Technical field

The present invention relates to a kind of new opplication of defined artemisine composition or combinations thereof, i.e., in skin of mammal The new opplication of skin nursing field includes：a）Prevention acted on by correcting dyskeratosis, postpone and/or treat mammal acne, The keratosiss caused by dyskeratosis such as dandruff, desquamation prurituss, dry chap, psoriasises, scleroderma, perifollicular keratosises Disease；b）By the lip of the softening of promotion cutinization or submissive mammal, skin, hair, refer to toenail, hoof etc., and promote suckling Animal lip, skin, hair, refer to the renewal of toenail, hoof etc., adjust their oiliness and gloss；c）By anti-pigmentation Promote skin lightening ruddy, prevention, delay and/or treatment mammal skin blackening, sallow dimness, mottle, acne print, Exposure to Sunlight are damaged The appearance of the pigmentation symptom such as wound, inflammation damnification；d）By the effect prevention of anti-cicatrization, postpone and/or treat suckling to move Thing scytitiss stimulate the cicatrix symptoms such as the cicatrix growth, acne print that the cicatrix that injury is caused grows, environmental stimuli injury is caused Occur；e）Skin elasticity effect is kept to strengthen skin elasticity and gloss, prevention, delay and/or treatment suckling by slow down aging Animal skin microgroove, wrinkle, sagging, atrophy, swelling, the appearance of corse sweat pore；f）Posted by antibacterium, antifungal, anti-skin Infested effect keeps the cleaning of mammal skin, and prevention, delay and/or treatment antibacterial, funguses, dermatozoon etc. are caused Mammal skin defective mode；G) by antiinflammatory, analgesia, hemostasis etc. effect elimination or alleviation scytitiss red and swollen heat pain, The defective modes such as bleeding；h）By promoting keratinization, correcting dyskeratosis, anti-pigmentation, suppress cicatrization, delaying skin old Change, keep skin elasticity, antiinflammatory, analgesia, hemostasis, antibacterium, antifungal, anti-dermatozoon etc. a series of to skin of mammal The beneficial effect of skin, eliminates or alleviates mammal skin defective mode so as to provide enhanced skin health and beauty.

By by the skin care compositionss of the artemisine composition containing safe and effective amount or combinations thereof such as health-oriented products, day Change product, health product or medicine etc. to be administered on the mammal for needing this kind of effect, these methods achievable and benefit.

Background technology

As the high speed development people of economy and society are also improved with beautiful requirement therewith to health, especially skin is protected Reason receives more extensive concern, and the feature and safety of skincare product is put forward higher requirement.Perplex people at present The skin problem of people masses is mainly：Acne, desquamation, the dimness blackening of skin sallow, sagging, the microgroove wrinkle that relaxes, residual cicatrix Acne print, red and swollen heat pain etc..Therefore with facial cream, facial film, Cleansing Foam, bath oil, shampoo, skin ointments agent etc. as representative on market Skin nursing products, with the addition of mostly to solve the active component of various skin problems.But these compositions are people mostly Work synthesis source, advocates natural today nature is pursued, and the activity of the natural origin of the various skin problems of energy effectively solving becomes Point, with extremely public expectation the features such as little of its green, environmental protection, safe, toxic and side effects and its consumption demand also exists Constantly increase.

Arteannuin is the present that Chinese Traditional Medicine gives the people of the world, safeguards people from world to preventing and treating the infectious diseases such as malaria People's health is significant.Slaughtering cry of a deer researcher within 2015 and Nobel prize's soul is obtained because of arteannuin, shows Accreditation of the whole world to artemisine composition, is that China's traditional medicine culture goes to the world, recognizes process by the people of the world In a monument.Artemisine composition has become the study hotspot of countries in the world at present, to its antitumor, parasiticide, controls Treat the effect such as systemic lupus erythematosus (sle) to conduct in-depth research.But above research all launches around drug research, For the elite that response country is deeply excavated in pools of traditional Chinese medicine, the unique advantage of Chinese medicine, propulsion Chinese medicine modern times are given full play to Change, the call for promoting Chinese medicine to go to the world, applicant is carried out widely to artemisine composition in line with rigorous realistic attitude Pharmacodynamics screening is studied, to making artemisine composition preferably be serviced by society.

Applicant carries out extensive Pharmacodynamics screening with artemisine composition or combinations thereof, and has surprisingly found that arteannuin Constituents or combinations thereof have promotion keratinization on mammal skin, correct dyskeratosis, suppression pigmentation, suppression scar Trace generation, delay skin aging, holding skin elasticity, elimination red and swollen heat pain, killing skin vermiform mite etc. have notable benefit Skin care active.Therefore applicants have discovered that the artemisine composition of safe and effective amount or combinations thereof and containing safe and effective amount Artemisine composition or combinations thereof skin care compositionss dermatosis or skin defective mode can be provided preventative or Therapeutic treatment.For example, applicant has found that artemisine composition or combinations thereof have prevention, postpone and/or the treatment food in one's mouth The hyperkeratotic conditions caused by dyskeratosis such as newborn animal acne, dandruff, psoriasises, scleroderma, perifollicular keratosises；Soften or The lip of submissive mammal, skin, hair, refer to toenail, hoof etc., and promote mammal lip, skin, hair, refer to toenail, hoof etc. Renewal, adjust their oiliness and gloss；Prevention, postpone and/or treatment mammal skin blackening, sallow dimness, mottle, The appearance of the pigmentation symptom such as acne print, sun exposure damage, inflammation damnification；Prevention, delay and/or treatment mammal skin scar Trace, the appearance of the cicatrix symptom such as acne print；Prevent, postpone and/or treat mammal skin microgroove, wrinkle, sagging, atrophy, swell The appearance of swollen, corse sweat pore；Keep the cleaning of mammal skin, prevention, delay and/or treatment antibacterial, funguses, skin parasitism Mammal skin defective mode caused by worm etc.；By promoting keratinization, correcting dyskeratosis, anti-pigmentation, suppression scar Trace formation, delay skin aging, holding skin elasticity, antiinflammatory, analgesia, hemostasis, antibacterium, antifungal, anti-dermatozoon etc. A series of effects beneficial to mammal skin, eliminate or alleviate mammal skin defective mode so as to provide enhanced skin Skin health and beauty.The above innovation for finding to advance health-oriented products, daily chemical products, health product or medicine, and will be right Public physical and mental healths and daily life produce far-reaching influence.

Content of the invention

The first aspect of the invention is to provide a kind of new opplication of defined artemisine composition or combinations thereof, I.e. in the new opplication of skin care applications；The second aspect of the invention be to provide a kind of skin care compositionss its include safety and have The artemisine composition of effect amount or combinations thereof and Dermatology and other active additives pharmaceutically acceptable and substrate；The present invention The 3rd aspect be to provide a kind of eliminate or alleviate mammal skin defective mode with provide enhanced skin health with Beautiful method, methods described includes to apply defined artemisine composition or combinations thereof or the present invention to mammal Skin care compositionss.

Artemisine composition as herein described or combinations thereof refer to arteannuin and its derivant and correlative and they Salt is included but is not limited to, arteannuin, dihydroarteannuin, artesunate, sodium artesunate, Artemether, arteether, arteannuin C₁₃ Derivant, arteannuin C₁₂Derivant, arteannuin C₄Derivant, deoxidation bridge arteannuin structure related compound, demethylation arteannuin Structure related compound, de- ketonic oxygen arteannuin structure related compound, steroid arteannuin structure related compound, lactams green grass or young crops Artemisin structure related compound, open loop arteannuin structure related compound, 4,5- epoxy carbon for arteannuin structure related compound, Arteannuin structure simplifies thing, other arteannuin structure related compounds and their salt；Or the group containing artemisine composition Compound or extract are included but is not limited to, Chinese medicine Herba Artemisiae Annuae（ARTEMISIAE ANNUAE HERBA）And its product, plant Artemisia annua （Artemisia annuaL.）And its product, other Compositae artemisias (Artemisia Linn. Sensu stricto, excl. Sect. Seriphidium Bess.) plant and its product, Herba Artemisiae Annuae tissue culture medium, artemisinin mother liquid etc.；Or be selected from The arbitrary composition of mentioned component.The source of artemisine composition or combinations thereof can be synthesis or include naturally but do not limit In natural product extraction, chemical complete synthesis, molecular design, biosynthesiss, histiocyte culture, fungal transformation, metabolic pathway Etc. approach.

