CN101897691B - Application of isothiocyanate compounds in promoting hair growth - Google Patents
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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 not yet announced), 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 the mankind's commonly encountered diseases and frequently-occurring disease, although they can not bring the direct human body painful to the patient, bring many harmful effects for patient's spirit, and make troubles for patient's life.Can be observed multi-form alopecia in the crowd, as androgen alopecia (androgenetic alopecia, AGA), alopecia areata, pseudopelade, seborrheic alopecia, growing period alopecia and telogen effluvim etc., wherein comparatively generally androgen alopecia.AGA all can occur in masculinity and femininity, and the probability that the male occurs occurs in front portion and the top of head generally higher than the women for the most of alopecias of male, and the women is the hair attenuation of whole head.
Result to nearly 6000 male investigation showed in 2003: suffering from various degree in 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 can be up to 31%.Due to the factor of the 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, surgery cost is high, and has operation risk; The patient that the alopecia area is larger in addition often needs repeatedly to transplant, and expense is higher, and is more difficult universal.
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 androgen levels increase relevant (Yin Xing equality, 5α-reductase 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 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 development, the relation of the pathogeny of AGA, particularly androgen and AGA is more clear.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 due 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 higherlevels 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 5α-reductase, 3alpha-Hydroxysteroid dehydrogenase etc., active lower testosterone (T) converts active higher dihydrotestosterone (DHT) to.Testosterone or dihydrotestosterone all must be combined by the androgen receptor in concentrating on Follicular Unit, enter nucleus and produce a series of biological effects, make intracellular cyclic adenosine monophosphate, and the anagen phase shortens or the hair follicle microminiaturization, thereby causes alopecia.Therefore, from pathogeny, lower the alopecia symptom that the androgen receptor overexpression can improve AGA.
On market, the drug main of hair growth will be divided three classes:
(1) the 5α-reductase inhibitor take finasteride as representative.This class medicine is by the inhibition 5α-reductase, thereby the reduction testosterone has weakened to the conversion of the higher dihydrotestosterone of activity the effect that in the organ, excessive androgen stimulates.But also there are some defectives in this medicine, such as recurrence etc. repeatedly after the sexual dysfunction that causes sexual impotence, drug withdrawal.In addition due to can't topical application, side effect make it not to be suitable for women, anemia of pregnant woman's forbidding (pay Guoqiang. the progress [J] for the treatment of androgenetic alopecia medicine. foreign medical science skin cypridology fascicle, 2000,26 (2): 68-72) etc.
(2) androgen antagonist comprises steroid and nonsteroidal.This class medicine reduces androgenic effect by androgen antagonist or with androgen competitive binding androgen receptor.Steroid such as cyproterone acetate, estrogen etc., such medicine have the androgenic effect of antagonism, but produce simultaneously womanlike side effect.Although the nonsteroidal androgen antagonist does not have the side effect of hormone, but owing to competing 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) as minoxidil, orally there is the untoward reaction such as fast reducing blood pressure in K ~+Channel Opener, therefore general external.But after this medicine drug withdrawal, easily recurrence, need life-time service.This not direct regulation and control of medicine androgen or androgen receptor, therefore not strong to the therapeutic effect of androgenetic alopecia in addition.
As from the foregoing, all there is certain side effect in the first-line drug of hair growth in the market, and curative effect is also not satisfactory.In addition, from the angle of beauty treatment, this area also lacks and can safely, effectively promote hair growth to reach the compositions of cosmetic result.
Therefore, this area can be effectively in the urgent need to developing, trichogenous compositions safely.
Summary of the invention
One of purpose of the present invention just is being to provide 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, provide derivant that isosulfocyanate compound shown in general formula I or its have general formula I I to promote application in the compositions of object hair growth in preparation:
R
1-X-NCS general formula I
In general formula I:
NCS is 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
In general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The group derived from following compound that connects of carbon atom: 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, the derivant that isosulfocyanate compound shown in general formula I or its have a general formula I I promotes application in the compositions of object hair growth in preparation:
R
1-X-NCS
General formula I
In general formula I:
NCS is 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
In general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The group derived from following compound that connects of carbon atom: 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 one or more in structural formula (1)～(8) compound:
In a preference, described isosulfocyanate compound is selected from one or more in 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 for the disease or the symptom that are selected from lower group: 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 mammal, the preferred mankind 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, acupoint plaster application, 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, take the gross weight of compositions as benchmark, isosulfocyanate compound shown in described compositions formula of I or its content with derivant of general formula I I are 0.001～99.9 % by weight.
