PDF

Info

Publication number
WO1990006102A1
WO1990006102A1 PCT/AU1989/000422 AU8900422W WO9006102A1 WO 1990006102 A1 WO1990006102 A1 WO 1990006102A1 AU 8900422 W AU8900422 W AU 8900422W WO 9006102 A1 WO9006102 A1 WO 9006102A1
Authority
WO
WIPO (PCT)
Prior art keywords
method
camosine
skin
active compound
composition
Prior art date
Application number
PCT/AU1989/000422
Other languages
French (fr)
Inventor
Geoffrey Walter Grigg
Gary Noel Hannan
Original Assignee
Peptide Technology Limited
Commonwealth Scientific And Industrial Research Organisation
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
Priority to AUPJ0675 priority Critical
Priority to AUPJ067588 priority
Application filed by Peptide Technology Limited, Commonwealth Scientific And Industrial Research Organisation filed Critical Peptide Technology Limited
Publication of WO1990006102A1 publication Critical patent/WO1990006102A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4151,2-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/04Sulfur, selenium or tellurium; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/64Proteins; Peptides; Derivatives or degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52Stabilizers
    • A61K2800/522Antioxidants; Radical scavengers

Abstract

The present invention provides a method for reducing or preventing collagen cross-linking in skin and/or damage to skin cell DNA. The method comprises treating the skin with a composition including an antioxidant compound. The antioxidant compound is selected from the group consisting of carnosine, homocarnosine, anserine, 3-methyl-L-histidine, L-alanyl-L-tyrosine, acyl homocarnosine, acetyl carnosine, iodo carnosine, di-iodo carnosine, anserine nitrate, carbenoxylone carnosine, analogues thereof and combinations thereof. The antioxidant compounds of choice are carnosine and homocarnasine with preference for carnosine.

Description

"COMPOUND AND METHOD FOR THE RETARDATION OF COLLAGEN

CROSS-LINKING"

Field of the Invention

The present invention relates to a method for reducing or preventing collagen cross-linking in skin and/or damage to skin cell DNA. In particular the present invention relates to the use of specific dipeptides and analogues thereof which have the capability of decreasing or preventing collagen cross-linking either during aging and/or following exposure to UV radiation. The method of the present invention is also applicable for decreasing DNA damage due to UV radiation. Background of the Invention

Oxidative stress and tissue damage by active oxygen species has been suggested as the basis for a number of diseases including cancer and aging (Halliwell and Gutteridge, 1985; Harman, 1987; Saul et al, 1987).

The levels and formation of highly reactive free radicals are known to be enhanced by ultraviolet radiation. Such reactive species can subsequently react with DNA, RNA, proteins and lipids. Natural defence mechanisms to such reactive and potentially damaging species are believed to exist and numerous molecules with anti-oxidant properties have been identified in tissues (eg vitamin E, camosine and ascorbic acid) . However, the physiological role of camosine and its analogues in vivo remains unclear.

Other roles suggested for camosine, in addition to being an efficient singlet-oxygen scavenger, include neutralization of lactic acid (Davey, I960), a copper chelator (Brown, 1981), an activator of myosin ATPase (Parker and Ring 1980) and a regulator of enzymes (Ikeda et al 1980) .

During the aging of mammalian skin the quantity of mature collagen cross-links increases, whereas the number of immature, reducible cross-links decreases (Ames, 1983). Although the nature of cross-links in other tissues (eg. tendon) may differ, the same general trend exists (Ames, 1983; Rattan et al, 1982). The rates of change in the amounts of cross-links for various species appears to reflect the differences in life span for the different species. For instance, the amount of one mature cross-link HHL (histidinohydroxylysinonorleucine) rises in a linear fashion in human skin up to age 40 years whereas in bovine skin the amount of HHL plateaus at 4 years (Kohen et al, 1988) . Cross-links arise from precursor lysine (Vizioli et al, 1983) or hydroxylysine (Boldyrev et al 1987) residues in collagen chains which are oxidatively deaminated. The aldehydes produced then condense with with similar residues to give aldols or with adjacent lysine or hydroxylysine residues to give Schiff-based compounds. The degree of cross-links in collagen also increases on UV irradiation. Thus there is a correlation between the rate of collagen cross-links and the rate of aging of skin and possibly other tissues. Summary of the Invention

The present invention consists in a method for reducing or preventing collagen cross-linking in skin and/or damage to skin cell DNA comprising treating the skin with a composition comprising a suitable excipient in combination with an active compound, the active compound being selected from the group consisting of camosine, homocamosine, anserine, 3-methyl-L-histidine, L-alanyl-L-tyrosine, acyl homoca osine, acetyl camosine, iodo camosine, di-iodo ca osine, anserine nitrate carbenoxylone camosine, analogs thereof and mixtures of two or more of the foregoing.

In a preferred embodiment of the present the active compound is a naturally occurring (e.g. found in human tissue) anti-oxidant compound such as carnosine (/2-alanyl-L-histidine) .

