CN1812764A - Self-assembled polymeric nanoparticles containing physiologically active ingredients and external application containing the nanoparticles - Google Patents

Abstract

The present invention relates to self-assembled polymeric nanoparticles containing physiologically active ingredients and to an external application containing the nanoparticles, in particular, relates to a self-assembled polymeric nanoparticles having amphiphilic polymeri, which comprises polycaprolactone as a hydrophobic block and polyethyleneglycol as a hydrophilic block to solubilize and entrap physiologically active ingredients in an aqueous solution, and to an external application for skin containing the particles.

Description

The self aggregation polymer nano granules and the externally-applied liniment that contains this nano-particle that contain physiologically active ingredient

Technical field

The externally-applied liniment that the present invention relates to contain the self aggregation polymer nano granules of physiologically active ingredient and contain this nano-particle.Particularly, the invention provides a kind of self aggregation polymer nano granules with amphipathic polymer, this amphipathic polymer contain polycaprolactone as hydrophobic block and Polyethylene Glycol as hydrophilic block with the physiologically active ingredient dissolving and be embedded in the aqueous solution, and provide a kind of containing of skin of described particulate externally-applied liniment that is used for.

Background technology

In recent years, (USP 5 for existing document, 338,761) reported the method for preparing nanometer or micron big or small emulsion grain, described granule contains medicine, lipid, glycerol, water and phospholipid or non-ionic surface active agent, also have document (USP 6,120,751) to report employing and have the phospholipid of electric charge other method as emulsifying agent.For example, nano-emulsion prepares like this: adopt high-pressure emulsification device (emulsifying machinery) handle by employing have specific hydrophilic-the Emulsion of partly filling a prescription that the surfactant of oleophylic ratio obtains.Liposome (liposome) is the granule of spherical or uncertain form, and described granule has the multilayer film that is formed by the lipid from plant or animal, has wherein held back various materials.Two kinds of preparations are widely used in the cosmetics.In addition, also have document (USP5,152,923, WO 91/06,286 and WO 91/06,287) to report and adopted microemulsion to prepare the method for nanoscale Emulsion, described microemulsion obtains when emulsifying agent, oil and water three-phase reach finite concentration.

But in above-mentioned routine techniques, because the film and the foreign minister of emulsion grain are in dynamic balance state, the composition in the Emulsion contacts with water, and oxidation or decomposition that this can cause composition cause granule rotten.In addition, because the chemistry of emulsion grain film or physical property are weak and unstable, so film is easy to be destroyed by the organic or inorganic pollutant possible hardly Long-term Storage.Therefore, adopt the nano-particle of low molecular weight emulsifier preparation can not be used for unsettled composition, its preparation is difficult.In addition, also have a large amount of problems of using surfactants, using a large amount of surfactants is in order to comprise the effective ingredient of high concentration, but this can cause skin irritation.

Yet, adopt the nano-emulsion granule to have such effect, in the time of promptly on being coated on skin, effective ingredient wherein discharges from granule simultaneously, because membrana granulosa is breaking on the skin or breaking in skin after by skin absorbs; Adopt another effect of nano-emulsion to be, can carry out MOLECULE DESIGN, thereby reduce and the contacting of foreign minister the membranization compound.For example, document (USP 4,663,161) has been reported employing snail shape (cochleate) to reduce inner material and to contact and increase the method that composition discharges outward.Therefore, when adopting low-molecular-weight material, need improve the technology of emulsion grain chemistry and physical stability and internal physiological composition chemical stability.Particularly, need to make the physiology composition effectively nanotechnology of release from preparation that is captured in the granule.

In order to overcome defective by the emulsion grain of low molecular weight material preparation, reported and adopted polymer to replace the method for lipid as hydrophobic core, wherein, adopt excessive surfactant with polymer dissolution in solvent, be dispersed into nano-scale, be cured by steaming solvent then (Colloids and Surface A, 210 (2002), 95-104).

Because nano-particle is very little, demonstrates the colloid unstability, in conventional method, adopt various surfactants or stabilizing agent, and, for the preparation nano-particle need be used the high-pressure emulsification technology that consumes a large amount of energy.In addition, conventional method also exists because Ostwald ripening (Ostwald ripening) problem, sedimentation problem or the flocculation problems that the colloid unstability causes, when increasing the solid constituent amount, colloidal conventional unstability becomes very serious, thereby, granule by the conventional method preparation can not comprise mass efficient composition (21th Proceedings of IFSCC International Congress), and 2000 (2000), 442-458).

For overcoming the problem of conventional method, studied the various new methods that stably capture active component, this is a particular importance for external, especially at cosmetics or medicine field.Particularly, in the hair growth promoting field, studied new liposome and gone up (Follicularliposomal delivery systems effectively effective ingredient is transmitted and is supplied to service, J. liposome Res., 2002,12:143-8), and broad research nano-carrier.

Summary of the invention

The externally-applied liniment that the present invention relates to contain the self aggregation polymer nano granules of physiologically active ingredient and contain this nano-particle.Particularly, the invention provides a kind of self aggregation polymer nano granules with amphipathic polymer, described amphipathic polymer contain polycaprolactone as hydrophobic block and Polyethylene Glycol as hydrophilic block with the physiologically active ingredient dissolving and be embedded in the aqueous solution, and provide a kind of containing of skin of described particulate externally-applied liniment that is used for.

Self aggregation polymer nano granules of the present invention is suitable for preparation and stablizes water-insoluble physiology component very much, and this is because polymer nano granules of the present invention has the character that captures soluble component owing to its self aggregation characteristic.

Can comprise ginsenoside, coenzyme Q10 in the physiology component that in the self aggregation polymer nano granules, captures of the present invention, be used for the active component of natural on-off cycles of hair growth, carry (finasteride) and cyclosporin as Fei Nasi, but be not limited thereto.

The amphipathic polymer that has the self aggregation characteristic and can be used for preparing nano-particle of the present invention is preferably polycaprolactone (PCL, the formula 1 of hydrophobic biodegradable; Component " A ") and the Polyethylene Glycol of hydrophilic biodegradable (PEG, formula 2; Component " B ") copolymer.Even A-B type diblock copolymer or A-B-A or B-A-B type triblock copolymer are most preferred, but many block types or graft type copolymer also are acceptables, to the type of copolymer without limits.

Preferably, hydrophobic polymer can be 500 to 100000 daltonian PCL for molecular weight, more preferably 1000 to 25000 dalton.Hydrophilic polymer can be 500 to 100000 daltonian PEG for molecular weight, more preferably 1000 to 25000 dalton.The part by weight of PCL and PEG is preferably 1: 9 to 9: 1, and more preferably 3: 7 to 7: 3, the part by weight of PCL and PEG most preferably was 6: 4.

[formula 1]

Wherein, n is 2 or greater than 2 integer.

[formula 2]

Wherein, m is 2 or greater than 2 integer.

The bonding of polycaprolactone of the present invention and Polyethylene Glycol (bonding) is preferably covalent bonding, as ester linkage, acid anhydride bonding, carbamate linkage, carboxylate bonding, amine bonding, amide linkage, secondary amine bonding, urethane bonds close, phosphodiester bond or hydrazone bonding.

The physiology component that captures and be contained in the nano-particle of the present invention can be all materials that if can be dissolved in the polymer, particularly those can not be by the water-insoluble component of conventional method preparation, for example, ginsenoside, coenzyme Q10, be used for the component of natural on-off cycles of hair growth, but be not limited thereto.

For example, can use rheum rhabarbarum (Rheum undulatum), genistein, Tangeretin (hesperetin), hesperidin (hesperidine), catechin (catechin), isoflavone, danazol (danazol), haloperidol (haloperidol), furosemide (furosemid), sorbide nitrate, chloromycetin (chloramfenicol), sulfamoxole (sulfamethoxazole), caffeine, cimetidine (cimethidine), diclofenac (diclofenac) Na, coenzyme Q10, vitamin E and its derivant, vitamin A and its derivant, provitamin D3 and its derivant, ursolic acid (ursolic acid), oleanolic acid (oleanolic acid), rosmarinic acid (rosmarinic acid), 18-β-enoxolone (glycyrrhetinicacid), glabridin (glabridin), aleuritic acid (aleuritic acid), polyphenol, Esculin, (-) epigallocatechin gallate (EGCG) (epigallocatechin gallate), turmeric acid (turmeric acid), the ginsenoside, tetrahydrocurcumin, Herba Centellae (centella asiatica), beta-carotene, asiaticoside (asiaticoside), farnesol (farnesol), cupreol, linoleic acid, acid and gamma-linolenic, resveratrol (resveratrol), Fructus Vitis viniferae phenol (vineatrol), Semen Ginkgo, triclosan (triclosan), minoxidil (minoxidil), natural oil, ceramide, sphingol, thuja leaf (Thujae occidentalis) extract, Radix Polygoni Multiflori (Polygoni multiflori Radix) extract, Radix Glycyrrhizae (Glycyrrhiza uralensis) extract, Semen Coicis (Coix lachryma-jobi var.ma-yuen) extract and Fei Nasi carry.

