CN101401775B

CN101401775B - Novel passive target skin whitening efficacy nanoemulsion for night and daylight and method of preparing the same

Info

Publication number: CN101401775B
Application number: CN2008101436402A
Authority: CN
Inventors: 杨永鹏; 朱晓亮; 董萍; 丁宇; 丁克祥
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-11-18
Filing date: 2008-11-18
Publication date: 2010-08-25
Anticipated expiration: 2028-11-18
Also published as: CN101401775A

Abstract

The invention relates to a novel passive targeting nano emulsion with skin whitening effect and a preparation method thereof. The invention uses a novel passive targeting transdermal delivery dosing system TDDS-nano emulsion as a carrier of a function component for whitening or lighting the skin, uses different physical and chemical properties, action mechanism and actual effect of each skin whitening function component, especially the action advantages of certain novel skin whitening function components, and provides skin whitening effect nano emulsion systems with two joint applications in morning and evening matched with each other. The two joint applied nano emulsion systems not only have minimum spherical grains, extremely even distribution of nano-scale grains, remarkable passive targeting function, good transdermal absorption and strong penetrability, but also have extremely even, exquisite, smooth and glossy texture of the nano emulsion, is quite comfortable after coating onthe face or the skin, has no stimulus and good stability; and the nano is light yellow, beautiful in appearance, bright and transparent, clear and crystalline, has light opalescence, and is adhesive but not sticky, thick but not heavy, oily but not greasy.

Description

Passive target ight and skin whitening efficacy nanoemulsion and preparation method thereof

Technical field

The present invention relates to medical cosmetology health promoting product and cosmetic formulations technology, refer in particular to and a kind ofly be successfully applied to the skin-whitening in the human medical beauty treatment and cutaneous pigmentation suppresses and desalination or alleviate the passive target ight of aspect such as skin splash and skin whitening efficacy nanoemulsion and preparation method thereof.

Background technology

(1) about the background technology of skin whitening efficacy composition:, present skin-whitening agents can be divided into: tyrosinase activity inhibitor, melanocyte toxic agents, influence melanocyte metabolism agent (melanocyte transportation blocker), opacifier (sunscreen), Reducing agent, chemical cracking-off agent, endothelin antagonist etc. by different action principles.Wherein, tyrosinase activity inhibitor mainly contains: compound containing mercury (as calomel, ammoniated mercury etc.), hydroquinone (hydroquinone), arbutin (hydroquinone glucoside), kojic acid (aspergillosis enzyme), Azelaic Acid (azelaic acid) etc.The melanocyte toxic agents mainly contains: four different cetylates, oil-soluble Radix Glycyrrhizae extract, hydroquinone etc.Influence melanocyte metabolism agent (melanocyte transportation blocker): as retinoic acid, linoleic acid etc.What opacifier (sunscreen) had mainly contained the shielding ultraviolet rays effect has two kinds of inorganic sunscreen and organic sunscreen agent.Inorganic sunscreen all is light tight material, can or scatter out ultraviolet and visible light reflection, mainly contains titanium dioxide (TiO ₂), zinc oxide (ZnO) etc., and reduce photocatalytic activity, and can mix with oils and fats substrate class through surface treatment.The organic sunscreen agent is generally transmission substance, the alternative absorption is harmful to ultraviolet and changes luminous energy into internal energy of molecular, mainly contains paraaminobenzoic acid esters (PABA), o-aminobenzoa class, salicylic acid esters, benzophenone, dibenzoyl methane class, p-methoxycinnamic acid esters, benzimidazole, benzyl Camphora class etc.The melanocyte Reducing agent mainly contains VC, VE and derivant thereof etc.The chemistry cracking-off agent mainly contains fruit acid (being also referred to as alpha hydroxy acid), trichloroacetic acid, carbolic acid, oleic acid or linoleic acid etc.Endothelin antagonist mainly is extract in the plant (licoflavone etc.), has the plain effect of blackening of antagonism Endothelin.The natural plants whitening composition mainly is to contain flavonoid, Polyphenols natural materials.Other novel whitening composition comprises nicotiamide, N-acetylglucosamine, fibroin albumen, intacellin etc.Other novel tyrosinase inhibitor comprises 2, the Arrcostab of 5-hydroxy benzoic acid (GA), catches the monomeric complex of melanin, activated protein enzyme acceptor 2 (PAR-2) inhibitor, unsaturated fatty acid etc.

(2) skin whitening or the transdermal drag delivery present situation of whitening: help the natural medicine of short skin functional component Transdermal absorption, as adding terpenoid: comprise monoterpene, sesquiterpene, triterpenoid compound; Quintessence oil: comprise Oleum menthae, Oleum Caryophylli, oil of rosemary, Oleum Rosae Rugosae, Jasmin oil, Essential lavender oil, Laurel wet goods; Alkaloid; Lactone; Other: is as menthol and Borneolum Syntheticum etc.Add the synthesising preparation that some help short skin whitening spot-removal function composition Transdermal absorption in addition, as organic acid and esters thereof: comprise fatty acid, fatty acid ester, amino-acid ester, lactams ester, cholinester etc.; Pyrrolidinone compounds; Phospholipid and phosphoric acid salt; Amide-type; Enzyme etc.Wherein pass by the most frequently used have dimethyl sulfoxide, sodium tetradecyl sulfate, laurocapram, lauric acid, cocoa butter, Oleum Terebinthinae, shark alkane etc., and laurocapram has become the object of reference of some new short transdermal agents.The possible mechanism of these short Transdermal absorption synthesising preparations is by the lipid of dissolving skin surface, makes epidermal protein qualitative change, simultaneously, by to modes such as functional component solubilising or hydrotropies, increasing its permeability that passes the keratodermatitis barrier and their diffusion and distributions in each layer of epidermis, thereby reach the purpose that promotes the functional component Transdermal absorption.And the mechanism of the short Transdermal absorption of laurocapram also may and cuticular layer between the lipid of matter have an effect, to increase its flowability, to reduce the diffusional resistance of natural functional component and bioactive substance etc.Although these short skin penetrating agent are the certain effect of performance aspect the functional component Transdermal absorption that promotes skin-whitening or brighten, but because of above-mentioned skin whitening functional component source difference, its physicochemical property is also inequality, water solublity is arranged, have fat-solublely, pure dissolubility is arranged, also some is that water oil is two molten or two insoluble, therefore, dissolubility and the stability that solves between above-mentioned short skin penetrant and skin-whitening or the whitening efficacy composition is all very difficult; And, the molecular weight of some skin-whitening or whitening efficacy composition is little, the molecular weight of some skin-whitening or whitening efficacy composition is big, molecular structure and form be obvious difference also, depend merely on the passive transdermal effect of above-mentioned short skin penetrant, the functional component that still is not enough to make skin-whitening or brightens is Transdermal absorption and the maximum biological action of performance successfully, some functional component even still can't Transdermal absorption and its due biological action of performance.Particularly along with above-mentioned short skin penetrant great majority are chemosynthesis or semi-synthetic preparation, increasing or use as working concentration are too frequent, and the cost of product is increased, and, the irritated rate and the zest of skin are strengthened, and toxic and side effects is more obvious; Simultaneously skin-whitening or the effect material that brightens mostly all to heat, to pH value, to illumination, to the oxidation reaction sensitivity, therefore, even above-mentioned short skin penetrant can promote the functional component Transdermal absorption, but because the unstability of skin-whitening or whitening efficacy composition, in the implementation process of concrete formulated product, make these functional component inactivations again easily and can't bring into play its corresponding effect.Liposome is a kind of carrier of short functional component Transdermal absorption preferably, it is to seal the hollow spheres body that forms by bimolecular lamellar lipid membrane, diameter is between 100-1000nm, because of its constituent and structure and biomembrane and cell membrane fairly similar, more easily make skin-whitening or whitening efficacy composition see through the keratodermatitis barrier and enter subcutaneous.Though, liposome truly has as the carrier system of skin-whitening or whitening efficacy composition and is beneficial to its biological effect of performance, and at skin-whitening or brighten performance application promise in clinical practice aspect the beautifying health cosmetics, but it is as carrier formulation, remain in some problems and still have to be overcome and solve: as liposome in preparation process, with an organic solvent too much, particularly organic solvents such as chloroform (chloroform), methanol use too much, not only cause cost to raise, and very big to preparation person's health effect, cause serious environmental pollution etc. simultaneously; The preparation of liposome is based on phospholipid (soybean phospholipid and lecithin) and cholesterol, phospholipid (soybean phospholipid and lecithin) costs an arm and a leg, not only increase product cost greatly, make the product cost price higher, and, very difficult, time-consuming, bothersome, the effort of its dissolving in preparation process, very trouble operates also.

Defective that exists in the prior art and deficiency:

Though skin whitening efficacy composition and cosmetic for skin whitening is of a great variety at present, some also has certain skin whitening or whitening function and effect really, but they exist many deficiencies and defective in practical application: 1. harm is big: as use the hazardness of skin-lightening cosmetic of mercurous compounds (mercuric chloride, ammoniated mercury or mercuric iodixde etc.) very big.Because hydrargyrum is the toxic heavy metal very big to the human body hazardness, be easy to be absorbed by normal skin, and can be rapidly in skin histology and cell inner accumulated, not only can cause skin pigment excessively calm and sensitization and neck surface contact dermatitis, but also can potential harm take place to whole body, the lighter can cause headache, insomnia, weak, asthenia, hypomnesis, weight loss, anemia, alopecia, stomatitis etc., muscle, skeleton, kidney, heart, central nervous system injury etc. can take place in weight person, even jeopardize general metabolism and vital movement.2. side effect is big: the toxicity of skin-lightening cosmetic that contains hydroquinone (hydroquinone) class as use is bigger, not only its physicochemical property is extremely unstable because of traditional and effective whitening and speckle dispelling composition hydroquinone, be easy to oxidation stain in air, and stronger cytotoxicity is arranged, melanocyte is destroyed, cause the permanent white macula of skin.And, because of hydroquinone is that hydroquinone belongs to benzene ring type compounds, does not get rid of and have certain carcinogenic, teratogenesis, cause gene mutation.The caused side effect of skin-lightening cosmetic that contains kojic acid and hydrogen peroxide as use is bigger.Because of kojic acid its less stable not only, easy oxidation Decomposition and make the preparation color burn, and, have the carcinogenecity the same theoretically with benzene because of the pyrans in its molecular structural formula is the directivity chemical compound the same with benzene; Moreover, a large amount of free free radicals also can be induced or accumulate to hydroxyl in the kojic acid structure and hydrogen peroxide, and its peroxidization and product thereof have certain gene mutation and carcinogenic probability of causing.3. zest is big: the zest of skin-lightening cosmetic that contains retinoic acid and fruit acid as use is very big.Concentration is excessive, life cycle is long as adding because Tretinoin A (Tretinoin) claims tretinoin or retinoic acid and fruit acid also to claim alpha-hydroxy acid again, is easy to cause zest, acid allergy, phototoxicity, the contact dermatitis to skin histology even causes gene mutation etc.And the grasp of the application concentration of retinoic acid and fruit acid is bad, using method is improper, can take place also that direct cutaneous is burnt (as dermathemia, edema, flushing, causalgia, flowing water, Scaling etc. occurring) and indirectly skin burn (mainly be meant the stimulation of daylight to treatment region skin, increase skin to ultraviolet absorption and skin to ultraviolet defence capability).4. poor stability: no matter be hydroquinone, kojic acid, or vitamin C and phenolic compound etc., because its physicochemical property is all unstable, especially relatively poor to external environment influence factors' such as illumination, oxygen, acid-base value (PH), temperature toleration, its functional component content and effect etc. are all obviously descended.And, still because its physicochemical property is all unstable, is easy to make the oxidized or autoxidation of its functional component and product colour is constantly deepened, and have a strong impact on the outward appearance and the interior quality of product.5. Transdermal absorption is poor: skin whitening efficacy composition and the skin whitening active substance of using mostly is water solublity greatly usually, even it is some pure dissolubility or oil-soluble, but because the tight barrier structure of epiderm skin, add the inherent physicochemical property of white-skinned face function composition, determined the general or very difficult Transdermal absorption of its Transdermal absorption effect and effect, so its skin-whitening effect is limited naturally; 6. prescription owes reasonable: some skin-whitening preparations or product exist that prescription is owed rationally, even rational phenomenon at present, as with arbutin and the same usefulness of vitamin C, but do not consider the influence of pH value.Usually the best pH value of arbutin use is reduced to below 6.0 whole pH value more than 6.0 and add vitamin C, answers powerful performance thereby influence these two kinds of functional components; In addition, the functional component concertedness of interpolation is relatively poor, influences the advantage performance of its functional component.7. DeGrain: a lot of white-skinned face function compositions that use at present, no matter be chemosynthesis or semi-synthetic or process modification, still separate from extracted form natural plant or from animal viscera, though isolated test has certain effect, but its skin whitening or whitening effect are all very general when reality is used, and particularly some comes from the extract of natural plants or medical herbs, though side effect is less, but its action effect is limited, some even not too big effect.Even use L-vitamin C, its working concentration need reach more than 10% just can have certain effect.8. the national cosmetic rules are forbidden: as ammoniated mercury, and hydroquinone (hydroquinone), hydrogen peroxide raw materials such as (hydrogen peroxide) is forbidden in cosmetics; The concentration or the dosage of its interpolation in cosmetics time of kojic acid, fruit acid have very strict restriction; 9. dosage form falls behind: cosmetic for skin whitening still adopts dosage forms such as unguentum that traditional handicraft produces, cream, Emulsion, gel, essence at present, and its stability is general, and Transdermal absorption is difficult to, and adds the drug loading deficiency, and curative effect is relatively poor.10. the structure of functional component and concentration: the functional component structure is relevant with its curative effect with concentration, but uses the white-skinned face function composition fully not recognize these problems as yet at present.β-arbutin is still adopted in application as arbutin at present mostly, but studies confirm that, the actual effect that alpha-arbutin is used is more obvious; Simple ascorbic skin and oral application effect are limited, but L-vitamin C and derivant thereof then external preparation for skin certain effect is arranged.In the skin-whitening preparation in the unit volume concentration of white-skinned face function composition or dosage also most important, the only competence exertion effect when enough concentration or dosage of white-skinned face function composition, and the technology of preparing of general conventional dosage forms is difficult to reach the drug loading (functional component dosage and dissolubility) with certain curative effect.

Summary of the invention

The objective of the invention is to be improved, innovate, a kind of novel passive target ight and skin whitening efficacy nanoemulsion and preparation method are provided at shortcoming that exists in the background technology and problem.

The prescription of ight skin whitening efficacy nano-emulsion of the present invention is formed and consumption:

Isopropyl myristate 2.0-8.0g, sad capric acid polyethyleneglycol glyceride 10-50g, polyglyceryl fatty acid ester 2-20g, triple distillation water 20-50g, essence 0.01-0.05g, a-Tocopheryl ferulate 1.0-6.0g, Kojic Acid Dipalmitate 0.5-5.0g, asiaticoside 0.1-3.0g, ubiquinone ₁₀0.1-5.0g, L-ascorbic acid-2-glucoside 1.0-6.0g, nicotiamide 1.0-6.0g, β-Fructus Rubi ketone glucoside 1.0-6.0g, alpha-arbutin 1.0-7.0g, β-arbutin 1.0-7.0g, cysteine 0.1-5.0mg, AR sodium hydroxide 0.2-1.0g, citric acid 0.2-2.0g, final accurately consumption amounts to 100g.

The prescription of skin whitening efficacy nanoemulsion of the present invention is formed and consumption:

Isopropyl myristate 5.0-20.0g, sad capric acid polyethyleneglycol glyceride 15.0-40.0g, polyglyceryl fatty acid ester 5.0-15.0g, triple distillation water 20.0-45.0g, vitamin e1 .5-5.5g, the different monooctyl ester 1.5-5.5g of ferulic acid, baicalin 0.2-2.0g, glabridin is used liquid 3.0-8.0g, L-ascorbic acid-2-glucoside 2.0-6.0g, vitamin PP factor 2.0-6.0g, N-acetylglucosamine 1.0-6.0g, β-Fructus Rubi ketone glucoside 2.0-6.0g, phenethyl resorcinol 0.1-1.5g, disodiumedetate 0.1-1.5g, citric acid 0.1-1.5g, sodium hydroxide 0.1-1.5g amounts to 100g.

The weight proportion of each raw material of the best of ight skin whitening efficacy nano-emulsion of the present invention is:

Isopropyl myristate 4.992g, sad capric acid polyethyleneglycol glyceride 30g, polyglyceryl fatty acid ester 10g, triple distillation water 33.15g, essence 0.01g, a-Tocopheryl ferulate 1.998g, Kojic Acid Dipalmitate 2.0g, asiaticoside 0.5g, ubiquinone ₁₀0.5g, L-ascorbic acid-2-glucoside 3.297g, nicotiamide 3.080g, β-Fructus Rubi ketone glucoside 3.080g, alpha-arbutin 3.080g, β-arbutin 3.080g, cysteine 2.0mg, AR sodium hydroxide 0.688g, citric acid 0.543g, final accurately consumption amounts to 100g.

The weight proportion of each raw material of the best of skin whitening efficacy nanoemulsion of the present invention is:

Isopropyl myristate 10.71g, sad capric acid polyethyleneglycol glyceride 24.27g, polyglyceryl fatty acid ester 8.09g, triple distillation water 31.78g, vitamin E2 .81g, the different monooctyl ester 2.64g of ferulic acid, baicalin 0.50g, glabridin is used liquid 5.068g, L-ascorbic acid-2-glucoside 2.7g, vitamin PP factor 3.074g, N-acetylglucosamine 3.02g, β-Fructus Rubi ketone glucoside 3.074g, phenethyl resorcinol 0.98g, disodiumedetate 0.169g, citric acid 0.676g, sodium hydroxide 0.439g amounts to 100g.

The preparation method of ight skin whitening efficacy nano-emulsion of the present invention is:

1) presses night using type nano-emulsion proportioning raw materials, with sodium hydroxide and citric acid, place container, add again after triple distillation water fully dissolves, add L-ascorbic acid 2-glucoside successively, fully after the dissolving, hold successively again and separate and add β-Fructus Rubi ketone glucoside, nicotiamide, alpha-arbutin, β-arbutin and cysteine; Above material can place the CQ-10 ultrasonator to carry out ultrasonic concussion accelerate dissolution; And to measure this solution pH value be 6.2 ± 0.2, is labeled as water (I) with colored marking pen;

2) with isopropyl myristate, place another container, take by weighing a-Tocopheryl ferulate, Kojic Acid Dipalmitate, asiaticoside, ubiquinone more respectively ₁₀And essence, be added to respectively in the container that has filled isopropyl myristate, abundant mixed dissolution, and be labeled as oil phase (II) with marking pen;

3) again with sad capric acid polyethyleneglycol glyceride (S): polyglyceryl fatty acid ester

Ratio, get sad capric acid polyethyleneglycol glyceride and polyglyceryl fatty acid ester respectively, and both are placed the 3rd container, and this container is placed rapidly on the liquid flash mixer, the liquid flash mixer opened, abundant mix homogeneously, make it to form emulsifying agent/co-emulsifier (S/C) mixture, behind the 3-5min, the closing liquid flash mixer, take off container, and be labeled as S/C mixture (III) with marking pen;

4) again according to oil phase (II): S/C (III): the ratio of water (I)=10%:40%:50%, the phase (I) of fetching water respectively earlier, S/C mixture (III) place the 4th container;

5) with after above-mentioned water (I), S/C mixture (III) two liquid-phase mixing, again under 25 ℃ of conditions of room temperature or in the natural room temperature, put it into and shake in the ultrasonator also about ultrasonic 2min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 2min, then, in this container, directly add oil phase (II) again, and with whole system in ultrasonator about ultrasonic 20min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 20min;

6) close ultrasonator or time constant-temperature magnetic stirring apparatus, getting it, to observe outward appearance little in this way faint yellow, limpid transparent, and fluidity and good dispersion have obviously visible opalescence, are ight skin whitening efficacy nano-emulsion;

7) ight skin whitening efficacy nano-emulsion is sub-packed in rapidly among the lucifuge glass container of different size, adds a cover, sterilization, packing, and place to preserve among drying, ventilation, the shady and cool room temperature and get final product.

The preparation method of skin whitening efficacy nanoemulsion of the present invention is:

1) by daily type nano-emulsion proportioning raw materials, disodiumedetate is placed container, add again after triple distillation water fully dissolves, add successively again after citric acid and NaOH fully dissolve, add the N-acetylglucosamine successively, L-ascorbic acid 2-glucoside, fully after the dissolving, add β-Fructus Rubi ketone glucoside more successively, the vitamin PP factor, the dissolving of above material can place the CQ-10 ultrasonator to carry out ultrasonic concussion accelerate dissolution; Slowly add glabridin again and use liquid, after treating to dissolve fully, measuring this solution pH value is 4.7 ± 0.2, is labeled as water (I) with colored marking pen;

2) with isopropyl myristate, place another container, getting vitamin E adds in the isopropyl myristate, place the ultrasonic mixing that carries out of ultrasonator concussion, add baicalin, phenethyl resorcinol again, also place ultrasonic the making it of ultrasonator concussion to dissolve fully, and be labeled as oil phase (II) with marking pen;

3) again with sad capric acid polyethyleneglycol glyceride (S): polyglyceryl fatty acid ester Ratio, get sad capric acid polyethyleneglycol glyceride and polyglyceryl fatty acid ester respectively, and both placed the 3rd container, add a cover, and this container placed rapidly on the liquid flash mixer, open the liquid flash mixer, fully mix homogeneously, make it to form emulsifying agent/co-emulsifier (S/C) mixture, behind the 3-5min, the closing liquid flash mixer adds the different monooctyl ester of ferulic acid, carry out mixing as stated above, and be labeled as S/C mixture (III) with marking pen;

4) according to oil phase (II): S/C (III): the ratio of water (I)=15%:35%:50%, the phase (I) of fetching water respectively earlier, S/C mixture (III) place the 4th container;

5) above-mentioned water (I), S/C mixture (III) two liquid phases are fully mixed after, again under 25 ℃ of conditions of room temperature or in the natural room temperature, put it into and shake in the ultrasonator also about ultrasonic 2min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 5min, then, in this container, directly add oil phase (II) again, and with whole system in ultrasonator about ultrasonic 10min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 20min;

6) close ultrasonator or time constant-temperature magnetic stirring apparatus, getting it, to observe outward appearance little in this way faint yellow, limpid transparent, and fluidity and good dispersion have obviously visible opalescence, are skin whitening efficacy nanoemulsion;

7) this skin whitening efficacy nanoemulsion is sub-packed in rapidly among the lucifuge glass container of different size, adds a cover, sterilization, packing, and place to preserve among drying, ventilation, the shady and cool room temperature and get final product.

