CN101897691A - Application of isothiocyanate compounds in promoting hair growth - Google Patents
Application of isothiocyanate compounds in promoting hair growth Download PDFInfo
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- CN101897691A CN101897691A CN2009100522316A CN200910052231A CN101897691A CN 101897691 A CN101897691 A CN 101897691A CN 2009100522316 A CN2009100522316 A CN 2009100522316A CN 200910052231 A CN200910052231 A CN 200910052231A CN 101897691 A CN101897691 A CN 101897691A
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- alopecia
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- ester
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Abstract
The invention provides application of isothiocyanate compounds in promoting hair growth, in particular relates to novel application of natural and artificially synthesized isothiocyanate compunds or derivatives and metabolites thereof in promoting hair growth, in particular treating and/or preventing hair loss (preferably androgenicalopecla), and related preventing, treating and/or beautifying methods thereof. The preparation of the invention can effectively prevent or treat hair loss, has few side effect of the conventional related medicament, and has wide clinical application and market developing prospect.
Description
Technical field
The present invention relates to chemistry, biology and field of medicaments, more specifically relate to isosulfocyanate compound application, especially its application in treating and/or preventing alopecia in promoting hair growth.
Related application
The present invention is based on the follow-up study of following patent application or patent:
The application of a kind of isosulfocyanate compound JC-5411 of natural and synthetic in the medicine of preparation prevention and treatment carcinoma of prostate, hepatocarcinoma, gastric cancer, pulmonary carcinoma, breast carcinoma, cervical cancer, melanoma and neuroblastoma, the patent No.: ZL200510040865.1, the applying date: on June 30th, 2005; Granted publication day: on January 7th, 2009;
The application of a kind of isosulfocyanate compound JC-5411 of natural and synthetic in the inhibitor of preparation transcription factor SP 1, application number: 200510095737.7, the applying date: on November 15th, 2005;
A kind of dispersant that is applicable to insoluble drug, application number: 200610038112.1, the applying date: on January 27th, 2006;
A kind of medicinal Emulsion that is applicable to insoluble drug and preparation method thereof (authorized but as yet bulletin), application number: 200410052816.5, the applying date: on July 14th, 2004;
The application of isosulfocyanate compound in prostatosis and skin carcinoma, application number: 200610126892.5, the applying date: on JIUYUE 11st, 2006;
Pct international patent: the application of isosulfocyanate compound in prostatosis and skin carcinoma, international application no: PCT/CN2006/003062, international filing date: on November 14th, 2006.
The content of above-mentioned patent application or patent is included this paper in as a reference in full with it.
Background technology
In the modern life, alopecia and alopecia have become human commonly encountered diseases and frequently-occurring disease, though they can not bring direct human body misery to the patient, bring many harmful effects for patient's spirit, and make troubles for patient's life.In the crowd, can be observed multi-form alopecia, as androgen alopecia (androgenetic alopecia, AGA), alopecia areata, pseudopelade, seborrheic alopecia, growing period alopecia and telogen effluvim etc., wherein androgen alopecia comparatively generally.AGA all can take place in masculinity and femininity, and the probability that the male is taken place generally is higher than the women, and the most of alopecias of male are occurred in the front portion and the top of head, and the women then is the hair attenuation of whole head.
Result to nearly 6000 male investigation showed in 2003: suffering from various degree among China 25-29 year male, the people of AGA accounts for 12% of this age bracket, 30-34 year accounts for 17%, 35-39 year accounts for 20%, and 40-44 year accounts for 24%, and the sickness rate in 45-49 year then can be up to 31%.Because the factor of aspects such as society, environment, in recent years, the AGA sickness rate improved constantly, and presented the trend that becomes younger.
The Therapeutic Method of AGA mainly contains Drug therapy and operative treatment (as hair grafting) two classes.Though hair grafting can improve the bad vision of alopecia, reaches certain cosmetic result, the surgery cost height, and have operation risk; The patient that the alopecia area is bigger often needs repeatedly to transplant in addition, and expense is higher, difficult popularizing.
The clinical manifestation of AGA usually diminishes for the head hair follicle, and trophophase shortens, and trophophase/resting stage hair follicle ratio descends, and diameter of hair diminishes, tails off, and the fine hair on birds or animals hair replaces terminal hair.Think that at present this disease is on the basis of certain heredodiathesis, with the androgen level increase relevant (Yin Xing equality, 5 in male hormone metabolism effect and inhibitor at the application of department of dermatologry, foreign medical science skin cypridology fascicle, 2004,30 (6): 375-377).As far back as the forties, Hamilton etc. just recognized relation between heredity and testosterone and the AGA (Hamilton JB.Male hormone is aprerequisite and an incitant in common bladness.Am J Anat 1942,71:451-480).
In recent years, along with molecular biological continuous development, it is clear that the relation of the pathogeny of AGA, particularly androgen and AGA more becomes.Under the normal physiological state, androgen plays certain stimulation facilitation to the growth promoter of hair in vivo, but can induce the mistake of taking off of some specific part hair.The inducement of AGA patient's alopecia district's alopecia; mainly be owing to the Developmental and Metabolic Disorder of androgen at the local skin tissue; and the enzyme relevant with male hormone metabolism and receptor activity and the quantity in the alopecia district increases (Hibberts NA etc.; Balding hair folliele dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp; Endocrinol; 1998; 156 (1): 59-65), the latter makes the scalp of easy alopecia produce powerful enlarge-effect to normal or higher androgen.For example, by the effect of 5,3alpha-Hydroxysteroid dehydrogenase etc., active lower testosterone (T) converts active higher dihydrotestosterone (DHT) to.Testosterone or dihydrotestosterone all must combine with the androgen receptor in concentrating on Follicular Unit, enter nucleus and produce a series of biological effects, make cyclic adenosine monophosphate reduction in the cell, and the anagen phase shortens or the hair follicle microminiaturization, thereby causes alopecia.Therefore, from pathogeny, the alopecia symptom of downward modulation androgen receptor overexpression can improvement AGA.
The drug main of treatment alopecia will be divided three classes on the market:
(1) with the finasteride is the 5 inhibitor of representative.This class medicine is by the inhibition 5, thereby the reduction testosterone has weakened the effect that excessive androgen stimulates in the organ to the conversion of the higher dihydrotestosterone of activity.But also there are some defectives in this medicine, such as recurrence etc. repeatedly after the sexual dysfunction that causes sexual impotence, the drug withdrawal.In addition because can't topical application, the hormonelike side effect make it not to be suitable for women, anemia of pregnant woman's forbidding (pay Guoqiang. the progress [J] of treatment androgenetic alopecia medicine. foreign medical science skin cypridology fascicle, 2000,26 (2): 68-72) or the like.
(2) androgen antagonist comprises steroidal class and nonsteroidal.This class medicine is by androgen antagonist or combine androgen receptor with androgen competitiveness and reduce androgenic effect.Steroidal class such as cyproterone acetate, estrogen etc., such medicine have the androgenic effect of antagonism, but produce womanlike side effect simultaneously.Though the nonsteroidal androgen antagonist does not have the side effect of hormone, but owing to compete acceptor site with all endogenous androgens, thereby can cause the male fetus tendency faggoty of male patient or female patient, and testis produces the feedback effect of overstimulation.
(3) potassium-channel opener, as minoxidil, so oral existence untoward reaction such as bring high blood pressure down fast is general external.But easily recurrence needs life-time service after this medicine drug withdrawal.This not direct regulation and control of medicine androgen or androgen receptor are therefore not strong to the therapeutic effect of androgenetic alopecia in addition.
As from the foregoing, all there is certain side effect in a line medicine for the treatment of alopecia in the market, and curative effect is also not satisfactory.In addition, from the angle of beauty treatment, this area also lacks and can promote hair growth to reach the compositions of cosmetic result safely, effectively.
Therefore, this area press for develop can be effectively, trichogenous compositions safely.
Summary of the invention
One of purpose of the present invention is just providing a kind of known compound---and the new purposes of isosulfocyanate compound in promoting hair growth, it is compositions related and use.