Skin as herein described refers to that the skin of mammal and its accessory organ include but is not limited to, skin, sweat gland, skin Adipose gland, fingernail, toenail, hair, lip, epidermis, corium etc..

Skin care compositionss as herein described refer to the artemisine composition comprising safe and effective amount or combinations thereof and skin Learn constituted with other active additives pharmaceutically acceptable and substrate various health-oriented products, cosmetics of everyday use, medicine, health product Etc. including but is not limited to, Emulsion class cosmetics, watery class cosmetics, powder class cosmetics, cream kind cosmetics, aerosol class are made up Product, hair based article, beauty class cosmetics, soaps, facial film, curative effect class cosmetics, sun-proof class cosmetics, tablet, powder, ball Agent, ointment, membranous patch, gel, capsule, granule, effervescent, fumigant, slow releasing agent etc. and other skin nursings are used Product.

Safe and effective amount as herein described refers to that the person skilled of this area is rationally judged using artemisine composition Or combinations thereof be enough to produce significant beneficial effect, and the amount be enough to avoid serious untoward reaction again, that is, provide rational Effective hazard ratio, its content is preferably from about 0.0001%～90%, even more preferably about 0.01%～35%, and most preferably about 1%～22% wherein The percentage ratio is counted with composition quality as 100%.

Skin defective mode as herein described is referred to due to the skin life caused by the intrinsic factor of body or extrinsic factor The state that reason health is weakened with aesthetic appearance is included but is not limited to, and abnormal cutaneous keratinization, desquamation prurituss, skin sallow are dark Light, skin darkening, skin aging are lax, skin lines wrinkle, skin turgor are thickened, atrophoderma is sagging, corse sweat pore, skin Inflammation is red and swollen, skin greasing is coarse, dry skin chap, dermatorrhagia pain, skin are caused by inflammation or environmental stimuli injury Pigmentation, skin by inflammation or environmental stimuli injury cause cicatrix growth etc..The acne of such as mammal, dandruff, The hyperkeratotic conditions caused by dyskeratosis such as psoriasises, scleroderma, perifollicular keratosises；Mammal lip, skin, hair, Refer to dry and chap of the skin or the excess oiliness of toenail, hoof etc.；Mammal skin blackening, sallow dimness, mottle, acne print, sun exposure damage, The appearance of the pigmentation symptom such as inflammation damnification；Mammal skin cicatrix, the appearance of the cicatrix symptom such as acne print；Skin of mammal Skin microgroove, wrinkle, sagging, atrophy, the appearance of corse sweat pore；Mammal skin is drawn by antibacterial, funguses, dermatozoon etc. Defective mode for rising etc..

Enhanced skin health as herein described is referred to as skin defective mode is mitigated or eliminated with beauty and makes skin Physiological health and aesthetic appearance recover or further enhance including but not limited to,

a）By correcting dyskeratosis effect prevention, postponing and/or treat mammal acne, dandruff, desquamation prurituss, dry chap Split, the hyperkeratotic conditions caused by dyskeratosis such as psoriasises, scleroderma, perifollicular keratosises；

b）By the lip of the softening of promotion cutinization or submissive mammal, skin, hair, refer to toenail, hoof etc., and promote suckling Animal lip, skin, hair, refer to the renewal of toenail, hoof etc., adjust their oiliness and gloss；

c）Promote skin lightening ruddy by anti-pigmentation, prevention, delay and/or treatment mammal skin blackening, The appearance of the pigmentation symptoms such as sallow dimness, mottle, acne print, sun exposure damage, inflammation damnification；

d）By the effect prevention of anti-cicatrization, postpone and/or treat the cicatrix that the injury of mammal skin inflammatory stimulus is caused Cicatrix growth that growth, environmental stimuli injury are caused, the appearance of the cicatrix symptom such as acne print；

e）Skin elasticity effect is kept to strengthen skin elasticity and gloss by slow down aging, prevention, delay and/or treatment suckling are moved Thing skin lines, wrinkle, sagging, atrophy, swelling, the appearance of corse sweat pore；

f）By antibacterium, antifungal, anti-dermatozoon effect keep mammal skin cleaning, prevention, postpone and/or Mammal skin defective mode caused by treatment antibacterial, funguses, dermatozoon etc.；

G) eliminated by the effect such as antiinflammatory, analgesia, hemostasis or alleviate the defective modes such as scytitiss red and swollen heat pain, bleeding；

h）By promoting keratinization, correcting dyskeratosis, anti-pigmentation, suppression cicatrization, delay skin aging, keep skin A series of works beneficial to mammal skin such as elasticity, antiinflammatory, analgesia, hemostasis, antibacterium, antifungal, anti-dermatozoon With, eliminate or alleviate mammal skin defective mode so as to provide enhanced skin health and beauty.

Administration as herein described refers to include but is not limited to by various route of administration, partial smearing, Local out dressing, mouth The mode such as taking, fumigate makes artemisine composition as herein described or combinations thereof or skin care compositionss as herein described act on skin Skin.

Other active additives as herein described and substrate refer to known in the field in current skin protection cosmetics of everyday use, medicine Applied in product, health product, healthy product or possible application the wide scope in addition to artemisine composition and combinations thereof Other optional active additives and substrate are included but is not limited to, oily raw material, silty raw material, colloid raw material, solvent materials, water Soluble polymer, preservative, thickening agent, acid-base class regulator, antioxidant, wetting agent, astringent, sunscreen, antibacterial, tune Reason agent, cracking-off agent, opacifier, prurituss, frosting agent, surfactant, skin transferral agent, skin feeling agent, Skin Soothing Agent, Skin healing agent, nourishing additive agent, trace element and hormoness additive, biological active substanceies additive, synthesis class nutrition add Plus agent, bioactive peptide, natural extract, additive biology, quintessence oil, essence, spice, pigment, coloring agent, adhesive, disintegrating agent, Filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, fluidizer, correctivess, suspending agent, coating material, figuration Agent, absorbent, diluent, flocculant and deflocculant, filter aid, release blocker, microcapsule, microsphere, liposome etc. and he Combination.

Dermatology as herein described refers to the compositionss and its contains component be applied to and suckling with pharmaceutically acceptable Animal skin contacts, without excessive toxicity, incompatibility, unstability, atopic reaction etc.；Or be applied in process Various route of administration are contacted with mammalian organism, anti-without excessive toxicity, incompatibility, unstability, allergia Should wait.

The acceptable substrate of pharmacology as herein described refers to that described substrate will not produce impact to pharmacological experiment, can With appropriate dispersion artemisine composition or combinations thereof, and as the negative control group in experiment.

By following non-limiting examples, specific embodiments of the present invention will be further described now and carry out Illustrate, example is served only for explaining the present invention, is not intended to limit the scope of the present invention.Content described herein is only this Basic explanation under spirit and range of condition, its object is to make those skilled in the art it will be appreciated that the present invention Content is simultaneously implemented according to this, it is impossible to only limit the scope of the claims of the present invention with following examples, to according to technical solution of the present invention Those of ordinary skill for, according to disclosed spirit, any equivalent transformation or modification are carried out to the present invention, Protection scope of the present invention all should be belonged to.

Embodiment 1：The preparation of arteannuin protective skin cream.

Following component can be made into arteannuin protective skin cream by the existing production technology of protective skin cream.

Component	Mass fraction %	Component	Mass fraction %
				Dihydroarteannuin	2.00	Vaseline	6.00
Lanoline	4.00	American Avocado Tree oil	4.00
				Hexadecanol	2.00	Essence	In right amount
Hexadecanol polyoxyethylene ether	1.50	Deionized water	Add to 100.00

 

Embodiment 2：The preparation of arteannuin shampoo.

Following component can be made into arteannuin shampoo by the existing production technology of shampoo.

Component	Mass fraction %	Component	Mass fraction %
				Arteannuin	3.00	Stearic acid	5.00
Sodium lauryl sulphate	20.00	Sodium hydroxide	0.75
				Oleum Cocois single ethanol amide	1.00	Essence	In right amount
Propylene glycol monostearate	2.00	Deionized water	Add to 100.00

 

Embodiment 3:The preparation of Herba Artemisiae Annuae facial film.

Following component can be made into Herba Artemisiae Annuae facial film by the existing production technology of facial film.