Beneficial effect of the present invention:

The present invention uses the carrier of novel passive target transdermal delivery drug-supplying system (TDDS)-nano-emulsion as skin-whitening or whitening efficacy composition, and utilize the different separately physicochemical property of skin whitening efficacy composition, mechanism of action and actual effect, particularly the effect advantage of some novel whitening functional components has at first been developed the ight of mutual coupling and the skin whitening efficacy nano-emulsion system of daily two kinds of use in conjunction.These the two kinds of coupling nano-emulsion systems not only particle diameter of spheroidal particle are minimum, nano-scale particle distributes extremely even, the passive target effect is obvious, Transdermal absorption is good, penetration capacity is strong, the dispersibility of white-skinned face function composition, lyotropy, pardon, parcel property, slow-releasing, controlled capability, mobile, stability, sense organs etc. all show well, and the nano-emulsion quality is extremely even, fine and smooth, lubricated, gloss, it is very comfortable to smear face or skin, nonirritant again, add the light yellow of nanometer, outward appearance is beautiful, glittering and translucent, as clear as crystal, and little band opalescence, glue and sticking, dense and not thick, oily but not greasy, have good stability.

Compare with present international and domestic like product or technology, the beneficial effect that the present invention brought is embodied in: 1. do not have hazardness: no matter be ight, or skin whitening efficacy nanoemulsion, all do not use any mercurous compounds great so-called skin whitening additives of hazardness such as (mercuric chloride, ammoniated mercury or mercuric iodixdes etc.), the substitute is and use some chelating agen (EDTA-Na ₂) and the material of compounds containing thiol groups (cysteine etc.) and the no any hazardness of antioxidant (coenzyme Q10), therefore actually use no hazardness.2. there is not obvious toxic-side effects: no matter be ight or skin whitening efficacy nanoemulsion, all do not use to contain the hydroquinone bigger skin whitening additives of cytotoxicity such as (hydroquinone), and be to use the skin whitening efficacy composition (can use) of some no cytotoxicities with same purpose effect as processes such as the Symwhite-377 approval whole world that Germany produces; Simultaneously, ight and skin whitening efficacy nanoemulsion do not use yet and contain toxic and side effects such as kojic acid and hydrogen peroxide obviously the white-skinned face function composition or the additive of (might induce side effect such as canceration), the substitute is physicochemical property is stable, effect is remarkable, toxic action is minimum Kojic Acid Dipalmitate and natural asiaticoside etc., therefore during practical application, have no side effect.3. nonirritant: no matter be ight, or skin whitening efficacy nanoemulsion, all do not use and contain retinoic acid and the chemical cracking-off agent very big such as hydroxy acid and fruit acid skin irritation, the substitute is raw materials such as using French plant extract Labrasol that produces and Oleique, strip off though have the cutin dissolving and the recessiveness of nature, potentiality, skin does not have flushing, no causalgia, nonirritant.4. good stability: the novel nano breast system itself that the present invention adopts has heat stability, even high speed centrifugation, its oil phase and water all segregation phenomenon can not occur, more traditional Emulsion and cream cream are more stable, and, no matter be ight or skin whitening efficacy nanoemulsion, all do not use and contain hydroquinone, kojic acid, vitamin C, physicochemical properties such as phenolic compound are all unstable, especially to illumination, oxygen, acid-base value (PH), the white-skinned face function composition that external environment influence factor's tolerations such as temperature are relatively poor, and the substitute is the metastable white-skinned face function composition of some physicochemical properties (vitamin C glucoside, the vitamin E ferulic acid, Kojic Acid Dipalmitate, the different monooctyl ester of ferulic acid etc.), and the coupling by the nano-emulsion carrier, make its stability better.5. Transdermal absorption is good: the particle diameter of the novel blank nano-emulsion that the present invention adopts (mainly is distributed in the scope of 30-40nm) between 0-80nm, has extremely small particle diameter, even added various dissimilar white-skinned face function composition or additives, its particle diameter also (mainly is distributed in the scope of 80-90nm) about 100nm, it is small to have particle diameter, be evenly distributed, be easy to the characteristics of Transdermal absorption; Simultaneously, the novel blank nano-emulsion system that the present invention adopts itself has the effect of dissolving horny layer of epidermis, skin barrier function is weakened, add that this system can also enlarge the effect in epidermis cell gap, can make the fracture of epidermis spine cell connecting filament, help the Transdermal absorption of skin whitening efficacy composition; And, white-skinned face function nano-emulsion of the present invention has solubilization, the functional component content of white-skinned face function composition in unit volume is improved greatly, thereby when being used, it forms high concentration white-skinned face function composition bank rapidly on skin surface, these white-skinned face function compositions form the passive target effect according to the high concentration gradient, accelerate transdermal penetration and absorption; 6. prescription is scientific and reasonable: the prescription of novel skin white-skinned face function nano-emulsion of the present invention is from removing melanin granule or the melanosome that is formed on horny layer of epidermis, carry out simultaneously forming relevant " three enzymes, one element " (tryrosinase with the skin melanocyte, the dopachrome interconvertible enzyme, dihydroxy indole carboxylic acid oxidative and Endothelin) active synchronous inhibition, melanin granule synthesizes restriction and the obstruction with transhipment, the antioxidation reduction of oxidized form melanin granule, the complexation of metals such as tyrosinase activity agonist copper ion, the protection of ultraviolet oxidative damage etc., add ight and daily being used alternatingly, the white-skinned face function composition is strengthened and use in conjunction, composition intersects mutually and is complementary, collaborative and potentiation; Special use by relevant buffer system and derivant thereof makes the bioavailability of its white-skinned face function composition higher, and it is more obvious to have complementary advantages, and prescription is science and reasonable more.7. effect is obvious: just because of nano-emulsion System Design advanced person of the present invention, prescription more science and rationally, add the particularly application of some new and effective whitening agents of white-skinned face function composition, and under the synergism of nano-emulsion system of the present invention, the Transdermal absorption of white-skinned face function composition obviously improves, and, white-skinned face function constituent structure, concentration are relevant with its curative effect, as alpha-arbutin and β-arbutin use in conjunction better effects if, the simple vitamin C effect of vitamin C glucoside is remarkable; The simple vitamin E effect of vitamin E ferulic acid is more superior; Simple nicotiamide of nicotiamide associating N-acetylglucosamine or simple N-acetyl glucosamine effect are more obvious; In addition, in the skin-whitening preparation in the unit volume concentration of white-skinned face function composition or dosage also most important, the only competence exertion effect when enough concentration or dosage of white-skinned face function composition, and the technology of preparing of general conventional dosage forms is difficult to reach the drug loading (functional component dosage and dissolubility) with certain curative effect, and skin whitening efficacy nano-emulsion of the present invention all possesses these characteristics and advantage.Therefore compare with similar in the world main product (main product that comprises some famous brands) at present, not only the mechanism of skin-whitening is clear and definite, and the onset time of whitening is shorter, and it is longer to hold time.As common 8 weeks of whitening product in the world be a course of treatment, product of the present invention is a course of treatment around only; Whitening product common 4 all onsets in the world, product of the present invention is 2 all onsets only; Not only show advantages of good skin whitening effect (whiteness increase), and skin-whitening effect also clearly (pale, bright, moistening etc.); 8. safety is better: novel whitening effect nanometer emulsion of the present invention is ight and daily product no matter, not only do not contain the ammoniated mercury that International or National cosmetics rules are expressly forbidden, hydroquinone (hydroquinone), hydrogen peroxide poisonous raw materials such as (hydrogen peroxide), do not add the kojic acid that International or National cosmetics rules expressly limit the use of yet, fruit acid, harmful substances such as trichloroacetic acid, even even some irritating antiseptic may occur to skin, penetrating agent, emulsifying agent or surfactant, co-emulsifier or cosurfactant etc. all do not add, therefore make the skin irritation of its practical application littler, safety is better.9. dosage form advanced person and forward position: what present cosmetic for skin whitening of the present invention adopted is the newtype drug targeting vector--the naked eyes sense organ of dosage forms such as the unguentum of the traditional handicraft production that the nano-emulsion carrier system adopts more at present, cream, Emulsion, gel, essence is better, stability is better, Transdermal absorption is stronger, use feeling is more comfortable, and actual effect is more remarkable; And, because technology of the present invention is simple, easy to operate, preparation easily, need not special instruments and equipment and energy is provided, can produce and prepare under the room temperature, neither destroy the content and the biological activity thereof of the white-skinned face function composition that is added, do not change the characteristic of nano-emulsion carrier system again, neither contaminated air and environment, can save time again and the energy, can also reduce cost and consume, and promotion and application easily.