In a preference, isosulfocyanate compound shown in described compositions formula of I or its content with derivant of general formula I I are 0.01～90 % by weight, more preferably 0.05～75 % by weight.
In another preference, described compositions exists with the form that can directly use, take the gross weight of compositions as benchmark, isosulfocyanate compound shown in general formula I or its content with derivant of general formula I I are 0.001～25 % by weight, preferred 0.005～20 % by weight, more preferably 0.05～10 % by weight.
In another preference, described compositions exists with the form of concentrate, can dilute it before use, take the gross weight of dilution as benchmark, isosulfocyanate compound shown in general formula I or its content with derivant of general formula I I are 0.001～25 % by weight, preferred 0.005～20 % by weight, more preferably 0.05～10 % by 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 one or more of lower group: 5α-reductase inhibitor, androgen antagonist or K ~+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 in conjunction with described other prevent and/or treat alopecia active substance, implement for the surgical operation of alopecia or give radiation treatment for 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 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;
In general formula I I:
R
1With X in the general formula I definition;
R
3For hydrogen or by sulphur atom with
The univalent perssad derived from following compound that connects of carbon atom: 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 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 one or more in (b1), and described water-soluble base is for being selected from one or more in (b2):
(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, HP-55, 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 one or more of lower group: 5α-reductase inhibitor, androgen antagonist or K ~+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.
Other side of the present invention due to the disclosure of this paper, is apparent 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 comparison of mice.
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 mice photos of administration;
Fig. 4 B: 11 days administration group mice photos of administration.
Fig. 5: 13 days mice photos of administration:
Fig. 5 A: 13 days negative control group mice photos of administration;
Fig. 5 B: 13 days administration group mice photos of administration.
Fig. 6: 18 days mice photos of administration:
Fig. 6 A: 18 days negative control group mice photos of administration;
Fig. 6 B: 18 days administration group mice photos of administration.
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 there is no 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 completed on this basis the present invention.
Isosulfocyanate compound
As used herein, term " isosulfocyanate compound ", " isosulfocyanate active substance " and " active substance of the present invention " are used interchangeably, and all refer to have compound, its derivant (derivant that especially has general formula I I), metabolite or their combination of the described structure of general formula I.
isosulfocyanate compound or derivatives thereof of the present invention, metabolite, include but not limited to the related BITC of Chinese invention patent 200610126892.5 (BITC), phenethyl isothiocyanate (PEITC), allyl group isosulfocyanate (AITC), SPITC (SPITC), and their conjugate (BITC-NAC of forming with N-acetylcystein respectively, PEITC-NAC, AITC-NAC and SPITC-NAC), correspond respectively to structural formula (1)～(8) herein.
In the present invention, have no particular limits for the method that obtains isosulfocyanate compound, such as it can extract, adopt the method preparation of chemosynthesis or half chemosynthesis etc. from natural plants (such as Caulis et Folium Brassicae junceae or Radix Raphani).The isosulfocyanate compound that uses in the present invention can obtain by commercially available approach, for example can be available from Jiexi Medical Science ﹠ Technology Co., Ltd., Wuxi City or SIGMA company.
The 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 the compositions of active component in 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) promotion 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 abnormal 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 abnormal androgen receptor from androgen receptor AR, AR upstream gene sp1 and AR downstream gene SPA three aspects.
Therefore, isosulfocyanate compound or derivatives thereof of the present invention, metabolite also can prevent and/or treat except promoting to prevent and/or treat common alopecia the androgenetic alopecia that common drug, food, health product or cosmetics are difficult to effectively prevention or treatment effectively.And, when preventing and/or treating alopecia, also can be used for treating the acne vulgaris or the seborrhea that cause because androgen is excessive, reach the effect of comprehensive beauty.
Thus, also provide isosulfocyanate compound and compositions thereof the purposes in promoting hair growth in the present invention, alopecia clinical treatment and/or prevention that it can be used for therapeutic purposes also can be used for 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 (such as 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 cosmetic conduct and learning; And other optional trichogenous active substance.