In a first aspect of the present invention, the application of derivant in the compositions of preparation promotion object hair growth that provides isosulfocyanate compound shown in the general formula I or its to have general formula I I:
R
1-X-NCS general formula I
In general formula I:
NCS is an isothiocyanate group;
X is-(CH
2)
n-, n is the integer of 0-4;
R
1Be polysubstituted or single the replacement or unsubstituted phenyl or C
2-4Thiazolinyl, described substituent group is selected from: sulfonic group, sulfamide groups, halogen, methyl, ethyl, methoxyl group, methyl mercapto, formamido group, acetylamino, methylamino, ethylamino, carboxyl and cyano group;
General formula I I
Among the general formula I I:
R
1W and X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The group that connects of carbon atom derived from following chemical compound: N-acetylcystein, glutathion, cysteine (C
1-C
6Alkyl) ester, cysteinyl aminoacid and cysteinyl aminoacid (C
1-C
6Alkyl) ester.
In a first aspect of the present invention, isosulfocyanate compound shown in the general formula I or its have the application of derivant in the compositions of preparation promotion object hair growth of general formula I I:
R
1-X-NCS
General formula I
In general formula I:
NCS is an isothiocyanate group;
X is-(CH
2)
n-, n is the integer of 0-4;
R
1Be polysubstituted or single the replacement or unsubstituted phenyl or C
2-4Thiazolinyl, described substituent group is selected from: sulfonic group, sulfamide groups, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, methyl mercapto, formamido group, acetylamino, methylamino, carboxyl and cyano group;
General formula I I
Among the general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The group that connects of carbon atom derived from following chemical compound: N-acetylcystein, glutathion, cysteine (C
1-C
6Alkyl) ester, cysteinyl aminoacid and cysteinyl aminoacid (C
1-C
6Alkyl) ester, what wherein aminoacid was more excellent has: glycine, glutamic acid, serine, alanine or methionine.
In an embodiment of the invention, described isosulfocyanate compound is for being selected from structural formula (1)～(8) chemical compound one or more:
In a preference, described isosulfocyanate compound is selected from one or more in the chemical compound shown in structural formula (1), (2), (5) or (6).
In a preference, described isosulfocyanate compound is available from animals and plants, chemosynthesis or half chemosynthesis.
In yet another embodiment of the present invention, described promotion hair growth is at being selected from down disease or the symptom of organizing: paratrichosis comes off or oligotrichosis.
In a preference, described compositions also suppresses the expression of androgen receptor, androgen receptor upstream gene Sp1 or androgen receptor downstream gene prostate specific antigen.
In another preference, described object is a mammal, preferred human or reward hair animal.
In yet another embodiment of the present invention, described paratrichosis comes off and is selected from: androgen alopecia, alopecia areata, pseudopelade, seborrheic alopecia, growing period alopecia or telogen effluvim.
In a preference, described paratrichosis comes off and is androgenetic alopecia.
In yet another embodiment of the present invention, described compositions is selected from: pharmaceutical composition, food, health product or cosmetics.
In yet another embodiment of the present invention, the dosage form of described compositions is selected from: bathe agent, lotion, liniment, tincture, oil preparation, ointment, plaster, paste, press agent, plaster, paster, liniment, membrane, gel, cataplasma, point-application agent, spray, aerosol, implant, Emulsion, shampoo, hair conditioner, suppository, tablet, capsule, pill, injection powder pin, injection or freeze dried powder.
In yet another embodiment of the present invention, be benchmark in the gross weight of compositions, isosulfocyanate compound shown in the described compositions formula of I or its content with derivant of general formula I I are 0.001～99.9 weight %.
In a preference, isosulfocyanate compound shown in the described compositions formula of I or its content with derivant of general formula I I are 0.01～90 weight %, more preferably 0.05～75 weight %.
In another preference, described compositions exists with the form that can directly use, gross weight in compositions is a benchmark, the content that isosulfocyanate compound shown in the general formula I or its have the derivant of general formula I I is 0.001～25 weight %, preferred 0.005～20 weight %, more preferably 0.05～10 weight %.
In another preference, described compositions exists with the form of concentrate, can dilute it before use, gross weight in dilution is a benchmark, the content that isosulfocyanate compound shown in the general formula I or its have the derivant of general formula I I is 0.001～25 weight %, preferred 0.005～20 weight %, more preferably 0.05～10 weight %.
In yet another embodiment of the present invention, described compositions also contains other active substance that prevents and/or treats alopecia.
In a preference, the described active substance that other prevents and/or treats alopecia is to be selected from down one or more that organize: 5 inhibitor, androgen antagonist or potassium-channel opener, preferred finasteride, epristeride, dutasteride, cyproterone acetate, estrogen, minoxidil or spironolactone.
In yet another embodiment of the present invention, before using described compositions, simultaneously or afterwards, be used described other prevent and/or treat alopecia active substance, implement at the surgical operation of alopecia or give radiation treatment at alopecia.
In a second aspect of the present invention, a kind of compositions is provided, it contains:
(A) isosulfocyanate compound shown in the general formula I of effective dose or its have the derivant of general formula I I:
R
1-X-NCS general formula I
In general formula I:
NCS is an isothiocyanate group;
X is-(CH
2)
n-, n is the integer of 0-4;
R
1Be polysubstituted or single the replacement or unsubstituted phenyl or C
2-4Thiazolinyl, described substituent group is selected from: sulfonic group, sulfamide groups, halogen, methyl, ethyl, methoxyl group, methyl mercapto, formamido group, acetylamino, methylamino, ethylamino, carboxyl and cyano group;
General formula I I
Among the general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The univalent perssad that connects of carbon atom derived from following chemical compound: N-acetylcystein, glutathion, cysteine (C
1-C
6Alkyl) ester, cysteinyl glycine, cysteinyl glycine (C
1-C
6Alkyl) ester, cysteinyl glutamic acid, cysteinyl glutamic acid (C
1-C
6Alkyl) ester, cysteinyl alanine, cysteinyl alanine (C
1-C
6Alkyl) ester, cysteinyl serine, cysteinyl serine (C
1-C
6Alkyl) ester, cysteinyl methionine, cysteinyl methionine (C
1-C
6Alkyl) ester;
(B) pharmaceutically acceptable carrier, food, health product or cosmetics acceptable carrier;
(C) one or more other prevent and/or treat the active substance of alopecia.
In an embodiment of the invention, the carrier in the described compositions is greasing base or water-soluble base.
In yet another embodiment of the present invention, described greasing base is for being selected from (b1) one or more, and described water-soluble base is for being selected from (b2) one or more:
(b1) vaseline, the vaseline lanonol, paraffin, liquid Paraffin, the liquid paraffin lanonol, ceresine, Cera Flava, white beeswax, Cera Flava, spermaceti, lanoline, Adeps Sus domestica, Adeps Caprae seu ovis, Oleum Sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil, soybean oil, rapeseed oil, Oleum sesami, Oleum Helianthi, almond oil, Oleum Ricini, olive oil, Oleum Gossypii semen, dimethicone, hydrogenated vegetable oil, median chain triglyceride oil, isopropyl myristate, stearic acid, hexadecanol, Synthetic Spermacet, octadecanol, face the phthalic acid diester, Brazil wax, acetone, petroleum ether, ethyl oleate or isopropyl palmitate; Or
(b2) distilled water, ethanol, isopropyl alcohol, glycerol, glycerinum amyli, monoethanolamine, the glycerol triacetate, Lac, carob, gelatin, guar gum, carrageenin, arabic gum, the tragakanta, Xanthan gum, chitosan, sodium alginate, methylcellulose, carmellose, carboxymethylcellulose calcium, carmethose, hyetellose, hymetellose, hyprolose, low-substituted hydroxypropyl cellulose, hypromellose, the hypromellose phthalate ester, carbomer, Polyethylene Glycol or veegum.
In yet another embodiment of the present invention, the described active substance that other prevents and/or treats alopecia is to be selected from down one or more that organize: 5 inhibitor, androgen antagonist or potassium-channel opener.
In a preference, described active substance is preferably: finasteride, epristeride, dutasteride, cyproterone acetate, estrogen, minoxidil or spironolactone.
In a third aspect of the present invention, a kind of beauty method is provided, described method comprises and gives derivant that isosulfocyanate compound shown in the object general formula I or its have general formula I I or compositions of the present invention to promote the growth of described object hair.
In a fourth aspect of the present invention, a kind of method that prevents and/or treats alopecia is provided, described method comprises that isosulfocyanate compound shown in the general formula I that needs the described object effective dose that prevents and/or treats or its have the derivant of general formula I I.