The present invention wants emphasis to solve the following technical problem: 1. safety issue: at first consider to adopt some to have natural or near natural characteristic, and safer skin whitening efficacy composition, as arbutin, a-Tocopheryl ferulate, L-ascorbic acid-2-glucoside, nicotiamide, the N-acetylglucosamine, β-Fructus Rubi ketone glucoside, the different monooctyl ester of ferulic acid, baicalin, glabridin, Symwhite-377 etc., replace that those countries forbid or very the harm of usefulness is big in skin-lightening cosmetic, toxicity is big, zest is big, side effect is big, raw materials such as poor stability are as kojic acid, compound containing mercury, hydroquinone (hydroquinone) and derivant thereof, vitamin C etc.2. validity problem: at first according to some principles of skin-whitening (as to forming removing of skin pigment; the reduction of oxidation melanocyte and decomposition; the inhibition of tyrosinase activity; the complexation of metal ion or chelating in the tryrosinase prothetic group; the Endothelin antagonism; the synthetic inhibition of melanin granule or melanosome; form the blocking-up of melanin granule or melanosome transportation; it is sun-proof that the prevention melanocyte forms etc.) carry out prescription; simultaneously according to these prescription optium concentrations and the most suitable consumption of dosage design; and adopt the citrate buffer system that the pH value in the nano-emulsion system is carried out balance adjustment and qualification; add and select suitable substrate and carrier system, to guarantee the effectiveness of preparation.3. the Transdermal absorption of skin whitening efficacy composition and stability problem: at first consider to adopt oil phase (isopropyl myristate), water (triple distillation water), emulsifying agent (sad capric acid polyethyleneglycol glyceride), co-emulsifier (polyglyceryl fatty acid ester) with the best to be mixed with thermodynamically stable blank nano-emulsion system, the skin-whitening nano-emulsion that forms with the fixed skin whitening efficacy composition of this stabilising system compatibility can be kept the stability and the effect persistency of whole nano-emulsion system and white-skinned face function composition simultaneously; And the nano-emulsion system that forms with isopropyl myristate, sad capric acid polyethyleneglycol glyceride, polyglyceryl fatty acid ester, triple distillation water etc. molecule granule and particle diameter is minimum, dispersing uniformity and mobile fabulous not only, and its distinctive physicochemical property and mechanism of action to skin surface carry out nature, recessiveness, non-red, painless, nonirritant, shallow is stripped off, to weaken the distinctive barrier function of epidermis, help the rapid osmotic of skin whitening efficacy composition and effectively absorption.Though nano-emulsion dosage form and technology have many technical characterstics and application advantage, and progressively begin to use as a kind of novel targeted medicament carrier system in international medical and health educational circles, and obtained significant effect, but this novel nano-emulsion dosage form and technology are to use in pharmaceutical sanitary field in the past always, be still a kind of new industry and technological achievement at cosmetics and skin-whitening industry, technological process and technical method still have many work to do.4. the problem of the collaborative and synergy of mutual aid: past nano-emulsion technology and preparation are as passive target carrier formulation system, be mainly used in the preparation and the prescription of monomer medicine or single component, and this nano-emulsion technology is used in skin whitening or whitening product, and many Synergistic compositions and nano-emulsion system need be carried out compound preparation, this is in its research and development and apply and have certain difficulty, and there are many technical knotty problems and challenge, the recipe design that comprises the skin-whitening nano-emulsion, the selection of basic ingredient and white-skinned face function composition and compatibility between the raw material and stability in the nano-emulsion system, the dissolubility of multiple white-skinned face function composition reaches coupling and the reasonability with the nano-emulsion system, collaborative and the synergy of the mutual aid of white-skinned face function composition etc., particularly increase and be similar to the such highly effective skin white-skinned face function composition of SymWhite377, and fill a prescription definite with synergy by the mutual aid each other of these ingredients is collaborative, on the basis of guaranteeing to keep the effect of skin-whitening monomer functional component performance Applied Biology, show effect advantages such as the collaborative and synergy of more efficiently mutual aid.Yet, the kind of white-skinned face function composition is many more, adding concentration or dosage adds big more, formation and stability influence to the nano-emulsion system are big more, even the particle grain size size of nano-emulsion molecule etc. also had a significant effect, therefore, outside forming effect advantage such as the collaborative and synergy of more efficiently mutual aid, the combination of nano-emulsion system and skin whitening efficacy composition and nano-emulsion system and good compatibility technology and stability are also most important, need test in a large number and research and solve.5. passive target problem: the strong lyotropy of nano-emulsion and high saturation make the skin whitening efficacy composition be able to reach dissolving to greatest extent in the nano-emulsion system, and this strong lyotropy and high saturation are the bases that makes the skin whitening efficacy composition form skin depot and Concentraton gradient and passive target infiltration and absorb, and therefore solving strong lyotropy and the high saturation problem of white-skinned face function composition in the nano-emulsion system is that the external skin nano-emulsion of whitening forms the key factor of targeting.6. the skin whitening efficacy applied in any combination problem of duplex preparation: cosmetic for skin whitening adds according to it and whether contains heliosensitivity in functional component and be divided into it daily and two kinds of ights.Contain the white-skinned face function composition Pear Power of arbutin and similar structures and photosensitization and require usually preferably to use evening, and the white-skinned face function composition that contains sunscreen and similar structures has sun-proof and the antiallergic effect requires preferably to use daytime usually.Strengthen or the raising skin whitening efficacy, reducing photosensitive or anaphylaxis etc. is the main flow and the direction of current skin-lightening cosmetic, should further break through on its application technology and using method.

Know-why of the present invention:

Skin whitening efficacy nano-emulsion preparation principle is: with isopropyl myristate (IPM) as oil phase, the sad capric acid polyethyleneglycol glyceride (Labrasol) of France's extracted form natural plant is as emulsifying agent, polyglyceryl fatty acid ester (Plurol Oleique) is a co-emulsifier, and distilled water is as water.Because the sad capric acid polyethyleneglycol glyceride of emulsifying agent helps the mutual blending of oil phase isopropyl myristate and water distilled water and forms emulsion droplet, and the co-emulsifier polyglyceryl fatty acid ester also is skin-whitening or brightens the essential condition that the external nano-emulsion forms.Particularly because polyglyceryl fatty acid ester and the special separately physicochemical property of sad capric acid polyethyleneglycol glyceride, the co-emulsifier polyglyceryl fatty acid ester can be inserted in the limitans with the sad capric acid polyethyleneglycol glyceride of emulsifying agent, form complex condensed film, improve the coagulability and the compliance of film, and can increase dissolubility with sad capric acid polyethyleneglycol glyceride, and further reduce interfacial tension, help forming more stable skin-whitening or brighten the external nano-emulsion.Sad capric acid polyethyleneglycol glyceride often is subjected to the restriction of dissolubility, and polyglyceryl fatty acid ester can make the dissolubility of sad capric acid polyethyleneglycol glyceride increase, the easier further dispersion of emulsion droplet, particularly sad capric acid polyethyleneglycol glyceride and polyglyceryl fatty acid ester are in isopropyl myristate and the further a large amount of absorption of distilled water boundary, both are reduced the concentration in continuous phase, interfacial tension become again on the occasion of, make it progressively to form stable external preparation for skin and whiten or brighten nano-emulsion.Owing to can make oil phase and water blending and form the nanometer emulsion droplet by emulsifying agent and co-emulsifier, and co-emulsifier can be inserted in the limitans of emulsifying agent, make it to form complex condensed film, improve the coagulability and the compliance of film, and can increase the dissolubility of emulsifying agent, further reduce interfacial tension, more stable after helping nano-emulsion and forming.Consider that emulsifying agent is subjected to the restriction of dissolubility, and co-emulsifier can make the dissolubility of emulsifying agent increase, the easier dispersion of emulsion droplet, particularly emulsifying agent and co-emulsifier are in oil phase and the further a large amount of absorption of aqueous phase interface, both are reduced the concentration in continuous phase, interfacial tension become again on the occasion of, make it progressively to form stabilized nano breast more.Meanwhile manage by oil-soluble white-skinned face function composition being dissolved among the oil phase isopropyl myristate, and water solublity white-skinned face function composition is dissolved among the water, and under the effect of compositions such as S/C mixture that sad capric acid polyethyleneglycol glyceride and polyglyceryl fatty acid ester form and distilled water and participating in, the formation external preparation for skin nano-emulsion of whitening naturally.

Different white-skinned face function compositions have different physicochemical properties and effect, and the actual concentration of adding is also variant.In general, the basis of prescription is oil phase, water, emulsifying agent (surfactant), co-emulsifier (cosurfactant), and the white-skinned face function composition in the prescription is according to the skin-whitening nano-emulsion principles of formulating prescriptions and according to designing.During the nano-emulsion of whitening preparation, can it be dissolved in the corresponding phase liquid respectively earlier according to the dissolubility of its functional component.After oil phase, emulsifying agent, co-emulsifier have been determined, can find out the nano-emulsion zone by pseudo-three-phase diagram, thereby determine their consumptions separately.In oil phase, water, emulsifying agent, four components of co-emulsifier, generally emulsifying agent and consumption thereof can be fixed, three summits of oil phase, water, three ingredients constitute equilateral triangles of co-emulsifier make phasor at constant temperature.Common way is: oil phase, emulsifying agent, the co-emulsifier mixed solution of definite composition are carried out titration with water.Whether with dropper carry out titration when adding water at every turn, stir simultaneously, examining then is transparent nano-emulsion or muddy nano-emulsion.Adding after water makes nano-emulsion reach complete equipilibrium, nano-emulsion should be transparent, clarification, flow and have opalescent liquid.Certainly also can be with emulsifying agent and co-emulsifier mixed solution a summit as equilateral triangle, then oil phase and water are formed pseudo-three-phase diagram as two other summit of equilateral triangle.

The principles of formulating prescriptions of the present invention:

The one, remarkable restraint of tyrosinase activity influences the formation of the generation of melanocyte in the melanocyte and transhipment, minimizing cutaneous pigmentation; The 2nd, have higher safety in utilization, and little to the human body skin zest, non-evident effect; The 3rd, the skin-whitening effect is more stable and lasting.The cosmetics that are used for skin-whitening simultaneously also answer emphasis to adhere to following Several principles: the legitimacy of (1) product: add anything but in the world or the white-skinned face function composition of national legislation forbidding, as ammoniated mercury, though whitening effect is fine, but body each system, particularly life-critical organ etc. are had tangible cumulative toxicity and long-term hazards, so mercurial is a contraband in the beautifying skin cosmetics; Hydroquinone uses the earliest, though whitening effect is better, strong impulse and suspicious carcinogenecity in use occur, and skin pigment uneven distribution etc. oneself be limited or forbid being used for cosmetic for skin whitening; Kojic acid also is once to allow used whitening agent, but reports that it has carcinogenecity, has also limited its use and corticosteroid hormone in developed country.(2) safety of Shi Yonging: to the white-skinned face function composition that uses and add must pay much attention to its stimulus to the sense organ, physicochemical irritation, photosensitivity reaction zest, immunoreation zest etc. to dermal application, promptly to note the raw material that uses or functional component have the obvious irritation abnormal flavour, avoid using too violent chemical cracking-off agent, the highly prudent whitening additive that uses with photosensitivity reaction, the functional component or the active substance that need not have allergic immune reaction are guaranteed the tight security that product uses as far as possible.(3) to the health giving quality of skin: the health giving quality of whitening is one of important indicator of weighing product quality, also is the key factor that future products is applied, and therefore good whitening product must possess corresponding curative effect.Yet skin-whitening is not merely to make skin whitening, and also needs to make skin more satin and exquisiteness, only makes skin more pale, bright, fine and smooth, smooth, so just can be referred to as skin-whitening truly.Therefore the skin-whitening product also should be paid attention to this several aspects effect simultaneously to the skin health giving quality.(4) products innovation: innovation is the marrow of science, the core of science and technology, the soul of achievement, and the key factor of product competitiveness also is the real motive of enterprise development especially.Therefore no matter be that aspects such as notion, dosage form, prescription, preparation technology and operating technology, application process at new product need actively innovation.The skin-whitening nano-emulsion has represented the glamour and the characteristic of world's modern high technology, and is at first proposed by us, and this is conceptive innovation; Adopting newfangled in the world passive target medicament carrier system-nano-emulsion technology to be used for beautifying skin, and prepare skin-whitening nano-emulsion dosage form, also is our up-to-date proposition, and this is to innovate on the dosage form; To have flexibility, nature, recessive shallow epidermis cutin strips off to remove and has formed or sedimentary skin melanocyte, adopt oxidation and removing free radicals then, reduction-oxidation type melanocyte, the restraint of tyrosinase activity, the control melanocyte forms melanosome and transhipment thereof, promote the melanocyte apoptosis, mutual aids such as prevention ultraviolet induction melanocyte metabolism enhancing are collaborative, the synergy prescription is formed, and this is to fill a prescription to form to go up innovation; Utilize the white-skinned face function composition organic compatibility of the big liquid phase of four in the nano-emulsion system with separate sources, different physicochemical properties, and prepare under special instruments and equipment and the natural room temperature need not, the stability and the good appearance sense organ that not only keep its product, and significantly reduce environmental pollution and energy resource consumption and reduce production costs etc., this is the innovation in preparation technology and operating technology; In addition, in actual applications, we at first propose and emphasize the duplex therapy scheme of skin-whitening nano-emulsion, can be when promptly using according to the age and the blee depth, and science is selected or whether decision adopts the duplex therapy, and this is the innovation aspect application process.

