AU2002258271A1 - Use of 3-position cyclosporin derivatives for hair growth - Google Patents
Use of 3-position cyclosporin derivatives for hair growthInfo
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- methyl
- cyclosporin
- leucine
- hair growth
- valine
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Description
USE OF 3-POSITION CYCLOSPORIN DERIVATIVES FOR HAIR GROWTH
Technical Field
The present invention relates to a hair growth promoting agent comprising a cyclosporin derivative as an active ingredient and more particularly, to a hair growth promoting agent comprising cyclosporin derivatives modified in the 3- position as an active ingredient.
Background Art
On average, the human scalp contains about 100,000 to 150,000 hairs. Each hair has three main stages of growth: anagen, catagen and telogen, after which the hair falls out. This hair growth cycle is repetitive and the duration of one cycle is different from other cycles, ranging approximately 3 to 6 years. Thus, the average adult normally loses about 50 to 100 hairs every day. In general, alopecia refers to a phenomenon wherein duration of the anagen growth phase is shortened and the percentage of hairs in the catagen and telogen phases increases, whereby the number of lost hairs is increased excessively and abnormally.
There are many theories to explain for loss of hair, including for example, poor blood circulation, excessive functioning of male sex hormone, excessive production and secretion of sebum, deterioration of scalp by peroxides, bacteria, etc., hereditary factors, aging, stress, etc. However, explicit mechanisms have not been revealed. Recently, the population suffering from hair loss is tending to increase, since changing dietary habits and stress imposed on individuals due to modern social environments, etc. has increased. Also, the age of the individuals affected by alopecia is dropping and furthermore, the population of female alopecia sufferers is rising.
One of preparations which are most commonly used for treatment and prevention of alopecia is one that contains minoxidil. There are two hair-regrowth agents which have received approval from the U.S. Food and Drug Administration, and minoxidil is one of those approved hair-regrowth agents. Minoxidil was originally developed as a hypertension drug for the purpose of reducing blood pressure. However, when using this drug, as a side effect, a trichogenous effect
was observed and thereafter, this drug became famous as a hair-regrowth agent. Although mechanisms by which minoxidil works as a hair-regrowth agent is not clearly understood, it is inferred that minoxidil increases blood flow by expansion of blood vessels, whereby roots of hairs are supplied with more nutrition and eventually, growth of hairs are promoted.
Such a model of blood flow increase has been indirectly supported by a recent report that minoxidil enhances the expression of vascular endothelial growth factor (VEGF), a growth factor associated with vasodilatation in the dermal papilla which is a main cell making up the hair roots. Also, other than the vasodilative effect of the minoxidil in the hair-restoring mechanism, it has been reported that minoxidil promotes activation of dermal papilla cells in the roots of hair incubated in vitro, and growth of hair follicles in a tissue culture of follicles in vitro. These facts indicate that minoxidil may work directly on the roots of hair as a growth factor. In addition, finasteride, a main component of Propecia which has started to be sold by Merck, is used for treatment of alopecia. It inhibits conversion of the male hormone testosterone into dihydrotestosterone, which is a more potent male hormone than testosterone. On December of 1997, the 1 mg finasteride tablet was approved by the US FDA as a hair-regrowth agent for treatment of male pattern hair loss in men only, and is now commercially available. In clinical studies, it has been demonstrated to have a significant trichogenous effect. However, there has been a report that finasteride may inhibit male sexual function as a side effect. Since neither finasteride nor minoxidil show superior effect in clinical tests, and there is concern about side effects, many researches are conducted to develop a new and improved hair-regrowth agents.
The cyclosporin family of drugs has immunosuppressive activity. It is also effective to inhibit growth of virus, fungus, protozoan, etc. and has various physiological effects such as nephrotoxicity, hepatotoxicity, hypertension, enlargement of periodontium, trichogenous effect, and so on, as side effects. Cyclosporin A, a representative cyclosporin, is a cyclic peptide having the following Chemical Formula, which comprises 11 amino acids, including several N-methyl amino acids and D-alanine at No. 8 residue.
[Structure Formula 1] -MeBmt— Abu— Sar— eLeu— Val— eLeu— Ala— DAIa— eLeu— MeLeu— MeVal- 1 2 3 4 5 6 7 8 9 10 11
where MeBmt is N-me1hyl-(4R)- [(E)-2-butenyl]-4-memyl-I1^1hreonine, Abu is I_-ot- aminobutyric acid, Sar is sarco- sine, MeLeu is N-methyl-L-leucineNal is L-valine, Ala is L- alanine, DAIa is D-alanine, MeVal is N-methyl-L-valine. The amino acid form of cyclosporin A of the above Chemical Formula 1 is L- configuration, unless otherwise specified. The residue numbering of amino acids starts from MeBmt and proceeds clockwise, i.e. 1 for MeBmt and 11 for the last MeVal (N-methyl-L- valine) as shown in the Structure Formula 1. Nomenclature of various derivatives including cyclosporins A to Z, follows methods commonly used (Helv. Chim. Acta, 1987, 70:13-36). For example, if Abu in the 2-position of cyclosporin A is substituted with L-alanine, L- threonine, L-valine or L-norvaline, the derivatives thus prepared are named cyclosporin B, cyclosporin C, cyclosporin D or cyclosporin G, respectively. Further, when the amino acid residues of the cyclosporin derivatives differ from those of cyclosporin A, the derivatives are named by describing the substituent. For example, if sarcosine, being the amino acid residue 3 of cyclosporin A, is substituted with N-methyl-D-Abu3 or N-methyl-D-Nva3, the derivatives thus prepared are named [N-methyl-D-Abu ] cyclosporin A or [N-methyl-D-Nva ] cyclosporin A, respectively. Meanwhile, a common method for abbreviating amino acids is employed, that is, N-methyl-L-leucine is abbreviated by MeLeu, N-methyl-L-isoleucine by MeHe, N- methyl-L-Valine by MeVal, N-methyl-L-alanine by MeAla, N-methyl-L-norvaline by MeNva, L-leucine by Leu, L-isoleucine by lie, sarcosine by Sar, L-serine by Ser, L-valine, Val, L-alanine by Ala, D-alanine by DAIa, famine-butyric acid by Abu, L-threonine by Thr, and L-norvaline by Nva. Further, as for a derivative of cyclosporin which is substituted with sulfur instead of a carbonyl oxygen at the amino acid residue 7, the name of the derivative may be cyclosporin 7- thioamide or [7ψ8 CS-NH] cyclosporin, according to different references (Helv. Chim. Acta.74: 1953-1990, 1991; J. Org. Che 58: 673-677, 1993; J. Org. Chem.59: 7249-7258, 1994).