Component	Mass fraction %	Component	Mass fraction %
				Herba Artemisiae Annuae extract	10.00	Glycerol	5.00
Polyvinylpyrrolidone	2.00	Ethanol	10.00
				Carboxymethyl cellulose	3.00	Essence	In right amount
Polyethylene Glycol	15.00	Deionized water	Add to 100.00

 

Experimental example 1：Artemisine composition of the present invention or the antiinflammatory action of combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.Kunming mouse 24 is taken, is randomly divided into 2 Group, i.e. matrix control group and 2% artemisine composition or combinations thereof group, each 12 per organizing.Dimethylbenzene 0.05mL is applied to mice Auris dextra, administer locally to respectively at 15min, 30min, 45min after stimulation the substrate of each group equivalent and 2% artemisine composition or its Compositionss, the disconnected neck of 60min puts to death animal, cuts left and right auricular concha, is taken at the same position of two ears with the card punch of diameter 8mm respectively Lower auricle weighs quality, is compared with the calculating each group auricular concha swelling degree of poor quality of two auricles.

1. artemisine composition of table or the acutely inflamed impact of combinations thereof xylol induced mice auricular concha (mean ± SD)

Group	Number of elements	Swelling
			Matrix control group	12	55.8±3.27
2% artemisine composition or combinations thereof group	12	22.5±2.96

P<0.01, compare with matrix control group

There is antiinflammatory action by the visible artemisine composition of table 1 or combinations thereof, there were significant differences with matrix control group.

Experimental example 2：Artemisine composition of the present invention or the analgesic activity of combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.Kunming mouse 30 is taken, is randomly divided into 2 Group, i.e. matrix control group and 2% artemisine composition or combinations thereof group, each 15 per organizing.Administer locally to the substrate of each group equivalent Cover with preservative film after 2% artemisine composition or combinations thereof administration, untie after immobilization with adhesive tape 30min, cleaned with normal saline Medicine, then dry, newly to prepare immediately 2.5% formalin, 30 μ L is wiped to the right metapedes back of the body subcutaneous injection of mice with dry absorbent cotton.Injection first After aldehyde, immediate record is licked per only mice first and licks the number of times for stinging right metapedes in the incubation period and 10min for stinging right metapedes.

2. artemisine composition of table or combinations thereof PARA FORMALDEHYDE PRILLS(91,95) cause the impact (mean ± SD) of mice pain

Group	Number of elements	Incubation period/s	Sufficient number of times is licked in 10min
				Matrix control group	15	7.9±1.55	25.4±5.2
2% artemisine composition or combinations thereof group	15	13.2±3.25	14.9±5.4

P<0.01, compare with matrix control group

There is analgesic activity by the visible artemisine composition of table 2 or combinations thereof, there were significant differences with matrix control group.

Experimental example 3：Artemisine composition of the present invention or the anastalsis of combinations thereof

Artemisine composition is with the acceptable solvent dispersion of pharmacology.Kunming mouse 24 is taken, is randomly divided into 2 groups, i.e. substrate Matched group and 2% artemisine composition or combinations thereof group, each 12 per organizing.Mice is fixed in Mus cylinder, tail point portion 2cm soaks Steep in 2% artemisine composition or combinations thereof solution or solvent, administration time 30min, after the 2h of interval, repeat administration 1 time. After last dose 30min, cut with profit and cut off at tail point 1.5cm in mice, when starting meter record bleeding when blood flows out naturally Between, drop of blood was drawn every 5 seconds with the cotton balls that oneself weighs in advance, until bleeding stops (depletion of blood when cotton balls is inhaled) naturally.Count as the following formula Calculate each group animal bleeds amount:Amount of bleeding=band blood cotton balls weight one initial cotton balls weight (mg).

The anastalsis (mean ± SD) that 3. artemisine composition of table or combinations thereof dock to mice

Group	Number of elements	Bleeding time/s	Amount of bleeding/mg
				Matrix control group	12	124.7±11.68	45.3±12.1
2% artemisine composition or combinations thereof group	12	113.1±12.77	25.3±8.7

P<0.05, compare with matrix control group

There is anastalsis by the visible artemisine composition of table 3 or combinations thereof, there were significant differences with matrix control group.

Experimental example 4：Artemisine composition of the present invention or the antibacterial actions of combinations thereof

Antibacterial group has or not colony growth through cultivating observation after 48h, with the medicine least concentration of the aseptic elder that is born as medicine most Low Mlc (MIC).

4. artemisine composition of table or combinations thereof are to common causative antibacterial minimum inhibitory concentration

Strain name	MIC/g%
		Staphylococcus aureuses	1.1
Propionibacterium acness	0.9
		Bacillus pyocyaneus	1.1
Lactobacilluss	1.0

By the visible artemisine composition of table 4 or combinations thereof to common causative antibacterial, especially cause the golden yellow of dermatosis Staphylococcuses, propionibacterium acness, bacillus pyocyaneus have certain inhibitory action.

Experimental example 5：Artemisine composition of the present invention or the antifungic action of combinations thereof

Funguses group does not increase through cultivating the bacterium scope for observing dibbling after 72h, and tapers into drying, is bacterial strain by Drug inhibition Least concentration (MIC).

5. artemisine composition of table or combinations thereof are to common skin funguses minimum inhibitory concentration

Strain name	MIC/g%
		Pityrosporum furfur	0.9
Candida albicans	0.9
		Epidermophyton	1.1

There is certain inhibitory action by the visible artemisine composition of table 5 or combinations thereof to common dermatophytess.

Experimental example 6：The anti-vermiform mite effect of artemisine composition of the present invention or combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.Paste overnight method using adhesive tape to obtain Human Demodex, is randomly divided into substrate group and 2% artemisine composition or combinations thereof group, per group 12.Inhaled with micropipettor The substrate of equivalent and 2% artemisine composition or each 200 μ L medicinal liquid Deca of combinations thereof are taken on wave carrier piece, with push jack by medicinal liquid Uniformly spread out, demodectic adhesive tape will be detected and be affixed on microscope slide, it is ensured that medicinal liquid is fully contacted with polypide.Then microscope slide is put In growth cabinet (30 DEG C of temperature, humidity 75%), basis of microscopic observation vermiform mite death condition after 12h.Dead criterion: Continuous Observation 1min under 400 power microscopes, demodicid mite body huge legendary turtle limb or the motionless person of sufficient pawl are tentatively judged as death, continue after 30min to see Examine still motionless person and be defined as death.

6. artemisine composition of table or combinations thereof are to demodectic killing action

Group	Number of elements	Dead number of elements	Mortality rate
				Matrix control group	12	0	0%
2% artemisine composition or combinations thereof group	12	10	83%

There is significant killing action to vermiform mite by the visible artemisine composition of table 6 or combinations thereof.

Experimental example 7：Artemisine composition of the present invention or the keratinization adjustment effect of combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.Take Kunming mouse 30, male and female half and half, It is randomly divided into substrate group and 2% artemisine composition or combinations thereof group.2 groups of mices distinguish the substrate of partial smearing equivalent daily Cover with preservative film after 2% artemisine composition or combinations thereof administration, untie after immobilization with adhesive tape 30min, cleaned with normal saline Medicine, then wiped with dry absorbent cotton dry, continuous 21 days, two times a day.Animal was put to death in the 22nd day, at root of the tail 2cm, taking rat-tail table Skin, fixes paraffin embedding with 10% formalin, and HE is dyeed, in the tail scale of light each mice of Microscopic observation.All scale epidermises There is continuously rows of granular cell person, be referred to as the scale for having granular layer to be formed, granular cell is flat or rhombus cell in epidermis Constituted, full of the cutin granule that thick deep basophilia, HE dyeing are transparent in avy blue in endochylema.Count rat-tail epidermis 100 Granular layer is had to form number in scale.

The impact (mean ± SD) that 7. artemisine composition of table or combinations thereof are formed to mice rat-tail granular cell

Group	Number of elements	Rat-tail per 100 scales in granular layer form number
			Matrix control group	15	7.3±1.1
2% artemisine composition or combinations thereof group	15	13.8±1.7

P<0.05, compare with matrix control group

Played the role of to promote keratinization, corrected dyskeratosis, with matrix control group by the visible artemisine composition of table 7 or combinations thereof There were significant differences.