The mechanism of action of skin-whitening nano-emulsion of the present invention:

First, utilize the matrix components (isopropyl myristate in the blank nano-emulsion system, sad capric acid polyethylene glycol glycerol acid esters, polyglycerol fatty acid fat, triple distillation water) metabolism of promotion keratin cell, make on the epidermis prickle cell layer, particularly aging cutin layer generation nature recessiveness is stripped off, thereby quicken the drainage of each layer of epidermis melanin granule and peel off, the melanin granule or the melanosome that form and be deposited on skin surface are removed naturally, tanned dead bark of original sunburn and gloomy aging cutin layer are upgraded, skin is reached gradually brighten and light, even can make original mottle thin out or alleviate; Simultaneously, this soft natural recessiveness is stripped off, skin is weakened the distinctive barrier function of white-skinned face function composition, thus make the passage amplification that the skin whitening efficacy composition absorbs by transdermal penetration or open, the speed of white-skinned face function composition transdermal penetration and absorption improves.Second, utilize the targeting vector drug-supplying system of the formed uniformity ultra micro of nano-emulsion molecular particle size, make skin whitening efficacy composition a-Tocopheryl ferulate, L-ascorbic acid-2-glucoside, nicotiamide, β-Fructus Rubi ketone glucoside, arbutin (alpha-arbutin and β-arbutin) etc. be easy to absorb, improve the concentration of using white-skinned face function composition in local epidermal tissue or the cell by dermal osmosis; Simultaneously, utilize the high carrying capacity characteristic of contained over-saturation state white-skinned face function composition in the nano-emulsion, make the epiderm skin face form white-skinned face function component gradient concentration and white-skinned face function composition epidermis bank rapidly, performance is to the skin targeting successive reaction of melanocyte and melanin granule, thereby brings into play the biological action of its skin-whitening.The 3rd, utilize small molecule antioxidant or free radical scavenger vitamin E, L-ascorbic acid-redox reaction such as 2-glucoside, make the oxidized form melanin granule or the melanosome partial reduction that form and be deposited on skin surface by oxidation reaction, the decomposition of accelerometer Intradermal melanin granule; Simultaneously, each metabolism intermediate of reduction melanocyte, the blocking-up DOPA is to the oxidation reaction process of melanocyte, and the redox reaction by small molecule antioxidant or free radical scavenger, suppress or alleviate the dopa reaction that causes because of free radical catalysis and oxidation reaction to strengthen, the epidermis melanocyte is generated and accumulation is controlled and reduced.The 4th, tryrosinase is to promote to generate melanic key in melanocyte, and utilization can effectively suppress the inhibitor of tyrosinase activity in the melanocyte, blocks the synthetic of DOPA, DOPA quinone and dopachrome, with the formation of blocking-up melanin granule; Simultaneously, by can with the direct bonded white-skinned face function composition of tryrosinase (β-Fructus Rubi ketone glucoside, SymWhite377 etc.), reduce the catalytic activity of tryrosinase, skin pigment generates and deposition to reduce, thereby makes skin whitening.The 5th, utilize the effectively melanocytic proliferation activity of control such as melanocyte antiblastic arbutin (alpha-arbutin and β-arbutin), kojic acid two isopropyl palmitates, and the skin melanocyte is generated through a series of biochemical reactions such as oxidations by phenylalanine or tyrosine in the stratum basale melanocyte just, therefore suppress melanocytic proliferation activity, can suppress the generation of melanocyte, thereby produce the effect of skin-whitening.The 6th, the white-skinned face function composition (nicotiamide and N-acetylglucosamine etc.) that utilization can disturb and effectively hinder melanosome to transmit between skin melanocyte and keratinocyte, can make established melanin granule can't be transported to skin surface, or be difficult in skin surface deposition, thereby, can effectively prevent or stop at skin surface to form melanin pigmentation, have the effect of skin-whitening.The 7th, utilize the functional component (baicalin etc.) that can prevent or alleviate ultraviolet and product damage thereof, prevent or alleviate ultraviolet induction melanocyte metabolism enhancing or influence the melanosome distribution can effectively prevent or stop and form melanin pigmentation at skin surface, particularly prevent or alleviate to cause the melanin that produces by long wave ultraviolet (UVA), and suppress or alleviate because the free radical that ultraviolet radiation caused generates to increase to reach the tryrosinase activating reaction is impelled the dual function that melanocyte forms to be increased, have the effect of skin-whitening.The 8th, the activity and the endothelin antagonist (glabridin, a-Tocopheryl ferulate etc.) that utilize " three enzymes, one element " inhibitor (glabridin etc.) can suppress " three enzymes, one element " (being tryrosinase, dopachrome interconvertible enzyme and DHICA oxidase and Endothelin) in the melanin building-up process break up and the tryrosinase activation melanocyte the Endothelin that the activation inhibitory action of melanocyte differentiation and tyrosinase activity, particularly endothelin antagonist inhibition ultra-vioket radiation produce.The 9th, utilize tyrosinase activity central copper ion prothetic group chelating agent (disodiumedetate EDTA-Na ₂, the kojic acid acid dipalmitate) bonded four copper ions on two subunits of chelating tryrosinase, the tyrosinase activity division center is changed, tyrosinase activity suppresses, thereby reduce it forms DOPA, dopachrome to tyrosine catalytic reaction, play skin whitening or whitening function, reduce cutaneous pigmentation.The tenth, add or suitably improve the generation of antioxidant with the prevention reactive oxygen species, or the white-skinned face function component content or concentration decay and the intensification of carrying out property of color that stop its further chain type oxidation reaction to cause, it is stable to keep skin-whitening nano-emulsion system.The effect of the antioxidant that adds mainly shows following several aspect: the effect of performance Reducing agent, can be oxidized as ascorbic acid prior to the white-skinned face function composition, thus the stability of the functional component of staying pale; Performance retardant of oxidation agent effect can stop its further chain type oxidation reaction or automatic oxidation reaction to carry out as the vitamin E that adds; Bring into play the synergist effect, can strengthen the usefulness of antioxidant as the citric acid that adds; The effect of performance chelating agen is as the EDTA-Na that adds ₂Can stop of the catalytic action of some metal ion to chain reaction in the white-skinned face function composition automatic oxidation reaction.The 11, ight skin whitening efficacy nano-emulsion by strictness control pH value at 6.0 biological actions that help bringing into play arbutin and vitamin C glucoside; And skin whitening efficacy nanoemulsion 5.0, is constantly deepened its strict control pH value with the decay and the color of slowing down the skin whitening efficacy composition owing to there is not the arbutin of interpolation can further reduce its pH value.Because, under acid condition, reduce pH value, help controlling the automatic oxidation reaction of white-skinned face function composition and nano-emulsion system, the further intensification of inhibition color.

Major technique design of the present invention:

According to the above-mentioned know-why of enumerating, the present invention will mainly design from the preparation of ight skin whitening efficacy nano-emulsion, two major parts of preparation of skin whitening efficacy nanoemulsion aspect technical conceive.

First part: the preparation of ight skin-whitening nano-emulsion: mainly comprise: 1. in the blank nano-emulsion system of ight skin-whitening the selection of four liquid phases with determine: at first select and blank nano-emulsion four individual system of definite ight skin-whitening in oil phase, water, emulsifying agent or surfactant mutually, co-emulsifier or cosurfactant, promptly select and definite isopropyl myristate as oil phase, sad capric acid polyethyleneglycol glyceride is as emulsifying agent or surfactant, polyglyceryl fatty acid ester is co-emulsifier or cosurfactant, and triple distillation water is as water; 2. the selection of functional component and definite in the ight skin-whitening nano-emulsion system, promptly (tryrosinase suppresses according to " three enzymes, one element ", the dopachrome interconvertible enzyme, the dihydroxy indole carboxylic oxidase, Endothelin) suppresses, melanocyte growth suppresses, the synthetic regulation and control of melanin granule or melanosome, melanin granule or melanosome transhipment restriction, the reduction of oxidized form melanocyte, skin-whitening principles such as copper ion complexation are selected and definite a-Tocopheryl ferulate, L-ascorbic acid-2-glucoside, nicotiamide, β-Fructus Rubi ketone glucoside, arbutin (alpha-arbutin and β-arbutin all can), the kojic acid acid dipalmitate, cysteine etc. are as the white-skinned face function composition; 3. the prescription ingredient of ight skin whitening efficacy nano-emulsion is determined: isopropyl myristate, sad capric acid polyethyleneglycol glyceride, polyglyceryl fatty acid ester, triple distillation water, essence, a-Tocopheryl ferulate, L-ascorbic acid-2-glucoside (AA2G ^TM), nicotiamide, β-Fructus Rubi ketone glucoside, arbutin (alpha-arbutin and β-arbutin), kojic acid acid dipalmitate, cysteine, coenzyme Q10, laurocapram penetrating agent, and the ight skin-whitening nano-emulsion integral framework of citric acid buffer system.

Second largest part: the preparation of daily skin-whitening nano-emulsion: mainly comprise: in the blank nano-emulsion system of 1. daily skin-whitening the selection of four liquid phases with determine: at first select and determine in blank nano-emulsion four individual system of daily skin-whitening oil phase, water, emulsifying agent or surfactant mutually, co-emulsifier or cosurfactant, promptly select and definite isopropyl myristate as oil phase, sad capric acid polyethyleneglycol glyceride is as emulsifying agent or surfactant, polyglyceryl fatty acid ester is co-emulsifier or cosurfactant, and triple distillation water is as water; 2. the selection of functional component and definite in the daily skin-whitening nano-emulsion system; be the protection (light-shading and sun) of emphasis to daylight middle-ultraviolet lamp irradiation damage; " three enzymes, one element " (tryrosinase; the dopachrome interconvertible enzyme; the dihydroxy indole carboxylic oxidase; Endothelin) inhibition; melanocyte growth and inhibition of proliferation; synthetic and the excretory regulation and control of melanin granule or melanosome; the transhipment restriction of melanin granule or melanosome; the reduction of oxidized form melanin granule or melanosome; the sun-proof principles of skin-whitening such as the ionic complexation of tyrosinase activity central copper are selected and definite natural Chinese medicine extract monomer-baicalin; rutin; vitamin E; the different monooctyl ester of ferulic acid; L-ascorbic acid-2-glucoside; the N-acetylglucosamine; the vitamin PP factor; the efficient whitening agent phenethyl resorcinol (Symwhite-377) of Germany; β-Fructus Rubi ketone glucoside; glabridin; EDTA-Na ₂Deng as the sun-proof functional component of skin-whitening; 3. the prescription ingredient of skin whitening efficacy nanoemulsion is determined: isopropyl myristate, sad capric acid polyethyleneglycol glyceride, polyglyceryl fatty acid ester, triple distillation water, essence, baicalin, rutin, vitamin E, the different monooctyl ester of ferulic acid, L-ascorbic acid-2-glucoside, N-acetylglucosamine, the vitamin PP factor, Germany efficient whitening agent Symwhite-377, β-Fructus Rubi ketone glucoside, glabridin, EDTA-Na ₂Daily skin-whitening nano-emulsion integral framework.