As used herein, term " contain " or " comprising " comprised " comprising ", " basically by ... consist of " and " by ... consist of ".As used herein, the composition of term " acceptable on pharmacy, bromatology, health care conduct and learning or cosmetic conduct and learning " is applicable to people and/or animal and without excessive bad side reaction (as toxicity, stimulation and allergy), the material of rational benefit/risk ratio is arranged namely.As used herein, term " effective dose " refers to and can produce 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 there is no undue toxicity after using.Suitable carrier is well known to those of ordinary skill in the art.Can find discussing fully about pharmaceutically acceptable excipient in " Lei Mingdun pharmaceutical science " (Remington ' s Pharmaceutical Sciences, Mack Pub.Co., N.J.1991).
In compositions of the present invention, isosulfocyanate active substance effective ingredient accounts for the 0.001-99.9wt% of composition total weight; Being preferably the 0.01-90wt% of composition total weight, is more preferably 0.05-75wt%, and surplus is the 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 content of isosulfocyanate 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 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 that contains middle dosage, 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 dilute before using), 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 once a day or repeatedly compositions of the present invention, 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 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 by adding the adjuvants such as surfactant, Percutaneous absorption enhancer, antiseptic, solvent, antioxidant, wetting agent, pH adjusting agent, coloring agent, spice, 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, acupoint plaster application, spray, aerosol, implant, Emulsion, shampoo and hair conditioner etc.
In an embodiment of the invention, described topical administration formulations can comprise following composition:
(a) natural or isosulfocyanate compound or derivatives thereof synthetic of 0-50 weight portion, metabolite, described isosulfocyanate compound includes but not limited to phenethyl isothiocyanate, BITC, allyl group isosulfocyanate, SPITC; Described derivant, metabolite include but not limited to the N-acetylcystein conjugate of isosulfocyanate compound, preferably, PEITC-NAC, BITC-NAC, AITC-NAC, SPITC-NAC;
(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 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, HP-55, 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 its other adjuvant that adds 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, gallbladder acid, cholate, salicylic acid, Oleum menthae, eucalyptus oil, eucalyptole, Oleum Terebinthinae, aminoacid, phospholipid, Camphora, limonene, beta-schardinger dextrin-, HP-β-CD, the mixture of one or more compositions of dimethyl-β-cyclodextrin.
(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, BHT (BHT), chlorocresol, propyl gallate, Pyrogallic acid ethyl ester or propyl ester, two uncle butylparaben phenol, BHA, citric acid, tartaric acid, ethylenediaminetetraacetic acid, disodiumedetate, sulfydryl dipropionic acid and sulphite, potassium metabisulfite, sodium pyrosulfite;
(v) other additive of 0-50 weight portion: described other composition comprises wetting agent, pH adjusting agent, sees toner, 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, Mel.
Described pH adjusting 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, E131, 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, delphinin color element, enidin, pelargonidin, the Radix Paeoniae anthocyanidin, phenethanol, titanium dioxide, ferrum oxide, hydrated ferric oxide., Alumina, the aluminum 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 the compositions take phenethyl isothiocyanate as effective ingredient, when the treatment relevant disease, it can be independent use, can be also the associating use, use or unite with one or more Western medicine and use or unite with Chinese herbal medicine and use or unite with radiation treatment and use or unite with gene therapy and use or unite use etc. with biological regulator as uniting 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 respectively the transcript and expression of abnormal androgen receptor from androgen receptor AR, AR upstream gene sp1 and AR downstream gene SPA three aspects, 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 for explanation the present invention 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 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 all specialties and scientific words and the one skilled in the art who uses in literary composition is familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the present invention.The use that better implementation method described in 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%
Technique: get recipe quantity white vaseline, liquid paraffin, yellow beeswax and join in beaker and heat, make its fusing, stir, add glyceryl monostearate, stir evenly.Take 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, until liquid gradually become thick after, stop stirring, and get final product.
Embodiment 1-2:
Prescription: BITC 0.75%
White vaseline 51.00%
Propylparaben 0.03%
Yellow beeswax 7.10%
Liquid paraffin 41.12%
Technique: get recipe quantity white vaseline, propylparaben, liquid paraffin, yellow beeswax and join in beaker and heat, make its fusing, stir.Take the recipe quantity BITC in another beaker, the liquid of above-mentioned mixing is joined in the beaker that BITC is housed mix homogeneously with the equivalent incremental method, continue to be stirred to natural cooling, until liquid gradually become thick after, stop stirring, and get final product.