Experimental example 8：The delay skin aging effect of artemisine composition of the present invention or combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.With people's normal skin fibroblast （NHDF）Secondary Culture obtains the preferable culture fluid of cell concentration for testing.The cell of culture is inoculated into Tissue Culture Dish In, cultivate 24h, whne cell growth to occupy culture dish area 80% when, suck culture medium, PBS one time, be subsequently adding 300（μL）PBS, is sealed with hyaline membrane, thinks 144mJ/cm²Exposure dose UVB irradiating cell 40s is clear with PBS immediately after irradiation Wash one time, be inoculated in the culture fluid of 2% artemisine composition or combinations thereof and blank culture fluid respectively, cultivate at 37 DEG C 72h.Wherein 1ml culture fluid is taken, for suppressing collagen protein catabolic enzyme（MMP-L1）The measure of generation, 1mL is used for cell survival The measure of power.The experiment is repeated 3 times.The collagen protein catabolic enzyme growing amount in culture fluid is determined using immune ELISA kit.

8. artemisine composition of table or inhibitory action of the combinations thereof to collagen protein catabolic enzyme

Group	MMP-L1 pheron quality mean concentration	MMP-L1 enzyme generates suppression ratio
			Blank control group	0.17	-
2% artemisine composition or combinations thereof group	0.07	-
			MMP-L1 enzyme generates suppression ratio	-	58.8%

Obvious suppression Skin Cell collagen protein is had to decompose zymogenesis by the visible artemisine composition of table 8 or combinations thereof, With skin anti-aging and the function of strengthening skin elasticity.

Experimental example 9：Artemisine composition of the present invention or the anti-pigmentation of combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.Cavia porcelluss 6 are taken, is gone per only back part of animal Hair, takes 2 from region, and UVB is irradiated and irradiated from UVB light source, and irradiation total amount is 2500mJ/cm², irradiate 2 area equation Region start coating after one week, the substrate of partial smearing equivalent and 2% artemisine composition or combinations thereof respectively, continuous 21 My god, two times a day.With Multi-functional skin survey during respectively in UVB pre-irradiation, after irradiating 1 week, 2 weeks, 3 weeks and 4 weeks after 1 week and medication The color change in each region of examination instrument measurement guinea pig back skin, carries out objective comparison.Biopsy divide as Microscopic observation after 4 weeks Analysis.Dyeed with Schmorl method, high power lenses count per square millimeter of epidermis cell number containing melanin granule of per part of sample.With Imokawa Method is dyeed, and high power lenses count per square millimeter of stratum basale number containing dopa-positive melanocytes of per part of sample.

9. artemisine composition of table or combinations thereof irradiate the impact (mean) of the measure of guinea pig skin color value to UVB

Group	Pre-irradiation	After irradiation	Medication 1 week	Medication 2 weeks	Medication 3 weeks	Medication 4 weeks
							Matrix control group	30	59	59	58	60	58
2% artemisine composition or combinations thereof group	31	58	56	51	47	41

P<0.05, medication is compared for 4 weeks with matrix control group

10. artemisine composition of table or combinations thereof have the pigmented inhibitory action of Cavia porcelluss (mean ± SD) to UVB

Group	The melanocyte of the DOPA positive（Individual/mm2）	Cell containing melanin granule（Individual/mm2）
			Matrix control group	773.18±68.52	2801.13±180.72
2% artemisine composition or combinations thereof group	566.97±82.67	2136.14±192.35

P<0.05, compare with matrix control group

By table 9,10 visible artemisine compositions or combinations thereof have resisting mammal pigmentation.

Experimental example 10：The anti-cicatrix of skin formation effect of artemisine composition of the present invention or combinations thereof

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.12 Japan large ear rabbits are anaesthetized, In bilateral rabbit ear veutro, lateral margin upper and lower parts do the square cutout of 2 diameter about 1cm, slit space 2.0cm, removal respectively Rabbit ear skin and subcutaneous tissue and perichondrium, cartilage-preserving, gauze pressing stops blooding.Substrate group will be randomly divided into per only ear wound surface With 2% artemisine composition or combinations thereof group, the gauze piece external application 5 of substrate or 2% artemisine composition or combinations thereof is soaked with Minute simultaneously retains, rear gauze wrapping, adopts same method dressing within 3,6,9,12,15,18,21 days after surgery.Wound surface is after surgery 12 days visible wound granulation tissue growths, the whole scar healings of 28 days visible wound surface, healing starts to occur being higher by surface for latter 18 days Hypertrophic cicatrix.Put to death animal within postoperative 50 days, specimen is cut, 10% formalin is fixed, cut into slices after paraffin embedding, HE is dyeed. 3 high power fields (× 200 times) being randomly selected in HE dyeing per a section, counts the fibroblast number in the constituent parts visual field, take Meansigma methodss.Calculate scar hyperplasia index（Hypertrophic Index, HI）：HE staining tissue slides use micrometer under low power lens Chi is measured, and calculates scar hyperplasia index by formula HI=A/B.The vertical height of A=cicatrix projection peak to credulous bone surface；B= The vertical height of cicatrix periphery normal skin skin edge to credulous bone surface.

When 50 days, the visible substrate group wound healing district's groups of perusal are knitted apparently higher than surrounding normal skin, show as cicatrix Central authorities are in papillae, and in pale red, matter is tough, and hypertrophy block is higher by surface.2% artemisine composition or the healing of combinations thereof group Area is slightly above normal skin, and color and luster is thin.HE staining tissue slides observe visible substrate group cicatrix blood capillary proliferation substantially, become Fiber finer karyon is big, intensive hypertrophy, be located at corium holostrome, collagen arrangement disorder.2% artemisine composition or combinations thereof group scar Trace tissue is relatively thin, and surfacing, level are in order, fibroblast significantly reduces.

Anti- cicatrix of skin formation effect (mean ± SD) of 11. artemisine composition of table or combinations thereof

Group	Scar hyperplasia index	Fibroblast number
			Matrix control group	3.18±0.86	86.01±2.87
2% artemisine composition or combinations thereof group	1.79±0.77	39.78±2.63

P<0.05, compare with matrix control group

Resisting mammal cicatrix of skin is had to form effect by the visible artemisine composition of table 11 or combinations thereof.

Experimental example 11：Artemisine composition of the present invention or therapeutical effect of the combinations thereof to rabbit Acne Model

Artemisine composition or combinations thereof are with the acceptable substrate dispersion of pharmacology.Male New Zealand rabbits 22 are taken, random point For substrate group and 2% artemisine composition or combinations thereof group.To preserved skin 2cm at 2 groups of new zealand rabbit ears medial surface syrinx openings × 2cm scope, smears coal tar 1 time daily, each 0.5mL, continuous 2 weeks.After 2 weeks, take skin at 2 new zealand rabbit modelings and live Inspection, pathology section examination, determine that model is formed.The left ear of 2 groups of animals distinguishes substrate and 2% arteannuin of partial smearing equivalent daily Constituents or combinations thereof, continuous 14 days, two times a day.Perusal in 15th day is simultaneously lived in animal ears corresponding site bark fetching skin Inspection, piece of tissue with 10% formalin fix, 10% nitric acid decalcification, paraffin embedding, section, HE is dyeed, tissues observed under the light microscopic Learn and change.

Histology's criterion of experimental acne：(-) no acne, infundibulum only has loose keratinocyte；(+) hair follicle The a small amount of keratinocyte being sticked together of infundibulum accumulation, funnel is not expanded；In (++) hair follicle, the cutin thromboembolism of moderate, stretches Enter sebaceous gland duct, with the hypertrophy of sebaceous gland duct, funnel is expanded；In (+++) hair follicle, close cutin thromboembolism causes hair follicle Severe is expanded, the obvious hypertrophy of sebaceous gland duct epithelium, and part sebaceous gland occurs dissolving time.

Perusal：Rabbit ear coating is after 2 weeks, it is seen that at Oleic acid, local organization is substantially coarse, thicken, hardening, and follicular orifice has Black keratotic plug, in blackhead shape, when opening coal tar crust, it is seen that attachment hair follicle keratotic plug thereon, its lower visible open increase Follicular orifice, follicular orifice swell in papulosquamous.After 2% artemisine composition or combinations thereof group medication 14 days, whole flap thickness Thinning, pliability increases, and local follicular orifice keratotic plug and acne are reduced, and pimple flattens minimizing, has part keratotic plug to leave a little after coming off The follicular orifice of shape depression.After substrate group medication 14 days, ear's still visible obvious hair follicle keratotic plug, follicular orifice bump pad is slightly put down.