Others of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Description of drawings
Fig. 1: the newborn hair growth velocity ratio of mice.
Fig. 2: the new piliation area of mice relatively.
Fig. 3: the new piliation weight ratio of mice.
Fig. 4: 11 days mice photos of administration:
Fig. 4 A: 11 days negative control group mices of administration photo;
Fig. 4 B: 11 days administration groups of administration mice photo.
Fig. 5: 13 days mice photos of administration:
Fig. 5 A: 13 days negative control group mices of administration photo;
Fig. 5 B: 13 days administration groups of administration mice photo.
Fig. 6: 18 days mice photos of administration:
Fig. 6 A: 18 days negative control group mices of administration photo;
Fig. 6 B: 18 days administration groups of administration mice photo.
The specific embodiment
The inventor is through extensive and deep research, found known compound---isosulfocyanate compound all has obvious facilitation for speed, area and the quality of hair growth, and almost do not have toxic and side effects, can be used for promoting safely and effectively hair growth.Thus, the inventor has developed and can be used for trichogenous compositions, and has finished the present invention on this basis.
Isosulfocyanate compound
As used herein, term " isosulfocyanate compound ", " isosulfocyanate active substance " and " active substance of the present invention " are used interchangeably, and all are meant chemical compound, its derivant (derivant that especially has general formula I I), metabolite or their combination with the described structure of general formula I.
Isosulfocyanate compound or derivatives thereof of the present invention, metabolite, include but not limited to the conjugate (BITC-NAC, PEITC-NAC, AITC-NAC and SPITC-NAC) that the related benzyl isothiocyanate (BITC) of Chinese invention patent 200610126892.5, phenethyl isothiocyanate (PEITC), allyl group isosulfocyanate (AITC), 4-sulfonic group phenyl isothiocyanate (SPITC) and they form with N-acetylcystein respectively, correspond respectively to structural formula (1)～(8) herein.
In the present invention, have no particular limits, can from natural plants (for example Caulis et Folium Brassicae junceae or Radix Raphani), extract, adopt the method preparation of chemosynthesis or half chemosynthesis etc. such as it for the method that obtains isosulfocyanate compound.Employed isosulfocyanate compound can obtain by commercially available approach among the present invention, for example can be available from Jiexi Medical Science ﹠ Technology Co., Ltd., Wuxi City or SIGMA company.
Trichogenous activity of isosulfocyanate compound and application
The invention provides the new purposes of isosulfocyanate compound in promoting hair growth.Isosulfocyanate compound or contain this compounds as composition of active components among the present invention can effectively promote the growth of hair (preferred hair), improves alopecia, the effect that plays prevention, treatment and/or improve looks.
Be not limited to theory, isosulfocyanate compound of the present invention can promote hair growth by following mechanism:
(1) promote hair growth position blood circulation: the hair growth influence factor studies show that, increases the blood circulation of local skin, helps the growth of hair.Isosulfocyanate compound of the present invention has local irritant effect to the hair growth position, can improve the blood circulation of site of administration, thereby promotes hair growth;
(2) suppress the transcript and expression of unusual androgen receptor: isosulfocyanate compound or derivatives thereof, metabolite can be respectively suppress the transcript and expression (can with reference to previously described Chinese patent application 200610126892.5) of unusual androgen receptor from androgen receptor AR, AR upstream gene sp1 and three aspects of AR downstream gene SPA.
Therefore, isosulfocyanate compound or derivatives thereof of the present invention, metabolite also can effectively prevent and/or treat the androgenetic alopecia that common drug, food, health product or cosmetics are difficult to effectively prevention or treatment except promoting to prevent and/or treat the common alopecia.And, when preventing and/or treating alopecia, also can be used for treating the acne vulgaris or the seborrhea that cause because of androgen is excessive, reach the effect of comprehensive beauty.
Thus, also provide isosulfocyanate compound and compositions thereof the purposes in promoting hair growth among the present invention, alopecia clinical treatment and/or prevention that it can be used for therapeutic purposes also can be used for the beauty treatment and/or the health care of non-therapeutic purposes.Perhaps, isosulfocyanate compound of the present invention and compositions thereof can be applied to other mammal, especially reward hair animal (for example pet dog, cat etc.).
Compositions and application process
Compositions of the present invention can be pharmaceutical composition (medicine), food, health product or cosmetics, wherein contains isosulfocyanate compound or derivatives thereof, the metabolite of effective dose; Acceptable carrier or excipient on pharmacy, bromatology, health care conduct and learning or the cosmetic conduct and learning; And other optional trichogenous active substance.
As used herein, term " contain " or " comprising " comprised " comprising ", " basically by ... constitute " and " by ... constitute ".As used herein, the composition of term " acceptable on pharmacy, bromatology, health care conduct and learning or the cosmetic conduct and learning " is applicable to people and/or animal and does not have excessive bad side reaction (as toxicity, stimulation and allergy), the material of rational benefit/risk ratio is promptly arranged.As used herein, term " effective dose " is meant and can produces function or amount active and that can be accepted by people and/or animal to people and/or animal.
As used herein, term " pharmaceutically acceptable carrier " refers to be used for the treatment of the carrier of agent administration, comprises various excipient and diluent.This term refers to some medicament carriers like this: they itself are not necessary active component, and do not have undue toxicity after using.Suitable carriers is well known to those of ordinary skill in the art." Lei Mingdun pharmaceutical science " (Remington ' s Pharmaceutical Sciences, Mack Pub.Co. can find discussing fully about pharmaceutically acceptable excipient in N.J.1991).
Isosulfocyanate active substance effective ingredient accounts for the 0.001-99.9wt% of composition total weight in the compositions of the present invention; Being preferably the 0.01-90wt% of composition total weight, more preferably is 0.05-75wt%, and surplus is materials such as pharmaceutically acceptable carrier and other additive.
In a preferred embodiment of the present invention, described compositions is unit dosage forms or multi-pharmaceutics, and wherein the isosulfocyanate content of active substance is the 0.001-3000mg/ agent, preferred 0.01-2000mg/ agent, more preferably 0.1-1500mg/ agent.
In a preference of the present invention, contain in the described compositions: the isosulfocyanate active substance of low dosage, for example 0.01-10mg/ agent, more preferably 0.05-8mg/ agent further preferably contains the 0.1-5mg/ agent; The isosulfocyanate active substance of dosage in containing, for example 1-1000mg/ agent; More preferably 5-800mg/ agent, further preferred 10-500mg/ agent, more preferably 15-200mg/ agent; Or the isosulfocyanate active substance of high dose (as the concentrate that can before using, dilute), for example its content is the 100-3500mg/ agent; More preferably 500-3000mg/ agent, further preferred 1000-2500mg/ agent, more preferably 1500-2000mg/ agent.
In another preference of the present invention, use compositions of the present invention once a day or repeatedly, for example 1,2,3,4,5 or 6 time.
Medicine, food, health product, the cosmetic composition that contains isosulfocyanate compound or derivatives thereof, metabolite of the present invention, except that as described in Chinese invention patent 200610126892.5, can be outside the various dosage forms of suitable for oral administration administration, can also be various topical administration formulations or other gastrointestinal tract external administration preparation.For example, topical administration formulations of the present invention, can also further be prepared into (including but not limited to): bathe agent, lotion, liniment, tincture, oil preparation, ointment, plaster, paste, press agent, plaster, paster, liniment, membrane, gel, cataplasma, point-application agent, spray, aerosol, implant, Emulsion, shampoo and hair conditioner etc. by adding adjuvants such as surfactant, Percutaneous absorption enhancer, antiseptic, solvent, antioxidant, wetting agent, pH regulator agent, coloring agent, spice.