Embodiment 1-3:
Prescription: allyl group isosulfocyanate 2.50%
White vaseline 91.00%
Vitamin E (tocopherol) 2.00%
Glyceryl monostearate 4.50%
Technique: get the recipe quantity white vaseline, vitamin E joins in beaker and heats, and makes its fusing, stirs, and adds glyceryl monostearate, stir evenly.Take 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, until liquid gradually become thick after, stop stirring, and get final product.
Embodiment 1-4:
Prescription: phenethyl isothiocyanate 5.00%
White vaseline 92.00%
Propylparaben 0.03%
Vitamin E (tocopherol) 2.97%
Technique: get recipe quantity white vaseline, propylparaben, vitamin E and join in beaker and heat, make its fusing, stir.Take 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, until liquid gradually become thick after, stop stirring, and get final product.
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%
Technique: PEITC-NAC, glycerol and triethanolamine are added in 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, and get final product.
Embodiment 1-6:
Prescription: SPITC 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%
Technique: sodium borate is added in distilled water, and heating for dissolving is cooled to room temperature, adds SPITC, 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.Under stirring, aqueous solution is slowly added the oil phase of equality of temperature, continue to be stirred to total condensation, and get final product.
Embodiment 2: the tincture research of isosulfocyanate compound
Prescription: phenethyl isothiocyanate 0.20%
Ethanol 79.80%
Propylene glycol 20.00%
Technique: get ethanol and propylene glycol and put in same beaker, mix homogeneously.Separately get a beaker, precision takes the phenethyl isothiocyanate of recipe quantity, pours a small amount of matrix solution into, after stirring, then adds a small amount of substrate, stir, and operation in accordance with the law, to the substrate of capacity, stirring stops, and get final product.
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%
Technique: get phenethyl isothiocyanate, Oleum Ricini, Semen Maydis oil and vitamin E mix homogeneously and get final product.
Embodiment 3-2
Prescription: PEITC-NAC 0.88%
Laurocapram 1.77%
Glycerol 8.85%
Distilled water 88.50%
Technique: get PEITC-NAC, laurocapram, glycerol dispersed with stirring, adding distil water is stirred to dissolving fully, and get final product.
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%
Technique: get the PEITC-NAC porphyrize and sieve, add appropriate 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, and get final product 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%
Technique: get polyvinyl alcohol and add distilled water, fully swelling, be heated into rubber cement liquid, and ethanol and propylene glycol mixing add PEITC-NAC to be stirred to entirely molten, add while stirring the polyvinyl alcohol glue serosity, stir evenly, and get final product.
Mould dose of research of the spray of embodiment 6. isosulfocyanate compounds
Prescription: SPITC 0.6%
Borneolum Syntheticum 0.12%
Mentholum 0.10%
Nipalgin 0.03%
Polyoxyethylene sorbitan monoleate 1.50%
Distilled water adds to 100%
Technique: get distilled water approximately 70ml to 100ml in beaker, add nipalgin be heated to the dissolving, solution lets cool to room temperature, adds SPITC, is stirred to dissolving, gets uniform solution; Separately get Borneolum Syntheticum, Mentholum, polyoxyethylene sorbitan monoleate and be stirred to dissolve, add in mentioned solution, adding distil water to 100%, and get final product.
Embodiment 7: the stability study of effective ingredient in ointment
Experimental apparatus:
S.C.101 type air blast Constant Temp. Oven: Jiaxing county, Zhejiang Province newly wins electric heating instrument plant, METTLER AE100 electronic balance: Switzerland Mei Tele company, SUMMIT HPLC: U.S. Dai An company.
Experimental technique:
Get in above-described embodiment 1-1,1-2,1-3 and 1-4 preparation appropriate, put in clean cillin bottle, add rubber stopper, 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
| |
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, in tested ointment, active component has good stability.