Om observation：After modeling 2 weeks, it is seen that hyperkeratosiss, the hypergranulosis of epidermis and follicular epithelium, acanthosiss, The hair follicle of adjacent expansion mutually merges, and follicular orifice and infundibulum are full of keratinization material, and extend to sebaceous gland, and follicular orifice keratotic plug is blocked up Plug, infundibulum of hair follicle portion full of keratinization material and expands in gyalectiform, and dermis telangiectasis are obvious, and perifollicolar diffuses scattered In inflammatory cell infiltration, based on small round cell, and a small amount of neutrophilic granulocyte.2% artemisine composition or combinations thereof group are used After medicine 14 days, epidermis is slightly thickened, and follicular orifice is slightly expanded, and is had loose keratinization material filling on a small quantity, is had no that infundibulum of hair follicle portion expands Big such as gyalectiform, less dermal inflammation cellular infiltration.After substrate group medication 14 days, it is seen that hyperkeratosiss, epidermis and follicular epithelium Granular layer, spinous layer still hypertrophy substantially, follicular orifice and infundibulum still see keratinization material buildup, infundibulum expands such as gyalectiform, intradermal There is more inflammatory cell infiltration.

There are correction dyskeratosis, resisting mammal Cuo by result above and the visible artemisine composition of table 12 or combinations thereof The effect of skin ulcer.

12. artemisine composition of table or combinations thereof are histopathologic impact (mean) on rabbit experiment ear acne

 

P<0. 05, compare with matrix control group.

技术领域

本发明涉及到所定义的青蒿素类成分或其组合物的一种新应用，即在哺乳动物皮肤护理领域的新应用包括：a）通过纠正异常角化作用预防、延迟和/或治疗哺乳动物痤疮、头屑、脱屑瘙痒、干燥皲裂、银屑病、硬皮病、毛囊周角化病等由异常角化所引起的角化病症；b）通过促进角化作用软化或柔顺哺乳动物的唇、皮肤、毛发、指趾甲、蹄等，并促进哺乳动物唇、皮肤、毛发、指趾甲、蹄等的更新，调节它们的油性与光泽；c）通过抗色素沉着作用促进皮肤亮白红润，预防、延迟和/或治疗哺乳动物皮肤变黑、灰黄暗淡、色斑、痘印、日晒损伤、炎症损伤等色素沉着症状的出现；d）通过抗瘢痕形成作用预防、延迟和/或治疗哺乳动物皮肤炎症刺激伤害造成的瘢痕生长、外界刺激伤害造成的瘢痕生长、痘印等瘢痕症状的出现；e）通过延缓衰老保持皮肤弹性作用增强皮肤弹性与光泽，预防、延迟和/或治疗哺乳动物皮肤细纹、皱纹、松垂、萎缩、肿胀、毛孔粗大的出现；f）通过抗细菌、抗真菌、抗皮肤寄生虫作用保持哺乳动物皮肤的清洁，预防、延迟和/或治疗细菌、真菌、皮肤寄生虫等所引起的哺乳动物皮肤不良状态；g) 通过抗炎、镇痛、止血等作用消除或缓解皮肤炎症红肿热痛、出血等不良状态；h）通过促进角化、纠正角化异常、抗色素沉着、抑制瘢痕形成、延缓皮肤老化、保持皮肤弹性、抗炎、镇痛、止血、抗细菌、抗真菌、抗皮肤寄生虫等一系列对哺乳动物皮肤有益的作用，消除或缓解哺乳动物皮肤不良状态从而提供增强的皮肤健康与美丽。

通过将含有安全有效量的青蒿素类成分或其组合物的护肤组合物如健康产品、日化产品、保健品或药品等施用到需要这类效果的哺乳动物上，可实现这些方法与益处。

背景技术

随着经济与社会的高速发展人们对健康与美丽的要求也随之提高，尤其是皮肤护理受到了更加广泛的关注，对护肤用品的功能性与安全性提出了更高的要求。目前困扰人民大众的皮肤问题主要是：痤疮、脱屑、皮肤灰黄暗淡变黑、松弛下垂、细纹皱纹、残留瘢痕痘印、红肿热痛等。因此市场上以面霜、面膜、洗面乳、沐浴乳、洗发露、皮肤软膏剂等为代表的皮肤护理产品，大多添加了用以解决各种皮肤问题的活性成分。然而这些成分大多为人工合成来源，在追求自然崇尚天然的今天，能有效解决各种皮肤问题的天然来源的活性成分，以其绿色、环保、安全性高、毒副作用小等特点倍受人民大众的期盼且其消费需求也在不断的增长。

青蒿素是传统中医药送给世界人民的礼物，对防治疟疾等传染性疾病维护世界人民健康具有重要意义。2015年屠呦呦研究员因青蒿素而获得诺贝尔生理学或医学奖，表明了全世界对青蒿素类成分的认可，是我国传统医药文化走向世界，为世界人民所认识进程中的一座丰碑。目前青蒿素类成分已成为世界各国的研究热点，对其抗肿瘤、抗寄生虫、治疗系统性红斑狼疮等作用进行了深入的研究。但是以上研究都是围绕药物研究而展开的，为响应国家深入发掘中医药宝库中的精华，充分发挥中医药的独特优势，推进中医药现代化，推动中医药走向世界的号召，申请者本着严谨求实的态度对青蒿素类成分进行广泛的药效学筛选研究，以期使青蒿素类成分更好的为社会大众所服务。

申请者以青蒿素类成分或其组合物进行广泛的药效学筛选，并惊奇的发现青蒿素类成分或其组合物在哺乳动物皮肤上具有促进角化、纠正角化异常、抑制色素沉着、抑制瘢痕生成、延缓皮肤老化、保持皮肤弹性、消除红肿热痛、杀灭皮肤蠕形螨等有着显著益处的皮肤护理活性。因此申请者发现安全有效量的青蒿素类成分或其组合物及含有安全有效量的青蒿素类成分或其组合物的护肤组合物可以对皮肤疾病或皮肤不良状态提供预防性或治疗性处理。例如，申请者已经发现青蒿素类成分或其组合物具有预防、延迟和/或治疗哺乳动物痤疮、头屑、银屑病、硬皮病、毛囊周角化病等由异常角化所引起的角化病症；软化或柔顺哺乳动物的唇、皮肤、毛发、指趾甲、蹄等，并促进哺乳动物唇、皮肤、毛发、指趾甲、蹄等的更新，调节它们的油性与光泽；预防、延迟和/或治疗哺乳动物皮肤变黑、灰黄暗淡、色斑、痘印、日晒损伤、炎症损伤等色素沉着症状的出现；预防、延迟和/或治疗哺乳动物皮肤瘢痕，痘印等瘢痕症状的出现；预防、延迟和/或治疗哺乳动物皮肤细纹、皱纹、松垂、萎缩、肿胀、毛孔粗大的出现；保持哺乳动物皮肤的清洁，预防、延迟和/或治疗细菌、真菌、皮肤寄生虫等所引起的哺乳动物皮肤不良状态；通过促进角化、纠正角化异常、抗色素沉着、抑制瘢痕形成、延缓皮肤老化、保持皮肤弹性、抗炎、镇痛、止血、抗细菌、抗真菌、抗皮肤寄生虫等一系列对哺乳动物皮肤有益的作用，消除或缓解哺乳动物皮肤不良状态从而提供增强的皮肤健康与美丽。以上发现必将推进健康产品、日化产品、保健品或药品的研发创新，并将对人民大众的身心健康和日常生活产生深远的影响。

发明内容

本发明的第一个方面在于提供所定义的青蒿素类成分或其组合物的一种新应用，即在皮肤护理领域的新应用；本发明的第二个方面在于提供一种护肤组合物其包含安全有效量的青蒿素类成分或其组合物及皮肤学与药学可接受的其他活性添加剂及基质；本发明的第三个方面在于提供一种消除或缓解哺乳动物皮肤不良状态以提供增强的皮肤健康与美丽的方法，所述方法包括向哺乳动物施用所定义的青蒿素类成分或其组合物或本发明的护肤组合物。