Major technique innovative point of the present invention:

First, nanoemulsions belongs to the thermodynamically metastable fixed system as novel transdermal delivery drug-supplying system (TDDS), use genus initiative still at skin whitening or aspect whitening, particularly with daily and ight white-skinned face function nano-emulsion according to different efficacies effect and physicochemical property use in conjunction, and utilize best nano-emulsion system to contain and parcel has the skin whitening efficacy composition of the collaborative and synergy effect of mutual aid, safety and effectiveness that product is used should come out at the top in like product.Second, nanoemulsions as two kinds of immiscible liquid according to a certain percentage, under the combined effect of surfactant and cosurfactant, form naturally thermodynamically stable, isotropic, good fluidity, as clear as crystal, glittering and translucent, trickle xanchromatic, slightly opalescent dispersion arranged, have good sense organ, and actual comfort is splendid.The 3rd, small, the blank nanometer particle size of the molecular particle size of nano-emulsion all＜80nm, and the effect nanometer emulsion particle diameter only is about about 100nm, and the nano-emulsion microparticle is oval, it is also very even to distribute, therefore, its, good absorbing effect fast to the dermal osmosis effect.The 4th, the composition of nano-emulsion is simple and clear, comprises that mainly four of oil phase, water, surfactant and cosurfactants are mutually.By this four phase liquid and hydrophile-lipophile balance value difference, can obtain oil-in-water type nanoemulsions (O/W), water-in-oil type nanoemulsion liquid (W/O) and doubly-linked ideotype nanoemulsions as required.Because of its dosage form adjustment and change very convenient, therefore can be in actual applications or according to the physicochemical property of season, skin type and functional component, prepare different nano-emulsions.The 5th, nano-emulsion preparation technology is terse, technical operation is simple, saves time to save trouble; And whole process of preparation does not need specific apparatus and equipment, laborsaving saving money; And, carry out nano-emulsion preparation can be under normal temperature condition spontaneous formation nano-emulsion system, do not need electric power and other energy, but both energy savings and cost are free from environmental pollution again.The 6th, the nano-emulsion system has solubilization, can improve the concentration and the dosage of the white-skinned face function composition in the unit volume solvent greatly, no matter be water miscible white-skinned face function composition, still oil-soluble white-skinned face function composition can reach solubilizing amount to greatest extent in nanoemulsions.The 7th, the heavy dose of solubilising of white-skinned face function composition in the nano-emulsion system, make the concentration of white-skinned face function composition in the fine droplet of nano-emulsion can reach very high, the interfacial film that this forms by surfactant molecule fast for the white-skinned face function composition, thereby, when it is used on skin of face, form white-skinned face function composition bank rapidly, and make it according to the gradient penetration rule, form from high to low, the passive target effect and the sustained-release and controlled release effect of ecto-entad, reach efficient release and significant curative effect.And skin whitening efficacy composition solubilising has been avoided and the contacting of continuous phase in the droplet of oil-in-water type nanoemulsions, can protect those white-skinned face function compositions that are easy to hydrolysis not to be decomposed or hydrolysis before arriving site of action.The 8th; therefore nano-emulsion can be prepared under temperature conditions Celsius about 25 ℃, for the activity of the thermo-labile skin whitening efficacy composition of protection and content, particularly protect the whiten factor, peptide class, enzyme, cell growth factor subclass isoreactivity material of all Placenta Hominiss to have important value.The 9th, nano-emulsion itself also has certain antibacterial action, need not add chemical preservative and just can prevent product rotten, and can certain inhibitory or killing effect be arranged to the certain micro-organisms that skin surface exists.The tenth, the characteristics of nano-emulsion maximum are its short dermal osmosis and Absorptions.It may mechanism mainly be: 1. increase epiderm skin horny layer double-layer of lipoid flowability, destroy horny layer aqueous passage, through approach such as hair follicle absorptions, effectively overcome the barrier action of horny layer to medicine, thereby skin whitening efficacy is become to be distributed into intradermal; 2. the uniqueness of nano-emulsion structure, make it all can produce significant solubilising effect to fat-soluble and water solublity skin whitening efficacy composition, thereby form skin whitening efficacy composition supersaturation system, increase the inside and outside drug concentrations gradient of skin greatly, thereby improve the transit dose of skin whitening efficacy composition; 3. some the substrate composition in the nano-emulsion can be as skin whitening efficacy composition penetration enhancer, thereby these substrate compositions promote Transdermal absorption by changing cuticular structure, the oil phase in the isopropyl myristate Chang Zuowei nano-emulsion for example, but it also is a kind of Transdermal absorption penetrating agent simultaneously, can promote the transdermal efficient of preparation greatly, thereby surfactant in the nano-emulsion and cosurfactant composition also can influence the infiltration that the keratodermatitis barrier increases the skin whitening efficacy composition; 4. thereby nano-emulsion can produce the express passway of a transdermal penetration by the connection between the cell plastid of strong hydration widening angle, and the collagenous fiber bundle in the corium is loosened to a certain extent, therefore, nano-emulsion can penetrate stratum corneum barrier by quick and a large amount of skin whitening efficacy compositions, rapid permeability advances the dermal tissue of skin, thereby brings into play its good biological effect and advantage.The 11, sad capric acid polyethylene glycol glycerol fat and polyglyceryl fatty acid ester that the skin-whitening nano-emulsion of our development adopts France to extract from natural plants, and the ratio of they and the shared nano-emulsion system nearly 90% of pure water, therefore, glue and sticking, oily but not greasy, dense and not thick, particularly they are little to the zest of skin, safety is good, few side effects, toxic action does not have, and have not damaged, no flushing, impercipient horny layer of epidermis nature recessiveness is stripped off.The 12, the skin-whitening nano-emulsion of our development adopts French sad capric acid polyethylene glycol glycerol fat that extracts from natural plants and polyglyceryl fatty acid ester also to have epiderm skin slight, shallow table and strips off effect, therefore has the effect of removing established cutaneous pigmentation preferably.But because this exfoliation effect, occur over just on the epidermis prickle cell layer, therefore, its exfoliation effect be accurate, natural, slowly, table is shallow, insusptibility, not rubescent.The 13, the skin-whitening nano-emulsion of our development also has tangible characteristics and advantage on prescription, as when carrying out the recipe design of this product, considered simultaneously: 1. weaken skin barrier function to promote the transdermal penetration and the absorption of the U.S. functional component of skin; 2. to inhibition of tyrosinase activity in the melanocyte; 3. to the complexation of the structural prothetic group copper ion of tryrosinase; 4. the inhibitory action that melanosome and melanin granule are formed; 5. to the secretion of melanosome and melanin granule with to the inhibitory action of skin surface transportation or transhipment; 6. established oxidized form melanosome and stripping off of melanin granule are removed; 7. the reduction of the oxidized form melanocyte that oneself is formed; 8. to the one plain synchronous inhibition of reacting of three enzymes; 9. to the protection of ultraviolet radiation and damage.The 14, on the selection of white-skinned face function composition and using, also adopt some effects lasting, few side effects, zest is little, and it is collaborative to have an obvious mutual aid, the white-skinned face function composition of synergy.As vitamin E, what we selected is a-Tocopheryl ferulate, and it has not only kept all biological functions of vitamin E, and, also added the good skin antioxidation of ferulic acid, sun-proof and tyrosinase activity inhibitory action; As vitamin C, what we selected is L-ascorbic acid-2-glucoside (AA-2G), and it has not only kept ascorbic all biological functions, and more ascorbic character is more stable, act on high-efficient and lasting more, Transdermal absorption and slow release controlled-release effect are better; Also have the arbutin application facet, what we selected is alpha-arbutin, and it is the epimer of β-arbutin, and its oxygen glycosidic bond is compared just in time opposite in spatial direction with the direction of β-arbutin.Therefore its chemical property of alpha-arbutin and curative effect are also more stable and lasting than β-arbutin effect; And alpha-arbutin just can the restraint of tyrosinase activity under low concentration very, and it is more obvious to suppress effect.The 15, adopt to add or suitably improve oxidation preventive content aspect skin whitening efficacy composition and the white-skinned face function nano-emulsion system stability stoping the generation of reactive oxygen species keeping, or stop its further chain type oxidation reaction.As add the effect that ascorbic acid and derivant thereof have the performance Reducing agent, and can be oxidized prior to the white-skinned face function composition, thus the stability of the functional component of staying pale; As add vitamin E and derivant and have performance retardant of oxidation agent effect, can stop its further chain type oxidation reaction or automatic oxidation reaction to carry out; As add citric acid and have performance synergist effect, can strengthen antioxidant usefulness; As add EDTA-Na2 and cysteine and have the effect of performance chelating agen, can stop metal ion to the catalytic action of chain reaction in white-skinned face function composition and the nano-emulsion system automatic oxidation reaction etc.The 16, the corresponding antioxidant that the present invention designs interpolation not only has the effect of keeping white-skinned face function composition and nano-emulsion system stability, and can increase the effect of whiten nano-emulsion white-skinned face function and effect, particularly by adjusting the acid-base value (pH value) of ight and the whole system of daily white-skinned face function nano-emulsion, the usefulness of white-skinned face function composition can not only be given full play to, system stability can also be effectively kept.