At present it is preferred that the active compound is camosine or homocamosine on a combination thereof and most preferably camosine. In a further preferred embodiment of the present invention the active compound is linked to another molecule, which molecule is such that the composition is improved in regard to skin permeation, skin application and tissue absorption. It is preferred that this other molecule is an amino acid or peptide.

The method of the present invention will generally involve topical application of the composition to the skin, however, the composition may be injected subcutaneously or intramuscularly or may be taken orally. The concentration of the active compound in the composition will depend upon the route of administration and may be at the direction of a physician, however, it is expected that the concentration of the active compound would be in the range of 1 to 100 mg per ml of a skin cream formulation for instance, the preferred range would be from 3 to 20 mg/ml.

It is believed the method of the present invention will reduce aging of the skin by decreasing or preventing collagen cross-linking due to exposure to UV radiation or sunlight. Given that the method is also capable of preventing DNA damage as a result of UV radiation, the method of the present invention has applicability in the prevention of skin cancer.

The composition according to the present invention may include, in addition to the active peptide molecules discussed above, a non-peptide compound which can inhibit or prevent cross-linking of collagen. Such compounds which may be advantageously included in the present composition include bilirubin, carotenoids, mannitol, reduced glutathione, selenium, uric acid, vitamin A, vitamin C and Vitamin E.

Detailed Description of the Invention

In order that the nature of the present invention may be more clearly understood, preferred forms thereof will now be described with reference to the following examples. Example 1 Mouse Skin Experiments

An example of the collagen cross-linking inhibitory activity of camosine is shown in Table 2 and the effects of UV irradiation on total reducible species in mouse skin in Table 1.

L-carnosine is available from the Sigma Chemical

Company or BDH Chemicals Ltd. Poole, England. ChromAr

HPLC grade acetonitrile was obtained through Mallinkrodt Australia Pty. Ltd. and all solvents were filtered and

3 degassed before us. KB(H )4 was purchased from CEA

France, through the Australian Atomic Energy Commission, with a specific activity of 50-70 Ci/mmol.

Dermal fibroblasts were cultured from primary explants of tissue derived from Swiss mice. The cells were maintained throughout in Dulbecco's Modified Eagles Medium (Gibco) and supplemented with 10% foetal bovine serum (Cytosystems Pty. Ltd.) and used between second and third passages. Skin sections were also obtained from neonatal Swiss mice. Sections were trimmed of as much subcutaneous material as possible and rinsed briefly in phosphate-buffered saline before following experimental procedure. All samples were incubated in varying concentrations of L-carnosine in phosphate-buffered saline (PBS) for 1 hour at 37°C prior to UV treatment. Prior to reduction with borohydride, samples were washed extensively in PBS at 40°C to remove as much as possible of contaminating protein, glycoprotein and glycosamino glycans with minimal disruption of the collagen structure. Both skin sections and open dishes of dermal fibroblasts were exposed for three hours at 920 uW/cm using a 24 watt germicidal ultraviolet lamp. Samples were kept moist through the UV treatment.

3 Reduction with KB(H ) . was carried out at room temperature in the same PBS buffer for 1 hour in the ratio of 100:1 wet weight of sample/borohydride. The reaction was stopped by the addition of 4M acetic acid to lower pH to 3.00. Samples were then dialysed against distilled water at 4 C until free of soluble radioactivity. Samples were hydrolyzed in Sequanal grade 6N hydrochloric acid under nitrogen for 22 hours at 110°. Each sample was then rotary evaporated to dryness twice from distilled water before being taken up in distilled water. Hydrolysates were neutralized with 0.5M NaOH before HPLC. HPLC was performed on a Pharmacia HPLC/FPLC system comprising a P3500 HPLC pump, LCC500 programmer, and using a heated column compartment.

Initial separations were performed on a Brownlees 25 cm x 0.46 cm Amino-Spheri 5 column at a temperature of 35°C and an eluent flow rate of 1.0 ml/minute. Column life was considerably lengthened by the use of a Brownlee 4.6 x 30 mm Amino-Spheri 5 pre-column guard cartridge, and a Brownlee 15 x 32 mm Anion Newguard in the solvent line. Brownlee columns were supplied through Activon Scientific Products Co Pty. Ltd. Australia.

The gradient system comprised two solvents. Solvent A contained 10 mM-potassium phosphate buffer, pH 4.3, and solvent B contained HPLC-grade acetonitrile diluted 50:7 (v/v) with water. A ino acids could be separated by using a gradient programme similar to that of the prior art, but the programme was modified for separation of reduced collagen components.

Programme 1 was as follows: 1.95% solvent B for 5 min; 2, linear gradient 95% - 70% solvent B over 15 in; 3, linear gradient 70% - 50% solvent B over 15 min; 4, 50% solvent B for 10 min; 5, linear gradient 50% - 95% solvent -B over 5 min.

Fractions of volume 0.5 ml were collected directly into 20 ml scintillation vials and 5.0 ml of Amersham PCSII high-efficiency phase combining scintillant was added. Counting was done in an LKB 1215 Rack beta II instrument.