本文所述的青蒿素类成分或其组合物是指青蒿素及其衍生物和相关物及他们的盐类包括但不限于，青蒿素、双氢青蒿素、青蒿琥酯、青蒿琥酯钠、蒿甲醚、蒿乙醚、青蒿素C₁₃衍生物、青蒿素C₁₂衍生物、青蒿素C₄衍生物、脱氧桥青蒿素结构相关化合物、脱甲基青蒿素结构相关化合物、脱羰基氧青蒿素结构相关化合物、甾类青蒿素结构相关化合物、内酰胺青蒿素结构相关化合物、开环青蒿素结构相关化合物、4,5-环氧碳代青蒿素结构相关化合物、青蒿素结构简化物、其他青蒿素结构相关化合物及他们的盐类；或含有青蒿素类成分的组合物或提取物包括但不限于，中药青蒿（ARTEMISIAE ANNUAE HERBA）及其制品、植物黄花蒿（Artemisia annua L.）及其制品、其他菊科蒿属(Artemisia Linn. Sensu stricto, excl. Sect. Seriphidium Bess.)植物及其制品、青蒿组织培养液、青蒿素母液等；或选自上述成分的任意组合物。青蒿素类成分或其组合物的来源可以是合成或自然包括但不限于，天然产物提取、化学全合成、化学半合成、生物合成、组织细胞培养、真菌转化、代谢通路等途径。

本文所述的皮肤是指哺乳动物的皮肤及其附属器官包括但不限于，皮肤、汗腺、皮脂腺、指甲、趾甲、毛发、唇、表皮、真皮等。

本文所述的护肤组合物是指包含安全有效量的青蒿素类成分或其组合物及皮肤学与药学可接受的其他活性添加剂及基质所组成的各种健康产品、日化用品、药品、保健品等包括但不限于，乳剂类化妆品、水状类化妆品、粉类化妆品、膏霜类化妆品、气溶胶类化妆品、发用类制品、美容类化妆品、皂类、面膜、疗效类化妆品、防晒类化妆品、片剂、散剂、丸剂、软膏剂、贴膜剂、凝胶剂、胶囊剂、颗粒剂、泡腾剂、熏蒸剂、缓释剂等及其他皮肤护理用品。

本文所述的安全有效量是指本领域的相关技术人员合理判断使用青蒿素类成分或其组合物足以产生显著的有益效果，且该量又足以避免严重的不良反应，即提供合理的效险比，其含量优选为约0.0001%～90%，更优选为约0.01%～35%，最优选为约1%～22%其中所述百分比是以组合物质量为100%计。

本文所述的皮肤不良状态是指由于机体的内在因素或外在因素所引起的皮肤生理健康与美学外观减弱的状态包括但不限于，皮肤角化异常、皮肤脱屑瘙痒、皮肤灰黄暗淡、皮肤变黑、皮肤衰老松弛、皮肤细纹皱纹、皮肤肿胀增厚、皮肤萎缩下垂、毛孔粗大、皮肤炎症红肿、皮肤油腻粗糙、皮肤干燥皲裂、皮肤出血疼痛、皮肤受炎症或外界刺激伤害造成的色素沉着、皮肤受炎症或外界刺激伤害造成的瘢痕生长等。例如哺乳动物的痤疮、头屑、银屑病、硬皮病、毛囊周角化病等由异常角化所引起的角化病症；哺乳动物唇、皮肤、毛发、指趾甲、蹄等的干燥龟裂或过度油腻；哺乳动物皮肤变黑、灰黄暗淡、色斑、痘印、日晒损伤、炎症损伤等色素沉着症状的出现；哺乳动物皮肤瘢痕，痘印等瘢痕症状的出现；哺乳动物皮肤细纹、皱纹、松垂、萎缩、毛孔粗大的出现；哺乳动物皮肤由细菌、真菌、皮肤寄生虫等所引起的不良状态等。

本文所述的增强的皮肤健康与美丽是指由于减轻或消除皮肤不良状态而使皮肤的生理健康与美学外观恢复或进一步增强包括但不限于，

a）通过纠正异常角化作用预防、延迟和/或治疗哺乳动物痤疮、头屑、脱屑瘙痒、干燥皲裂、银屑病、硬皮病、毛囊周角化病等由异常角化所引起的角化病症；

b）通过促进角化作用软化或柔顺哺乳动物的唇、皮肤、毛发、指趾甲、蹄等，并促进哺乳动物唇、皮肤、毛发、指趾甲、蹄等的更新，调节它们的油性与光泽；

c）通过抗色素沉着作用促进皮肤亮白红润，预防、延迟和/或治疗哺乳动物皮肤变黑、灰黄暗淡、色斑、痘印、日晒损伤、炎症损伤等色素沉着症状的出现；

d）通过抗瘢痕形成作用预防、延迟和/或治疗哺乳动物皮肤炎症刺激伤害造成的瘢痕生长、外界刺激伤害造成的瘢痕生长、痘印等瘢痕症状的出现；

e）通过延缓衰老保持皮肤弹性作用增强皮肤弹性与光泽，预防、延迟和/或治疗哺乳动物皮肤细纹、皱纹、松垂、萎缩、肿胀、毛孔粗大的出现；

f）通过抗细菌、抗真菌、抗皮肤寄生虫作用保持哺乳动物皮肤的清洁，预防、延迟和/或治疗细菌、真菌、皮肤寄生虫等所引起的哺乳动物皮肤不良状态；

g) 通过抗炎、镇痛、止血等作用消除或缓解皮肤炎症红肿热痛、出血等不良状态；

h）通过促进角化、纠正角化异常、抗色素沉着、抑制瘢痕形成、延缓皮肤老化、保持皮肤弹性、抗炎、镇痛、止血、抗细菌、抗真菌、抗皮肤寄生虫等一系列对哺乳动物皮肤有益的作用，消除或缓解哺乳动物皮肤不良状态从而提供增强的皮肤健康与美丽。

本文所述的施用是指通过各种给药途径包括但不限于，局部涂抹、局部外敷、口服、熏蒸等方式使本文所述的青蒿素类成分或其组合物或本文所述的护肤组合物作用于皮肤。

本文所述的其他活性添加剂及基质是指本领域所公知的在目前护肤日化用品、药品、保健品、健康品中已有应用或可能应用的除青蒿素类成分及其组合物以外的宽范围的任选的其他活性添加剂及基质包括但不限于，油质原料、粉质原料、胶质原料、溶剂原料、水溶性聚合物、防腐剂、增稠剂、酸碱类调节剂、抗氧化剂、保湿剂、收敛剂、防晒剂、杀菌剂、调理剂、剥脱剂、遮光剂、止痒剂、磨砂剂、表面活性剂、皮肤助渗剂、皮肤感觉剂、皮肤舒缓剂、皮肤愈合剂、营养添加剂、微量元素和激素类添加剂、生理活性物质添加剂、合成类营养添加剂、活性肽、天然提取物、生物学添加剂、精油、香精、香料、色素、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、助悬剂、包衣材料、赋形剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂、微囊、微球、脂质体等以及他们的组合。

本文所述的皮肤学与药学可接受的是指所述组合物及其含有组分适用于与哺乳动物皮肤相接触，而没有过度的毒性、不相容性、不稳定性、变应性反应等；或适用于在经过各种给药途径与哺乳动物机体相接触，而没有过度的毒性、不相容性、不稳定性、变应性反应等。

本文所述的药理学可接受的基质是指所述的基质不会对药理学实验产生影响，可以恰当的分散青蒿素类成分或其组合物，并作为实验中的阴性对照组。

现在将借助以下非限制性实例对本发明的具体实施方案作进一步的描述并进行举例说明，所举实例只用于解释本发明，并非用于限定本发明的范围。本文所述内容仅为本发明精神和范围条件下的基本说明，其目的在于使本领域内的技术人员能够理解本发明的内容并据以实施，不能仅以以下实施例来限定本发明的专利范围，对依据本发明技术方案的普通技术人员来说，依据本发明所揭示的精神实质对本发明进行任何等效变换或修饰，均应属于本发明的保护范围。

实施例1：青蒿素护肤霜的制备。

如下组分通过护肤霜现有生产工艺可制成青蒿素护肤霜。

组分	质量分数%	组分	质量分数%
				双氢青蒿素	2.00	凡士林	6.00
羊毛脂	4.00	鳄梨油	4.00
				十六醇	2.00	香精	适量
十六醇聚氧乙烯醚	1.50	去离子水	加至100.00