Particularly, following material can be used for retraining the hypertrophy of cancerous cell or tumor cell, improve the activity of antitumor agent: the Radix Ginseng saponin, particularly by the ginsenoside of formula 3 expression, for example, ginsenoside Rh1, Rh2, F1 (formula 4a) and compound K (formula 4b), glucose is bonded on the panaxcoside aglucon in the structure of compound K, and 20-oxygen-[L-arabinose and pyranoside base (1-＞6)-D-glucopyranosyl]-20 (S)-protopanaxadiols, two glucoses are bonded on the panaxcoside aglucon in its structure.

[formula 3]

In the formula 3, R1, R3 are glucose or H; R2 is glucose, H or OH; One of at least be glucose among R1, R2 and the R3.Ginsenoside (Ginsenoside) is a kind of in the Radix Ginseng saponin (ginseng saponin), and any ginsenoside all can be used for the present invention.That is to say, can adopt natural type or biotransformation type from Radix Ginseng.

The ginsenoside of preferred formula 3 expressions.

[formula 4a] [formula 4b]

Ginseng saponin F 1 compound K

In addition, the coenzyme Q10 by following formula 5 expressions can be included in the self aggregation polymer nano granules of the present invention.

[formula 5]

In addition, self aggregation polymer nano granules of the present invention can be used for comprising and carries active component effective but that be difficult to prepare, and described active component is used for natural on-off cycles of hair growth and hair grows.Thisly be used for the example that natural on-off cycles of hair growth or hair grow component and comprise: Fei Nasi carries, minoxidil, the thuja leaf extract, Radix Polygoni Multiflori extract, Radix Glycyrrhizae extract, the Semen Coicis extract, isoflavone, genistein, Tangeretin, hesperidin, catechin, vitamin E and its derivant, vitamin A and its derivant, provitamin D3 and its derivant, ursolic acid, oleanolic acid, rosmarinic acid, 18-β-enoxolone, farnesol, β-sitoesterol, linoleic acid, gamma-Linolenic acid, resveratrol, ceramide, sphingol etc.

Particularly, cyclosporin can be applied to alopecia areata, cyclosporin is a kind of important immunosuppressant, can be by being administered orally in the organ transplantation patient, and be used for the treatment of psoriasis.According to reports, cyclosporin has growth hair activity in zoopery.It is a kind of active component that natural on-off cycles of hair growth and hair grow that is used for that Fei Nasi carries, and is the specific inhibitor of two type 5s, when oral administration, can prevent that testosterone from changing into dihydrotestosterone, so it can be used for treating prostatitis or alopecia areata.Above-mentioned insoluble physiological component is commercially available or be used for the present invention by those skilled in the art preparation.In addition, plant extract is easy to obtain or preparation.

A kind of preparation method that contains the self aggregation polymer nano granules of physiologically active component, this method comprises the steps:

(a) preparation contains polycaprolactone as hydrophobic block and the Polyethylene Glycol amphipathic polymer as hydrophilic block, forms block copolymer;

(b) amphipathic polymer and physiologically active components dissolved are also stirred the preparation solution mixture in organic solvent;

(c) will by (a) and (b) preparation solution mixture be poured in the aqueous solution, obtain nano-particle; And

(d) remove organic solvent.

The content in nano-particle according to the effect of physiologically active component and purpose control physiologically active component is benchmark with the gross weight of nano-particle, is preferably 1 to 50 weight %, more preferably 20 to 50 weight %.When the amount of physiologically active component greater than 50% the time, the physiologically active component can not and flow out from nano-particle by effective embedding, this can cause cohesion, thereby causes variable color or spoiled.

The mean diameter of nano-particle is preferably 1 to 1000 nanometer, more preferably 10 to 500 nanometers.

The method that adopts PCL-PEG copolymer of the present invention to prepare the self aggregation polymer nano granules that contains the physiologically active component in aqueous solution comprises: disperse the PCL-PEG copolymer and carry out the method for ultrasonic Treatment; Copolymer is dispersed or dissolved in the organic solution, then method by extracting or remove organic solvent by distillation with excessive water; Be dispersed or dissolved in copolymer in the organic solution and adopt homogenizer or the high-pressure emulsification device carries out vigorous stirring, steam the method for solvent then; Copolymer is dispersed or dissolved in the organic solution, slowly adds the method for entry etc. then.

Be preparation polymer nano granules of the present invention in aqueous solution, the organic solvent that is used for biodegradable PCL-PEG copolymer is selected from least a of the group be made up of acetone, dimethyl sulfoxine, dimethyl formamide, N-Methyl pyrrolidone, diox, oxolane, ethyl acetate, acetonitrile, butanone, dichloromethane, chloroform, methanol, ethanol, ether (ethylether), ether (diethylether), hexane, petroleum ether or its mixture.

In nano-particle of the present invention, the physiologically active component is caught to combine in the hydrophobic core of self aggregation polymer nano granules, and the hydrophilic polymer chain alignment is on the surface of nano-particle, and this makes nano-particle stably be scattered in aqueous phase.The nano-particle that is scattered in aqueous phase has nanoparticle size, and colloidal stability is also very high.When this nano-particle was used for the external preparation for skin coating composition, said composition was stable, and this is because the physiologically active component can be not directly and formulation components or contact skin, is easy to be formulated as cream, lotion, astringent etc.The externally-applied liniment of above-mentioned preparation has the effect that the physiologically active component is improved skin, and the absorbability that demonstrates skin, scalp or service improves.In addition, self aggregation amphipathic polymer of the present invention can be degraded in health, is very safe therefore.

The preparation of externally-applied liniment of the present invention is unqualified, can be following any one preparation: the hair care agent, the dandruff therapeutic agent, send out frost, ointment, demineralized water (soft water), skin soft agent, nutritive water, eye cream, nourishing cream, massage cream, cleansing cream, cleaning foam, clean water, powder, the element (essence) of refining, facial film, profit precursor emulsion (body lotion), profit body frost (body cream), profit body oil (body oil), the profit body element (body essence) of refining, the cosmetic base material, foundation cream, hair dye, shampoo, Rinsing (rinse), profit body cleaning agent (body cleaner), toothpaste, cleaning agent for mouth cavity, lotion, gel, paster (patch) or spray.In addition, according to its purposes and purpose, those skilled in the art can select and add any component that can be dissolved in the solvent that is used for liniment.

Description of drawings

Fig. 1 is the feature by the self aggregation polymer nano granules that contains the Q10 coenzyme of transmission electron microscope (transmission electron microscope) acquisition;

Fig. 2 is the feature by the self aggregation polymer nano granules that contains the thuja leaf extract of transmission electron microscope acquisition;

Fig. 3 is the feature by the self aggregation polymer nano granules that contains the ginsenoside of transmission electron microscope acquisition;

Fig. 4 is for being absorbed in the feature that contains the self aggregation polymer nano granules of minoxidil in hirsutism Cavia porcellus (hairy Guinea) service;

Fig. 5 is absorbed in the feature that contains the self aggregation polymer nano granules of minoxidil in the organ of rat side.

The specific embodiment

Below, with reference to following examples and EXPERIMENTAL EXAMPLE explanation the present invention.But protection scope of the present invention is not subjected to the restriction of these embodiment.

[reference example 1] preparation ginsenoside's (Radix Ginseng saponin of purification)

Radix Ginseng Rubra (KT﹠amp with 2 kilograms; G company) adds in 4 liters of aqueous methanol, reflux and extract for 3 times, precipitate 6 days down at 15 ℃ then.By filtering and centrifugalize residue and filtrate (remainders), then, filtrate decompression is concentrated to obtain extract.Extract is suspended in water, and 1 liter of ether extraction of reuse 5 times to be to remove pigment, then, with 500 milliliters of 1-butanols with water layer extraction 3 times.Distilled water wash is handled and use to the 1-butanols layer of above-mentioned acquisition with 5%KOH, and concentrating under reduced pressure then is with acquisition 1-butanol extract.Extract (1-butanol extract) is dissolved in the small amount of methanol, to wherein adding a large amount of ethyl acetate to obtain precipitation.With drying precipitate, to obtain the Radix Ginseng saponin extract (yield: 5%) of 100 gram purification.