Main points for attention during the invention process:

1. product is prepared used container and must be cleaned in accordance with regulations and sterilize, and the most handy strong acid soaks back water and dashes, and clear water is cleaned again, and dry with distilled water immersion the back, and places after the baking oven high-temperature sterilization drying standby; Used container all will prevent to contain impurity or pollutions such as metal ion and microorganism when carrying out the product preparation in addition; 2. carrying out product when preparation, must hig diligence raw materials quality and source.After in the end determining formula material and preparation method, no longer change raw material sources in principle, in order to avoid influence product quality, stability and result of use; 3. when carrying out the product preparation, though the interpolation of oil phase, water, emulsifying agent/co-emulsifier order is unimportant in the nano-emulsion system, but it is accurate that its additive capacity requires, and no matter be ight or skin whitening efficacy nanoemulsion, the order that various water solublity or oil-soluble white-skinned face function composition or additive raw material add in water or the water process for preparation can not be made mistakes, and after fully dissolving, the raw material that must wait a kind of adding could add a kind of raw material down again, in order to avoid muddiness occurs, influence the preparation of whole nano-emulsion system; 4. when preparation white-skinned face function nano-emulsion, need select and definite S/C mass ratio (km value), and definite S/C mass ratio (km value) 1,2,3,4, be to carry out the oily biphase binary liquid test of titration water and last definite by ability after the pseudo-ternary phase diagram analysis, only, be only comparatively ideal km value determining and calculating the km value that obtains maximum nano-emulsion zone.Therefore, reality must be through the such test and the analysis and the calculating in maximum nano-emulsion zone when carrying out the preparation of white-skinned face function nano-emulsion.The present invention adopts drafting pseudo-ternary phase diagram method to carry out the preparation of nano-emulsion, selection is mixed in proportion water and oil phase and is prepared into binary liquid, as volumetric solution binary liquid is carried out titration with the S/C mixed liquor simultaneously, in titration process, only need to observe the once phase-change process like this, reduced the error that twice phase transformation occur when carrying out titration as volumetric solution and produce, also can shorten the time and the accuracy of preparation greatly with water or oil phase.But, the present invention determines that by scientific experimentation the Km value is 3, but at actual product when preparation, surfactant (S) and the cosurfactant of carrying out

In this ratio still must be after mixing also will be more abundant mixing, in order to avoid influence preparation effect and quality; 5. oil phase Semen Myristicae isopropyl ester (IPM) dissolution velocity of (comprising vitamin E) when fat-soluble white-skinned face function composition of dissolving or additive is slower usually, for increasing work efficiency or dissolution velocity, under situation with good conditionsi, can adopt ultrasonic the concussion to quicken the dissolving of functional component or additive, make sure to keep in mind not adopt the method for high-temperature digestion, in order to avoid destroy functional component; 6. because the proportion or the different relation of density of liquid solution, when carrying out the product preparation, the capacity of selected preparation container must be a bit larger tham the product volume of actual preparation, as prepare the 1000g product, need to select the preparation container of 1500-2000mL, like this, both be convenient to each composition and fully mixed and dissolve, also be convenient to ultrasonic concussion or stirring and evenly mixing, and be unlikely to overflow outward.7. because product of the present invention itself has the characteristics of certain bacteria growing inhibiting, therefore, other interpolation antiseptic is not arranged in the formula for a product, so when carrying out the product preparation, except that the preparation container must carry out strictness cleaning and sterilization, also should under aseptic condition and according to the sterile working, require to operate as far as possible when specifically preparing in strict accordance with rule of operation, avoid product nano-emulsion product to be polluted, influence product quality.8. product of the present invention don't fail to lucifuge be packed, also place cool place, drying, ventilation, lucifuge place to preserve as far as possible.In addition, after product uses at ordinary times, need not place low temperature or refrigerator to preserve, but must seal tightly, be positioned over natural room temperature and get final product.9. because the present invention adopts more white-skinned face function composition or auxiliary additive, the functional component of these interpolations may be molten water-soluble or the pure molten or water of oil oily hold concurrently molten, therefore, during actual the preparation, should be according to functional component dissolution characteristics separately, earlier solid or liquid functional component are dissolved among the homophase, in case of necessity (when oil phase or aqueous phase dissolved degree are not enough) even need earlier some composition is dissolved in a part in the surfactant.But functional component belongs to water solublity usually, among then earlier it being soluble in the aqueous phase; Belong to oil-soluble as functional component, then it is dissolved among the oil phase earlier; Belong to pure dissolubility as functional component, then earlier it is dissolved among the pure agent, be dissolved in respectively again among oil phase or water or emulsifying agent/co-emulsifier system, afterwards, carry out the nano-emulsion preparation in every ratio of the present invention's design again.10. the reasonable coupling of main white-skinned face function composition and molten very crucial altogether among the present invention, and, select surfactants/cosurfactants (S/C) system not only to need to mate mutually with each functional component.Colourless, tasteless, odorless, transparent and high safety, best to the non-irritating S/C system of skin.And the adding proportion of S/C is extremely important, though nano-emulsion is just more stable more for a long time for the S/C of Tian Jiaing in theory, holding time also can be longer, if but excessive interpolation S/C not only can increase the preparation cost of nano-emulsion, and, its zest to skin is increased greatly, therefore, when the actual nano-emulsion of whitening is prepared, should grasp and control well the consumption of S/C, its addition is advisable to guarantee the keeping metastable lowest dose level of nano-emulsion in principle.Because of functional component addition in prescription and the preparation can influence the formation and the stability of nano-emulsion, therefore, when adding back each liquid phase of nano-emulsion as functional component muddiness appears once more or when not dissolving, still can estimate according to pseudo-three-phase diagram earlier, in the last agitation phases of nano-emulsion process for preparation, adopt water titration or pure titration, or emulsifying agent/co-emulsifier mixture titration, or emulsifying agent or the independent titration of co-emulsifier, until nano-emulsion clarify fully with transparent till.

Description of drawings

Fig. 1 is ight skin whitening efficacy nano-emulsion preparation technology's flow process of the present invention and technology path

Fig. 2 is skin whitening efficacy nanoemulsion preparation technology flow process of the present invention and technology path

The specific embodiment

The main preparation raw material of the blank nano-emulsion of skin-whitening of the present invention: isopropyl myristate (IPM), sad capric acid polyethyleneglycol glyceride (Labrasol), polyglyceryl fatty acid ester (Plurol Oleique CC497), triple distillation water.2. main functional component in the ight white-skinned face function nano-emulsion: a-Tocopheryl ferulate, Kojic Acid Dipalmitate, asiaticoside, auxiliary enzymes Q10, L-ascorbic acid-2-glucoside (AA2G ^TM), nicotiamide, β-Fructus Rubi ketone glucoside, alpha-arbutin, β-arbutin, cysteine.3. main functional component in the daily white-skinned face function nano-emulsion: vitamin E, the different monooctyl ester of ferulic acid, baicalin, glabridin are used liquid, L-ascorbic acid-2-glucoside (AA2G ^TM), N-acetylglucosamine, the vitamin PP factor, β-Fructus Rubi ketone glucoside (Fructus Rubi glycosides), phenethyl resorcinol (Symwhite-377); 4. auxiliary element: essence, EDTA-Na ₂, sodium hydroxide (AR), citric acid etc.

The present invention prepares main equipment and software:

The container of analytical balance, balance for weighing medicine, liquid flash mixer, time constant-temperature magnetic stirring apparatus, ultrasonic concussion instrument, quartz ampoule glass aqua bi-distilling apparatus, certain specification, flask, beaker, suction pipe, burette etc.In addition, also have analysis software Origin 7.0 pattern analysis systems (U.S. Microcal company).

The present invention fills a prescription and forms and consumption:

External is whitened, and blank nano-emulsion prescription is formed and consumption (100g is an example with preparation): distilled water 35-45g (final accurately consumption 40g), isopropyl myristate 10-20g (final accurately consumption 15g), sad capric acid polyethyleneglycol glyceride (Labrasol) 30-36g (final accurately consumption 33.75g), polyglyceryl fatty acid ester (PlurolOleique CC497) 10-13g (final accurately consumption 11.25g), final accurately consumption amounts to 100g.

Embodiment one: ight skin whitening efficacy nano-emulsion (100g is an example with preparation)

1, accurately take by weighing 0.688g sodium hydroxide and 0.543g citric acid respectively with analytical balance, place through among the 100mL conical flask of decontamination, add again after 33.15g triple distillation water fully dissolves, take by weighing and add 3.297g L-ascorbic acid 2-glucoside successively, fully after the dissolving, add 3.080g β-Fructus Rubi ketone glucoside more successively, 3.080g nicotiamide, 3.080g alpha-arbutin, 3.080g β-arbutin and 2.0mg cysteine (* β-Fructus Rubi ketone glucoside, nicotiamide, alpha-arbutin, β-arbutin and cysteine need to add respectively after the dissolving successively again, and can not add simultaneously); The dissolving of above material can place the CQ-10 ultrasonator to carry out ultrasonic concussion accelerate dissolution; After treating to dissolve fully, measuring this solution pH value is 6.2 ± 0.2, if any deviation, then adjusts PH and arrives within this scope.Clearly be labeled as water (I) 50g with colored marking pen, and with this solution as water.

2, accurately take by weighing the isopropyl myristate of 4.992g weight with analytical balance, place another through among the 25mL conical flask of decontamination; Take by weighing 1.998g a-Tocopheryl ferulate, 2.0g Kojic Acid Dipalmitate, 0.5g asiaticoside, 0.5g ubiquinone more respectively ₁₀With 0.01g essence, be added to respectively among the 25mL conical flask that has filled the 4.992g isopropyl myristate, fully mix, make it to dissolve fully, and with clear oil phase (II) 10g that is labeled as of marking pen.

3, according to the sad capric acid polyethyleneglycol glyceride (S) that has designed in advance: the ratio of polyglyceryl fatty acid ester (C)=3:1, accurately take by weighing sad capric acid polyethyleneglycol glyceride of 30g and 10g polyglyceryl fatty acid ester respectively, and both are placed among the clean conical flask of 50mL of the 3rd process decontamination; Add a cover, and this conical flask placed rapidly on the liquid flash mixer, open the liquid flash mixer, and it is transferred to the II shelves, fully mix homogeneously makes it to form emulsifying agent/co-emulsifier (S/C) mixture, behind the 3-5min, the closing liquid flash mixer takes off conical flask, and with clear S/C mixture (III) 40g that is labeled as of marking pen.

4, according to oil phase (II): S/C (III): the ratio of water (I)=10%:40%:50%, the phase of fetching water respectively (I) 50g, S/C mixture (III) 40g place among the 4th the clean conical flask of the 200mL through decontamination.

5, with after above-mentioned water (I), S/C mixture (III) two liquid-phase mixing, again under 25 ℃ of conditions of room temperature or in the natural room temperature, put it into and shake in the ultrasonator also about ultrasonic 2min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 2min, then, in this container, directly add oil phase (II) 10g again, and with whole system in ultrasonator about ultrasonic 20min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 20min.

6, close ultrasonator or time constant-temperature magnetic stirring apparatus, take off the 200mL conical flask, observe its outward appearance little in this way faint yellow, limpid transparent, fluidity and good dispersion, obviously visible opalescence person is arranged, be the 100g ight skin whitening efficacy nano-emulsion of external preparation for skin.

7, this 100g ight skin whitening efficacy nano-emulsion is sub-packed in rapidly among the lucifuge glass container of different size, adds a cover, sterilization, packing, and place to preserve among drying, ventilation, the shady and cool room temperature and get final product.

8, according to International or National or enterprise's relevant criterion and requirement, stochastic sampling from above-mentioned packing product, and carry out the related system that national departments concerned requires and detect, after waiting to judge or estimating it and meet national relevant regulations and standard, promptly can be used as launch and sell.