In an embodiment of the invention, described topical administration formulations can comprise following composition:
(a) 0-50 weight portion isosulfocyanate compound or derivatives thereof natural or synthetic, metabolite, described isosulfocyanate compound include but not limited to phenethyl isothiocyanate, benzyl isothiocyanate, allyl group isosulfocyanate, 4-sulfonic group phenyl isothiocyanate; Described derivant, metabolite include but not limited to the N-acetylcystein conjugate of isosulfocyanate compound, preferably, phenethyl isothiocyanate-N-acetylcystein conjugate, benzyl isothiocyanate-N-acetylcystein conjugate, allyl group isosulfocyanate-N-acetylcystein conjugate, 4-sulfonic group phenyl isothiocyanate-N-acetylcystein conjugate;
(b) 0-1000 weight portion carrier for active principle, described carrier for active principle is selected from greasing base, water-soluble base:
(b1) greasing base, described greasing base is selected from: vaseline, the vaseline lanonol, paraffin, liquid Paraffin, the liquid paraffin lanonol, ceresine, Cera Flava, white beeswax, Cera Flava, spermaceti, lanoline, Adeps Sus domestica, Adeps Caprae seu ovis, Oleum Sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil, soybean oil, rapeseed oil, Oleum sesami, Oleum Helianthi, almond oil, Oleum Ricini, olive oil, Oleum Gossypii semen, dimethicone, hydrogenated vegetable oil, median chain triglyceride oil, isopropyl myristate, stearic acid, hexadecanol, Synthetic Spermacet, octadecanol, face the phthalic acid diester, Brazil wax, acetone, petroleum ether, ethyl oleate, the mixture of one or more compositions in the isopropyl palmitate.
(b2) water-soluble base, described water-soluble base is selected from: distilled water, ethanol, isopropyl alcohol, glycerol, glycerinum amyli, monoethanolamine, the glycerol triacetate, Lac, carob, gelatin, guar gum, carrageenin, arabic gum, the tragakanta, Xanthan gum, chitosan, sodium alginate, methylcellulose, carmellose, carboxymethylcellulose calcium, carmethose, hyetellose, hymetellose, hyprolose, low-substituted hydroxypropyl cellulose, hypromellose, the hypromellose phthalate ester, carbomer, Polyethylene Glycol, the mixture of one or more compositions of veegum etc.Topical administration formulations of the present invention is characterized in that, can also further be prepared into other suitable dosage form by adding following adjuvant, and other adjuvant that it added comprises:
(i) 0-200 weight portion emulsifying agent, described emulsifying agent is selected from albumin, casein, lecithin, carbomer, lanoline, lanonol, cholesterol, spermol, docusate sodium, Ethylene Glycol Palmitostearate, glyceryl palmitostearate, the newborn soap of triethanolamine stearic acid, sodium lauryl sulphate, glyceryl monostearate, glyceryl monooleate, Polysorbate, the anhydrous sorbitol fatty acid ester, paregal O, polyoxyethylene nonylphenol ether, Brij30, polyoxyethylene stearic acid ester, the VE succinic acid macrogol ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, Polyethylene Glycol, polyvinylpyrrolidone, polyoxyethylene alkyl ether, propylene glycol alginate, sorbitan ester, stearic acid, the anion emulsifing wax, the mixture of one or more compositions of nonionic emulsifing wax etc.;
(ii) 0-20 weight portion Percutaneous absorption enhancer, described Percutaneous absorption enhancer is selected from: Tetrahydrofurfuryl polyethylene glycol ether, α-pyrrolidone, the N-N-methyl 2-pyrrolidone N-, the 5-N-methyl 2-pyrrolidone N-, 1-5-dimethyl pyrrole ketone, N-N-ethyl pyrrole N-ketone, 5-carboxy pyrrole ketone, ethanol, propylene glycol, decanol, glycerol, ethyl acetate, dimethyl sulfoxine, dimethyl formamide, dimethyl acetylamide, decyl methyl sulfoxide, oleic acid, oleate, linoleic acid, linoleate, lauric acid, laurate, myristic acid, isopropyl myristate, laurocapram and homologue thereof, carbamide, cholic acid, cholate, salicylic acid, Oleum menthae, eucalyptus oil, eucalyptole, Oleum Terebinthinae, aminoacid, phospholipid, Camphora, limonene, beta-schardinger dextrin-, HP-, the mixture of one or more compositions of dimethyl-.
(iii) 0-50 weight portion antiseptic, described antiseptic is selected from: hexedine, imidazolidine urea, sorbic acid, 2-furancarboxylic acid, captan, diethylene glycol monomethyl ether, hexene ethylene glycol, Benasept, hibitane, benzoic acids, chlorocresol, cresol, parabens, chlorobutanol, benzalkonium chloride, benzethonium chloride, cetrimonium bromide, bronopol, chlorhexidine, butyl hydroxybenzoate, methyl hydroxybenzoate, propyl hydroxybenzoate, ethyl hydroxybenzoate, to the mixture of one or more compositions of chloro-m-xylene, phenoxyethanol, sodium propionate;
(iv) 0-50 weight portion antioxidant, described antioxidant is selected from: the mixture of one or more compositions in VE, VC, sodium ascorbate, ascorbyl palmitate ester, butylated hydroxyanisole, fourth hydroxy-methylbenzene (BHT), chlorocresol, propyl gallate, Jiao's property end gallate-based ethyl ester or propyl ester, two uncle butylparaben phenol, BHA, citric acid, tartaric acid, ethylenediaminetetraacetic acid, disodiumedetate, sulfydryl dipropionic acid and sulphite, potassium metabisulfite, the sodium pyrosulfite;
(v) other additive of 0-50 weight portion: described other composition comprises wetting agent, pH regulator agent, coloring agent, spice etc.
Described wetting agent can be selected from: one or more mixture in glycerol, propylene glycol, butanediol, sorbitol, xylitol, Cyclomethicone, trehalose, pyrrolidone sodium carboxylate, Polyethylene Glycol, sodium lactate, mucopolysaccharide, sulphuric acid ointment element, ceramide, hyaluronic acid, chitin, chitosan, (anchoring filament wetting agent) acetyl group hyaluronic acid, the Mel.
Described pH regulator agent can be selected from: citric acid, potassium citrate, citric acid, fumaric acid, lactic acid, tartaric acid, hydrochloric acid, phosphoric acid, acetic acid, malic acid, sodium hydroxide etc., ammonia, dimethanolamine, meglumine, potassium hydroxide, one or more mixture of tartaric acid.
Described coloring agent can be selected from: amaranth, curcumin, riboflavin, tartrazines, D C Yellow No. 10, sunset yellow, carmine, light red, erythrosine, Ponceaux, A Luola is red, patent blue 5, indigo carmine, brilliant blue FCF, chlorophyll, chlorophyll and CHLOROPHYLLINE ketone complex, green S, caramel (caramel), brilliant black BN, active carbon, capsanthin, carotenoid, capsorubin, lycopene, phylloxanthin, canthaxanthin, beet red, anthocyanin, anthocyanidin, the delphinin pigment, enidin, pelargonidin, the flower of Paeonia lactiflora Pal1. pigment, phenethanol, titanium dioxide, ferrum oxide, hydrated ferric oxide., Alumina, aluminium powder, bronze powder, calcium carbonate, canthaxanthin, the mixture of one or more compositions of Muscovitum etc.
Described corrective incense agent can be selected from: the mixture of one or more compositions of Oleum menthae, Mentholum, Camphora, Borneolum Syntheticum, essence, dimethyl ether, ethyl acetate, ethyl vanillin etc.
In medicine of the present invention, food, health product, cosmetic composition, more excellent in being the compositions of effective ingredient with the phenethyl isothiocyanate, when the treatment relevant disease, it can be independent use, also can be the associating use, use or unite use etc. with biological regulator as uniting to use or unite to use or unite to use or unite to use or unite with gene therapy with radiation treatment with Chinese herbal medicine with one or more Western medicine with surgical operation.
Advantage of the present invention
Compared with prior art, superiority of the present invention is:
1. the present invention has proved that first isosulfocyanate compound can effectively promote hair growth, thereby provides new approach for alopecia clinical prevention and/or treatment, beauty treatment or health care;
2. the invention provides the combination formula that isosulfocyanate compound is the topical administration formulations of effective ingredient, said preparation is for promoting that hair growth is very effective; And the active component isosulfocyanate compound can be used safely in human body through the FDA authentication, has high security;
3. the present invention has disclosed the mechanism of action of the uniqueness of isosulfocyanate compound treatment androgenetic alopecia: isosulfocyanate compound or derivatives thereof, metabolite suppress the transcript and expression of unusual androgen receptor respectively from androgen receptor AR, AR upstream gene sp1 and three aspects of AR downstream gene SPA, thereby effectively treat the androgen alopecia.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1: the ointment research of isosulfocyanate compound
Embodiment 1-1:
Prescription: phenethyl isothiocyanate 0.05%
White vaseline 50.00%
Yellow beeswax 4.95%
Liquid paraffin 40.00%
Glyceryl monostearate 5.00%
Technology: get recipe quantity white vaseline, liquid paraffin, yellow beeswax and join in the beaker and heat, make its fusing, stir, add glyceryl monostearate, stir evenly.Take by weighing the recipe quantity phenethyl isothiocyanate in another beaker, the liquid of above-mentioned mixing is joined in the beaker that phenethyl isothiocyanate is housed mix homogeneously with the equivalent incremental method, continue to be stirred to natural cooling, treat liquid become gradually thick after, stop to stir, promptly.