[reference example 2] prepares the ginsenoside by enzyme hydrolysis

The 10 Radix Ginseng saponins that restrain purification that reference example 1 is obtained are dissolved in 100 milliliters of citrate buffers (pH 5.5), to wherein adding 1 gram naringinase that is obtained by penicillium (penicillium sp.) and the 1 gram pectase that is obtained by aspergillosis (Aspergillus sp.), 40 ℃ of following stirring reactions are 48 hours in water-bath.Carry out thin layer chromatography and whether consume, after the substrate full consumption is fallen, reactant mixture was heated 10 minutes so that reaction stops detecting substrate.Then,, filter and concentrate reactant mixture extraction 3 times with commensurability ether, obtain 1050 milligrams of Radix Ginseng saponin mixture handling with enzyme, this mixture comprises 440 milligrams of compound Ks, and 150 milligrams of ginseng saponin Fs 1 have ginsenoside's (yield: 10.5%) of 1-4 glucose with other.

[preparation embodiment 1-9] preparation PCL-PEG block copolymer

PCL-PEG block copolymer preparation method described in the present embodiment only is reference, and copolymer of the present invention is not limit therewith.

PCL-PEG block copolymer of the present invention is by carrying out the ring-opening polymerisation preparation to the polycaprolactone monomer.

According to table 1, with the methoxyl group PEG[of specified quantitative hereinafter, be referred to as " mPEG " (formula 6)] and catalyst S n (Oct) ₂(Sigma, St.Louis, MO, the U.S.) adds to glass flask, and described glass flask contains the hexamethyldisiloxane by the silanization with hydroxyl reaction, again to wherein adding polycaprolactone monomer and uniform mixing.Said mPEG (Fluka Chemie GmbH, Buchs, Switzerland) is PEC, and the end of PEC is replaced to prevent reaction by methoxyl group, and another terminal hydroxyl can carry out polyreaction.

[formula 6]

The flask that will comprise mixture is connected with vacuum tube, and vacuum then, is placed to carry out polymerization down at 120 ℃ except that anhydrating and sealing.After 24 hours, polymeric polymer dissolution in dichloromethane, is carried out recrystallization with excessive methanol, obtain pure PCL-PEG copolymer.

Adopt gel permeation chromatography (hereinafter, being referred to as " GPC ") to measure the molecular weight of the PCL-PEG of above-mentioned acquisition.GPC is Agilent 110 series (Agilent Technologies, Palo Alto, CA, the U.S.), and polymer detects with refractive index (RI) detector, post be three PL gel columns (300 * 7.5 millimeters, aperture=10 ³, 10 ⁴With 10 ⁵), flow velocity is 1.0 ml/min, and mobile phase is oxolane (THF).

[table 1] preparation PCL-PEG block copolymer

	PCL monomer (gram)	MPEG (gram)	The molecular weight of mPEG (dalton)	Sn(Oct) 2(gram)	The molecular weight of polymeric PCL-PEG (dalton)
						Preparation embodiment 1	33	66	5000	0.5	6900
Preparation embodiment 2	50	50	5000	0.5	8500
						Preparation embodiment 3	60	40	5000	0.5	11000
Preparation embodiment 4	66	33	5000	0.5	13500
						Preparation embodiment 5	75	25	5000	0.5	18700
Preparation embodiment 6	80	20	5000	0.5	24300
						Preparation embodiment 7	50	50	3500	0.5	5400
Preparation embodiment 8	50	50	2000	0.5	3200
						Preparation embodiment 9	50	50	1000	0.5	1700

[preparation embodiment 10-11] preparation polycaprolactone-altogether-polyethyleneglycol block copolymer

With an end is that 10 gram mono methoxy polyethylene glycols (molecular weight 5000) and 10 internal ester monomers of restraining oneself of hydroxyl add in 50 milliliters of dry flasks, restrains Sn (Oct) to wherein adding 0.05 ₂As catalyst.In flask, add magnetism stick, mixture was carried out application of vacuum 30 minutes with teflon-coating, then that the flask sealing is tight.The flask of above-mentioned sealing is placed 150 ℃ of oil baths and carried out polymerization 6 hours.

Polymerizate is hard solid, shaped, polymerizate is dissolved fully with 20 milliliters of dichloromethane and with excessive ether sedimentation.This process is repeated 3 times to remove unreacted monomer and oligomer.With sedimentary product vacuum drying 12 hours at room temperature, obtain 17.3 gram polycaprolactone-block-polyethyleneglycol block copolymers at last.

By ¹H NMR (nuclear magnetic resonance, NMR) analyzes confirmation, and polycaprolactone carries out copolymerization in the end open loop of an ethyoxyl Polyethylene Glycol.By indicating the peak integration of an ethyoxyl Polyethylene Glycol and polycaprolactone, find that number-average molecular weight (Mn) is 9200.

100 gram Polyethylene Glycol [O, O '-two-(aminopropyl) polypropylene glycol-block-Polyethylene Glycol-block-polypropylene glycol of primary amine will be had endways; Weight average molecular weight (Mw) 1900] and 20 the gram acetone add in 500 milliliters of reaction flasks, be heated to 90 ℃ of dissolvings.Above-mentioned dissolved solution is heated to 100 ℃, adds 100 gram polycaprolactones (Mw is 80000), then, stirs 1 hour down at 100 rev/mins.The homogeneous solution of preparation stirred 5 hours down at 300 rev/mins, then, was cooled to room temperature.After reaction is finished, be dispersed in polymer product in the distilled water and stir with purification and remove unreacted Polyethylene Glycol, repeats 3 times, obtain 188 block copolymers that restrain Polyethylene Glycol and polycaprolactone at last.

[preparation embodiment 12-13] preparation Polyethylene Glycol and poly-D, the block copolymer of L-lactic acid-be total to-hydroxyacetic acid

With methoxy poly (ethylene glycol) (molecular weight 5000) that end is a hydroxyl of 5 grams, 7 gram D, L-lactic acid and 3 gram hydroxyacetic acid add in 20 milliliters of dry flasks, to wherein adding 0.025 gram Sn (Oct) ₂As catalyst.In flask, add magnetism stick, mixture was carried out application of vacuum 30 minutes with teflon-coating, then, that the flask sealing is tight.The flask of above-mentioned sealing is placed 130 ℃ of oil baths and carried out polymerization 6 hours.

Polymerizate is hard solid, shaped, and polymerizate is dissolved fully and precipitates with excessive ether with 20 milliliters of dichloromethane.This process is repeated 3 times to remove unreacted monomer and oligomer.With sedimentary product vacuum drying 12 hours at room temperature, obtain 12.7 gram Polyethylene Glycol and poly-D at last, the block copolymer of L-lactic acid-altogether-hydroxyacetic acid.

By ¹H NMR analyzes confirmation, D, and L-lactic acid and hydroxyacetic acid carry out copolymerization in the end open loop of an ethyoxyl Polyethylene Glycol.Find that by gel permeation chromatography (GPC) number-average molecular weight (Mn) is 12500.

2 gram Polyethylene Glycol [O, O '-two-(aminopropyl) polypropylene glycol-block-Polyethylene Glycol-block-polypropylene glycol of primary amine will be had endways; Weight average molecular weight (Mw) 900] add in the 50ml reaction flask, be heated to 90 ℃ of dissolvings.Above-mentioned dissolved solution is heated to 100 ℃, adds the poly-D of 20 grams, L-lactic acid-altogether-hydroxyacetic acid (RG502, Boehringer Ingumheim; Mw 11000), then, stirred 1 hour down at 100 rev/mins.The homogeneous solution of preparation stirred 3 hours down at 300 rev/mins, then, was cooled to room temperature.After reaction is finished, be dispersed in the distilled water and stir polymer product with purification and remove unreacted Polyethylene Glycol, repeats 3 times, obtain 20.4 gram Polyethylene Glycol and poly-D at last, the block copolymer of L-lactic acid-be total to-hydroxyacetic acid.