 

实施例2：青蒿素洗发露的制备。

如下组分通过洗发露现有生产工艺可制成青蒿素洗发露。

组分	质量分数%	组分	质量分数%
				青蒿素	3.00	硬脂酸	5.00
十二烷基硫酸钠	20.00	氢氧化钠	0.75
				椰子油单乙醇酰胺	1.00	香精	适量
丙二醇单硬脂酸酯	2.00	去离子水	加至100.00

 

实施例3: 青蒿面膜的制备。

如下组分通过面膜现有生产工艺可制成青蒿面膜。

组分	质量分数%	组分	质量分数%
				青蒿提取物	10.00	甘油	5.00
聚乙烯吡咯烷酮	2.00	乙醇	10.00
				羧甲基纤维素	3.00	香精	适量
聚乙二醇	15.00	去离子水	加至100.00

 

实验例1：本发明青蒿素类成分或其组合物的抗炎作用

青蒿素类成分或其组合物以药理学可接受的基质分散。取昆明种小鼠24只，随机分为2组，即基质对照组与2%青蒿素类成分或其组合物组，每组各12只。二甲苯0.05mＬ涂于小鼠右耳，刺激后分别于15min、30min、45min局部给予各组等量的基质与2%青蒿素类成分或其组合物，60min断颈处死动物，剪下左右耳壳，用直径8mm的打孔器分别在两耳的同一部位取下耳片称取质量，以两耳片的质量差计算各组耳壳肿胀度进行比较。

表1. 青蒿素类成分或其组合物对二甲苯所致小鼠耳壳急性炎症的影响(mean± SD)

组别	只数	肿胀度
			基质对照组	12	55.8±3.27
2%青蒿素类成分或其组合物组	12	22.5±2.96

P<0.01，与基质对照组比较

由表1可见青蒿素类成分或其组合物有抗炎作用，与基质对照组有显著差异。

实验例2：本发明青蒿素类成分或其组合物的镇痛作用

青蒿素类成分或其组合物以药理学可接受的基质分散。取昆明种小鼠30只，随机分为2组，即基质对照组与2%青蒿素类成分或其组合物组，每组各15只。局部给予各组等量的基质与2%青蒿素类成分或其组合物给药后保鲜膜覆盖，胶布固定30min后解开，以生理盐水洗净药物，再用干药棉拭干，立即给小鼠右后足背皮下注射新配制的2.5%甲醛溶液30μL。注射甲醛后立即记录每只小鼠首次舔咬右后足的潜伏期及10min内舔咬右后足的次数。

表2. 青蒿素类成分或其组合物对甲醛致小鼠疼痛的影响(mean±SD)

组别	只数	潜伏期/s	10min内舔足次数
				基质对照组	15	7.9±1.55	25.4±5.2
2%青蒿素类成分或其组合物组	15	13.2±3.25	14.9±5.4

P<0.01，与基质对照组比较

由表2可见青蒿素类成分或其组合物有镇痛作用，与基质对照组有显著差异。

实验例3：本发明青蒿素类成分或其组合物的止血作用

青蒿素类成分以药理学可接受的溶媒分散。取昆明种小鼠24只，随机分为2组，即基质对照组与2%青蒿素类成分或其组合物组，每组各12只。将小鼠固定于鼠筒中，尾尖部2cm浸泡于2%青蒿素类成分或其组合物溶液或溶媒中，给药时间30min，间隔2h后，重复给药1次。末次给药30min后，以利剪在小鼠距尾尖1.5cm处剪断，待血液自然流出时开始计录出血时间，每隔5秒用己事先称重的棉球吸取血滴，直至出血自然停止(棉球吸时无血)。按下式计算各组动物出血量:出血量=带血棉球重量一初始棉球重量(mg)。

表3. 青蒿素类成分或其组合物对小鼠断尾的止血作用(mean±SD)

组别	只数	出血时间/s	出血量/mg
				基质对照组	12	124.7±11.68	45.3±12.1
2%青蒿素类成分或其组合物组	12	113.1±12.77	25.3±8.7

P<0.05，与基质对照组比较

由表3可见青蒿素类成分或其组合物有止血作用，与基质对照组有显著差异。

实验例4：本发明青蒿素类成分或其组合物的抗细菌作用

细菌组经培养48h后观察有无菌落生长，以无菌落生长者的药物最低浓度为药物的最低抑菌浓度(MIC)。

表4. 青蒿素类成分或其组合物对常见致病细菌最低抑菌浓度

菌种名	MIC/g%
		金黄色葡萄球菌	1.1
痤疮丙酸杆菌	0.9
		绿脓杆菌	1.1
乳酸杆菌	1.0

由表4可见青蒿素类成分或其组合物对常见致病细菌，尤其是引起皮肤疾病的金黄色葡萄球菌、痤疮丙酸杆菌、绿脓杆菌有一定的抑制作用。

实验例5：本发明青蒿素类成分或其组合物的抗真菌作用

真菌组经培养72h后观察点种的菌范围不增大，且逐渐变小干燥，为菌株已被药物抑制的最低浓度(MIC)。

表5. 青蒿素类成分或其组合物对常见皮肤真菌最低抑菌浓度

菌种名	MIC/g%
		糠秕孢子菌	0.9
白色念珠菌	0.9
		表皮癣菌	1.1

由表5可见青蒿素类成分或其组合物对常见的皮肤真菌有一定的抑制作用。

实验例6：本发明青蒿素类成分或其组合物的抗蠕形螨作用

青蒿素类成分或其组合物以药理学可接受的基质分散。采用透明胶带粘贴过夜法获取人体蠕形螨，随机分成基质组和2%青蒿素类成分或其组合物组，每组12只。用微量移液器吸取等量的基质和2%青蒿素类成分或其组合物各200μL药液滴加于载波片上，用推片将药液均匀铺开，将检出蠕形螨的胶带贴于载玻片上，保证药液与虫体充分接触。然后将载玻片置于人工气候箱(温度30℃，湿度75%)，12h后显微镜下观察蠕形螨死亡情况。死亡判断标准:在400倍显微镜下连续观察1min，螨体鳌肢或足爪不动者初步判断为死亡，30min后继续观察仍不动者确定为死亡。

表6. 青蒿素类成分或其组合物对蠕形螨的杀灭作用

组别	只数	死亡只数	死亡率
				基质对照组	12	0	0%
2%青蒿素类成分或其组合物组	12	10	83%

由表6可见青蒿素类成分或其组合物对蠕形螨有显著的杀灭作用。

实验例7：本发明青蒿素类成分或其组合物的角化调节作用

青蒿素类成分或其组合物以药理学可接受的基质分散。取昆明种小鼠30只，雌雄各半，随机分成基质组和2%青蒿素类成分或其组合物组。2组小鼠每天分别局部涂抹等量的基质与2%青蒿素类成分或其组合物给药后保鲜膜覆盖，胶布固定30min后解开，以生理盐水洗净药物，再用干药棉拭干，连续21天，一天2次。于第22天处死动物，在距尾根2cm处取鼠尾表皮，以10%甲醛溶液固定石蜡包埋，HE染色，在光镜下观察每个小鼠的尾部鳞片。凡鳞片表皮有连续成行的颗粒细胞者，称为有颗粒层形成的鳞片，颗粒细胞为表皮中扁平或菱形细胞所组成，胞浆内充满粗大深嗜碱性、HE染色呈深兰色透明的角质颗粒。计数鼠尾表皮100个鳞片中有颗粒层形成数。

表7. 青蒿素类成分或其组合物对小鼠鼠尾颗粒细胞形成的影响(mean±SD)

组别	只数	鼠尾每100个鳞片中颗粒层形成数
			基质对照组	15	7.3±1.1
2%青蒿素类成分或其组合物组	15	13.8±1.7

P<0.05，与基质对照组比较

由表7可见青蒿素类成分或其组合物有促进角化、纠正异常角化的作用，与基质对照组有显著差异。

实验例8：本发明青蒿素类成分或其组合物的延缓皮肤老化作用

青蒿素类成分或其组合物以药理学可接受的基质分散。以人正常皮肤成纤维细胞（NHDF）传代培养得到细胞浓度较好的培养液用于实验。将培养的细胞接种到细胞培养皿中，培养24h，待细胞生长至占据培养皿面积80％时，吸去培养基，PBS清洗一遍，然后加入300（μL）PBS，以透明膜封口，以为144mJ／cm²照射剂量UVB照射细胞40s，照射后立即用PBS清洗一遍，分别接种到2%青蒿素类成分或其组合物的培养液与空白培养液中，在37℃培养72h。取其中1ml培养液，用于抑制胶原蛋白分解酶（MMP-L1）生成的测定，1mL用于细胞存活力的测定。该实验重复3次。利用免疫ELISA试剂盒测定培养液中的胶原蛋白分解酶生成量。