TOTAL REDUCIBLE SPECIES IN YOUNG MOUSE SKIN

TABLE 1

Tissue U.V. Treatment Total (3H) CPM

Skin section Skin (exterior) 10000 Skin (exteror) 24000 Skin (interior) 11000 Skin (interior) 27000 Skin cells Fibroblasts 19000 Fibroblasts 38000

2mg samples were treated with normal light or U.V. light for 2.5 hours then reduced with KB(3H)4 and hydrolyzed prior to HPLC.

Figure imgf000009_0001

Samples were treated as in Table 1 with or without protection by camosine solution. Example 2

Dermal Fibroblasts Experiments

Primary cultures of mouse dermal fibroblasts (MDF) were isolated from new born mouse skin and were serially passaged in DMEM medium with high glucose plus 10% foetal calf serum for no more than four passages before experimentation. Prior to UV exposure, cell layers were washed with 50 mis of PBS to remove all traces of growth medium. The MDF were then incubated with 25 is of PBS with or without 10 mM camosine for 1 hour at 37°C. All the procedures were carried out with minimum exposure to outside light.

At the end of the incubation period the replicate cell populations were exposed to 0,2,4 or 6 minutes of UV A light. Following irradiation the cell monolayers were scraped and transferred to centrifuge tubes containing

PBS. After centrifugation the supernatant was removed and the cell pellets resuspended in 30 mis of PBS. All samples were then washed for 3 days at 4 C. The PBS changed twice daily.

3 The samples were then reduced with KB[ H]. and acid hydrolysed. The hydrosylates were rotary evaporated, neutralised and lyophilised before HPLC analysis

(Smolensk! et al, 1983 Biochem J., 213_, 525-532). HPLC fractions of 0.5 mis were collected directly into 20ml scintilation vials and 5ml of Amersham PCS II high efficiency phase combining scintillant added. Counting was carried out in a LKB 1215 Rack Beta II. The results of these Experiments are shown in Figures 1-6. Mouse dermal fibroblasts were scraped and washed in PBS. The isolated cell suspension was then processed for HPLC using the methods described.

The profile shown in Figure 1 is a representation of a typical non ultraviolet irradiated sample (CONTROL) . The fractions in region 40 to 90 consist of isolated reducible collagen crosslinks. The difference in peax height is indicative of the amount of a particular type of crosslinking amino acid complex present in the sample.

The profile shown in Figure 2 depicts the alteration in isolated crosslinks after a 2 minute exposure to UV A light. The major peak at fraction no. 55 has disappeared and there has been a positional shift of the peak at fraction. 83 to 87.

It is speculated that these differences represent modifications of the crosslinking amino acid complexes due to interaction of free radicals generated by the action of UV on water molecules.

As shown in Figure 3 after 4 minutes exposure to UV A light the profile of reducible crosslinks is showing a large increase in crosslinking amino acid complexes in the region from fraction 55 to 75.

As shown in Figure 4, after 6 minutes of UV A exposure there is a marked change in the content of reducible crosslinking amino acid complexes present in fractions 55 to 75. This probably results from modifications of the less complex crosslinks leading to an accumulation in fractions 55 to 75 and possibly the formation of entirely new crosslinks due to the interaction of free radicals. Figure 5 shows the results obtained when mouse dermal fibroblasts are exposed for 6 minutes to UV A in the presence of 10 mM camosine. As can be seen there is a marked difference in the profile of isolated crosslinks in comparison to that shown in Figure 4. Figure 6 shows a comparison of profiles produced when MDF cells were exposed to 2 minutes UV A or to 6 minutes UV A but in the presence of 10 mM ca osine. It is obvious from this overlay of profiles that camosine has protected the MDF cells from the effects of UV A as seen by the decrease in peaks from fractions 55-75. Summary

When 10 mM camosine is present in the bathing solution over MDF during exposure to UV A there is a 70% reduction in the formation of altered reducible crosslinks produced. This is exemplified by the appearance of the HPLC profile i.e. the 6 minute UV A exposure + 10 mM camosine profile resembles that of the 2 minute UV A exposure profile. Example 3 Human Fibroblasts (MRC-5) with UV A Light Experiments The human lung fibroblast cell strain (MRC-5) was used to examine the degree of protection camosine would give to human collagen when exposed to UV A light.

Fibroblasts are responsible for the maintenance of connective tissue in animals. They actively secrete collagen propeptides into the interstitial spaces, a proportion of which are deposited into the extracellular matrix as connective tissue collagen.

A similar protocol to that used for the MDF cells was employed in these experiments, however, the UV A exposure time was increased to 15 minutes. This was done to increase the collagen crosslinking changes that had been evident with the 6 minute UV A exposure of MDF cells. The results of these experiments are shown in Figures 7-10. In Figure 7, populations of MRC-5 at similar cell numbers to that of MDF were scraped and processed for HPLC. These cells were not treated with UV A i.e. - CONTROL - the profile was similar to that produced by the MDF cells but there were differences. The major collagen crosslinking peaks were in the region from fractions 40-90. Figure 8 shows the HPLC profile obtained when MRC-5 cells were exposed to 15 minutes UV A light in the presence of 10 mM camosine. The profile is similar to that of the control (Fig. 7) and very different from the 15 minute UV A exposure in the absence of camosine ( Fig . 9 ) .