The poly-D of [preparation embodiment 14] preparation, L-lactic acid-altogether-ethylene glycol copolymer

With methoxy poly (ethylene glycol) (molecular weight 5000) that end is a hydroxyl of 5 grams, 5 gram D, L-lactic acid adds in 20 milliliters of dry flasks, to wherein adding 0.025 gram Sn (Oct) ₂As catalyst.In flask, add magnetism stick, mixture was carried out application of vacuum 30 minutes with teflon-coating, then, that the flask sealing is tight.The flask of above-mentioned sealing is placed 130 ℃ of oil baths and carried out polymerization 6 hours.

Polymerizate is hard solid, shaped, polymerizate is dissolved fully with 20 milliliters of dichloromethane and with excessive ether sedimentation.This process is repeated 3 times to remove unreacted monomer and oligomer.With sedimentary product vacuum drying 12 hours at room temperature, obtain the poly-D of 13.1 grams at last, L-lactic acid-block-polyethyleneglycol block copolymer.

By ¹H NMR analyzes confirmation, D, and L-lactic acid carries out copolymerization in the end open loop of an ethyoxyl Polyethylene Glycol.Find that by gel permeation chromatography (GPC) number-average molecular weight (Mn) is 13700.

The graft block copolymer of [preparation embodiment 15] preparation polymine and polycaprolactone

The 2 gram grafting polyethylene imines (Mw is 900) that end had primary amine add to 50 milliliters of reaction flasks, are heated to 90 ℃ of dissolvings.Above-mentioned dissolved solution is heated to 100 ℃, adds 20 gram polycaprolactones (Mw is 80000), then, stirs 1 hour down at 100 rev/mins.The homogeneous solution of preparation stirred 5 hours and was cooled to room temperature.After reaction is finished, be dispersed in the distilled water and stir polymer product with purification and remove unreacted Polyethylene Glycol, repeats 3 times, obtain 21.2 block copolymers that restrain polymine and polycaprolactone at last.

The linear block copolymers of [preparation embodiment 16] preparation polymine and polycaprolactone

The 2 gram linear polyethylene imines (Mw is 900) that end had primary amine add to 50 milliliters of reaction flasks, are heated to 90 ℃ of dissolvings.Above-mentioned dissolved solution is heated to 100 ℃, adds 20 gram polycaprolactones (Mw is 80000), then, stirs 1 hour down at 100 rev/mins.The homogeneous solution of preparation stirred 5 hours and was cooled to room temperature.After reaction is finished, be dispersed in the distilled water and stir polymer product with purification and remove unreacted Polyethylene Glycol, repeats 3 times, obtain 19.1 block copolymers that restrain polymine and polycaprolactone at last.

[embodiment 1-20] employing polycaprolactone-be total to-polyethyleneglycol block copolymer preparation contains ginsenoside's polymer nano granules

With polycaprolactone-common-polyethyleneglycol block copolymer (Mw=10000 dalton, the weight ratio of polycaprolactone and Polyethylene Glycol=1: 1) and the ginsenoside be dissolved in 50 milliliters of organic solvents, then, mixture solution is poured in the 50 ml water solution to cause self aggregation, the formation nano-particle.Remove organic solvent by distillation or dialysis, acquisition contains the aqueous solution of ginsenoside's nano-particle.The ginsenoside who is used for embodiment is the ginsenoside in the reference example 1 and 2, and described ginsenoside obtains by the saponin extract of handling from Radix Ginseng (Araliaceae) (Panax ginseng C.A.Meyer (Araliaceae)) with enzyme.

[table 2] contains the preparation condition of ginsenoside's nano-particle

	Amphipathic polymer and consumption	The ginsenoside	Organic solvent	Remove organic solvent
					Embodiment 1	Preparation embodiment 1,1.5 gram	0.5 gram	Ethanol	Distillation
Embodiment 2	Preparation embodiment 1,10 gram	1.2 gram	Ethanol	Distillation
					Embodiment 3	Preparation embodiment 1,25 gram	2.5 gram	Ethanol	Distillation
Embodiment 4	Preparation embodiment 2,1.5 grams	0.5 gram	Ethanol	Distillation
					Embodiment 5	Preparation embodiment 2,10 grams	1.2 gram	Ethanol	Distillation
Embodiment 6	Preparation embodiment 2,25 grams	2.5 gram	Ethanol	Distillation
					Embodiment 7	Preparation embodiment 3,1.5 grams	0.5 gram	Ethanol	Distillation
Embodiment 8	Preparation embodiment 3,10 grams	1.2 gram	Ethanol	Distillation
					Embodiment 9	Preparation embodiment 3,25 grams	2.5 gram	Ethanol	Distillation
Embodiment 10	Preparation embodiment 4,8 grams	1.2 gram	Ethanol	Distillation
					Embodiment 11	Preparation embodiment 4,8 grams	1.2 gram	Dimethyl sulfoxine	Dialysis
Embodiment 12	Preparation embodiment 4,8 grams	1.2 gram	Dimethyl formamide	Dialysis
					Embodiment 13	Preparation embodiment 4,8 grams	1.2 gram	Acetonitrile	Dialysis
Embodiment 14	Preparation embodiment 4,8 grams	1.2 gram	Oxolane	Dialysis
					Embodiment 15	Preparation embodiment 4,8 grams	1.2 gram	Acetone	Dialysis
Embodiment 16	Preparation embodiment 5,8 grams	1.2 gram	Ethanol	Distillation
					Embodiment 17	Preparation embodiment 6,8 grams	1.2 gram	Ethanol	Distillation
Embodiment 18	Preparation embodiment 7,8 grams	1.2 gram	Ethanol	Distillation
					Embodiment 19	Preparation embodiment 8,8 grams	1.2 gram	Ethanol	Distillation
Embodiment 20	Preparation embodiment 9,8 grams	1.2 gram	Ethanol	Distillation

[embodiment 21-40] adopts the preparation of PCL-PEG block copolymer to contain the polymer nano granules of coenzyme Q10

With PCL-PEG block copolymer (Mw=10000 dalton, the weight ratio of PCL and PEG=1: 1) and coenzyme Q10 be dissolved in 50 milliliters of organic solvents shown in the table 3, then, mixture solution poured in the 50 ml water solution carry out self aggregation, form nano-particle.Method according to table 3 is removed organic solvent by distillation or dialysis, and acquisition contains the aqueous solution of the nano-particle of coenzyme Q10.The preparation condition of nano-particle that contains coenzyme Q10 is as shown in table 3.

[table 3]

	Amphipathic polymer and consumption	Coenzyme Q10	Organic solvent	Remove organic solvent
					Embodiment 21	Preparation embodiment 1,1.5 gram	0.5 gram	Acetone	Distillation
Embodiment 22	Preparation embodiment 1,1.8 gram	1.2 gram	Acetone	Distillation
					Embodiment 23	Preparation embodiment 1,5.0 gram	2.5 gram	Acetone	Distillation
Embodiment 24	Preparation embodiment 2,1.5 grams	0.5 gram	Acetone	Distillation
					Embodiment 25	Preparation embodiment 2,1.8 grams	1.2 gram	Acetone	Distillation
Embodiment 26	Preparation embodiment 2,5.0 grams	2.5 gram	Acetone	Distillation
					Embodiment 27	Preparation embodiment 3,1.5 grams	0.5 gram	Acetone	Distillation
Embodiment 28	Preparation embodiment 3,1.8 grams	1.2 gram	Acetone	Distillation
					Embodiment 29	Preparation embodiment 3,5.0 grams	2.5 gram	Acetone	Distillation
Embodiment 30	Preparation embodiment 4,1.8 grams	1.2 gram	Acetone	Distillation
					Embodiment 31	Preparation embodiment 4,1.8 grams	1.2 gram	Dimethyl sulfoxine	Dialysis
Embodiment 32	Preparation embodiment 4,1.8 grams	1.2 gram	Dimethyl formamide	Dialysis
					Embodiment 33	Preparation embodiment 4,1.8 grams	1.2 gram	Acetonitrile	Dialysis
Embodiment 34	Preparation embodiment 4,1.8 grams	1.2 gram	Oxolane	Dialysis
					Embodiment 35	Preparation embodiment 4,1.8 grams	1.2 gram	Acetic acid	Dialysis
Embodiment 36	Preparation embodiment 5,1.8 grams	1.2 gram	Acetone	Distillation
					Embodiment 37	Preparation embodiment 6,1.8 grams	1.2 gram	Acetone	Distillation
Embodiment 38	Preparation embodiment 7,1.8 grams	1.2 gram	Acetone	Distillation
					Embodiment 39	Preparation embodiment 8,1.8 grams	1.2 gram	Acetone	Distillation
Embodiment 40	Preparation embodiment 9,1.8 grams	1.2 gram	Acetone	Distillation

[embodiment 41-43] preparation contains the polymer nano granules of thuja leaf extract

With polycaprolactone as shown in table 4-common-polyethyleneglycol block copolymer (Mn=9200; The weight ratio of polycaprolactone and Polyethylene Glycol=1: 1) and the thuja leaf extract be dissolved in the 50 gram acetone and evenly stir.After having dissolved, pour in 50 ml distilled waters lentamente solution and stirring.Stir after 1 minute, solution is heated to 50-60 ℃ and stirring once more, remove acetone, acquisition at last contains the dispersion soln of the nano-particle of thuja leaf extract.