Embodiment 1-2:
Prescription: benzyl isothiocyanate 0.75%
White vaseline 51.00%
Propylparaben 0.03%
Yellow beeswax 7.10%
Liquid paraffin 41.12%
Technology: get recipe quantity white vaseline, propylparaben, liquid paraffin, yellow beeswax and join in the beaker and heat, make its fusing, stir.Take by weighing recipe quantity benzyl isothiocyanate in another beaker, the liquid of above-mentioned mixing is joined in the beaker that the benzyl isothiocyanate is housed mix homogeneously with the equivalent incremental method, continue to be stirred to natural cooling, treat liquid become gradually thick after, stop to stir, promptly.
Embodiment 1-3:
Prescription: allyl group isosulfocyanate 2.50%
White vaseline 91.00%
Vitamin E (tocopherol) 2.00%
Glyceryl monostearate 4.50%
Technology: get the recipe quantity white vaseline, vitamin E joins in the beaker and heats, and makes its fusing, stir, add glyceryl monostearate, stir evenly.Take by weighing the recipe quantity allyl group isosulfocyanate in another beaker, the liquid of above-mentioned mixing is joined in the beaker that allyl group isosulfocyanate is housed mix homogeneously with the equivalent incremental method, continue to be stirred to natural cooling, treat liquid become gradually thick after, stop to stir, promptly.
Embodiment 1-4:
Prescription: phenethyl isothiocyanate 5.00%
White vaseline 92.00%
Propylparaben 0.03%
Vitamin E (tocopherol) 2.97%
Technology: get recipe quantity white vaseline, propylparaben, vitamin E and join in the beaker and heat, make its fusing, stir.Take by weighing the recipe quantity phenethyl isothiocyanate in another beaker, the liquid of above-mentioned mixing is joined in the beaker that phenethyl isothiocyanate is housed mix homogeneously with the equivalent incremental method, continue to be stirred to natural cooling, treat liquid become gradually thick after, stop to stir, promptly.
Embodiment 1-5:
Prescription: PEITC-NAC 1.49%
Glycerol 9.91%
Triethanolamine 0.40%
Stearic acid 12.88%
Vaseline 0.99%
Liquid paraffin 5.95%
Glyceryl monostearate 3.96%
Distilled water 64.42%
Technology: PEITC-NAC, glycerol and triethanolamine are added in the distilled water heating for dissolving.Get vaseline, stearic acid, liquid paraffin, glyceryl monostearate heating and melting formation oil phase.Under stirring oil phase is slowly added in the aqueous solution of equality of temperature, continue to be stirred to total condensation, promptly.
Embodiment 1-6:
Prescription: 4-sulfonic group phenyl isothiocyanate 0.29%
Sodium borate 0.67%
Cera alba 6.73%
Hexadecanol 7.69%
Vaseline 17.31%
Liquid paraffin 41.35%
Sorbitan fatty acid ester 80 2.88%
Lanoline 1.92%
Distilled water 21.16%
Technology: sodium borate is added in the distilled water, and heating for dissolving is cooled to room temperature, adds 4-sulfonic group phenyl isothiocyanate, and stirring and dissolving gets transparent and homogeneous solution.Get vaseline, cera alba, hexadecanol, liquid paraffin, sorbitan fatty acid ester 80, lanoline heating and melting formation oil phase.Stir the oil phase that down aqueous solution is slowly added equality of temperature, continue to be stirred to total condensation, promptly.
Embodiment 2: the tincture research of isosulfocyanate compound
Prescription: phenethyl isothiocyanate 0.20%
Ethanol 79.80%
Propylene glycol 20.00%
Technology: get ethanol and propylene glycol and put in the same beaker mix homogeneously.Other gets a beaker, and precision takes by weighing the phenethyl isothiocyanate of recipe quantity, pours a spot of matrix solution into, after stirring, adds a small amount of substrate again, stir, and operation in accordance with the law, to the substrate of capacity, stirring stops, promptly.
Embodiment 3: the liniment research of isosulfocyanate compound
Embodiment 3-1
Prescription: phenethyl isothiocyanate 2.00%
Oleum Ricini 20.00%
Vitamin E 1.00%
Semen Maydis oil 77.00%
Technology: get phenethyl isothiocyanate, Oleum Ricini, Semen Maydis oil and vitamin E mix homogeneously promptly.
Embodiment 3-2
Prescription: PEITC-NAC 0.88%
Laurocapram 1.77%
Glycerol 8.85%
Distilled water 88.50%
Technology: get PEITC-NAC, laurocapram, glycerol dispersed with stirring, adding distil water is stirred to dissolving fully, promptly.
Embodiment 4: the paste research of isosulfocyanate compound
Prescription: PEITC-NAC 0.88%
Tragakanta 1.77%
Hypromellose 1.00%
Glycerol 7.85%
Distilled water 88.50%
Technology: get the PEITC-NAC porphyrize and sieve, add an amount of distilled water and grind well.Get the recipe quantity hypromellose, the adding distil water swelling is complete.After tragakanta and glycerol being mixed well, with hypromellose and PEITC-NAC solution mixing, adding distil water is to full dose, promptly again.
The liniment research of embodiment 5. isosulfocyanate compounds
Prescription: PEITC-NAC 2.50%
Ethanol 60.00%
Polyvinyl alcohol 2.50%
Propylene glycol 10.00%
Distilled water 25.00%
Technology: get polyvinyl alcohol and add distilled water, fully swelling is heated into rubber cement liquid, ethanol and propylene glycol mixing, and adding PEITC-NAC is stirred to molten entirely, adds the polyvinyl alcohol glue serosity while stirring, stirs evenly, promptly.
Mould dose of research of the spray of embodiment 6. isosulfocyanate compounds
Prescription: 4-sulfonic group phenyl isothiocyanate 0.6%
Borneolum Syntheticum 0.12%
Mentholum 0.10%
Nipalgin 0.03%
Polyoxyethylene sorbitan monoleate 1.50%
Distilled water adds to 100%
Technology: get the about 70ml to 100ml of distilled water in beaker, add nipalgin and be heated to dissolving, solution is put and is chilled to room temperature, adds 4-sulfonic group phenyl isothiocyanate, is stirred to dissolving, gets uniform solution; Other gets Borneolum Syntheticum, Mentholum, polyoxyethylene sorbitan monoleate and stirs and make dissolving, adds in the above-mentioned solution, and adding distil water to 100%, promptly.
Embodiment 7: the stability study of effective ingredient in the ointment
Experimental apparatus:
S.C.101 type air blast Constant Temp. Oven: Jiaxing, Zhejiang Province county newly wins electric heating instrument plant, METTLER AE100 electronic balance: Switzerland Mei Tele company, SUMMIT HPLC: U.S. Dai An company.
Experimental technique:
It is an amount of to get among the foregoing description 1-1,1-2,1-3 and the 1-4 preparation, puts in the clean cillin bottle, adds rubber stopper, and aluminium lid is airtight, and put under 60 ℃ of conditions and place, in the 0th, 5, sampling in 10 days, high performance liquid chromatography is investigated the variation of content.
Experimental result:
Experimental result is as shown in table 1:
Table 1. stability study experimental result
| Embodiment | 60 ℃ of 10 days active component were compared (%) with 0 day |
| 1-1 | 102.11 |
| 1-2 | 98.6 |
| 1-3 | 102.2 |
| 1-4 | 100.9 |
Discussion of results:
The above results shows: under this development test condition, tried that active component has good stability in the ointment.