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%
Technique: white vaseline+yellow beeswax+liquid paraffin+propylparaben is put same beaker, is heated to 100 ℃, is stirred to evenly.Stirring is cooled to approximately 70～80 ℃, adds glyceryl monostearate, stirs, and adds vitamin E, stirs.Approximately 70 ℃ of insulations are standby.Separately get a 25ml small beaker, precision takes the phenethyl isothiocyanate of recipe quantity, pours appropriate matrix solution into, and 70 ℃ of insulations are stirred to evenly, continue to add appropriate substrate, is stirred to evenly, and operation in accordance with the law is until capacity is stirred to evenly.Stir cooling, near thickness the time, packing.
Administering mode:
Get respectively the assigned address that the about above-mentioned ointment of 0.05g spreads upon the pharmaceuticals researcher, observe and record change of skin in the administration phase, comprise red, swell, itch, pain, the irritative symptoms in various degree such as peppery.
Table 2. phenethyl isothiocyanate ointment irritation test
Result and discussion: above-mentioned experiment shows, tested isosulfocyanate compound external preparation has certain zest to human body skin.Relatively various dose group human body irritative response as seen, the amount positive correlation of active component in this zest and tested medicine, namely along with the increase of the amount of active component in tested medicine, the corresponding increase of zest.After low dose group 2 hours, zest disappears substantially.After high dose group 2 hours, the zest after arm, inboard arm and ear disappears substantially, and certain zest is still arranged at relatively responsive eyelid and lip top, but the damage untreated that zest causes, recovery naturally.
The hair growth influence factor studies show that: increase the blood circulation of local skin, help the growth of hair.This experimental study shows, in tested medicine, active component is similar to Fructus Capsici, Bulbus Allii and Mylabris tincture, 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 1010 digital cameras.
Animal model: be in telogen 7 the week age male C3H/HeN mice, be purchased from Yangzhou University's Experimental Animal Center.Supply conventional food and drinking water, temperature 20-26 ℃, light and shade replaces time 12h/12h.
Drug therapy: tested Mus is random packet by weight, one group of administration, one group of negative control, 9 every group.It is 3 * 4cm that every tested Mus back is shaved off area
2Hair as pilot region.The administration group is administered once every day, and 7 days weekly, administration was 18 days altogether.Be at every turn 0.2% PEITC tincture 200 μ l to concentration, be uniformly coated on pilot region.The self administration of medication first day rises, and observes 20 days.Negative control group is given the blank substrate of equal volume, parallel comparison simultaneously.
Observation and appraisal:
The test initial stage is carried out observation and comparison to test Mus treatment region hair growth situation and medicine skin irritation every other day.When tested Mus viewing area color burn, when namely pink changes to lead, change into and observing every day, and the comparison of taking pictures.
(1) newborn hair growth evaluation
The hair growth velocity ratio is: when hair growth the first sign (skin color deepens, and the melanocyte in hair follicle begins synthesis of melanin) occurring from mice processed zone, according to the evaluation criterion of table 3, estimate the hair growth speed of tested 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, tested Mus is marked, reach with tested 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 approximately 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 approximately 20% mice reaches ++ or higher, in the time of the 12nd day, approximately 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, the anagen of impelling tested mice to enter sooner.
New piliation Area comparison: 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 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 accordingly.
The new piliation Area comparison of table 4.
| Numbering | Negative control group processing region hair coverage rate % | Administration group processing region hair |
| 1 | 91.7 | 100 |
| 2 | 98.0 | 100 |
| 3 | 67.0 | 100 |
| 4 | 99.1 | 100 |
| 5 | 87.5 | 100 |
| 6 | 97.8 | 100 |
| 7 | 83.0 | 100 |
| 8 | 69.0 | 100 |
| 9 | 98.2 | 100 |
| Meansigma methods | 87.9 | 100 |
In table 4, two groups of data P＜0.05, have significant difference.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 administration the 20th day, see in appearance, and 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 respectively every mice in negative control group and administration group, shave at the same position of processing region and get 1 * 1cm
2The new piliation in zone is used respectively scales/electronic balance weighing after merging.The results are shown in Figure 3, the gross weight of shaving the new piliation of mice of getting 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 is still 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 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 whole experimentation, negative control group is not observed any irritative symptoms; During the initial stage, skin is red in administration deepens for the administration group, examines after a while visible trickle decortication, but to the middle and late stage of administration, above-mentioned symptom weakens gradually until disappear.