[table 4] contains the nano-particle content of thuja leaf extract

Component	Embodiment 41	Embodiment 42	Embodiment 43
				Polycaprolactone-block-Polyethylene Glycol	2.5 gram	2.5 gram	2.5 gram
The thuja leaf extract	1.5 gram	2.5 gram	0.5 gram

[embodiment 44] preparation contains the polymer nano granules of minoxidil

With the poly-D of 2.5 grams, L-lactic acid-be total to-polyethyleneglycol block copolymer (Mn=13700) and 2.5 gram minoxidils are dissolved in the solvent mixture of being made up of 25 gram acetone and 25 gram ethanol, evenly stir.After having dissolved, pour in 50 ml distilled waters lentamente solution and stirring.After stirring 1 minute, solution is heated to 50-60 ℃ also stirs once more except that desolvating, acquisition at last contains the dispersion liquid of the nano-particle of 2.5 gram minoxidils.

[embodiment 45-47] adopts the polycaprolactone-polyethylene glycol block copolymer preparation to contain the polymer nano granules that Fei Nasi puies forward (component that a kind of natural on-off cycles of hair growth and hair grow)

Polycaprolactone-altogether-polyethyleneglycol block copolymer (Mw=10000 dalton, the weight ratio of polycaprolactone and Polyethylene Glycol=1: 1) and Fei Nasi carried be dissolved in equably in 50 milliliters of organic solvents.After having dissolved, mixture solution poured in the 50 ml water solution carry out self aggregation, form nano-particle.After stirring 1 minute, remove the aqueous solution of organic solvent with the nano-particle that obtains to contain Fei Nasi and carry by distillation or dialysis.It is as shown in table 5 that preparation contains the reaction condition of the nano-particle that Fei Nasi carries.

[table 5]

	Amphipathic polymer and consumption (gram)	Fei Nasi carries	Organic solvent	Remove organic solvent
					Embodiment 45	Preparation embodiment 1,2.5	0.2 gram	Acetone	Distillation
Embodiment 46	Preparation embodiment 1,2.5	1.0 gram	Acetone	Distillation
					Embodiment 47	Preparation embodiment 1,2.5	2.0 gram	Acetone	Distillation

[embodiment 48-59] adopts the polycaprolactone-polyethylene glycol block copolymer preparation to contain the polymer nano granules of cyclosporin (component that a kind of natural on-off cycles of hair growth and hair grow)

As shown in table 6, with polycaprolactone-common-polyethyleneglycol block copolymer (Mw=10000 dalton, the weight ratio of polycaprolactone and Polyethylene Glycol=1: 1) and the cyclosporin uniform dissolution in 50 milliliters of organic solvents, mixture solution poured in the 50 ml water solution carry out self aggregation, form nano-particle.Remove organic solvent by distillation or dialysis, acquisition contains the aqueous solution of the nano-particle of cyclosporin.

[table 6]

	Amphipathic polymer and consumption (gram)	Cyclosporin (gram)	Organic solvent	Remove organic solvent
					Embodiment 48	Preparation embodiment 1,1.5	0.5	Acetone	Distillation
Embodiment 49	Preparation embodiment 1,2.0	1.0	Acetone	Distillation
					Embodiment 50	Preparation embodiment 1,5.0	0.5	Acetone	Distillation
Embodiment 51	Preparation embodiment 2,1.5	0.5	Acetone	Distillation
					Embodiment 52	Preparation embodiment 2,2.0	1.0	Acetone	Distillation
Embodiment 53	Preparation embodiment 2,5.0	0.5	Acetone	Distillation
					Embodiment 54	Preparation embodiment 3,1.5	0.5	Ethanol	Distillation
Embodiment 55	Preparation embodiment 3,2.0	1.0	Ethanol	Distillation
					Embodiment 56	Preparation embodiment 3,5.0	0.5	Ethanol	Distillation
Embodiment 57	Preparation embodiment 4,1.5	0.5	Dimethyl sulfoxine	Dialysis
					Embodiment 58	Preparation embodiment 4,1.8	1.0	Dimethyl formamide	Dialysis
Embodiment 59	Preparation embodiment 4,1.8	0.5	Acetonitrile	Dialysis

[EXPERIMENTAL EXAMPLE 1] adopts dynamic light scattering method to measure nanoparticle size

Adopt Zetasizer 3000Hsa (Malvern, Britain) to measure the average-size of the nano-particle for preparing among the embodiment 1-59.Angle of scattering is 90 °, and temperature is 25 ℃.The result is as shown in table 7.

[table 7]

	Average-size (average diameter; Nanometer)
		Embodiment 1	247.2
Embodiment 2	148.2
		Embodiment 3	42.2
Embodiment 4	212.4
		Embodiment 5	271.8
Embodiment 6	49.3
		Embodiment 7	223.4
Embodiment 8	256.8
		Embodiment 9	54.3
Embodiment 10	243.2
		Embodiment 11	284.2
Embodiment 12	296.1
		Embodiment 13	276.2
Embodiment 14	249.3
		Embodiment 15	98.9
Embodiment 16	95.4
		Embodiment 17	86.8
Embodiment 18	72.3
		Embodiment 19	53.2
Embodiment 20	68.6
		Embodiment 21	56.2
Embodiment 22	64.2
		Embodiment 23	53.2
Embodiment 24	212.4
		Embodiment 25	271.8
Embodiment 26	278.3
		Embodiment 27	223.4
Embodiment 28	256.8
		Embodiment 29	201.3
Embodiment 30	243.2
		Embodiment 31	284.2
Embodiment 32	296.1
		Embodiment 33	276.2
Embodiment 34	249.3
		Embodiment 35	198.9
Embodiment 36	295.4
		Embodiment 37	286.8
Embodiment 38	72.3
		Embodiment 39	53.2
Embodiment 40	48.6
		Embodiment 41	45.2
Embodiment 42	120.0
		Embodiment 43	278.3
Embodiment 44	45.2
		Embodiment 45	67.8
Embodiment 46	146.2
		Embodiment 47	226.5
Embodiment 48	56.2
		Embodiment 49	64.2
Embodiment 50	53.2
		Embodiment 51	212.4
Embodiment 52	271.8
		Embodiment 53	278.3
Embodiment 54	223.4
		Embodiment 55	256.8
Embodiment 56	201.3
		Embodiment 57	243.2
Embodiment 58	284.2
		Embodiment 59	296.1

[EXPERIMENTAL EXAMPLE 2] measures the skin absorbs of the nano-particle that contains the ginsenoside

The skin of cutting hirsutism Cavia porcellus is also fixed with the Franz diffusion cell, then, top position is placed in buffer with 3 kinds of sample treatment of table 8 and with lower position, simultaneously stirring buffer 18 hours under 32 ℃.Adopt the liquid chromatograph measurement to be absorbed into amount in the skin from ginsenoside's compound K.

[table 8]

	The ginsenoside's amount that absorbs	The ginsenoside's that absorbs of unit are amount per hour
			Ethanol (10%), butanediol (5%), ginsenoside's (1%)	366 micrograms	40 micrograms/centimetre 2Hour
Embodiment 3	576 micrograms	64 micrograms/centimetre 2Hour
			The microemulsion that contains 1% ginsenoside	485 micrograms	54 micrograms/centimetre 2Hour

Find out from The above results, will get well about 159% than the absorbent properties of microemulsion formulation by the nano-particle of the embodiment of the invention 3 preparations.