Embodiment 8: phenethyl isothiocyanate ointment irritation test
Prescription 8-1: phenethyl isothiocyanate 0.05%
White vaseline 50.00%
Yellow beeswax 2.50%
Propylparaben 0.03%
Liquid paraffin 45.42%
Vitamin E (tocopherol) 1.00%
Glyceryl monostearate 1.00%
Prescription 8-2: phenethyl isothiocyanate 5.00%
White vaseline 50.00%
Yellow beeswax 2.50%
Propylparaben 0.03%
Liquid paraffin 40.47%
Vitamin E (tocopherol) 1.00%
Glyceryl monostearate 1.00%
Technology: white vaseline+yellow beeswax+liquid paraffin+propylparaben is put same beaker, is heated to 100 ℃, is stirred to evenly.Stirring is cooled to about 70～80 ℃, adds glyceryl monostearate, stirs, and adds vitamin E, stirs.About 70 ℃ of insulations are standby.Other gets a 25ml small beaker, and precision takes by weighing the phenethyl isothiocyanate of recipe quantity, pours an amount of matrix solution into, and 70 ℃ of insulations are stirred to evenly, continue to add an amount of substrate, is stirred to evenly, and operation in accordance with the law until capacity, is stirred to evenly.Stir cooling, during extremely near thickness, packing.
Administering mode:
Get the assigned address that the above-mentioned ointment of about 0.05g spreads upon the pharmaceuticals researcher respectively, observe and in the record administration phase skin change, comprise red, swell, itch, pain, irritative symptoms in various degree such as peppery.
Table 2. phenethyl isothiocyanate ointment irritation test
Result and discussion: above-mentioned experiment shows that the isosulfocyanate compound external preparation of being tested has certain zest to human body skin.Compare various dose group human body irritative response as seen, this zest and the amount positive correlation that is subjected to active component in the reagent thing, promptly along with the increase that is subjected to the amount of active component in the reagent thing, the corresponding increase of zest.After the low dose group 2 hours, zest disappears substantially.After the high dose group 2 hours, the zest behind arm, inboard arm and the ear disappears substantially, and certain zest is still arranged at Min Gan eyelid and lip top relatively, but the damage untreated that zest causes is recovered naturally.
The hair growth influence factor studies show that: increase the blood circulation of local skin, help the growth of hair.This experimental study is the result show, is subjected to that active component is similar to Fructus Capsici, Bulbus Allii and Mylabris tincture in the reagent thing, and skin is had local irritant effect, can improve the medicine-feeding part blood circulation, thereby promotes hair growth.
Embodiment 9: the mice hair growth promoting test of isosulfocyanate compound
Materials and methods:
Reagent: phenethyl isothiocyanate (PEITC), synthetic by Jiexi Medical Science ﹠ Technology Co., Ltd., Wuxi City, HPLC measures its content (＞99%); Other reagent is commercially available chemical pure or analytical pure product.
Equipment: Mettler AE 100 electronic balances, Mettler PE 360 electronic balances, VWR V-200/20-200 μ l liquid-transfering gun, lucky board double-edged razor blade, Olympus μ l010 digital camera.
Animal model: be in the male C3H/HeN mice in 7 ages in week of telogen, purchase Experimental Animal Center in Yangzhou University.Supply conventional food and drinking water, temperature 20-26 ℃, light and shade replaces time 12h/12h.
Drug therapy: tried Mus random packet by weight, one group of administration, one group of negative control, 9 every group.Being tried the Mus back with every, to shave off area be 3 * 4cm
2Hair as pilot region.The administration group is administered once every day, and 7 days weekly, administration was 18 days altogether.At every turn be 0.2% PEITC tincture 200 μ l, be uniformly coated on pilot region to concentration.Self administration of medication rose in first day, observed 20 days.Negative control group is given the blank substrate of equal volume, parallel comparison simultaneously.
Observe and estimate:
The test initial stage is observed comparison to test Mus treatment region hair growth situation and medicine skin irritation every other day.When being tried Mus viewing area color burn, promptly pink changes into and observing every day when lead changes, and the comparison of taking pictures.
(1) newborn hair growth evaluation
The hair growth velocity ratio is: when hair growth first sign (skin color deepens, and the melanocyte in the hair follicle begins synthesis of melanin) occurring from the processed zone of mice, according to the evaluation criterion of table 3, estimate the hair growth speed of being tried Mus.
Table 3. hair growth speed standards of grading
| The phenomenon of visual observations | Scoring |
| Pink skin | - |
| Local color deepens to present lead | + |
| Overwhelming majority processing region color burn | ++ |
| Color is further deepened, near black | +++ |
| The new piliation of local appearance | ++++ |
| Form newborn hair area in blocks | +++++ |
According to table 3, marked to trying Mus, reached to try Mus ++ or the percentage rate of the mice of higher (fully anagen) is to administration natural law mapping (Fig. 1), the growth of assessing hair.
As can be seen from Figure 1, the administration of administration group is in the time of the 11st day, and about 30% mice reaches ++ or higher, in the time of the 12nd day, 100% mice reaches ++ or higher; The negative control group administration is in the time of the 11st day, and about 20% mice reaches ++ or higher, in the time of the 12nd day, about 30% mice reaches ++ or higher, in the time of the 16th day, mice ability 100% reaches ++ or higher.This explanation administration group hair growth speed obviously is better than negative control group, means that the hair growth amortization period has been shortened in the use of medicine, impels the anagen of tried mice and enter sooner.
New piliation area compares: administration is in the time of the 18th day, and the processing region of all mices of administration group has all covered the close and thick new piliation of one deck, and coverage rate is 100%, and still has the processing region of part mice all not become mildewed in the negative control group.Measure the region area that do not become mildewed, the average hair coverage rate that calculates negative control group mice processing region is 87.9%, the results are shown in Table 4, and (Fig. 2) compared in mapping in view of the above.
The new piliation area of table 4. relatively
Two groups of data P＜0.05 have significant difference in the table 4.The result of the test explanation, the new piliation area of administration group mice processing region is significantly greater than negative control group.
New piliation mass ratio is: after the administration the 20th day, see that in appearance although the processing region of test Mus all has new piliation, the new piliation of administration group processing region is closeer and long, and negative control group is rarer and short.For this difference of quantitative study, get every mice in negative control group and the administration group respectively, shave at the same position of processing region and get 1 * 1cm
2The new piliation in zone is used scales/electronic balance weighing respectively after the merging.The results are shown in Figure 3, the gross weight of shaving the new piliation of getting of mice with homalographic is 0.0157g in negative control group, and the administration group is 0.0278g, and negative control group only is 56.5% of administration group.This illustrates that from the quality angle of new piliation trial drug has promoted the growth of new piliation really.
New piliation direct visual comparison: as seen from Figure 4, administration the 11st day, administration group mice overwhelming majority processing region color burn, and negative control group mice processing region still is a pink; As seen from Figure 5, administration the 13rd day, administration group mice processing region color is further deepened and visible new piliation, and the color of negative control group mice processing region begins to deepen; As seen from Figure 6, administration the 18th day, the new piliation of administration group mice processing region is close, long, thick, and the negative control group major part is then rare, short, thin, therefore can find out intuitively that the growth of the new piliation of administration group mice is significantly better than negative control group.
(2) zest evaluation: in the whole experiment, negative control group is not observed any irritative symptoms; Skin is red during the initial stage deepens in administration for the administration group, examines visible trickle decortication after a while, but to the middle and late stage of administration, above-mentioned symptom weakens gradually until disappearance.
Conclusion:
Be in the male C in 7 ages in week of telogen
3The H/HeN mice is in case shaved hair, skin pinkiness (the vision sign of hair growth amortization period).According to bibliographical information, first sign the anagen of tried Mus is that the melanocyte in the hair follicle begins synthesis of melanin, thereby causes skin color to be deepened, and can observe the growth course of new piliation.
The difference of administration group and matched group is observed and has been studied in this test respectively from the speed of growth, growth area and growth quality three aspects of new piliation.Comprehensive above-mentioned result of the test as can be known, no matter be the hair growth speed of processing region, still grow area or stand density, the administration group all obviously is better than negative control group.These presentation of results: the active component isosulfocyanate compound in the trial drug can effectively promote the growth of new piliation really.
Embodiment 10: phenethyl isothiocyanate is to the influence of central nervous system, cardiovascular, respiratory system
Reagent: phenethyl isothiocyanate (PEITC), synthetic by Jiexi Medical Science ﹠ Technology Co., Ltd., Wuxi City, HPLC measures its content (＞99%); Other reagent is commercially available chemical pure or analytical pure product.