Conclusion:
Be in telogen 7 the week age male C
3The H/HeN mice is in case shaved hair, skin pinkiness (the vision sign of hair growth amortization period).According to bibliographical information, the first sign the anagen of tested Mus is that the melanocyte in 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 respectively in this test from the speed of growth, growth area and the 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 trial drug can effectively promote the growth of new piliation really.
Embodiment 10: the impact of phenethyl isothiocyanate on 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 10.0 for windows softwares.
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, An Limo Science and Technology Ltd. provides by Nanjing, 20～25 ℃ of ambient temperatures, relative humidity 40%～70%.
Test method and result
The central nervous system:
One time per os gives the mice 30mg/kg phenethyl isothiocyanate of dosage, observes phenethyl isothiocyanate to the impact of central nervous system of mice.Result is as follows:
(1) qualitative observation and semi-quantitative assessment test: per os gives after phenethyl isothiocyanate 30,60,90,120 minutes, and the appearance of animal, hair, posture, gait are normal, without effects such as anesthesia, hypnosis, calmness, without position chanP; Movable normal to the pain sensation and luminous reflectance, pupillary reflex is normal; On mice righting reflex, passive state, amyostasia, sialorrhea and nystagmus without impact.
(2) keep away dark test: per os gives 30,60,90,120 minutes each incubation periods time period after phenethyl isothiocyanate, errors number, administration group and matched group relatively, there was no significant difference.
(3) open area test site test: after administration 90 minutes, administration group male mice was lifted the forelimb number of times more than matched group (p＜0.01), all the other indices after administration 30,60,90,120 minutes, administration group and matched group comparison, difference that there are no significant.
(4) blance test: after administration 30,60,90,120 minutes, administration group and matched group relatively, indices there are no significant difference.
Cardiovascular and respiratory system:
One time per os gives the Beagle dog 3mg/kg phenethyl isothiocyanate of dosage, observes it to the impact of Beagle dog cardiovascular, respiratory system.After administration 0,5,15,30,60,90,120,240 minute, administration group and matched group relatively, difference that there are no significant.
In sum, have no phenethyl isothiocyanate to the obvious impact of central nervous system, cardiovascular and respiratory system under this experimental condition.
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, the SYSMEXXT-2000i Hematometer, 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 processed 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, select the male rat of 123～149g body weight by the body weight random packet, select the female rats of 116～142g body weight to divide at random female group of contrast, the male group of contrast, female group of administration and the male group of administration, every group each 20 by body weight.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.In experimentation without animal dead.
(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.The variation of food feed efficiency rate has no evident regularity.
(3) routine urinalysis: the urine outward appearance has no significantly abnormal.Routine urianlysis is without 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 male rat group GLU latter stage, and outside female rats group CREA was lower slightly, all the other indices 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 checks: each organizes organ coefficient and matched group without significant difference (p＞0.05).
(9) histopathologic examination: administration group and matched group have no between two groups notable difference.
The experimental result explanation, under this experiment condition, the weight of animals of administration group and matched group, blood, routine urinalysis, clotting time, blood biochemical and pathologic diagnosis and 0mg/kg group be no significant difference relatively.The tested medicine of this explanation life-time service is safe.
The eighties in last century, tested medicine is found the pulmonary carcinoma of might prevent to smoke bringing out.Last century Mo, it is clinical as the I phase of pulmonary carcinoma prophylactic that FDA (Food and Drug Adminstration) (FDA) has ratified tested medicine.2008, this office has ratified again tested medicine, and to enter the II phase clinical.As the prophylactic of Healthy People 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 the 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 as each piece document is quoted separately as a reference.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 limited range equally.
Claims (1)
1. the application of isosulfocyanate compound phenethyl isothiocyanate shown in formula (2) in the compositions of preparation promotion object hair growth, wherein said compositions is take phenethyl isothiocyanate as unique active component:
Formula (2).
2. application as claimed in claim 1, is characterized in that, described promotion hair growth is for the disease or the symptom that are selected from lower group: paratrichosis comes off or oligotrichosis.
3. application as claimed in claim 2, 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.
4. application as claimed in claim 1, is characterized in that, described compositions is selected from: pharmaceutical composition or cosmetics.
5. application as claimed in claim 1, is characterized in that, the dosage form of described compositions is selected from: lotion, liniment, tincture, oil preparation, ointment, plaster, paste, press agent, plaster, membrane, gel, spray or Emulsion.