Embodiment two: skin whitening efficacy nanoemulsion (100g is an example with preparation)

1, accurately takes by weighing disodiumedetate (EDTA-Na respectively with analytical balance ₂) 0.169g places through among the 100mL conical flask of decontamination, add again after 31.78g triple distillation water fully dissolves, add successively again after 0.676g citric acid and 0.439gNaOH fully dissolve, take by weighing and add 3.02g N-acetylglucosamine successively, 2.7g L-ascorbic acid 2-glucoside, fully after the dissolving, add 3.074g β-Fructus Rubi ketone glucoside more successively, 3.074g the vitamin PP factor, the dissolving of above material can place the CQ-10 ultrasonator to carry out ultrasonic concussion accelerate dissolution; Slowly add glabridin again and use liquid 5.068g, after treating to dissolve fully, measuring this solution pH value is 4.7 ± 0.2, if any deviation, then adjusts PH and arrives within this scope.Clearly be labeled as water (I) 50g with colored marking pen, and with this solution as water.

2, accurately take by weighing the 10.71g isopropyl myristate with analytical balance, place another through among the 50mL conical flask of decontamination, taking by weighing the 2.81g vitamin E adds in the 10.71g isopropyl myristate, place the ultrasonic mixing that carries out of ultrasonator concussion, add 0.50g baicalin, 0.98g phenethyl resorcinol (Symwhite-377) again, also place ultrasonic the making it of ultrasonator concussion to dissolve fully, and with clear oil phase (II) 15g that is labeled as of marking pen.

3, according to the sad capric acid polyethyleneglycol glyceride (S) that has designed in advance: the ratio of polyglyceryl fatty acid ester (C)=3:1, accurately take by weighing sad capric acid polyethyleneglycol glyceride of 24.27g and 8.09g polyglyceryl fatty acid ester respectively, and both are placed among the clean conical flask of 50mL of the 3rd process decontamination; Add a cover, and this conical flask placed rapidly on the liquid flash mixer, open the liquid flash mixer, and it is transferred to the II shelves, fully mix homogeneously makes it to form emulsifying agent/co-emulsifier (S/C) mixture, behind the 3-5min, the closing liquid flash mixer adds the different monooctyl ester of 2.64g ferulic acid, carries out mixing as stated above.Take off conical flask, and with clear S/C mixture (III) 35g that is labeled as of marking pen.

4, according to oil phase (II): S/C (III): the ratio of water (I)=15%:35%:50%, fetch water respectively earlier phase (I) 50g, S/C mixture (III) 35g place among the 4th the clean conical flask of the 200mL through decontamination.

5, above-mentioned water (I), S/C mixture (III) two liquid phases are fully mixed after, again under 25 ℃ of conditions of room temperature or in the natural room temperature, put it into and shake in the ultrasonator also about ultrasonic 2min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 5min, then, in this container, directly add oil phase (II) 15g again, and with whole system in ultrasonator about ultrasonic 10min, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 20min.

6, close ultrasonator or time constant-temperature magnetic stirring apparatus, take off the 200mL conical flask, observe its outward appearance little in this way faint yellow, limpid transparent, fluidity and good dispersion, obviously visible opalescence person is arranged, be the 100g skin whitening efficacy nanoemulsion of external preparation for skin.

7, this 100g skin whitening efficacy nanoemulsion is sub-packed in rapidly among the lucifuge glass container of different size, adds a cover, sterilization, packing, and place to preserve among drying, ventilation, the shady and cool room temperature and get final product.

Embodiment of the present invention only is the description that preferred implementation of the present invention is carried out; be not that design of the present invention and scope are limited; do not breaking away under the preceding topic of design philosophy of the present invention; engineers and technicians and scholar make technical scheme of the present invention in this area various modification and improvement; all should fall into protection scope of the present invention; the technology contents that the present invention asks for protection all is documented in claims.

Claims

1. passive target ight and skin whitening efficacy nanoemulsion is characterized in that the prescription of ight skin whitening efficacy nano-emulsion is formed and consumption:

Isopropyl myristate 2.0-8.0g, sad capric acid polyethyleneglycol glyceride 10-50g, polyglyceryl fatty acid ester 2-20g, triple distillation water 20-50g, essence 0.01-0.05g, a-Tocopheryl ferulate 1.0-6.0g, Kojic Acid Dipalmitate 0.5-5.0g, asiaticoside 0.1-3.0g, ubiquinone ₁₀0.1-5.0g, L-ascorbic acid-2-glucoside 1.0-6.0g, nicotiamide 1.0-6.0g, β-Fructus Rubi ketone glucoside 1.0-6.0g, alpha-arbutin 1.0-7.0g, β-arbutin 1.0-7.0g, cysteine 0.1-5.0mg, AR sodium hydroxide 0.2-1.0g, citric acid 0.2-2.0g;

The prescription of skin whitening efficacy nanoemulsion is formed and consumption:

Isopropyl myristate 5.0-20.0g, sad capric acid polyethyleneglycol glyceride 15.0-40.0g, polyglyceryl fatty acid ester 5.0-15.0g, triple distillation water 20.0-45.0g, vitamin E 1.5-5.5g, the different monooctyl ester 1.5-5.5g of ferulic acid, baicalin 0.2-2.0g, glabridin is used liquid 3.0-8.0g, L-ascorbic acid-2-glucoside 2.0-6.0g, vitamin PP factor 2.0-6.0g, N-acetylglucosamine 1.0-6.0g, β-Fructus Rubi ketone glucoside 2.0-6.0g, phenethyl resorcinol 0.1-1.5g, disodiumedetate 0.1-1.5g, citric acid 0.1-1.5g, sodium hydroxide 0.1-1.5g.

2. passive target ight according to claim 1 and skin whitening efficacy nanoemulsion, wherein the weight proportion of each raw material of the best of ight skin whitening efficacy nano-emulsion is:

Isopropyl myristate 4.992g, sad capric acid polyethyleneglycol glyceride 30g, polyglyceryl fatty acid ester 10g, triple distillation water 33.15g, essence 0.01g, a-Tocopheryl ferulate 1.998g, Kojic Acid Dipalmitate 2.0g, asiaticoside 0.5g, ubiquinone ₁₀0.5g, L-ascorbic acid-2-glucoside 3.297g, nicotiamide 3.080g, β-Fructus Rubi ketone glucoside 3.080g, alpha-arbutin 3.080g, β-arbutin 3.080g, cysteine 2.0mg, AR sodium hydroxide 0.688g, citric acid 0.543g;

The weight proportion of each raw material of the best of skin whitening efficacy nanoemulsion is:

Isopropyl myristate 10.71g, sad capric acid polyethyleneglycol glyceride 24.27g, polyglyceryl fatty acid ester 8.09g, triple distillation water 31.78g, vitamin E2 .81g, the different monooctyl ester 2.64g of ferulic acid, baicalin 0.50g, glabridin are used liquid 5.068g, L-ascorbic acid-2-glucoside 2.7g, vitamin PP factor 3.074g, N-acetylglucosamine 3.02g, β-Fructus Rubi ketone glucoside 3.074g, phenethyl resorcinol 0.98g, disodiumedetate 0.169g, citric acid 0.676g, sodium hydroxide 0.439g.

3. according to the preparation method of the described ight skin whitening efficacy of claim 1 nano-emulsion, it is characterized in that may further comprise the steps:

1) presses night using type nano-emulsion proportioning raw materials, with AR sodium hydroxide and citric acid, place container, add again after triple distillation water fully dissolves, add L-ascorbic acid 2-glucoside successively, fully after the dissolving, dissolve successively again and add β-Fructus Rubi ketone glucoside, nicotiamide, alpha-arbutin, β-arbutin and cysteine; Above material places the CQ-10 ultrasonator to carry out ultrasonic concussion accelerate dissolution; And to measure this solution pH value be 6.2 ± 0.2, is labeled as water (I) with colored marking pen;

3) again with sad capric acid polyethyleneglycol glyceride (S): the ratio of polyglyceryl fatty acid ester (C)=3: 1, get sad capric acid polyethyleneglycol glyceride and polyglyceryl fatty acid ester respectively, and both are placed the 3rd container, and this container placed rapidly on the liquid flash mixer, open the liquid flash mixer, abundant mix homogeneously, make it to form emulsifying agent/co-emulsifier (S/C) mixture, behind the 3-5min, the closing liquid flash mixer, take off container, and be labeled as S/C mixture (III) with marking pen;

4) again according to oil phase (II): S/C (III): the ratio of water (I)=10%: 40%: 50%, the phase (I) of fetching water respectively earlier, S/C mixture (III) place the 4th container;

5) with after above-mentioned water (I), S/C mixture (III) two liquid-phase mixing, again under 25 ℃ of conditions of room temperature or in the natural room temperature, put it into concussion and ultrasonic 2min in the ultrasonator, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 2min, then, in this container, directly add oil phase (II) again, and, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin with whole system ultrasonic 20min in ultrasonator ^-1Rotating speed magnetic agitation 20min;

6) close ultrasonator or time constant-temperature magnetic stirring apparatus, take off container, observe its outward appearance little faint yellow, limpid transparent, fluidity and good dispersion, obviously visible opalescence is arranged, be ight skin whitening efficacy nano-emulsion;

4. according to the preparation method of the described skin whitening efficacy nanoemulsion of claim 1, it is characterized in that may further comprise the steps:

1) by daily type nano-emulsion proportioning raw materials, disodiumedetate is placed container, add again after triple distillation water fully dissolves, add successively again after citric acid and sodium hydroxide fully dissolve, add the N-acetylglucosamine successively, the L-ascorbic acid-2-glucoside, fully after the dissolving, add β-Fructus Rubi ketone glucoside more successively, the vitamin PP factor, the dissolving of above material places the CQ-10 ultrasonator to carry out ultrasonic concussion accelerate dissolution; Slowly add glabridin again and use liquid, after treating to dissolve fully, measuring this solution pH value is 4.7 ± 0.2, is labeled as water (I) with colored marking pen;

3) again with sad capric acid polyethyleneglycol glyceride (S): the ratio of polyglyceryl fatty acid ester (C)=3: 1, get sad capric acid polyethyleneglycol glyceride and polyglyceryl fatty acid ester respectively, and both are placed the 3rd container, add a cover, and this container placed rapidly on the liquid flash mixer, open the liquid flash mixer, abundant mix homogeneously, make it to form emulsifying agent/co-emulsifier (S/C) mixture, behind the 3-5min, the closing liquid flash mixer adds the different monooctyl ester of ferulic acid, carry out mixing as stated above, and be labeled as S/C mixture (III) with marking pen;

4) according to oil phase (II): S/C (III): the ratio of water (I)=15%: 35%: 50%, the phase (I) of fetching water respectively earlier, S/C mixture (III) place the 4th container;

5) above-mentioned water (I), S/C mixture (III) two liquid phases are fully mixed after, again under 25 ℃ of conditions of room temperature or in the natural room temperature, put it into concussion and ultrasonic 2min in the ultrasonator, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin ^-1Rotating speed magnetic agitation 5min, then, in this container, directly add oil phase (II) again, and, perhaps under 25 ℃ of conditions of room temperature or in the natural room temperature, start the time constant-temperature magnetic stirring apparatus, with 200rpmmin with whole system ultrasonic 10min in ultrasonator ^-1Rotating speed magnetic agitation 20min;

6) close ultrasonator or time constant-temperature magnetic stirring apparatus, take off container, observe its outward appearance little faint yellow, limpid transparent, fluidity and good dispersion, obviously visible opalescence is arranged, be skin whitening efficacy nanoemulsion;