So far, possible development of cyclosporin as a hair-regrowlh agent has been studied by many research groups. Particularly, researches involving animal hair regrowth tests, human alopecia areata (J. Am Acad. Dermatol., 1990, 22:242-250), human male pattern alopecia (J. Am Acad. Dermatol., 1990, 22:251-253 and Skin Pharmacol., 1994, 7:101-104), and inhibition effect of hair loss by chemotherapy in animal models (Am. J. Pathol., 1997, 150:1433-1441) have been widely conducted, hi comparative experiments on mouse's back, it is shown that cyclosporin has a hair regrowth effect about 100 times superior to minoxidil Based on such
findings, there have been attempts to utilize cyclosporin as a treatment for male pattern alopecia, and many applications for patents have been filed.
For example, Japanese Patent Publication Kokai Nos. Sho 60-243008, Sho 62-19512 and Sho 62-19513 disclose use of cyclosporin derivatives as a hair regrowth agent. Also, Europe Patent Publication No. 0414632B1 teaches a cyclosporin derivative modified in the 8- position, and PCT Publication No. 93/17039 teaches isocyclosporin. Moreover, United States Patent No. 5,807,820 and British Patent No. 2,218,334A disclose cyclosporins with excellent transdermal absorption, pursuant to the use of cyclosporins as hair restorers.
Disclosure of the Invention
Therefore, the present invention has been made in view of the above problems associated with side effects of cyclosporin A, and it is an object of the present invention to provide a hair growth promoting agent comprising a cyclosporin derivative as an active ingredient, which exerts an excellent hair growth-promotion ability.
In accordance with one aspect of the present invention, the above and other objects can be accomplished by the provision of a hair growth promoting agent comprising a 3- position analog of cyclosporin represented by the below Formula 1, as an active ingredient, which is prepared by synthesizing a variety of derivatives thereof and evaluating their hair growth promoting effects, with an aim of developing a novel agent for promoting hair growth. [Formula 1]
A- B-C- D-E-F-G- H-l- J-K
I I wherein:
A represents N-me l-(4R) -[(E)-2-butmyl]-4-me%l-I^threonine, (2S,3R,4R,6E)- 3-sulfhydryl-4-me yl-2-(methylamino)-6-octenoic acid or (2S,4R,6E)-3-oxo-4-methyl-2- (methylamino)-6-octenoic acid; B represents L-aminoburyric acid (Abu), L-alanine (Ala), L-threonine (Thr), L-valine
(Val) or L-norvaline (Nva);
C represents a D-amino acid represented by the general formula 1 ,
[General formula 1]
CH3NH-CH(R)-COOH in which,
R is one selected from the group consisting of hydrogen, Ci- straight or branched
alkyl, alkenyl or alkynyl moieties, substituted or unsubstituted with one or more selected from the group consisting of amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino,
and -X- R' represented by the general formula 2 below, [General formula 2] -X-R in which,
X is oxygen or sulfur, and
R' is one selected from the group consisting of hydrogen, and -C6 straight or branched alkyl, alkenyl or alkynyl moieties, substituted or unsubstituted with one or more selected from the group consisting of amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alleylamino, and dialkylamino;
D represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-valine; E represents L-valine or L-norvaline;
F represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; G represents L-alanine or L-alanine thioamide ([7ψ8 CS-NH], NH-CHCH3-CS-);
H represents a D-amino acid represented by the general formula 3, [General formula 3] -NH-CH(CH2R)-COOH in which, R' is hydrogen or X-R represented by the general formula 4,
[General formula 4] -X-R' in which,
X is oxygen or sulfur, and R is one selected from the group consisting of hydrogen, and Ci-C6 straight or branched alkyl, alkenyl or alkynyl moieties, substituted or unsubstituted with one or more selected from the group consisting of amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, and dialkylamino;
I represents N-methyl-L-leucine, γ-hydroxy-N-methyl-L-leucine or L-leucine; J represents N-methyl-L-leucine, γ-hydroxy-N-methyl-L-leucine or L-leucine; and,
K represents N-methyl-L-valine or L-valine.
In accordance with another aspect of the invention, there is provided a hair growth promoting agent comprising a 3-position analog of cyclosporin with an excellent hair growth promoting effect, represented by Formula 2 below, as an active ingredient.
(Formula 2]
MeBmt-A'-B'-C'-D'-E'-F'-G'-H'-l'-MeVal
wherein:
MeBmt represents N-methyl-(4R)-4-[(E)-2-butenyl]-4-me l-L-1hreonine;
L-alanine, L-threonine, L-valine or L-norvaline;
B' represents N-methyl-D-aminobutyric acid, N-methyl-D-norvaline, D-2- (me ylamino)hexa-4-ynoyl, D-2-(methylamino)pent-4-ynoyl, D-2-meti ylthio-sarcosine, N- methyl-O-propenyl-D-serine or N-methyl-D-serine;
C represents N-methyl-L-leucine, γ-hydroxy-N-methyl-L-leucine or L-valine; D' represents L-valine or L-norvaline;
E' represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; F represents L-alanine or L-alanine thioamide ([7ψ8 CS-NH], NH-CHCH3-CS-); G' represents D-alanine or D-serine;
H' represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; I' represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; and,
MeVal represents N-methyl-L-valine.
In accordance with another aspect of the invention, there is provided a hair growth promoting agent comprising a 3-position analog of cyclosporin with an excellent hair growth promoting effect, represented by Formula 3 below, as an active ingredient, [Formula 3]
MeBmt-A"-B"- eLeu-Val-MeLeu-Ala-DAIa-MeLeu-MeLeu-MeVal
wherein:
MeBmt represents N-methyl-(4R)-4-[(E)-2-butmyl]- me A" represents L-alanine, L-threonine, L-valine or L-norvaline; B" represents N-methyl-D-aminobutyric acid, N-methyl-D-norvaline, D-2-
(methylamino)hexa-4-ynoyl, D-2-(methylamino)pent-4-ynoyl, D-2-methylthio-sarcosine, N- methyl-O-propenyl-D-serine or N-methyl-D-serine; MeLeu represents N-me%l-L-leucine;
Val represents L-valine; Ala represents L-alanine; DAIa represents D-alanine; and, MeVal represents N-methyl-L-valine.
hi accordance with yet another aspect of the present invention, there is provided a hair growth promoting agent, whose composition comprising a 3-position analog of cyclosporin may be formulated in the form of liquid formualtions, sprays, gels, pastes, emulsions, creams, conditioners or shampoos.