Experimental data statistics: carry out date processing with SPSS 10.0for windows software.
Experimental animal: cleaning level ICR mice, 7 ages in week, body weight 18～20g, male and female half and half are provided by Shanghai Slac Experimental Animal Co., Ltd., 20～25 ℃ of ambient temperatures, relative humidity 40%～70%.
Regular grade Beagle dog, 10～11 monthly ages, body weight 8～11kg, male and female half and half are provided by Nanjing An Limo Science and Technology Ltd., 20～25 ℃ of ambient temperatures, relative humidity 40%～70%.
Test method and result
The central nervous system:
One time per os gives mice 30mg/kg the phenethyl isothiocyanate of dosage, observes the influence of phenethyl isothiocyanate to central nervous system of mice.The result is as follows:
(1) qualitative observation and semi-quantitative assessment test: per os gives behind the phenethyl isothiocyanate 30,60,90,120 minutes, and the appearance of animal, hair, posture, gait are normal, effects such as no anesthesia, hypnosis, calmness, no position variation; Movable normal to the pain sensation and luminous reflectance, pupillary reflex is normal; Mice righting reflex, passive state, amyostasia, sialorrhea and nystagmus there is not influence.
(2) keep away dark test: per os gives 30,60,90,120 minutes each incubation periods time period behind the phenethyl isothiocyanate, errors number, administration group and matched group relatively, there was no significant difference.
(3) open area test site test: after the administration 90 minutes, administration group male mice was lifted the forelimb number of times more than matched group (p＜0.01), all the other every indexs after administration 30,60,90,120 minutes, administration group and matched group comparison, difference that there are no significant.
(4) blance test: after the administration 30,60,90,120 minutes, administration group and matched group relatively, every index there are no significant difference.
Cardiovascular and respiratory system:
One time per os gives Beagle dog 3mg/kg the phenethyl isothiocyanate of dosage, observes its influence to Beagle dog cardiovascular, respiratory system.After the administration 0,5,15,30,60,90,120,240 minute, administration group and matched group relatively, difference that there are no significant.
In sum, under this experimental condition, do not see the obvious influence of phenethyl isothiocyanate to central nervous system, cardiovascular and respiratory system.
Embodiment 11: phenethyl isothiocyanate life-time service safety testing
Reagent: phenethyl isothiocyanate (PEITC), synthetic by Jiexi Medical Science ﹠ Technology Co., Ltd., Wuxi City, HPLC measures its content (＞99%); Other reagent is commercially available chemical pure or analytical pure product.
Equipment: the auspicious H-100 Urine Analyzer of Changchun enlightening, the CELL-DYN3700 cellanalyzer, SYSMEXXT-2000i blood cell instrument, Japan Hitachi 7020 automatic biochemical analyzers, the complete pathology equipment of Shamd is made paraffin embedding, section, HE dyeing, olympus microscope om observation is done histological examination, and experimental data is handled with SPSS 10.0 software statistics.
Experimental animal: cleaning level SD rat, female, hero half and half, body weight 80～100g is provided by Shanghai Slac Experimental Animal Co., Ltd., 20～25 ℃ of ambient temperatures, relative humidity 40%～70%.
Test method: experimental animal quarantine 5 days, the male rat of selecting 123～149g body weight select the female rats of 116～142g body weight to divide female group of contrast, the male group of contrast, female group of administration and the male group of administration, every group each 20 at random by body weight by the body weight random packet.Administration group per os every day gastric infusion.6 days weekly, 6 totally months.Medicine dilutes with Semen Maydis oil by 20mg/kg, and matched group gives Semen Maydis oil.The follower body weight change is adjusted the single administration amount weekly.
Result of the test:
(1) general behavior and animal dead situation: the animal general behavior shows no obvious abnormalities.There is not animal dead in the experimentation.
(2) body weight, food ration and food are raised rate: the variation of administration group body weight gain, food ration and matched group be unknown significance difference relatively.Food is raised efficiency change and is not seen evident regularity.
(3) routine urinalysis: the urine outward appearance is not seen significantly unusual.Routine urianlysis does not have significant difference (p＞0.05).
(4) hematological examination: blood routine examination there was no significant difference (p＞0.05).
(5) reticulocyte count: administration group and matched group be there was no significant difference (p＞0.05) relatively.
(6) prothrombin time inspection: administration group and matched group be there was no significant difference (p＞0.05) relatively.
(7) blood biochemical is learned and checked: test is slightly high except that male rat group GLU latter stage, and outside female rats group CREA was lower slightly, all the other every index administration groups and matched group be there was no significant difference relatively.
(8) gross anatomy and organ coefficient inspection: gross anatomy: show no obvious abnormalities.
Organ coefficient is checked: each organizes organ coefficient and matched group does not have significant difference (p＞0.05).
(9) histopathologic examination: administration group and matched group are not seen between two groups notable difference.
The experimental result explanation, under this experiment condition, administration group and animals of control group body weight, blood, routine urinalysis, clotting time, blood biochemical and pathological tissue inspection and 0mg/kg group be no significant difference relatively.It is safe that this explanation life-time service is subjected to the reagent thing.
The eighties in last century, be subjected to the reagent thing to be found the pulmonary carcinoma that to prevent smoking to bring out.Last century end, FDA (Food and Drug Adminstration) (FDA) has ratified to be subjected to the reagent thing clinical as the I phase of pulmonary carcinoma prophylactic.2008, it is clinical that this office has ratified to be subjected to the reagent thing to enter the II phase again.As the prophylactic of healthy people's life-time service, its safety is the factor of paying close attention to the most in the medicine checking process.The checking that the result of present embodiment and FDA are more strict has all confirmed the high security of active medicine of the present invention.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (15)
1. derivant with general formula I I of isosulfocyanate compound shown in the general formula I or its promotes application in the compositions of object hair growth in preparation:
R
1-X-NCS
General formula I
In general formula I:
NCS is an isothiocyanate group;
X is-(CH
2)
n-, n is the integer of 0-4;
R
1Be polysubstituted or single the replacement or unsubstituted phenyl or C
2-4Thiazolinyl, described substituent group is selected from: sulfonic group, sulfamide groups, halogen, methyl, ethyl, methoxyl group, methyl mercapto, formamido group, acetylamino, methylamino, ethylamino, carboxyl and cyano group;
General formula I I
Among the general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The group that connects of carbon atom derived from following chemical compound: N-acetylcystein, glutathion, cysteine (C
1-C
6Alkyl) ester, cysteinyl aminoacid and cysteinyl aminoacid (C
1-C
6Alkyl) ester.
2. application as claimed in claim 1 is characterized in that:
R
1Be polysubstituted or single the replacement or unsubstituted phenyl or C
2-4Thiazolinyl, described substituent group is selected from: sulfonic group, sulfamide groups, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, methyl mercapto, formamido group, acetylamino, methylamino, carboxyl and cyano group;
R
3For hydrogen or by sulphur atom with
The group that connects of carbon atom derived from following chemical compound: N-acetylcystein, glutathion, cysteine (C
1-C
6Alkyl) ester, cysteinyl aminoacid and cysteinyl aminoacid (C
1-C
6Alkyl) ester, wherein said aminoacid is selected from down group: glycine, glutamic acid, serine, alanine or methionine.
3. application as claimed in claim 1 is characterized in that, described isosulfocyanate compound is for being selected from structural formula (1)～(8) chemical compound one or more:
4. application as claimed in claim 1 is characterized in that, described promotion hair growth is at being selected from down disease or the symptom of organizing: paratrichosis comes off or oligotrichosis.
5. application as claimed in claim 1 is characterized in that, described paratrichosis comes off and is selected from: androgen alopecia, alopecia areata, pseudopelade, seborrheic alopecia, growing period alopecia or telogen effluvim.
6. application as claimed in claim 1 is characterized in that, described compositions is selected from: pharmaceutical composition, food, health product or cosmetics.
7. application as claimed in claim 1, it is characterized in that the dosage form of described compositions is selected from: bathe agent, lotion, liniment, tincture, oil preparation, ointment, plaster, paste, press agent, plaster, paster, liniment, membrane, gel, cataplasma, point-application agent, spray, aerosol, implant, Emulsion, shampoo, hair conditioner, suppository, tablet, capsule, pill, injection powder pin, injection or freeze dried powder.