Figure 9 shows the profile produced when MRC-5 cells were exposed to 15 minures UV A light. The region from fractions 40 through 90 are extensively increased indicating a putative incorporation of newly produced crosslinking complexes into the cellular collagen.

Figure 10 shows an overlay of HPLC profiles isolated from the MRC-5 control and from the MRC-5 after 15 minutes exposure to UV A in the presence of 10 mM camosine. Again, there is a great deal of similarity between the two profiles indicating that camosine is protecting the collagen from free radical attack. Summary

The results from these experiments also supports the premise that camosine protects collagen against UV A induced crosslinking. This is shown by the remarkable similarity between the MRC-5 control HPLC profile and that of the MRC-5 cells that have been exposed to 15 minutes UV A in the presence of camosine. Also, the marked changes in the profile obtained from the MRC-5 cells that had UV A exposure but no camosine present would indicate that camosine is extremely effective in its protection of collagen against crosslinking. These experiments which had a 150% increase in UV A exposure time still demonstrated a greater than 70% protection with 10 mM camosine. Example 4 Rat Tail Tendon Experiments

Isometric melting has been widely used to determine a number of age related changes in collagen (Mitchell and Rigby, 1975 BBA, 3!93, 531-541). Robins and Bailey (1975 Biochem J., 149, 381-385) have proposed that the density of collagen crosslinks is constant with time but as ageing occurs, the labile reducible aldimine bonds formed from lysine and hydroxylysine, are converted to a thermally stable, non-reducible bond which accounts for the age related -collagen changes .

This method of isometric melting was used to examine how UV light may alter the collagen crosslinking. Rat tail tendon, which had been used for a number of other collagen ageing studies (Mitchell and Rigby, 1975 BBA, 393, 531-541; Rigby and Mitchell, 1978, BBA, 532, 65-70 and BBA, 544, 62-68; Rigby et al, 1977, BBRC, 79(2), 400-405 was used in these experiments. This method has many advantages over other methods as it is a direct measure of age related crosslinking changes. As the present application has relevance to photoageing and in particular collagen crosslinking by UV light this method makes it possible to make quantitative measurements of the extent of UV crosslinking with time. Further, this method enables the effectiveness of camosine and other antioxidants in protecting the tendons against UV induced free radicals to be determined. Materials and Methods The technique of isometric melting was applied to the rat tail tendon in order to determine the effects of photoageing.

Ninety day old Sprague-Dawley rats were used in these experiments. Isolation of Tendons

The tail was removed by excision and transported to the laboratory in ice. the tendons were then carefully dissected out on a saline moistened surgical pad to prevent drying. Each tendon was then measured and cut in half. The top half of the tendon was used for experiments while the bottom was kept at 4 C as a physical control. UV Irradiation and Isometric Measurement

The experimental half of the tendon was incubated at 4°C in the appropriate test solution for 20 hours prior to UV exposure. Following this exposure the tendons were washed in PBS and kept at 4°C until analysed.

The- isometric apparatus consisted of a strain gauge - Shinkho transducer type UL-lOOgm connected to an amplifier. After attachment to the strain gauge the sample was immersed in a jacketed pyrex bath containing PBS. During the experiments the bath was heated with a Tamson circulating water heater. To measure the temperature increase a FLUKE thermocouple model 80TK was fixed to a region next to the tendon attachment site. Measurements of force and temperature were recorded simultaneously with an ICI DP600 dual pen chart recorder.

For analysis the tendon was re-cut to a standard length of 3cm before attachment to the isometric apparatus. The attached tendon was then immersed into the bath of PBS at 20°C and a tension of 1 gram applied.

After a relaxation period of 15 minutes the apparatus was turned on and the temperature increase at a rate of 1 C per minute until melting occurred. Final measurements were then obtained from the chart recorder. To determine the exposure time needed to produce a measurable change in tendon crosslinking a time course experiment was carried out. The results of this experiment are shown in Figure 11. It was found that an exposure of 180 minutes using a light source that consisted of 4 UV A tubes and 2 UV B tubes gave a reproducible result. This time period was used for the following experiments.

Camosine, homo camosine and anserine were used to pretreat replicate tendons. These were then exposed to UV AB for 180 minutes The results from these experiments are shown in Figure 12. In these experiments camosine and homoca osine at 10 and 100 mM effectively protected the tendons against UV induced crosslinking. Whilst no protective effect was observed with anserine at 10 mM it is believed that anserine may provide a protective effect at higher concentrations. (Unfortunately anserine was not tested as higher concentrations due to its lack of availability) .

Figure 13 shows the results obtained when a set of other di and tri peptides were examined for their ability to protect tendons against UV induced crosslinking in comparison to camosine. It was found that none of those tested protected tendons against UV induced crosslinking. Two of the peptides contained histidine and still were inactive. These results suggest that camosine is probably acting via its antioxidant property to protect against UV induced collagen crosslinking.