Brief Description of the Drawings
The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawing, in which:
Fig. 1 is a l-NMR spectrum of [N-methyl-D-Abu3] cyclosporin A; Fig.2 is a 13C-NMR spectrum of [N-methyl-D-Abu3] cyclosporin A; Fig.3 is a Ti-NMR spectrum of [N-methyl-D-Nva3] cyclosporin A;
Fig.4 is a 13C-NMR spectrum of [N-methyl-D-Nva3] cyclosporin A;
1 ^
Fig.5 is a H-NMR spectrum of p-2-(methylamino)hexa-4-ynoyl ] cyclosporin A;
Fig. 6 is a 13C-NMR spectrum of P-2-(memylamino)hexa-4-ynoyl3] cyclosporin A;
Fig.7 is a 1H-NMR spectrum of P-2-(methylamino)pent-4-ynoyl3] cyclosporin A; Fig. 8 is a 13C-NMR spectrum of p-2-(methylamino)pent-4-ynoyl3] cyclosporin A;
Fig.9 is
cyclosporin A;
Fig. 10 is a 13C-NMR spectrum of [D-2-(methylthio)-Sar3] cyclosporin A;
Fig. 11 is a 1H-NMR spectrum of [N-methyl-O-propenyl-D-Ser3] cyclosporin A;
Fig. 12 is a 13C-NMR spectrum of [N-methyl-O-propenyl-D-Ser3] cyclosporin A; Fig. 13 is a ^-NMR spectrum of [N-methyl-D-Ser3] cyclosporin A; and
Fig. 14 is a 13C-NMR spectrum of [N-methyl-D-Ser3] cyclosporin A.
Best Mode for Carrying Out the Invention
Hereinafter, the present invention will be described in detail, in conjunction with various examples. These examples are provided only for illustrative purposes, and the present invention is not to be construed as being limited to those examples.
With the aim of developing a novel agent with hair growth promoting effect, the present inventors chemically synthesized a variety of 3-position analogs of cyclosporin, and hair growth promoting effects thereof were examined. Thus, the invention provides a hair growth promoting agent comprising a cyclosporin derivative as an active ingredient,
Example 1: Synthesis of 3-position analog of cyclosporin
A general method for the alkylation of cyclosporin A was as follows.
Tetrahydrofiiran (IHF) was added with diisopropyl amine ((i-Pr^NH) and added with a solution of n-butyl Hthium (BuLi) in hexane under nitrogen atmosphere at -78 °C, followed by stirring for 30 min. To the solution of LDA (lithium diisopropylamide) thus prepared, cyclosporin A in THF was added, stirred for 1 hr, and electrophile was added.
1-1: Synthesis of [N-methyl-D-Abu3] cyclosporin A: Compound 1
According to the general method above, to a solution of 10 equivalents of LDA was added 1.0 g cyclosporin A in 50 ml THF at -78 °C . The reaction mixture was stirred for 2 hrs at -78 °C and added with 0.4 ml ethyliodide. After the temperature of the solution reached room temperature, the solution was further stirred for 24 hrs and added with 20 ml water, followed by concentration. The residue was added with ether (Et2O), washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous MgSO4. After concentrating, the residue was subjected to silica gel column chromatography (100 g silica gel, dichloromethane : methylalcohol = 96 : 4), followed by HPLC to give 0.1 g of the title compound.
Molecular weight of the compound was determined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure, Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for 'H-NMR and on 150 MHz (Bruker) for C-NMR, and the spectra are shown in Figs. 1 and 2, respectively.
1-2: Synthesis of [N-methyl-D-Nva3] cyclosporin A: Compound 2
According to the general method, to a solution of 10 equivalents of LDA was added 1.0 g cyclosporin A in 50 ml THF at -78 °C . The reaction mixture was stirred for 2 hrs at -78 °C and added with 0.41 ml propyliodide. After the temperature of the solution reached room temperature, the solution was further stirred for 24 hrs and added with 20 ml water, followed by concentration. The residue was added with ether (Et2O), washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous MgSO4. After
concentrating, the residue was subjected to silica gel column chromatography (100 g silica gel, dichloromethane : methylalcohol = 96 : 4), followed by HPLC to give 0.12 g of the title compound. Molecular weight of the compound was determined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure, Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for Ti-NMR and on 150 MHz (Bruker) for 13C-NMR, and the spectra are shown in Figs.3 and 4, respectively.
1-3: Synthesis |P-2-(methylamino)hexa-4-ynoyl3] cyclosporin A: Compound 3 According to the general method, to a solution of 10 equivalents of LDA was added 1.0 g cyclosporin A in 50 ml THF at -78 °C . The reaction mixture was stirred for 2 hrs at -78 °C and added with 0.73 ml l-bromo-2-butyne. After the temperature of the solution reached room temperature, the solution was further stirred for 24 hrs and added with 20 ml water, followed by concentration. The residue was added with ether (Et2O), washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous MgSO . After concentrating, the residue was subjected to silica gel column chromatography (100 g silica gel, dichloromethane : methylalcohol = 96 : A), followed by HPLC to give 0.13 g of the title compound. Molecular weight of the compound was detemiined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure, Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for !H-NMR and on 150 MHz (Bruker) for 13C-NMR, and the spectra are shown in Figs.5 and 6, respectively.
1-4: Synthesis of PD-2-(methylamino)pent-4-ynoyl3] cyclosporin A: Compound 4
According to the general method, alkylation was performed employing THF (200 ml), (i-PrhNH (3.2 ml), BuLi (8 ml), cyclosporin A (3.76 g) in 50 ml THF and propargyl bromide (3.57 g). After the temperature of the solution reached room temperature, the solution was further stirred for 24 hrs and added with 40 ml water, followed by concentration. The residue was added with ether (Et2O), washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous MgSO . After concentrating, the residue was subjected to silica gel column chromatography (100 g silica gel, dichloromethane : methylalcohol = 96 : 4), followed by HPLC to give the title compounds 3 (0.18 g) and 4 (0.08 g). Molecular weight of the compound was determined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure, Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for I-NMR and on 150 MHz (Bruker) for 13C-NMR, and the spectra are shown in Figs.7 and 8, respectively.
1-5: Synthesis of p-2-fmethylthioySar3] cyclosporin A: Compound 5
According to the general method, alkylation was performed employing THF (100 ml), (i-Pr^NH (1.6 ml), BuLi (4.0 ml), cyclosporin A (1.0 g) in 30 ml THF and methyl disulfide (Me2S2) (1.5 ml). The solution was stirred for 14 hrs at 0 °C and added with 20 ml water, followed by concentration. The residue was added with ether (Et2O), washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous
MgSO . After concentrating, the residue was subjected to silica gel column chromatography
(100 g silica gel, dichloromethane : methylalcohol = 50 : 1 ~ 96 : 4), followed by HPLC to give the title compounds 5 (0.36 g) and 6 (0.05 g). Molecular weight of the compound was determined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure,
Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for
Η-NMR and on 150 MHz (Bruker) for 13C-NMR, and the spectra are shown in Figs.9 and 10, respectively.