8. application as claimed in claim 1 is characterized in that, described compositions also contains other active substance that prevents and/or treats alopecia.
9. application as claimed in claim 1, it is characterized in that, before using described compositions, simultaneously or afterwards, be used described other prevent and/or treat alopecia active substance, implement at the surgical operation of alopecia or give radiation treatment at alopecia.
10. compositions, it contains:
(A) isosulfocyanate compound shown in the general formula I of effective dose or its have the derivant of general formula I I:
R
1-X-NCS general formula I
In general formula I:
NCS is an isothiocyanate group;
X is-(CH
2)
n-, n is the integer of 0-4;
R
1Be polysubstituted or single the replacement or unsubstituted phenyl or C
2-4Thiazolinyl, described substituent group is selected from: sulfonic group, sulfamide groups, halogen, methyl, ethyl, methoxyl group, methyl mercapto, formamido group, acetylamino, methylamino, ethylamino, carboxyl and cyano group;
General formula I I
Among the general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The univalent perssad that connects of carbon atom derived from following chemical compound: N-acetylcystein, glutathion, cysteine (C
1-C
6Alkyl) ester, cysteinyl glycine, cysteinyl glycine (C
1-C
6Alkyl) ester, cysteinyl glutamic acid, cysteinyl glutamic acid (C
1-C
6Alkyl) ester, cysteinyl alanine, cysteinyl alanine (C
1-C
6Alkyl) ester, cysteinyl serine, cysteinyl serine (C
1-C
6Base) ester, cysteinyl methionine or cysteinyl methionine (C
1-C
6Alkyl) ester;
(B) pharmaceutically acceptable carrier, food, health product or cosmetics acceptable carrier;
(C) one or more other prevent and/or treat the active substance of alopecia.
11. compositions as claimed in claim 10 is characterized in that, the carrier in the described compositions is greasing base or water-soluble base.
12. compositions as claimed in claim 11 is characterized in that, described greasing base is for being selected from (b1) one or more, and described water-soluble base is for being selected from (b2) one or more:
(b1) vaseline, the vaseline lanonol, paraffin, liquid Paraffin, the liquid paraffin lanonol, ceresine, Cera Flava, white beeswax, Cera Flava, spermaceti, lanoline, Adeps Sus domestica, Adeps Caprae seu ovis, Oleum Sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil, soybean oil, rapeseed oil, Oleum sesami, Oleum Helianthi, almond oil, Oleum Ricini, olive oil, Oleum Gossypii semen, dimethicone, hydrogenated vegetable oil, median chain triglyceride oil, isopropyl myristate, stearic acid, hexadecanol, Synthetic Spermacet, octadecanol, face the phthalic acid diester, Brazil wax, acetone, petroleum ether, ethyl oleate or isopropyl palmitate; Or
(b2) distilled water, ethanol, isopropyl alcohol, glycerol, glycerinum amyli, monoethanolamine, the glycerol triacetate, Lac, carob, gelatin, guar gum, carrageenin, arabic gum, the tragakanta, Xanthan gum, chitosan, sodium alginate, methylcellulose, carmellose, carboxymethylcellulose calcium, carmethose, hyetellose, hymetellose, hyprolose, low-substituted hydroxypropyl cellulose, hypromellose, the hypromellose phthalate ester, carbomer, Polyethylene Glycol or veegum.
13. compositions as claimed in claim 10 is characterized in that, the described active substance that other prevents and/or treats alopecia is to be selected from down one or more that organize: 5 inhibitor, androgen antagonist or potassium-channel opener.
14. comprising, a beauty method, described method give among derivant that isosulfocyanate compound shown in the object general formula I or its have general formula I I or the claim 10-13 each described compositions to promote the growth of described object hair.
15. a method that prevents and/or treats alopecia, described method comprise that isosulfocyanate compound shown in the general formula I that needs the described object effective dose that prevents and/or treats or its have the derivant of general formula I I.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100522316A CN101897691B (en) | 2009-05-31 | 2009-05-31 | Application of isothiocyanate compounds in promoting hair growth |
| PCT/CN2010/073332 WO2010139252A1 (en) | 2009-05-31 | 2010-05-28 | Use of isothiocyanates for promoting growth of hairs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100522316A CN101897691B (en) | 2009-05-31 | 2009-05-31 | Application of isothiocyanate compounds in promoting hair growth |
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| Publication Number | Publication Date |
|---|---|
| CN101897691A true CN101897691A (en) | 2010-12-01 |
| CN101897691B CN101897691B (en) | 2013-06-05 |
Family
ID=43223836
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100522316A Active CN101897691B (en) | 2009-05-31 | 2009-05-31 | Application of isothiocyanate compounds in promoting hair growth |
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| Country | Link |
|---|---|
| CN (1) | CN101897691B (en) |
| WO (1) | WO2010139252A1 (en) |
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| CN102860976A (en) * | 2012-09-10 | 2013-01-09 | 皖南医学院 | Nourishing hair-care liquid shampoo and preparation method thereof |
| CN103083544A (en) * | 2012-12-10 | 2013-05-08 | 汤燕 | Traditional Chinese medicine for treating gray hair |
| CN104117064A (en) * | 2013-04-28 | 2014-10-29 | 无锡杰西医药科技有限公司 | Combined application of isothiocyanate compound and hormone medicine |
| CN104173272A (en) * | 2013-05-27 | 2014-12-03 | 无锡杰西医药科技有限公司 | Sustained release preparation of isothiocyanate compound |
| CN106146429A (en) * | 2015-04-21 | 2016-11-23 | 天津国际生物医药联合研究院 | The structure of isosulfocyanate precursor compound, prepare and apply |
| US10010520B2 (en) | 2013-08-13 | 2018-07-03 | Jc (Wuxi) Company, Inc. | Combined application of isothiocyanate compound and anti-cancer medicine |
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| CN114931546A (en) * | 2022-04-20 | 2022-08-23 | 江苏联环药业股份有限公司 | Epipret external preparation for preventing and treating androgenetic alopecia |
| WO2023061118A1 (en) * | 2021-10-15 | 2023-04-20 | 北京化工大学 | Pharmaceutical composition for improving and treating leukotrichia and/or alopecia and preparation method therefor |
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| JP2021511813A (en) * | 2018-02-02 | 2021-05-13 | コモンウェルス サイエンティフィック アンド インダストリアル リサーチ オーガナイゼーション | Protection of bioactive substances and / or precursors thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63500520A (en) * | 1985-06-20 | 1988-02-25 | フア−マコン，インコ−ポレイテツド | Allyl isothiocyanate and its use for preventing hair loss |
| FR2826261B1 (en) * | 2001-06-26 | 2005-03-25 | Lmd | TOPICAL COMPOSITION COMPRISING A CYTOTOXIC PRODUCT AND ITS USE IN THE TREATMENT OF ALOPECHE |
| FR2902325B1 (en) * | 2006-06-20 | 2009-12-04 | Oreal | USE OF 3H-1,2-DITHIOLE-3-THIONE, ANETHOLE DITHIOMLETHIONE, SULFORAPHE, PHENETHYL ISOTHIOCYANATE, 6-METHYL-SULPHINYL) HEXYL ISOTHIOCYANATE AND ALLYL ISOTHIOCYANATE FOR THE TREATMENT OF CANITIA |
-
2009
- 2009-05-31 CN CN2009100522316A patent/CN101897691B/en active Active
-
2010
- 2010-05-28 WO PCT/CN2010/073332 patent/WO2010139252A1/en active Application Filing
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| CN102860976A (en) * | 2012-09-10 | 2013-01-09 | 皖南医学院 | Nourishing hair-care liquid shampoo and preparation method thereof |
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| CN104117064B (en) * | 2013-04-28 | 2021-02-26 | 无锡杰西医药股份有限公司 | Combined application of isothiocyanate compounds and hormone drugs |
| CN104117064A (en) * | 2013-04-28 | 2014-10-29 | 无锡杰西医药科技有限公司 | Combined application of isothiocyanate compound and hormone medicine |
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| WO2014190898A1 (en) * | 2013-05-27 | 2014-12-04 | Cheng Jingcai | Preparation of isothiocyanate compounds |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2010139252A1 (en) | 2010-12-09 |
| CN101897691B (en) | 2013-06-05 |
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