Figure 14 shows comparison of tendon data from Figure 12 with Sm measurements for glutathione at 10 mM (10GSH). Glutathione appears more effective using this method of measurement. Anserine (10A) is not working at this concentration. It is important to note that glutathione would not be available to act as free radical scavenger in vivo at this concentrations. Summary

The results from these experiments using isometric melting techniques prove conclusively that camosine acts effectively in protecting the rat tail tendon against UV induced collagen crosslinking. Also from the results of the other di and tri peptides tested, it is also obvious that the camosine effect is specific and occuring because of its antioxidant property.

Claims

CLAIMS :
1. A method for reducing or preventing collagen crosslinking in skin and/or damage to skin cell DNA comprising treating the skin with a composition comprising a suitable excipient in combination with an active compound, the active compound being selected from the group consisting of camosine, homoca osine, anserine, 3-methyl-L-histidine, L-alanyl-L-tyrosine, acyl homocamosine, acetyl camosine, iodo camosine, di-iodo camosine, anserine nitrate, carbenoxylone ca osine, analogues thereof and combinations thereof.
2. A method as claimed in claim 1 in which the active compound is camosine or homocamosine or a combination thereof.
3. A method as claimed in claim 2 in which the active compound is camosine.
4. A method as claimed in any one of claims 1-3 in which the active compound is linked to another molecule, which molecule is such that the composition is improved in regard to skin permeation, skin application and tissue absorption.
5. A method as claimed in claim 4 in which the molecule is an amino acid or peptide.
6. A method as claimed in any one of claims 1-5 in which the method involves topical application of the composition to the skin.
7. A method as claimed in any one of claims 1-6 in which the composition includes a compound selected from the group consisting of bilirubin, carotenoids, mannitol, reduced glutathione, selenium, uric acid, vitamin A, vitamin C, vitamin E and combinations therof.
8. A method for reducing or preventing collagen crosslinking in skin due to exposure to UV light, said method comprising treating the skin with a composition comprising a suitable excipient in combination with an active compound, the active compound being selected f_com the group consisting of ca osine, homocamosine, anserine, 3-methyl-L-histidine, L-alanyl-L-tyrosine, acyl homocamosine, acetyl camosine, iodo camosine, di-iodo camosine, anserine nitrate, carbenoxylone camosine, analogues thereof and combinations thereof.
9. A method as claimed in claim 8 in which the active compound is camosine or homocamosine or a combination thereof.
10. A method as claimed in claim 9 in which the active compound is camosine.
11. A method as claimed in any one of claims 8-10 in which the active compound is linked to another molecule, which molecule is such that the composition is improved in regard to skin permeation, skin application and tissue absorption.
12. A method as claimed in claim 11 in which the molecule is an amino acid or peptide.
13. A method as claimed in any one of claims 8-12 in which the method involves topical application of the composition to the skin.
14. A method as claimed in any one of claims 8-13 in which the composition includes a compound selected from the group consisting of bilirubin, carotenoids, mannitol, reduced glutathione, selenium, uric acid, vitamin A, vitamin C, vitamin E and combinations therof.
PCT/AU1989/000422 1988-09-28 1989-09-28 Compound and method for the retardation of collagen cross-linking WO1990006102A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AUPJ0675 1988-09-28
AUPJ067588 1988-09-28

Publications (1)

Publication Number Publication Date
WO1990006102A1 true WO1990006102A1 (en) 1990-06-14

Family

ID=3773405

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1989/000422 WO1990006102A1 (en) 1988-09-28 1989-09-28 Compound and method for the retardation of collagen cross-linking

Country Status (2)