[EXPERIMENTAL EXAMPLE 3] measures the skin absorbs of the nano-particle that comprises coenzyme Q10

The skin of cutting hirsutism Cavia porcellus is also fixed with the Franz diffusion cell, then, top position is placed in buffer with 3 kinds of sample treatment of table 9 and with lower position, simultaneously stirring buffer 18 hours under 32 ℃.Adopt the liquid chromatograph measurement to be absorbed into the amount of the coenzyme Q10 in the skin.For comparing, carry out identical experiment with the liposome that contains 1% coenzyme Q10.

[table 9]

	The coenzyme Q10 amount that absorbs	The amount of the coenzyme Q10 that absorbs of unit are per hour
			10% capric acid/Trivent OCG solution	0	0
Embodiment 24	37.53 microgram	2.68 microgram/centimetre 2Hour
			The liposome that contains 1% coenzyme Q10	23.68 microgram	1.69 microgram/centimetre 2Hour

As seen from Table 9, the absorbent properties by the nano-particle that contains coenzyme Q10 of the present invention preparation are about 159% of liposome.

[EXPERIMENTAL EXAMPLE 4] measures the skin absorbs of the nano-particle that contains minoxidil

In the nano-particle process of preparation embodiment 44, add fluorescent material Rubren (tetraphenyl aphthacene) as probe (label), the nano-particle of preparation is coated on the hirsutism Cavia porcellus by the paster (closed patch) that seals cuts on the plucked skin and last 6 hour of flank organ of rat.The tissue that obtains is downcut 40 micron thickness with preparation frozen section (cryosection), with the cell (nucleated cell) of DAPI dyeing, adopt with focal argon laser scanning microscopy (Zeiss) measurement and measure then by the Rubren that service absorbs in the skin with the labelling nucleation.

Find that from The above results the Concentraton gradient that absorbs the nano-particle that contains minoxidil in the skin is identical at the skin place, higher near tee concentration, granule is absorbed by service.

[EXPERIMENTAL EXAMPLE 5] measures the skin absorbs of the nano-particle that contains cyclosporin

The skin of cutting hirsutism Cavia porcellus is also fixed with the Franz diffusion cell, then, top position is placed in buffer with 3 kinds of sample treatment of table 10 and with lower position, simultaneously stirring buffer 18 hours under 32 ℃.The measurement of employing liquid chromatograph is absorbed into the cyclosporin amount in the skin.

[table 10]

	The cyclosporin amount that absorbs	The amount of the cyclosporin that absorbs of unit are per hour
			10% capric acid/Trivent OCG solution	0	0
Embodiment 51	37.53 microgram	2.68 microgram/centimetre 2Hour
			The liposome that contains 1% cyclosporin 1	23.68 microgram	1.69 microgram/centimetre 2Hour

[notes] liposome ¹Be the comparative experiments sample.

As seen from Table 10, the nano-particle of the embodiment of the invention 51 has than the better absorbent properties of liposome.

[EXPERIMENTAL EXAMPLE 6] contains the effect of nano-particle in natural on-off cycles of hair growth of minoxidil or thuja leaf extract

Be test hair growth promoting effect, the effect of the nano-particle for preparing in the embodiment of the invention compares with the hair growth promoting component that does not capture in nano-particle.

47-53 days mice (C57BL/6) back hair of birth is removed, applied 100 microlitre laboratory samples, 10 mices of every kind of sample application every day at the back of mice.

The length and the extent of growth assessing hair growth result of hair is 0 to 3 grade behind the hair according to removing.Be relatively hair growth effect, 30% alcoholic solution is coated on every mice in contrast.The result is as shown in table 11.

[table 11]

Experiment material	Time
			After 10 days	After 20 days
	Negative control (ethanol)	0.25±0.25			1.42±0.30
Positive control (minoxidil 2.5%)			1.22±0.24	2.65±0.47
	Thuja leaf extract (2.5%)	0.67±0.41			1.98±0.52
The nano-particle of embodiment 41			0.91±0.28	2.56±0.32
	The nano-particle of embodiment 42	0.82±0.32			2.42±0.23
The nano-particle of embodiment 43			0.76±0.15	2.13±0.40
	The nano-particle of embodiment 44	1.65±0.43			2.86±0.42

Find out from The above results, the nano-particle that contains minoxidil of the embodiment of the invention 44 demonstrates than the better hair growth effect of same concentrations minoxidil, in addition, the nano-particle that contains the thuja leaf extract of embodiment of the invention 41-43 also demonstrates than the better hair growth effect of thuja leaf extract.Find out that from the result of embodiment 41-43 the concentration of active component and the ratio of nano-particle are very important for growing or growing of hair.

[EXPERIMENTAL EXAMPLE 7] contains the effect of nano-particle in natural on-off cycles of hair growth that Fei Nasi puies forward

Be test hair growth promoting effect, the effect of the nano-particle for preparing among the embodiment of the invention 45-47 compares with the hair growth promoting component that does not capture in nano-particle.

With 47-53 days the hair removing of mice (C57BL/6) back of birth, apply 100 microlitre laboratory samples, 10 mices of every kind of sample application every day at the back of mice.

The length and the extent of growth assessing hair growth result of hair is 0 to 3 grade behind the hair according to removing.Be relatively hair growth effect, the Fei Nasi of same amount (1%) carried being dissolved in 30% alcoholic solution and being coated on every mice go up as negative control.With cyclosporine dissolved in wherein as positive control.The result is as shown in table 12.

[table 12]

Experiment material	Time
			After 10 days	After 20 days
	Negative control	0.26±0.24			1.52±0.28
Positive control (0.5% cyclosporin)			1.05±0.35	2.55±0.27
	The nano-particle of embodiment 46	0.55±0.23			1.95±0.22

Find out from The above results, demonstrate than containing the low hair growth effect of 5% cyclosporin, demonstrate that same concentrations Fei Nasi carries better hair growth effect in the ethanol than being dissolved in though the present invention contains the nano-particle that Fei Nasi carries.

[EXPERIMENTAL EXAMPLE 8] contains the effect of nano-particle in natural on-off cycles of hair growth of cyclosporin

Be test hair growth promoting effect, the effect of the nano-particle of preparation compares with the hair growth promoting component that does not capture in nano-particle in the embodiment of the invention 48～59.

With 47-53 days the hair removing of mice (C57BL/6) back of birth, apply 100 microlitre laboratory samples, 10 mices of every kind of sample application every day at the back of mice.

The length and the extent of growth assessing hair growth result of hair is 0 to 3 grade behind the hair according to removing.Be relatively hair growth effect, 30% alcoholic solution is coated on every mice in contrast.The result is as shown in table 13.

[table 13]

Experiment material	Time
			After 10 days	After 20 days
	Negative control (ethanol)	0.26±0.24			1.52±0.28
Positive control (0.5% cyclosporin)			1.05±0.35	2.55±0.27
	The nano-particle of embodiment 48	1.18±0.22			2.68±0.32
The nano-particle of embodiment 51			1.24±0.26	2.82±0.21
	The nano-particle of embodiment 54	1.34±0.15			2.86±0.16

Find out from The above results, the nano-particle of the embodiment of the invention demonstrates the better hair growth effect of hair growth active component than same concentrations, in addition, find out that the concentration of active component is very important for the growth of hair from embodiment 48,51 and 54.

[EXPERIMENTAL EXAMPLE 9] contains the antioxidant effect of the nano-particle of coenzyme Q10 to Skin Cell

Concentration according to table 14,100 microlitre HCSS (4-hydroxyethyl piperazine ethanesulfonic acid (HEPES) buffering contrast saline solution) are applied on the dermal fibroblast, adopt the board-like reader of fluorescence (Ex=485 nanometer, Em=530 nanometer) to measure the fluorescence of initial oxidation to the dichlorofluorescein (DCF) of ROS (active oxygen).Begin to carry out UVB (ultraviolet B radiation) irradiation (30 millis are burnt/centimetre ²), back 3 hours of irradiation back and irradiation just, adopt the board-like reader of fluorescence (Ex=485 nanometer, Em=530 nanometer) to measure fluorescence respectively.For comparing, the liposome that contains 1% coenzyme Q10 is carried out identical experiment.Table 14 has shown epipolic comparative result (%), with % as unit with UVB irradiation not comparing after 3 hours with the matched group of sample treatment.