1-6: Synthesis of N-methyl-O-propenyl-D-Ser3] cyclosporin A: Compound 6 According to the general method, [D-methykerine3] cyclosporin A (0.62 g, 0.5 mmol), tetrabutylammonium chloride (0.11 g, 0.5 mmol), and aryl bromide (0.24 g, 2.0 mmol) were dissolved in dichloromethane (50 ml), then added with 30 % NaOH (1.5 ml), and the mixture was stirred for 2 hrs. After adding with 50 ml dichloromethane, the solution was washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous MgSO4. The concentrated residue was subjected to silica gel column chromatography (100 g silica gel, dichloromethane : methylalcohol = 97 : 3), followed by
HPLC to give 0.4 g of the title compound. Molecular weight of the compound was determined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure,
Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for Η-NMR and on 150 MHz (Bruker) for 13C-NMR, and the spectra are shown in Figs. 11 and
12, respectively.
1-7: Synthesis of [N-methyl-D-Ser3] cyclosporin A: Compound 7 According to the general method, to a solution of 10 equivalents of LDA was added 1.0 g cyclosporin A in 50 ml THF at -78 °C . The reaction mixture was stirred for 2 hrs at -78 °C and added with 2.0 g paraformaldehyde. After the temperature of the solution reached room temperature, the solution was further stirred for 24 hrs and added with 20 ml water, followed by concentration. The residue was added with ether (Et2O), washed with water and a solution of saturated sodium chloride in sequence, and dried over anhydrous MgSO4. After
concentrating, the residue was subjected to silica gel column chromatography (100 g silica gel, dichloromethane : methylalcohol = 96 : 4), followed by HPLC to give 0.3 g of the title compound. Molecular weight of the compound was determined by FAB MS (ZMS AX 505H) analysis. To confirm the molecular structure, Nuclear Magnetic Resonance (NMR) measurements were performed on 600 MHz (Bruker) for TL-NMR and on 150 MHz (Bruker) for C-NMR, and the spectra are shown in Figs. 13 and 14, respectively.
Preparative example 1: hair tonic
1-1: Preparation of hair tonic containing [N-methyl-D-Abu3] cyclosporin A Individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table
1 below. It was found that the composition 1 of Table 1 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 1 : Formulation of hair tonic (unit: weight %) Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0
[N-melhyl-D-Abu3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor lypical typical lypical colarant typical lypical typical water balance balance balance
1-2: Preparation of hair tonic containing [N-methyl-D-Nva ] cyclosporin A Individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table
2 below. It was found that the composition 1 of Table 2 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 2: Formulation of hair tonic
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0
[N-melhyl-D-Nva3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor lypical lypical lypical colarant lypical lypical lypical water balance balance balance
1-3: Preparation of hair tonic containing [D-2-(methylamitιo hexa-4-ynoyl3] cyclosporin A
Individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table 3 below. It was found that the composition 1 of Table 3 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 3 : Formulation of hair tonic
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0
[D-2-(memylamino)hexa-4-ynoyl3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor typical typical typical colarant typical typical lypical water balance balance balance
1-4: Preparation of hair tonic containing P-2-(methylamino>pent-4-vnoyl3]
cyclosporin A
Individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table 4 below. It was found that the composition 1 of Table 4 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 4: Formulation of hair tonic
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0 fD-2-(methylarnino)pent-4-ynoyl 3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor typical typical typical colarant typical typical typical water balance balance balance
1-5: Preparation of hair tonic containing IP-2-methylthio-Sar3] cyclosporin A Individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table 5 below. It was found that the composition 1 of Table 5 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 5: Formulation of hair tonic
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0
[D-2-(me1hylthio>Sar3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor typical typical typical colarant typical typical typical water balance balance balance
1-6: Preparation of hair tonic containing [N-methyl-O-propenyl-D-Ser3] cyclosporin A individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table 6 below. It was found that the composition 1 of Table 6 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 6: Formulation of hair tonic
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0 pSf-methyl-O-propenyl -D-Ser3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor lypical typical typical colarant typical typical typical water balance balance balance
1-7: Preparation of hair tonic containing [N-methvl-D -Ser3] cyclosporin A
Individual ingredients were mixed and stirred, and the mixtures were completely dissolved to prepare three hair growth promoting tonics, with compositions as shown in Table 7 below. It was found that the composition 1 of Table 7 has a hair growth promoting effect at a level similar to a conventional hair tonic containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 7: Formulation of hair tonic
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 ethanol 40.0 40.0 40.0
[N-methyl-D-Ser3] cyclosporin A 0.1 1.0 8.0 tocopherol acetate 0.1 0.1 0.1 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Tween20 0.5 0.5 0.5 flavor typical typical typical colarant typical lypical lypical water balance balance balance
Preparative example 2: hair cream
2-1 : Preparation of hair cream containing [N-methyl-D-Abu3] cyclosporin A Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair creams, with compositions as shown in Table 8 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
It was found that the composition 1 of Table 8 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 8: Formulation of hair cream (unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5 glycerin monostearate 3.0 3.0 3.0 polyoxyethyleneoctyldodecylelher 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3
[N-melhyl-D-Abu3] cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyefhylenegrycol 5.0 5.0 5.0 water balance not including flavor and colorant flavor typical typical typical colorant lypical typical typical
2-2: Preparation of hair cream containing [N-methyl-D-Nva3] cyclosporin A Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair creams, with compositions as shown in
Table 9 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
It was found that the composition 1 of Table 9 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 9: Formulation of hair cream
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5 glycerin monostearate 3.0 3.0 3.0 polyoxyethyleneoctyldodecylether 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3
[N-methyl-D-Nva3] cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyethyleneglycol 5.0 5.0 5.0 water balance not including flavor and colorant flavor typical typical typical colorant lypical typical typical
2-3: Preparation of hair cream containing |D-2-(metfaylamino hexa-4-ynoyl3] cyclosporin A
Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair creams, with compositions as shown in Table 10 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
It was found that the composition 1 of Table 10 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later
Table 10: Formulation of hair cream
(unit weight %) ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5 glycerin monostearate 3.0 3.0 3.0 polyoxyethyleneoctyldodecylether 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3
P-2-(methylamino)hexa-4-ynoyl 3]cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyefhyleneglycol 5.0 5.0 5.0 water balance not including flavor and colorant flavor typical typical typical colorant typical typical lypical
2-4: Preparation of hair cream mtaining [D-2-(methylamino>pent-4-vnoyl3] cyclosporin A
Individual oil-phase and water-phase ingredients were mixed in a separate container, and each rnixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair creams, with compositions as shown in
Table 11 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
It was found that the composition 1 of Table 11 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin as evaluated in an animal experiment according to the Test Example described later.