Country Link
EP (1) EP0436611A4 (en)
WO (1) WO1990006102A1 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0449787A2 (en) * 1990-03-21 1991-10-02 SETRA S.r.l. Pharmaceutical, dietetic or veterinary compositions with eumetabolic activity
FR2668365A1 (en) * 1990-10-25 1992-04-30 Sederma Sa Use in cosmetics of N-acetyl peptides endowed with biological activity
WO1993004690A1 (en) * 1991-09-09 1993-03-18 Peptide Technology Limited Method for the treatment of the complications and pathology of diabetes
DE4307983A1 (en) * 1993-03-13 1994-09-15 Beiersdorf Ag Active ingredients and cosmetic and dermatological preparations
WO1995010294A1 (en) * 1993-10-15 1995-04-20 Bruschettini S.R.L. Pharmaceutical compositions containing n-acetylcarnosine for the treatment of cataract
EP0688559A1 (en) * 1995-07-07 1995-12-27 Shiseido Company Limited Skin anti-ageing composition
FR2722094A1 (en) * 1994-07-05 1996-01-12 Jcb Cosmetiques Compsn. causing retention of skin colour after tanning
WO1998006278A1 (en) * 1996-08-12 1998-02-19 Harris, Roger Methods and compositions for increasing the anaerobic working capacity in tissues
FR2756565A1 (en) * 1996-12-04 1998-06-05 Oreal Novel histidine derivatives and their use in cosmetics or pharmacy
US5795859A (en) * 1991-07-05 1998-08-18 Peptide Technology Limited Peptide which abrogates TNF and/or LPS toxicity
FR2775973A1 (en) * 1998-03-13 1999-09-17 Oreal New histidine derivatives useful as radical scavengers in cosmetic and pharmaceutical compositions
US5965596A (en) * 1997-08-12 1999-10-12 Harris; Roger Methods and compositions for increasing the anaerobic working capacity in tissue
FR2778917A1 (en) * 1998-05-25 1999-11-26 Oreal New histidine derivatives, process for the preparation and uses
FR2779060A1 (en) * 1998-05-26 1999-12-03 Oreal Stabilization of retinoid compositions useful for combatting skin and hair aging, irritation, inflammation, immunosuppression or acne
DE19958121A1 (en) * 1999-12-02 2001-06-28 Max Planck Gesellschaft Tyrosine and tryptophan-containing peptides as antioxidants
WO2001052808A1 (en) * 2000-01-19 2001-07-26 Geoffrey Walter Grigg Treatment of uv induced immunosuppression
WO2002026940A1 (en) * 2000-09-26 2002-04-04 The Beta Peptide Foundation Pty Ltd Compositions and methods for delaying, preventing, rejuvenating or reversing senescence in cells
EP1210940A2 (en) * 2000-12-04 2002-06-05 Yaizu Suisankagaku Industry Co., Ltd. Antifatigue composition
EP1297830A1 (en) * 2001-09-28 2003-04-02 Flamma Fabbrica Lombarda Ammino Acidi S.p.a. Use of alpha- or beta-amino acids, of the corresponding esters or of dipeptides of these amino acids with histidine derivatives in the prevention or treatment of tissue damage caused by a atmospheric ozone
US6919326B1 (en) 1998-08-24 2005-07-19 Toshio Miyata Carbonyl-stress improving agent and peritoneal dialysate
AU782821B2 (en) * 2000-01-19 2005-09-01 Geoffrey Walter Grigg Treatment of UV induced immunosuppression
US7504376B2 (en) 1996-08-12 2009-03-17 Natural Alternatives International Methods and compositions for increasing the anaerobic working capacity in tissues
WO2009033771A2 (en) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2009079126A1 (en) 2007-12-19 2009-06-25 Avon Products, Inc. Topical compositions comprising non-proteogenic amino acids and methods of treating skin
US8329207B2 (en) 2005-05-23 2012-12-11 Natural Alternatives International, Inc. Compositions and methods for the sustained release of beta-alanine
US9440098B2 (en) * 2002-08-06 2016-09-13 Naina Sachdev Antiwrinkle composition and age reversal complex
WO2017101976A1 (en) * 2015-12-15 2017-06-22 Symrise Ag Preparations comprising carnosines

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3424781A1 (en) * 1983-07-06 1985-01-17 Nagai Kineshiro Use of L-carnosine for tumour treatment
GB2143732A (en) * 1983-07-06 1985-02-20 Kineshiro Nagai Homocarnosine for antitumor formulation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2609393A1 (en) * 1988-02-23 1988-07-15 Serobiologiques Lab Sa Composition which is useful, in particular, as a base material for the preparation of pharmaceutical, in particular dermatological and/or cosmetic, compositions, comprising a nitrogenous substance, in particular amino acids, oligo- or polypeptides, proteins, and their derivatives, and pharmaceutical or cosmetic composition thus prepared

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3424781A1 (en) * 1983-07-06 1985-01-17 Nagai Kineshiro Use of L-carnosine for tumour treatment
GB2143732A (en) * 1983-07-06 1985-02-20 Kineshiro Nagai Homocarnosine for antitumor formulation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DERWENT ABSTRACT Accession no. 83-810824/45, Class B04, JP,A, 58-164516 (NAGAI K.), 29 September 1983 (29.09.83) *
See also references of EP0436611A4 *