[table 14]

Sample	Concentration
						10ppm	5ppm	2.5ppm	1.25ppm	0.625ppm
	Embodiment 24	62.6	67.6	74.8	79.1						74.9
The liposome that contains 1% coenzyme Q10						87.1	93.8	96.3	89.4	85.5

As seen from Table 14, the present invention's nano-particle of containing coenzyme Q10 is suppressing more effective aspect the ROS generation than the liposome that contains coenzyme Q10.

[experimental example 10] comprises the biosynthesis of ginsenoside's nano-particle collagen

Human fibroblasts is cultivated on 24 orifice plate culture medium, and the ginsenoside's of containing table 15 that will be prepared by the nano-particle and the following comparative example 1 of embodiment 3 methods preparation microemulsion is diluted to 1/100, and adds in the culture medium.Cultivate after 3 days, add 0.5 milliliter of DMEM culture medium (Dulbecos modified eagles medium) that contains 10% hyclone (FBS), add 10 microgram L[2,3,4,5-3H]-Ci of proline (Ci of L[2,3,4,5-3H]-proline).After 24 hours, collect cell and culture medium on each hole, washing in 5%TCA (trichloroacetic acid).Then, be divided into 2 developmental tubes; The type i collagen enzyme that adds 1 unit/microlitre in a developmental tube was cultivated 90 minutes down at 37 ℃, and another developmental tube is placed down at 4 ℃.

Then, in all developmental tubes, add 0.05 milliliter of 50%TCA, and, descended centrifugal 10 minutes at 12000 rev/mins 4 ℃ of following placements 20 minutes.Then, adopt scintillation counter (scintillationcounter) to measure supernatant and sedimentary DPM value (decays of per minute), contain the biosynthesis of the preparation collagen of same amount ginsenoside's embodiment 3 and comparative example 1 according to formula 1 calculating.The results are shown in Table 15.

[calculating formula 1]

ICB (collagen biosynthesis rate of increase)={ collagen DMP/ (total collagen DMP-collagen DMP) * 5.4+ collagen DMP} * 100

[comparative example 1]

Component	Comparative example 1
		Hydration lecithin	2.5
Hydration lysophosphatidylcholine (lysophosphatidylcholine)	0.15
		Propylene glycol	4.0
Ethanol	6.5
		The ginsenoside	1.5
EDTA	0.05
		Glycerol	4.0
Betanin	1.0
		Distilled water	To 100

[table 15]

Ginsenoside's concentration (%)	Collagen biosynthesis rate of increase (%)
			Embodiment 3	Comparative example 1
	1×10 -8	7			5
1×10 -7			35	24
	1×10 -6	40			35
1×10 -5			59	45
	1×10 -4	73			50

As seen from Table 15, compare with the ginsenoside's who does not capture character, the ginsenoside who captures in nano-particle of the present invention demonstrates the more excellent biosynthetic character of promotion collagen.

Following preparation adopts the foregoing description preparation.

[preparation 1～9] cream

O/W (oil-in-water type) emulsion formulations, described preparation comprises the nano-particle that contains the ginsenoside of embodiment, and is shown in table 16.

[table 16]

Component	Preparation 1	Preparation 2	Preparation 3	Preparation 4	Preparation 5	Preparation 6	Preparation 7	Preparation 8	Preparation 9
										The lipotropy monostearate	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
The glyceryl stearate	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
										Cetostearyl alcohol (Cetostearyl Alcohol)	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Paraffin	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
										Squalene	1.2	1.2	1.2	1.2	1.2	1.2	1.2	1.2	1.2
Polysorbate60	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4
										The cetyl ethylhexoate	2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0
Liquid paraffin	2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0
										Methyl parahydroxybenzoate	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Propyl p-hydroxybenzoate	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05
										Silicone oil	4.0	4.0	4.0	4.0	4.0	4.0	4.0	4.0	4.0
Educate phenol acetas (Tocopheryl acetate)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
										Distilled water	To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100
Urea	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
										Glycerol	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0
Butanediol	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
										Triethanolamine	0.18	0.18	0.18	0.18	0.18	0.18	0.18	0.18	0.18
CVP Carbopol ETD2050	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
										Embodiment 1	25.0	-	-	-	-	-	-	-	-
Embodiment 4	-	25.0	-	-	-	-	-	-	-
										Embodiment 5	-	-	25.0	-	-	-	-	-	-
Embodiment 6	-	-	-	25.0	-	-	-	-	-
										Embodiment 8	-	-	-	-	25.0	-	-	-	-
Embodiment 10	-	-	-	-	-	25.0	-	-	-
										Embodiment 16	-	-	-	-	-	-	25.0	-	-
Embodiment 17	-	-	-	-	-	-	-	25.0	-
										Embodiment 18	-	-	-	-	-	-	-	-	25.0

[preparation 10～18] soft water (skin soft agent) preparation

The demineralized water preparation comprises the nano-particle that contains the ginsenoside of embodiment, and is shown in table 17.

[table 17]

Component	Preparation 10	Preparation 11	Preparation 12	Preparation 13	Preparation 14	Preparation 15	Preparation 16	Preparation 17	Preparation 18
										Betanin	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
Natto gum	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
										Cellulose gum	0.08	0.08	0.08	0.08	0.08	0.08	0.08	0.08	0.08
Ethanol	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0
										Polyoxyethylene hydrogenated Oleum Ricini	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Tocopherol acetate	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
										Polysorbate60	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0
Glycerol	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0
										Embodiment 1	10.0	-	-	-	-	-	-	-	-
Embodiment 2	-	10.0	-	-	-	-	-	-	-
										Embodiment 3	-	-	10.0	-	-	-	-	-	-
Embodiment 4	-	-	-	10.0	-	-	-	-	-
										Embodiment 5	-	-	-	-	10.0	-	-	-	-
Embodiment 6	-	-	-	-	-	10.0	-	-	-
										Embodiment 15	-	-	-	-	-	-	10.0	-	-
Embodiment 19	-	-	-	-	-	-	-	10.0	-
										Embodiment 20	-	-	-	-	-	-	-	-	10.0
Antiseptic	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity
										Pigment	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity
Distilled water	To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100

[preparation 19-27] cream

O/W emulsion formulations, described preparation comprise that embodiment 21,24-26,28,30,36-38 contain the nano-particle of coenzyme Q10, and be shown in table 18.

[table 18]

Component	Preparation
										19	20	21	22	23	24	25	26	27
	The lipotropy monostearate	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0										3.0
Tristerin										1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
	Cetostearyl alcohol	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5										1.5
Paraffin										0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
	Squalene	1.2	1.2	1.2	1.2	1.2	1.2	1.2	1.2										1.2
Polysorbate60										0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4
	The cetyl ethylhexoate	2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0										2.0
Liquid paraffin										2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0	2.0
	Methyl parahydroxybenzoate	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2										0.2
Propyl p-hydroxybenzoate										0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05
	Silicone oil	4.0	4.0	4.0	4.0	4.0	4.0	4.0	4.0										4.0
Tocopherol acetas										0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
	Distilled water	To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100										To 100
Urea										0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
	Glycerol	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0										5.0
Butanediol										3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
	Triethanolamine	0.18	0.18	0.18	0.18	0.18	0.18	0.18	0.18										0.18
CVP Carbopol ETD2050										0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
	Embodiment 21	25.0	-	-	-	-	-	-	-										-
Embodiment 24										-	25.0	-	-	-	-	-	-	-
	Embodiment 25	-	-	25.0	-	-	-	-	-										-
Embodiment 26										-	-	-	25.0	-	-	-	-	-
	Embodiment 28	-	-	-	-	25.0	-	-	-										-
Embodiment 30										-	-	-	-	-	25.0	-	-	-
	Embodiment 36	-	-	-	-	-	-	25.0	-										-
Embodiment 37										-	-	-	-	-	-	-	25.0	-
	Embodiment 38	-	-	-	-	-	-	-	-										25.0

[preparation 28-36] skin preparation

Skin preparation, described preparation comprise the polymer nano granules of embodiment 21～26,35,39,40, and be shown in table 19.