Table 11 : Formulation of hair cream
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5 glycerin monostearate 3.0 3.0 3.0 polyoxyethyleneoctyldodecylefher 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3
[D-2-(methylarnino)pent-4-ynoyl3] cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyethyleneglycol 5.0 5.0 5.0 water balance: riot including flavoi •and colorant flavor typical typical typical colorant typical typical typical
2-5: Preparation of hair cream containing [D-2-methvlthio-Sar3] cyclosporin A
Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair creams, with compositions as shown in Table 12 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients. It was found that the composition 1 of Table 12 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 12: Formulation of hair cream
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5 glycerin monostearate 3.0 3.0 3.0 polyoxyethyleneoctyldodecylether 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3
[D-2-methylthio-Sar3] cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyethyleneglycol 5.0 5.0 5.0 water balance not including flavor and colorant flavor typical typical typical colorant typical lypical lypical
2-6: Preparation of hair cream containing [N-methyl-O-propenvl-D-Ser3] cyclosporin A Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were aώϊiixed to prepare three hair creams, with compositions as shown in Table 13 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
It was found that the composition 1 of Table 13 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 13: Formulation of hair cream (unit: weight %)__
Ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5
glycerin monostearate 3.0 3.0 3.0 polyoxyelhyleneoctyldodecylether 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3
[N-methyl-O-propenyl-D -Ser 3] cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyefhyleneglycol 5.0 5.0 5.0 water balance not including flavoi •and colorant flavor typical lypical typical colorant typical typical typical
2-7: Preparation of hair cream containing [N-methyl-D-Ser3] cyclosporin A Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair cream, with compositions as shown in Table 14 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
It was found that the composition 1 of Table 14 has a hair growth promoting effect at a level similar to a conventional hair cream containing 0.1 % cyclosporin A, as evaluated in an animal experiment according to the Test Example described later.
Table 14: Formulation of hair' cream
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 paraffin 5.0 5.0 5.0 cetostearyl alcohol 5.5 5.5 5.5 petrolatum 5.5 5.5 5.5 glycerin monostearate 3.0 3.0 3.0 polyoxyethyleneoctyldodecylether 3.0 3.0 3.0 propylparaben 0.3 0.3 0.3 pSf-methy-D-Ser3] cyclosporin A 0.1 1.0 8.0 glycerin 7.0 7.0 7.0 dipropyleneglycol 20.0 20.0 20.0 polyefhyleneglycol 5.0 5.0 5.0
water balance not including flavor and colorant flavor typical typical typical colorant typical typical lypical
Preparative example 3: shampoo
3-1 : Preparation of shampoo containing [N-methyl-D-Abu ,3η ] cyclosporm A All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant. Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in Table 15 below.
Table 15: Formulation of shampoo (unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0
(30 wf% aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0 propyleneglycol 2.0 2.0 2.0 methyl paraoxyberrzoic acid 0.2 0.2 0.2 ehtanol 2.0 2.0 2.0
[N-methyl-D-Abu3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 flavor typical typical typical colorant typical typical typical water balance balance balance
3-2: Preparation of shampoo containing [N-methyl-D-Nva ] cyclosporin A
All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant. Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in Table 16 below.
Table 16: Formulation of shampoo
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0
(30 wt% aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0 propyleneglycol 2.0 2.0 2.0 methyl paraoxybenzoic acid 0.2 0.2 0.2 ehtanol 2.0 2.0 2.0
[N-methyl-D-Nva3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 flavor typical typical lypical colorant lypical typical typical water balance balance balance
3-3: Preparation of shampoo containing p-2-(methylamino hexa-4-ynoyl3] cyclosporin A
All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant. Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in Table 17 below.
Table 17: Formulation of shampoo
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0 (30 wl% aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0
Propyleneglycol 2.0 2.0 2.0 methyl paraoxybetKoic acid 0.2 0.2 0.2
Ethanol 2.0 2.0 2.0
[p-2-(rnefhylamino)hexa-4-ynoyl 3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3 Flavor typical lypical typical Colorant typical typical typical Water balance balance balance
3-4: Preparation of shampoo containing [D-2-(me ylarnino>pent-4-ynoyl3] cyclosporin A
All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant. Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in Table 18 below.
Table 18: Formulation of shampoo
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0 (30 wt% aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0 propyleneglycol 2.0 2.0 2.0 methyl paraoxybenzoic acid 0.2 0.2 0.2 ehtanol 2.0 2.0 2.0
P-2-(methylamino)pent-4-ynoyl 3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3 flavor typical typical typical colorant typical typical typical water balance balance balance
3-5: Preparation of shampoo containing [D-2-methylthio-Sar3] cyclosporin A
All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant. Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in
Table 19 below.
Table 19: Formulation of shampoo
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0 (30 wt% aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0
Propyleneglycol 2.0 2.0 2.0 methyl paraoxybenzoic acid 0.2 0.2 0.2
Ethanol 2.0 2.0 2.0
[D-2-methylthio-Saι3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Flavor lypical typical typical
Colorant typical typical typical
Water balance balance balance
3-6: Preparation of shampoo containing [N-methyl-O-propenyl-D-Ser3] cyclosporin A All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant. Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in Table 20 below.
Table 20: Formulation of shampoo
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0 (30 wt% aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0
Propyleneglycol 2.0 2.0 2.0 methyl paraoxybenzoic acid 0.2 0.2 0.2
Ethanol 2.0 2.0 2.0
[N-methyl-O-propenyl-D-Sei3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3
L-menthol 0.3 0.3 0.3
Flavor typical typical typical
Colorant lypical typical typical
Water balance balance balance
3-7: Preparation of shampoo containing [N-methyl-D-Ser3] cyclosporin A All individual ingredients, except flavor, colorant and water, were mixed and the mixture was completely dissolved by heating, while stirring. After cooling to room temperature, the mixture was mixed with flavor and colorant Water was finally added to adjust to 100 % the total weight, to prepare three shampoos, with compositions as shown in Table 21 below.
Table 21: Formulation of shampoo
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 sodium POE laurylsulfuric acid
40.0 40.0 40.0
(30 wt aqueous solution) palm oil fattyacid diethanolamide 3.0 3.0 3.0 propyleneglycol 2.0 2.0 2.0 methyl paraoxybenzoic acid 0.2 0.2 0.2 ehtanol 2.0 2.0 2.0
[N-methyl-D-Ser3] cyclosporin A 1.0 3.0 10.0 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 flavor typical typical typical colorant typical typical typical water balance balance balance
Preparative example 4: hair conditioner
4-1 : Preparation of hair conditioner containing [N-methyl-D-Abu3] cyclosporin A
Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 22 below. Water was added to adjust to 100 % the total weight including the
oil-phase and water-phase ingredients.