表8. 青蒿素类成分或其组合物对胶原蛋白分解酶的抑制作用

组别	MMP-L1酶蛋白质量平均浓度	MMP-L1酶生成抑制率
			空白对照组	0.17	-
2%青蒿素类成分或其组合物组	0.07	-
			MMP-L1酶生成抑制率	-	58.8%

由表8可见青蒿素类成分或其组合物有明显抑制皮肤细胞胶原蛋白分解酶生成作用，具有皮肤抗老化与增强皮肤弹性的功能。

实验例9：本发明青蒿素类成分或其组合物的抗色素沉着作用

青蒿素类成分或其组合物以药理学可接受的基质分散。取豚鼠6只，每只动物背部去毛，取2个相离区域，UVB照射选用UVB光源照射，照射总量为2500mJ/cm²，照射2个面积相等的区域一周后开始涂药，分别局部涂抹等量的基质与2%青蒿素类成分或其组合物，连续21天，一天2次。分别在UVB照射前、照射后1周和用药后1周、2周、3周和4周时以多功能皮肤测试仪测量豚鼠背部皮肤各区域的颜色变化，进行客观比较。4周后组织活检并作镜下观察分析。以Schmorl法染色，高倍镜计数每份样品每平方毫米表皮含黑素颗粒细胞数。以Imokawa法染色，高倍镜计数每份样品每平方毫米表皮基底层含多巴阳性黑素细胞数。

表9. 青蒿素类成分或其组合物对UVB照射豚鼠皮肤颜色值的测定的影响(mean)

组别	照射前	照射后	用药1周	用药2周	用药3周	用药4周
							基质对照组	30	59	59	58	60	58
2%青蒿素类成分或其组合物组	31	58	56	51	47	41

P<0.05，用药4周与基质对照组比较

表10. 青蒿素类成分或其组合物对UVB有豚鼠色素沉着的抑制作用(mean±SD)

组别	多巴阳性的黑素细胞（个/mm2）	含黑素颗粒的细胞（个/mm2）
			基质对照组	773.18±68.52	2801.13±180.72
2%青蒿素类成分或其组合物组	566.97±82.67	2136.14±192.35

P<0.05，与基质对照组比较

由表9，10可见青蒿素类成分或其组合物有抗哺乳动物色素沉着作用。

实验例10：本发明青蒿素类成分或其组合物的抗皮肤瘢痕形成作用

青蒿素类成分或其组合物以药理学可接受的基质分散。将12只日本大耳白兔麻醉，在双侧兔耳腹侧内侧缘上、下部位分别做2个直径约1cm的正方形切口，切口间隔2.0cm，去除兔耳皮肤和皮下组织和软骨膜，保留软骨，纱布压迫止血。将每只耳朵创面随机分为基质组与2%青蒿素类成分或其组合物组，浸有基质或2%青蒿素类成分或其组合物的纱布块外敷5分钟并保留，后纱布包扎，在术后3、6、9、12、15、18、21天采用同样的方法换药。创面在术后12天可见创面肉芽组织生长，28天可见创面全部瘢痕愈合，愈合后18天开始出现高出皮面的增生性瘢痕。术后50天处死动物，切取标本，10%甲醛溶液固定，石蜡包埋后切片，HE染色。在HE染色每张切片随机选取3个高倍视野(×200倍)，计数各单位视野的成纤维细胞数，取平均值。计算瘢痕增生指数（Hypertrophic Index，HI）：HE染色组织切片于低倍镜下用测微尺测量，按公式HI=A/B计算瘢痕增生指数。A=瘢痕凸起最高点至耳软骨表面的垂直高度；B=瘢痕周边正常皮肤皮缘至耳软骨表面的垂直高度。

50天时肉眼观察可见基质组创面愈合区组织明显高于周围正常皮肤，表现为瘢痕中央呈乳头状突起，呈淡红色，质韧，增生块高出皮面。2%青蒿素类成分或其组合物组愈合区略高于正常皮肤，色泽较淡。HE染色组织切片观察可见基质组瘢痕毛细血管增生明显、成纤维细胞核大、密集增生、位于真皮全层、胶原排列紊乱。2%青蒿素类成分或其组合物组瘢痕组织较薄，表面平整、层次有序、成纤维细胞明显减少。

表11. 青蒿素类成分或其组合物的抗皮肤瘢痕形成作用(mean±SD)

组别	瘢痕增生指数	成纤维细胞数
			基质对照组	3.18±0.86	86.01±2.87
2%青蒿素类成分或其组合物组	1.79±0.77	39.78±2.63

P<0.05，与基质对照组比较

由表11可见青蒿素类成分或其组合物有抗哺乳动物皮肤瘢痕形成作用。

实验例11：本发明青蒿素类成分或其组合物对家兔痤疮模型的治疗作用

青蒿素类成分或其组合物以药理学可接受的基质分散。取雄性新西兰兔22只，随机分为基质组与2%青蒿素类成分或其组合物组。对2组新西兰兔双耳内侧面耳管开口处备皮2cm×2cm范围，每日涂抹煤焦油1次，每次0.5mL，连续2周。2周后，取2只新西兰兔造模处皮肤活检、病理切片观察，确定模型形成。2组动物左耳每天分别局部涂抹等量的基质与2%青蒿素类成分或其组合物，连续14天，一天2次。第15天肉眼观察并于动物双耳相应部位取皮肤活检，组织块以10%福尔马林固定，10%硝酸脱钙，石蜡包埋，切片，HE染色，于光镜下观察组织学改变。

实验性粉刺的组织学判定标准：(-)无粉刺，漏斗部仅有松散的角化细胞；(+)毛囊漏斗部积聚少量的粘连在一起的角化细胞，漏斗不扩张；(++)毛囊中中等量的角质栓塞，伸入皮脂腺导管，伴随皮脂腺导管的增生，漏斗扩张；(+++)毛囊中紧密的角质栓塞引起毛囊重度扩张，皮脂腺导管上皮明显增生，部分皮脂腺发生退行变。

肉眼观察：兔耳涂药2周后，可见油酸处局部组织明显粗糙、增厚、变硬，毛囊口有黑色角栓，呈黑头粉刺状，揭开煤焦油痂时，可见附着其上的毛囊角栓，其下可见开放增大的毛囊口，毛囊口隆起呈丘疹状。2%青蒿素类成分或其组合物组用药14天后，整个皮片厚度变薄，柔软度增加，局部毛囊口角栓及粉刺减少，丘疹变平减少，有部分角栓脱落后遗留点状凹陷的毛囊口。基质组用药14天后，耳部仍可见明显的毛囊角栓，毛囊口隆起处略平。

光镜观察：造模2周后，可见角化过度，表皮和毛囊上皮的颗粒层增厚，棘层肥厚，相邻扩张的毛囊相互融合，毛囊口及漏斗部充满角化物质，并向皮脂腺延伸，毛囊口角栓堵塞，毛囊漏斗部充满角化物质并扩大呈壶状，真皮上层毛细血管扩张明显，毛囊周围弥漫散在炎性细胞浸润，以小圆形细胞为主，及少量中性粒细胞。2%青蒿素类成分或其组合物组用药14天后，表皮轻度增厚，毛囊口轻度扩张，有少量疏松角化物质充填，未见毛囊漏斗部扩大如壶状，较少真皮炎症细胞浸润。基质组用药14天后，可见角化过度，表皮及毛囊上皮的颗粒层、棘层仍增生明显、毛囊口及漏斗部仍见角化物质堆积，漏斗部扩大如壶状，真皮内有较多炎性细胞浸润。

由以上结果及表12可见青蒿素类成分或其组合物有纠正异常角化、抗哺乳动物痤疮的作用。

表12. 青蒿素类成分或其组合物对家兔实验性耳痤疮组织病理学的影响(mean)

 

P<0. 05，与基质对照组比较。