6. application as claimed in claim 1, is characterized in that, the dosage form of described compositions is selected from: bathe agent, liniment, aerosol, paster or cataplasma.
7. application as claimed in claim 1, is characterized in that, the dosage form of described compositions is acupoint plaster application, shampoo or hair conditioner.
8. application as claimed in claim 1, is characterized in that, described compositions also contains acceptable carrier or excipient on pharmacy or cosmetic conduct and learning.
9. application as claimed in claim 1, is characterized in that, before using described compositions, simultaneously or afterwards, implements for the surgical operation of alopecia or give radiation treatment for alopecia.
10. application as claimed in claim 8, is characterized in that, described carrier is greasing base or water-soluble base.
11. application as claimed in claim 10 is characterized in that, described greasing base is for being selected from one or more in (b1), and described water-soluble base is for being selected from one or more in (b2):
(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 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, ditridecyl phthalate, Brazil wax, ethyl oleate or isopropyl palmitate,
(b2) glycerinum amyli, carob, gelatin, guar gum, carrageenin, arabic gum, tragakanta, Xanthan gum, chitosan, sodium alginate, methylcellulose, carmellose, carmethose, hyetellose, hymetellose, hyprolose, low-substituted hydroxypropyl cellulose, hypromellose, HP-55, carbomer or Polyethylene Glycol.
12. comprising, the beauty method of non-therapeutic purposes, described method give the compositions of object take isosulfocyanate compound phenethyl isothiocyanate shown in formula (2) as unique active component to promote the growth of described object hair:
Formula (2).
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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| CN101897691A CN101897691A (en) | 2010-12-01 |
| CN101897691B true CN101897691B (en) | 2013-06-05 |
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| CN2009100522316A Active CN101897691B (en) | 2009-05-31 | 2009-05-31 | Application of isothiocyanate compounds in promoting hair growth |
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| WO (1) | WO2010139252A1 (en) |
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| CN102860976B (en) * | 2012-09-10 | 2014-08-13 | 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 |
| 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 |
| CN104173272B (en) * | 2013-05-27 | 2021-07-06 | 无锡杰西医药股份有限公司 | Sustained-release preparation of isothiocyanate compounds |
| JP6456383B2 (en) | 2013-08-13 | 2019-01-23 | ジェイシー(ウーシー) カンパニー, インコーポレーテッドJc (Wuxi) Company, Inc. | Combination of isothiocyanate compounds and anticancer drugs |
| 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 |
| EP3745873A4 (en) * | 2018-02-02 | 2021-10-27 | Commonwealth Scientific and Industrial Research Organisation | Protecting a bioactive and/or precursor thereof |
| CN109432400A (en) * | 2018-12-27 | 2019-03-08 | 深圳市福美富基因科技有限公司 | A kind of trichogenous composition and its application |
| CN113694188A (en) * | 2021-10-15 | 2021-11-26 | 北京化工大学 | Pharmaceutical composition for improving and treating white hair and/or alopecia and preparation method thereof |
| 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 |
| TWI827310B (en) * | 2022-10-14 | 2023-12-21 | 臺北榮民總醫院 | Use of isothiocyanate structural modified compound for preventing or treating liver disease |
| CN117783507B (en) * | 2024-02-27 | 2024-06-04 | 广州科方生物技术股份有限公司 | Component liquid commonly used in (1-3) -beta-D glucan and galactomannan detection, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229105A (en) * | 2006-06-20 | 2008-07-30 | 莱雅公司 | Use of 3h-1,2-dithiole-3-thione, anethole dithiolethione, sulphoraphane, phenethyl isothiocyanate, 6-(methylsulphinyl)hexyl isothiocyanate and allyl isothiocyanate for the treatment of canities |
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| 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 |
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| CN101229105A (en) * | 2006-06-20 | 2008-07-30 | 莱雅公司 | Use of 3h-1,2-dithiole-3-thione, anethole dithiolethione, sulphoraphane, phenethyl isothiocyanate, 6-(methylsulphinyl)hexyl isothiocyanate and allyl isothiocyanate for the treatment of canities |
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| WO2010139252A1 (en) | 2010-12-09 |
| CN101897691A (en) | 2010-12-01 |
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