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0449787A3 (en) * 1990-03-21 1992-03-04 Setra S.R.L. Pharmaceutical, dietetic or veterinary compositions with eumetabolic activity
EP0449787A2 (en) * 1990-03-21 1991-10-02 SETRA S.r.l. Pharmaceutical, dietetic or veterinary compositions with eumetabolic activity
FR2668365A1 (en) * 1990-10-25 1992-04-30 Sederma Sa Use in cosmetics of N-acetyl peptides endowed with biological activity
US5795859A (en) * 1991-07-05 1998-08-18 Peptide Technology Limited Peptide which abrogates TNF and/or LPS toxicity
WO1993004690A1 (en) * 1991-09-09 1993-03-18 Peptide Technology Limited Method for the treatment of the complications and pathology of diabetes
US5561110A (en) * 1991-09-09 1996-10-01 Peptide Technology Limited Method for the treatment of the complications and pathology of diabetes
DE4307983A1 (en) * 1993-03-13 1994-09-15 Beiersdorf Ag Active ingredients and cosmetic and dermatological preparations
WO1995010294A1 (en) * 1993-10-15 1995-04-20 Bruschettini S.R.L. Pharmaceutical compositions containing n-acetylcarnosine for the treatment of cataract
FR2722094A1 (en) * 1994-07-05 1996-01-12 Jcb Cosmetiques Compsn. causing retention of skin colour after tanning
EP0688559A1 (en) * 1995-07-07 1995-12-27 Shiseido Company Limited Skin anti-ageing composition
US5747049A (en) * 1995-07-07 1998-05-05 Shiseido Company, Ltd. Cosmetic composition
US6077520A (en) * 1995-07-07 2000-06-20 Shiseido Company, Ltd. Cosmetic composition
US6426361B2 (en) 1996-08-12 2002-07-30 Roger Harris Method and compositions for increasing the anaerobic working capacity in tissues
US8470865B2 (en) 1996-08-12 2013-06-25 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
US8993610B2 (en) 1996-08-12 2015-03-31 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
USRE45947E1 (en) 1996-08-12 2016-03-29 Natural Alternatives International, Inc. Method and compositions for increasing the anaerobic working capacity in tissues
WO1998006278A1 (en) * 1996-08-12 1998-02-19 Harris, Roger Methods and compositions for increasing the anaerobic working capacity in tissues
US6680294B2 (en) 1996-08-12 2004-01-20 Natural Alternatives International Methods and compositions for increasing the anaerobic working capacity in tissues
US7825084B2 (en) 1996-08-12 2010-11-02 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
US7504376B2 (en) 1996-08-12 2009-03-17 Natural Alternatives International Methods and compositions for increasing the anaerobic working capacity in tissues
US8067381B1 (en) 1996-08-12 2011-11-29 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
US6172098B1 (en) 1996-08-12 2001-01-09 Roger Harris Methods and compositions for increasing the anaerobic working in tissues
US8129422B2 (en) 1996-08-12 2012-03-06 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
WO1998024770A1 (en) * 1996-12-04 1998-06-11 L'oreal New histidine derivatives, preparation process, and their use as free antiradical agents
FR2756565A1 (en) * 1996-12-04 1998-06-05 Oreal Novel histidine derivatives and their use in cosmetics or pharmacy
US6255344B1 (en) 1996-12-04 2001-07-03 L'oreal S.A. Histidine derivatives, preparation, process, and their use as free antiradical agents
US6562789B2 (en) 1996-12-04 2003-05-13 L'oreal S.A. Histidine derivatives, preparation process, and their use as free antiradical agents
US5965596A (en) * 1997-08-12 1999-10-12 Harris; Roger Methods and compositions for increasing the anaerobic working capacity in tissue
WO1999047504A1 (en) * 1998-03-13 1999-09-23 L'oreal Novel histidine derivatives preparation method and uses
FR2775973A1 (en) * 1998-03-13 1999-09-17 Oreal New histidine derivatives useful as radical scavengers in cosmetic and pharmaceutical compositions
US6180116B1 (en) 1998-05-25 2001-01-30 L'oreal Histidine derivatives, preparation process and uses
FR2778917A1 (en) * 1998-05-25 1999-11-26 Oreal New histidine derivatives, process for the preparation and uses
EP0962453A1 (en) * 1998-05-25 1999-12-08 L'oreal Histidine derivatives, process for their preparation and their uses
US6358514B1 (en) 1998-05-26 2002-03-19 L'oreal Combination of a retinoid with a histidine derivative
EP0972511A1 (en) * 1998-05-26 2000-01-19 L'oreal Association of a retinoid with a histidine derivative
FR2779060A1 (en) * 1998-05-26 1999-12-03 Oreal Stabilization of retinoid compositions useful for combatting skin and hair aging, irritation, inflammation, immunosuppression or acne
US7297689B2 (en) 1998-08-24 2007-11-20 Kiyoshi Kurokawa Method for preparing peritoneal dialysate
US6919326B1 (en) 1998-08-24 2005-07-19 Toshio Miyata Carbonyl-stress improving agent and peritoneal dialysate
US7745613B2 (en) 1998-08-24 2010-06-29 Toshio Miyata Method for preparing peritoneal dialysate
DE19958121A1 (en) * 1999-12-02 2001-06-28 Max Planck Gesellschaft Tyrosine and tryptophan-containing peptides as antioxidants
US8232243B2 (en) 1999-12-02 2012-07-31 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Tyrosine- and tryptophan-containing peptides as antioxidants
WO2001052808A1 (en) * 2000-01-19 2001-07-26 Geoffrey Walter Grigg Treatment of uv induced immunosuppression
AU782821B2 (en) * 2000-01-19 2005-09-01 Geoffrey Walter Grigg Treatment of UV induced immunosuppression
WO2002026940A1 (en) * 2000-09-26 2002-04-04 The Beta Peptide Foundation Pty Ltd Compositions and methods for delaying, preventing, rejuvenating or reversing senescence in cells
US6855727B2 (en) 2000-12-04 2005-02-15 Yaizu Suisankagaku Industry Co., Ltd. Muscular fatigue-controlling composition and method for providing muscular fatigue-controlling effect
EP1210940A3 (en) * 2000-12-04 2003-05-07 Yaizu Suisankagaku Industry Co., Ltd. Antifatigue composition comprising an imidazole compound
EP1210940A2 (en) * 2000-12-04 2002-06-05 Yaizu Suisankagaku Industry Co., Ltd. Antifatigue composition
EP1297830A1 (en) * 2001-09-28 2003-04-02 Flamma Fabbrica Lombarda Ammino Acidi S.p.a. Use of alpha- or beta-amino acids, of the corresponding esters or of dipeptides of these amino acids with histidine derivatives in the prevention or treatment of tissue damage caused by a atmospheric ozone
US9440098B2 (en) * 2002-08-06 2016-09-13 Naina Sachdev Antiwrinkle composition and age reversal complex
US9668994B2 (en) 2003-04-10 2017-06-06 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
US9907770B2 (en) 2003-04-10 2018-03-06 Natural Alternatives International, Inc. Methods and compositions for increasing the anaerobic working capacity in tissues
US9907769B2 (en) 2005-05-23 2018-03-06 Natural Alternatives International, Inc. Compositions and methods for the sustained release of betaalanine
US8329207B2 (en) 2005-05-23 2012-12-11 Natural Alternatives International, Inc. Compositions and methods for the sustained release of beta-alanine
US8394402B2 (en) 2005-05-23 2013-03-12 Natural Alternatives International, Inc. Compositions and methods for the sustained release of beta-alanine
US8496958B2 (en) 2005-05-23 2013-07-30 Natural Alternatives International, Inc. Compositions and methods for the sustained release of beta-alanine
US8980307B2 (en) 2005-05-23 2015-03-17 Natural Alternatives International, Inc. Compositions and methods for the sustained release of beta-alanine
US9636315B2 (en) 2005-05-23 2017-05-02 Natural Alternatives International, Inc. Compositions and methods for the sustained release of beta-alanine
WO2009033771A2 (en) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2009033771A3 (en) * 2007-09-11 2009-05-22 Gerald Bacher Use of a peptide as a therapeutic agent
WO2009079126A1 (en) 2007-12-19 2009-06-25 Avon Products, Inc. Topical compositions comprising non-proteogenic amino acids and methods of treating skin
EP2229138A4 (en) * 2007-12-19 2015-01-28 Avon Prod Inc Topical compositions comprising non-proteogenic amino acids and methods of treating skin
EP2229138A1 (en) * 2007-12-19 2010-09-22 Avon Products, Inc. Topical compositions comprising non-proteogenic amino acids and methods of treating skin
WO2017101976A1 (en) * 2015-12-15 2017-06-22 Symrise Ag Preparations comprising carnosines