Table 22: Formulation of hair conditioner
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0
[N-methyl-D-Abu3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0 stearyldimelhyl berrzylammonium chloride
8.0 8.0 8.0
(25 wt% aqueous solution) methyl paraoxybenzoic acid 0.2 0.2 0.2 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor typical typical typical colorant typical typical typical
4-2: Preparation of hair conditioner containing [N-methyl-D-Nva3] cyclosporin A individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 23 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
Table 23: Formulation of hair conditioner
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0 pSF-methyl-D-Nva3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0
stearyldimethyl benzylammonium chloride
8.0 8.0 8.0
(25 wt% aqueous solution) methyl paraoxybenzoic acid 0.2 0.2 0.2 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor typical typical typical colorant typical typical typical
4-3: Preparation of hair conditioner containing [D-2-(methylamino hexa-4-ynoyl3] cyclosporin A
Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 24 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
Table 24: Formulation of hair conditioner
(unit: weight %)
Ingredients Comp. 1 Comp.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0
[D-2-(methylarnino)hexa-4-ynoyl 3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0 stearyldimethyl benzylammonium chloride
8.0 8.0 8.0
(25 wt% aqueous solution) methyl paraoxybenzoic acid 0.2 0.2 0.2 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor typical lypical lypical colorant typical lypical typical
4-4: Preparation of hair conditioner containing P-2-(methylarnino pent-4-vnoyl3] cyclosporin
Individual oil-phase and water-phase ingredients were mixed in a separate container, and each rnixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 25 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
Table 25: Formulation of hair conditioner
(unit: weight %) ingredients Comp. 1 Comp.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0
[D-2-(methyIarnino)pent-4-ynoyl 3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0 stearyldimethyl benzylammonium chloride
8.0 8.0 8.0
(25 wt% aqueous solution) methyl paraoxybenzoic acid 0.2 0.2 0.2 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor typical typical typical colorant typical typical typical
4-5: Preparation of hair conditioner containing [D-2-methylthio-Sar3] cyclosporin A Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 26 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
Table 26: Formulation of hair conditioner
(unit weight %) ingredients Comp. 1 Comρ.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0
[D-2-melhylthio-Sar 3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0 stearyldimethyl beiEylammonium chloride
8.0 8.0 8.0
(25 wt% aqueous solution) methyl paraoxybenzoic acid 02 02 02 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor lypical lypical typical colorant typical typical typical
4-6: Preparation of hair conditioner containing [N-methyl-O-propenyl-D-Ser3] cyclosporin A individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 27 below. Water was added to adjust to 100 % the total weight mcluding the oil-phase and water-phase ingredients.
Table 27: Formulation of hair conditioner
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0 pSf-methyl-O-propenyl-D-Ser3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0 stearyldimethyl benzylammonium chloride 8.0 8.0 8.0
(25 wr% aqueous solution) methyl paraoxybenzoic acid 0.2 0.2 0.2 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor typical typical typical colorant typical typical typical
4-7: Preparation of hair conditioner αmtaining [N-methyl-D-Ser3] cyclosporin A Individual oil-phase and water-phase ingredients were mixed in a separate container, and each mixture was completely dissolved by heating to 80 °C. Two phases of the ingredients were mixed, emulsified, and cooled to room temperature. Additives such as flavor and colorant were admixed to prepare three hair conditioners, with compositions as shown in Table 28 below. Water was added to adjust to 100 % the total weight including the oil-phase and water-phase ingredients.
Table 28: Formulation of hair conditioner
(unit weight %)
Ingredients Comp. 1 Comp.2 Comp.3 cetanol 3.0 3.0 3.0 self-emulsifiable glycerol-monostearate 2.0 2.0 3.0 squalene 10.0 10.0 10.0
[N-methyl-D-Ser3] cyclosporin A 1.0 5.0 10.0 propyleneglycol 2.0 2.0 2.0 stearyldimethyl benzylammonium chloride
8.0 8.0 8.0
(25 wt% aqueous solution) methyl paraoxybenzoic acid 0.2 0.2 0.2 salicylic acid 0.3 0.3 0.3 L-menthol 0.3 0.3 0.3 water balance balance balance flavor typical typical typical colorant typical typical typical
Test Example: Test for hair growth promoting effect of cyclosporin derivatives of the invention
Female C57BL/6 mice of ages 6 to 7 weeks were utilized After removing hairs on the middle of the back with an electric shaver, the mice were weighed and randomly assigned to the test groups with an even distribution of weights. The mice were given one day for adaptation. From the next day, mice were applied once a day on their backs with cyclosporin A and the cyclosporin A derivatives (Compounds 1 to 7) prepared by HPLC in Example 1 in amounts of 100 ul (cone. 0.1% w/v) for 30 days. The results were determined by visual approach, in terms of degrees of hair regrowth. With respect to respective hair-removed areas, rates of new hair growth were examined and compared.
As can be seen in Table 29, cyclosporin derivatives of the invention have a significant hair growth promoting effect, compared to the control in which mice were applied with a vehicle only. Further, the derivatives show a similar level of hair growth promoting effect, with respect to cyclosporin A. Meanwhile, over a course of 30 days, as comparing the appearance of the backs, the mice of the control and all test groups showed no specific skin irritation.
Table 29: Evaluation of cyclosporin derivatives based on hair regrowth in mice
Compound vehicle cyclosporin A 1 2 3 4 5 6 7 applied
Area rate of hair
35 91 95 91 95 96 93 94 90 regrowth (%)
On the basis of the foregoing results, the cyclosporin derivatives of the invention may be formulated in any form including liquid formulations, sprays, gels, pastes, emulsions, creams, conditioners, shampoos, and the like. A variety of forms are available though, considering their high commercial demand, hair tonics, creams, conditioners, and shampoos are provided herein. As revealed in the above the Test Example, the cyclosporin derivatives exhibit an excellent hair growth promoting effect, compared to the control.
Industrial Applicability
As apparent from the above description, the present invention provides a hair growth promoting agent comprising a cyclosporin A derivative substituted in the 3-position of cyclosporin A as an active ingredient, which exhibits an excellent hair growth promoting effect
Claims (11)
1. A hair growth promoting agent comprising a 3-position analog of cyclosporin represented by Formula 1, as an active ingredient [Formula 1]
A-B-C-D-E-F-G-H-l-J-K
I 1 in which
A represents N-methyl-(4R)-4-[(E)-2-butmyl] -methyl-I^ttoeonine, (2S,3R,4R,6E)- 3-sulfhydryl-4-methyl-2-(methylamino)-6-octenoic acid or (2S,4R,6E)-3-oxo-4-methyl-2- (methylarnino)-6-octenoic acid; B represents
acid (Abu), L-alanine (Ala), L-threonine (Thr), L-valine
C represents a D-amino acid represented by the general formula 1 ,
[General formula 1]
CH3NH-CH(R)-COOH in which,
R is one selected from the group consisting of hydrogen, -C6 straight or branched alkyl, alkenyl or alkynyl moieties, substituted or unsubstituted with one or more selected from the group consisting of amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, and dialkylamino, and -X- R' represented by the general formula 2 below, [General formula 2]
-X-R' in which,
X is oxygen or sulfur, and
R is one selected from the group consisting of hydrogen, and -C6 straight or branched alkyl, alkenyl or alkynyl moieties, substituted or unsubstituted with one or more selected from the group consisting of amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, and dialkylamino;
D represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-valine; E represents L-valine or L-norvaline; F represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine;
G represents L-alanine or l-alanine thioamide ([V CS-NH], NH-CHCH3-CS-);
H represents a D-amino acid represented by the general formula 3, [General formula 3] -NH-CH(CH2R)-COOH in which, R is hydrogen or -X- R'represented by the general formula 4,
[General formula 4]
-X-R' in which,
X is oxygen or sulfur, and R is one selected from the group consisting of hydrogen, and -C6 straight or branched alkyl, alkenyl or alkynyl moieties, substituted or unsubstituted with one or more selected from the group consisting of amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, and diall ylamino;
I represents N-methyl-L-leucine, γ-hydroxy-N-methyl-L-leucine or L-leucine; J represents N-methyl-L-leucine, γ-hydroxy-N-methyl-L-leucine or L-leucine; and,
K represents N-methyl-L-valine or L-valine.
2. The hair growth promoting agent as set forth in claim 1, wherein the 3-position analog of cyclosporin is represented by Formula 2: [Formula 2]
θBmt-A'-θ'-C'-D'-E'-F'-Q'-H'-l'-MθVal
in which
MeBmt represents N-methyl-(4R)^[(E)-2-butenyl]- methyl-L-ttoeonine;
acid, l-alanine, I_-threonine, L-valine or L-norvaline; B' represents N-methyl-D-aminobutyric acid, N-methyl-D-norvaline, D-2- (methylamino)hexa-4-ynoyl, D-2-(methylamino)pent-4-ynoyl, D-2-methylthio-sarcosine, N- methyl-O-propenyl-D-serine or N-methyl-D-serine;
C represents N-methyl-L-leucine, γ-hydroxy-N-methyl-L-leucine or L-valine; D' represents L-valine or L-noiyaline;
E represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; F represents L-alanine or L-alanine thioamide ([7ψ8 CS-NH], NH-CHCH3-CS-);
G' represents D-alanine or D-serine;
H represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; T represents N-methyl-L-leucine, γ-hydroxy N-methyl-L-leucine or L-leucine; and, MeVal represents N-methyl-Iy-valine.
3. The hair growth promoting agent as set forth in claim 1, wherein the 3-position analog of cyclosporin is represented by Formula 3: [Formula 3]
eBmt-A'-B"- eLeu- al-MeLeu- Ala- DAIa- eLeu-Me Leu -MeVal
in which MeBmt represents N-methyl-(4R)- [(E)-2-but yl]- methyl-l^threonine;
A" represents L-alanine, l-threonine, L-valine or l-norvaline; B" represents N-methyl-D-aminobutyric acid, N-methyl-D-norvaline, D-2- (methylamino)hexa-4-ynoyl, D-2-(methylamino)pent-4-ynoyL D-2-methylthio-sarcosine, N- methyl-O-propenyl-D-serine or N-methyl-D-serine; MeLeu represents N-methyl-L-leucine;
Val represents L-valine; Ala represents L-alanine; DAIa represents D-alanine; and, MeVal represents N-methyl-I^valine.
4. The hair growth promoting agent as set forth in claim 1 , comprising [N-methyl-D-
Abu3] cyclosporin A as an active ingredient.
5. The hair growth promoting agent as set forth in claim 1, comprising [N-methyl-D- Nva ] cyclospoπn A as an active ingredient
6. The hair growth promoting agent as set forth in claim 1, comprising [D-2- (methylamino)hexa-4-ynoyl3] cyclosporin A as an active ingredient
7. The hair growth promoting agent as set forth in claim 1, comprising p-2-
(methylarnino)pent-4-ynoyl3] cyclosporin A as an active ingredient.
8. The hair growth promoting agent as set forth in claim 1, comprising [D-2- methylthio-Sar3] cyclosporin A as an active ingredient.
9. The hair growth promoting agent as set forth in claim 1, comprising [N-methyl-O- propenyl-D-Ser3] cyclosporin A as an active ingredient.
10. The hair growth promoting agent as set forth in claim 1, comprising [N-methyl- D-Ser3] cyclosporin A as an active ingredient.
11. The hair growth promoting agent as set forth in any one of claims 1 to 10, which is formulated in a form selected from the group consisting of liquid formulation, spray, gel, paste, emulsion, cream, conditioner and shampoo.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2001-0025682A KR100465012B1 (en) | 2001-05-11 | 2001-05-11 | Use of 3-position cyclosporin derivatives for hair growth |
| KR2001/25682 | 2001-05-11 | ||
| PCT/KR2002/000879 WO2002092032A1 (en) | 2001-05-11 | 2002-05-11 | Use of 3-position cyclosporin derivatives for hair growth |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002258271A1 true AU2002258271A1 (en) | 2003-05-01 |
| AU2002258271B2 AU2002258271B2 (en) | 2006-06-29 |
Family
ID=19709334
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002258271A Expired AU2002258271B2 (en) | 2001-05-11 | 2002-05-11 | Use of 3-position cyclosporin derivatives for hair growth |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US6790830B2 (en) |
| EP (1) | EP1387660B1 (en) |
| JP (1) | JP4214181B2 (en) |
| KR (1) | KR100465012B1 (en) |
| CN (1) | CN1248671C (en) |
| AT (1) | ATE473730T1 (en) |
| AU (1) | AU2002258271B2 (en) |
| BR (1) | BRPI0209619B8 (en) |
| CA (1) | CA2446971C (en) |
| DE (1) | DE60237003D1 (en) |
| ES (1) | ES2348225T3 (en) |
| MX (1) | MXPA03010027A (en) |
| PL (1) | PL208536B1 (en) |
| RU (1) | RU2291682C2 (en) |
| TR (1) | TR200301931T2 (en) |
| WO (1) | WO2002092032A1 (en) |
| ZA (1) | ZA200308532B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020039528A (en) * | 2000-11-22 | 2002-05-27 | 조명재 | Use of cyclosporin 7-thioamide derivatives for hair growth |
| KR100865211B1 (en) * | 2001-10-26 | 2008-10-23 | 주식회사 엘지생활건강 | Nonimmunosuppressive [?-hydroxy-n-methyl-l-leucine4]cyclosporin derivatives for protection from antineoplastic chemotherapy-induced hair loss |
| US6987090B2 (en) * | 2002-05-09 | 2006-01-17 | Lg Household & Health Care Ltd. | Use of 3-position cyclosporin derivatives for hair growth |
| US20090041442A1 (en) * | 2006-03-06 | 2009-02-12 | Rouse Jr Martin D | Thermal Vaporizer Apparatus |
| US7696165B2 (en) | 2006-03-28 | 2010-04-13 | Albany Molecular Research, Inc. | Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders |
| US7696166B2 (en) | 2006-03-28 | 2010-04-13 | Albany Molecular Research, Inc. | Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders |
| DE102008060549A1 (en) | 2008-12-04 | 2010-06-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Drug-peptide construct for extracellular accumulation |