Also Published As

Publication number Publication date
EP0436611A4 (en) 1992-03-11
EP0436611A1 (en) 1991-07-17

Similar Documents

Publication Publication Date Title
Gahring et al. Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum.
Penner et al. Intracellularly injected tetanus toxin inhibits exocytosis in bovine adrenal chromaffin cells
Picard et al. Aminoguanidine inhibits oxidative modification of low density lipoprotein protein and the subsequent increase in uptake by macrophage scavenger receptors
JP3730603B2 (en) Skin external composition for alleviating sagging and dark circles under the eyes
KR100678238B1 (en) Process for the preparation of immunomodulatory polysaccharides from aloe
Spencer et al. Oxidative stress via hydrogen peroxide affects proopiomelanocortin peptides directly in the epidermis of patients with vitiligo
US6521669B1 (en) Hydroxystilbene compounds for reducing/inhibiting protein glycation
Benson et al. Studies on a non-melatonin pineal anti-gonadotrophin
EP1021161B1 (en) Use of ellagic acid and its derivatives in cosmetics and dermatology
US4918055A (en) Method of stimulating melanocytes by topical application of analogs of alpha-MSH, and compositions for use in same
CA2749750C (en) Skin care compositions and methods of use thereof
CA2257579C (en) Genistein as a preventive against ultraviolet induced skin photodamage and cancer
JP5122060B2 (en) Anti-aging agent
EP0759292B1 (en) Use of alpha type melanocytes stimulating hormone derivatives to stimulate the hairgrowth
Lorite et al. Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF)
JP2003531833A (en) Use of compatible solutes as substances with free radical scavenging properties
Menon et al. A comparative study of the physical and chemical properties of melanins isolated from human black and red hair
JP2004501953A (en) The use of cosmetics or creatine and / or creatine derivatives to dermatological preparations
ES2347949T3 (en) Application of cassia alata extracts of plant.
JP4299463B2 (en) Cosmetic treatment methods to prevent the skin aging action
EP1827109A2 (en) Use of natural plant extracts in cosmetics compositions
JP4117774B2 (en) N- acylaminoamide elastase inhibitor family of compounds with at least one anti-inflammatory agent cosmetic or dermatological composition comprising a combination of compounds
Lajtha et al. Turnover of myelin proteins in mouse brain in vivo
Kornguth et al. Isolation and partial characterization of a tubulin-like protein from human and swine synaptosomal membranes
Chang et al. Expression of nitric oxide synthases in keratinocytes after UVB irradiation

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE

AK Designated states

Kind code of ref document: A1

Designated state(s): AU JP US

WWE Wipo information: entry into national phase

Ref document number: 1989910999

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1989910999

Country of ref document: EP

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i
WWW Wipo information: withdrawn in national office

Ref document number: 1989910999

Country of ref document: EP