| WO2010138422A1 (en) * | 2009-05-27 | 2010-12-02 | Allergan, Inc. | Cyclosporin derivatives for enhancing the growth of hair |
| US8470376B2 (en) | 2009-06-15 | 2013-06-25 | Kao Corporation | NFAT signal inhibitor and calcineurin inhibitor |
| RU2630690C9 (en) | 2010-12-15 | 2017-12-28 | КонтраВир Фармасьютикалз, Инк. | Cyclosporin analogs molecules modified by 1 and 3 amino acids |
| RU2479872C1 (en) * | 2012-01-11 | 2013-04-20 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Курский государственный медицинский университет" Министерства здравоохранения и социального развития Российской Федерации | Method for correction of ischemic disorders caused by reperfusion liver injury |
| EP2705856A1 (en) | 2012-09-07 | 2014-03-12 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. | Compounds for the treatment of neurodegenerative disorders |
| KR102469342B1 (en) * | 2021-06-14 | 2022-11-21 | 주식회사 오리엔트바이오 | Controlled-release intralesional injection composition comprising cyclic peptides and method for preparing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60243008A (en) | 1984-05-17 | 1985-12-03 | Wakamoto Pharmaceut Co Ltd | Hair producing and growing tonic |
| EP0194972B1 (en) * | 1985-03-11 | 1992-07-29 | Sandoz Ag | Novel cyclosporins |
| JPS6219512A (en) | 1985-07-17 | 1987-01-28 | Shiseido Co Ltd | Hair tonic |
| JPS6219513A (en) | 1985-07-17 | 1987-01-28 | Shiseido Co Ltd | Hair tonic |
| CH679119A5 (en) * | 1988-05-13 | 1991-12-31 | Sandoz Ag | |
| GB8916901D0 (en) * | 1989-07-24 | 1989-09-06 | Sandoz Ltd | Improvements in or relating to organic compounds |
| US5284826A (en) * | 1989-07-24 | 1994-02-08 | Sandoz Ltd. | 0-hydroxyethyl and acyloxyethyl derivatives of [ser]8 cyclosporins |
| GB9203886D0 (en) * | 1992-02-24 | 1992-04-08 | Sandoz Ltd | Improvements in or relating to organic compounds |
| JPH07316023A (en) * | 1994-05-26 | 1995-12-05 | Shiseido Co Ltd | Hair tonic |
| ATE209216T1 (en) * | 1995-07-17 | 2001-12-15 | Chem Ag C | CYCLOSPORINE DERIVATIVES WITH ANTI-HIV EFFECT |
| FR2757521B1 (en) * | 1996-12-24 | 1999-01-29 | Rhone Poulenc Rorer Sa | NOVEL CYCLOSPORIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| MXPA00012218A (en) * | 1998-06-12 | 2002-04-24 | Chem Ag C | Novel cyclosporins. |
| FR2780061B1 (en) * | 1998-06-22 | 2001-09-07 | Rhone Poulenc Rorer Sa | NOVEL PROCESS FOR THE PREPARATION OF CYCLOSPORIN DERIVATIVES |
| JP2002538092A (en) | 1999-03-05 | 2002-11-12 | ザ・ユニバーシティ・オブ・テキサス・サウスウエスタン・メディカル・センター | Method of treating hair loss using a non-immunosuppressant |
| EP1233738A1 (en) * | 1999-11-19 | 2002-08-28 | LG Household & Health Care Ltd. | Use of nonimmunosuppressive cyclosporin derivatives for hair growth |
| KR100316604B1 (en) * | 1999-11-19 | 2001-12-12 | 성재갑 | Use of a nonimmunosuppressive cyclosporin A derivative for hair growth |
| US6521595B1 (en) * | 1999-11-19 | 2003-02-18 | Lg Chemical, Ltd. | Nonimmunosuppressive [γ-hydroxy-methylleucine4] cyclosporin A, hair growth stimulator and external composition for skin using the same |
| KR20020039528A (en) * | 2000-11-22 | 2002-05-27 | 조명재 | Use of cyclosporin 7-thioamide derivatives for hair growth |
| KR100360716B1 (en) * | 2000-11-22 | 2002-11-13 | 주식회사 엘지생활건강 | Use of cyclosporin A 7-thioamide derivatives for hair growth |
| KR100681670B1 (en) * | 2001-02-14 | 2007-02-09 | 주식회사 엘지생활건강 | Use of [ ?-hydroxy-N-methyl-L-leucine9 ] cyclosporin A for hair growth |
| KR100695610B1 (en) * | 2001-05-15 | 2007-03-14 | 주식회사 엘지생활건강 | Topical compositions containing nonimmunosuppressive cyclosporin derivatives for treating hair loss |
| KR100695611B1 (en) * | 2001-05-17 | 2007-03-14 | 주식회사 엘지생활건강 | The use of Nonimmunosuppressive [?-hydroxy-N-methyl -L-leucine4] cyclosporin derivatives for treating hair loss |
-
2001
- 2001-05-11 KR KR10-2001-0025682A patent/KR100465012B1/en active IP Right Grant
-
2002
- 2002-05-09 US US10/141,723 patent/US6790830B2/en not_active Expired - Lifetime
- 2002-05-11 EP EP02728237A patent/EP1387660B1/en not_active Expired - Lifetime
- 2002-05-11 CN CNB028096754A patent/CN1248671C/en not_active Expired - Lifetime
- 2002-05-11 AT AT02728237T patent/ATE473730T1/en not_active IP Right Cessation
- 2002-05-11 RU RU2003135846/15A patent/RU2291682C2/en active
- 2002-05-11 TR TR2003/01931T patent/TR200301931T2/en unknown
- 2002-05-11 DE DE60237003T patent/DE60237003D1/en not_active Expired - Lifetime
- 2002-05-11 WO PCT/KR2002/000879 patent/WO2002092032A1/en active Application Filing
- 2002-05-11 JP JP2002588951A patent/JP4214181B2/en not_active Expired - Lifetime
- 2002-05-11 MX MXPA03010027A patent/MXPA03010027A/en active IP Right Grant
- 2002-05-11 BR BRPI0209619A patent/BRPI0209619B8/en not_active IP Right Cessation
- 2002-05-11 CA CA2446971A patent/CA2446971C/en not_active Expired - Lifetime
- 2002-05-11 ES ES02728237T patent/ES2348225T3/en not_active Expired - Lifetime
- 2002-05-11 AU AU2002258271A patent/AU2002258271B2/en not_active Expired
- 2002-05-11 PL PL366407A patent/PL208536B1/en unknown
- 2002-11-25 US US10/303,281 patent/US6762164B2/en not_active Expired - Lifetime
-
2003
- 2003-10-31 ZA ZA200308532A patent/ZA200308532B/en unknown
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