[table 19]

Component	Preparation
										28	29	30	31	32	33	34	35	36
	Betanin	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0										3.0
Natto gum										3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0	3.0
	Cellulose gum	0.08	0.08	0.08	0.08	0.08	0.08	0.08	0.08										0.08
Ethanol										5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0
	Polyoxyethylene hydrogenated Oleum Ricini	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5										0.5
Tocopherol acetate										0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
	Polysorbate60	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0										5.0
Glycerol										5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0	5.0
	Embodiment 21	10.0	-	-	-	-	-	-	-										-
Embodiment 22										-	10.0	-	-	-	-	-	-	-
	Embodiment 23	-	-	10.0	-	-	-	-	-										-
Embodiment 24										-	-	-	10.0	-	-	-	-	-
	Embodiment 25	-	-	-	-	10.0	-	-	-										-
Embodiment 26										-	-	-	-	-	10.0	-	-	-
	Embodiment 35	-	-	-	-	-	-	10.0	-										-
Embodiment 39										-	-	-	-	-	-	-	10.0	-
	Embodiment 40	-	-	-	-	-	-	-	-										10.0
Antiseptic										On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity
	Pigment	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity	On a small quantity										On a small quantity
Distilled water										To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100	To 100

The storage of [EXPERIMENTAL EXAMPLE 11] coenzyme Q10 in preparation

Adopt preparation 20 checking coenzyme Q10s stability during Long-term Storage in preparation.In the constant temperature bath of 25 ℃ and 45 ℃, preserve preparation, take out sample, measure the quantity of coenzyme Q10.For comparing, the composition of reference table 18 prepares the cream that contains liposome, and described liposome contains 1% coenzyme Q10, carries out identical experiment.The result is shown in table 20.

[table 20]

	Condition	7 days	15 days	30 days	45 days
						Preparation 20	25℃	100％	94％	90％	87％
45℃	100％	91％	86％	83％
					The cream that contains liposome		25℃	100％	93％	88％	82％
45℃	100％	87％	75％	62％

As seen from Table 20, during Long-term Storage, the coenzyme Q10 of polymer nano granules of the present invention is more more stable than liposome.Thereby, by coenzyme Q10 being captured the activity that in polymer nano granules of the present invention, can keep coenzyme Q10.

[preparation 37] skin preparation

Skin preparation, described preparation contain the nano-particle that contains minoxidil of embodiment 44, and be shown in table 21.

[table 21]

Component	Content (weight %)
		Water	To 100
EDTA-2Na	0.02
		DL-panthenol (panthenol)	0.1
Trehalose	2.0
		Glycerol	3.0
Butanediol	3.0
		PEG-1500	1.0
Rose water (Rose water)	1.0
		Bio-HE	0.01
Soypol sp	0.01
		Ethanol	5.0
Propyl p-hydroxybenzoate	0.02
		Methyl parahydroxybenzoate	0.12
Tagat CH 60	0.35
		C-940	6.0
SPA (recuperating) alkali	0.5
		KOH(10％)	0.24
The nano-particle of embodiment 4	25.0

[preparation 38] hair care formulations

Haircare composition, said composition contain the nano-particle of embodiment 41-43 and embodiment 44, and the nano-particle of embodiment 41-43 contains the thuja leaf extract, and the nano-particle of embodiment 44 contains minoxidil, and is shown in table 22.

[table 22]

Component	Content (weight %)
		Ethanol	55.0
Oleum Ricini	5.0
		Glycerol	3.0
Piroctone olamine (Piroctone Olamine)	0.1
		The nano-particle of embodiment 41-44	1.0
Spice, pigment	In right amount
		Distilled water	To 100

[preparation 39] hair liquid preparation

The hair fluid composition, described compositions contains the nano-particle of embodiment 41-43 and embodiment 44, and the nano-particle of embodiment 41-43 contains the thuja leaf extract, and the nano-particle of embodiment 44 contains minoxidil, and is shown in table 23.

[table 23]

Component	Content (weight %)
		Polyoxyethyl propyl butyl ether (40 P.O.)	15.0
Polyoxyethyl propyl butyl ether phosphate ester (40 P.O.)	15.0
		1,3 butylene glycol	5
95% ethanol	50
		Tocopherol acetas	0.1
The nano-particle of embodiment 41-43	5.0
		Spice,	In right amount
Pigment	In right amount
		Edetic acid	In right amount
Distilled water	To 100

[preparation 40] dandruff treatment preparation

The dandruff therapeutic combination, described compositions contains the nano-particle of embodiment 41-43 and embodiment 44, and the nano-particle of embodiment 41-43 contains the thuja leaf extract, and the nano-particle of embodiment 44 contains minoxidil, and is shown in table 24.

[table 24]

Component	Content (weight %)
		1,3 butylene glycol	0.5
Four-2-ethyl, six tetramethylolmethanes	1.2
		95% ethanol	60
The nano-particle of embodiment 41-44	2
		Spice	In right amount
Dimethyl ether/LPG (95/5)	To 100

[preparation 41] suppurative mastitis preparation

The suppurative mastitis compositions, described compositions contains the nano-particle of embodiment 41-44, and is as shown in Table 25.

[table 25]

Component	Content (weight %)
		Liquid paraffin	5.0
The cetyl stearyl alcohol	5.5
		Vaseline	5.5
Glyceryl monostearate	3.0
		Polyoxyethylene (being added with 20 moles)-2-octyl-decyl ether	3.0
Tocopherol acetas	0.05
		Propyl p-hydroxybenzoate	0.3
The nano-particle of embodiment 41-44	5
		Macrogol 4000	5.0
Glycerol	7.0
		Spice	In right amount
Distilled water	To 100

[preparation 42] hair spray formulations

Hairspray compositions, described compositions contains the nano-particle of embodiment 41-44, and is shown in table 26.

[table 26]

Component	Content (weight %)
		CVP Carbopol ETD2050	0.7
Polyvinylpyrrolidine	2.0
		Glycerol	4.0
Sodium hydroxide	In right amount
		Ethanol	20.0
Embodiment 41-44 nano-particle	2
		Polyoxyethylene octyl-decyl ether	In right amount
Spice	In right amount
		Egtazic acid (Edetic acid)	In right amount
Distilled water	To 100

[preparation 43] eruption preparation

The hair spray compositions, described compositions contains the nano-particle of embodiment 41-44, and is shown in table 27.

[table 27]

Component	Content (weight %)
		Allyl resin alkanol amine salt (50%)	3.5
Cetyl alcohol	0.05
		Silicone oil (methyl phenyl silicone)	0.15
Ethanol	45
		The nano-particle of embodiment 41-44	1
Spice	In right amount
		Dimethyl ether	45
LPG	5.0

[preparation 44] shampoo

Shampoo Compositions, described compositions contains the nano-particle of embodiment 41-44, and is shown in table 28.

[table 28]

Component	Content (weight %)
		Sodium lauryl sulphate	16
Cocos nucifera oil aminopropyl betanin (Cocoaminopropyl betaine)	2
		Jaguar (jaguar) C13S	0.1
The nano-particle of embodiment 41-44	3
		Distilled water	To 100

[preparation 45] cream

The O/W emulsion composition, described compositions contains the nano-particle of embodiment 46, and is shown in table 29.

[table 29]

Component	Content (weight %)
		Liquid paraffin	5.0
The cetyl stearyl alcohol	5.5
		Vaseline	5.5
Glyceryl monostearate	3.0
		Polyoxyethylene (being added with 20 moles)-2-octyl-decyl ether	3.0
Tocopherol acetas	0.05
		Propyl p-hydroxybenzoate	0.3
Macrogol 4000	5.0
		Glycerol	7.0
Spice	In right amount
		Distilled water	To 100
Embodiment 46	1

[preparation 46] analeptic

The O/W emulsion composition, described compositions contains the nano-particle of embodiment 46, and is shown in table 30.

[table 30]

Component	Content (weight %)
		Ethanol	55.0
Oleum Ricini	5.0
		Glycerol	3.0
Burnt octanone amine (Pyroctoneamine)	0.1
		Spice, pigment	In right amount
Distilled water	To 100
		Embodiment 46	0.5

[preparation 47～52] cream

The O/W emulsion composition, it comprises the nano-particle of embodiment 48,51～53,55,57, and is shown in table 31.

[table 31]

Component	Preparation 47	Preparation 48	Preparation 49	Preparation 50	Preparation 51	Preparation 52
							Liquid paraffin	5.0	5.0	5.0	5.0	5.0	5.0
The cetyl stearyl alcohol	5.5	5.5	5.5	5.5	5.5	5.5
							Vaseline	5.5	5.5	5.5	5.5	5.5	5.5
Glyceryl monostearate	3.0	3.0	3.0	3.0	3.0	3.0
							Polyethylene glycol oxide (being added with 20 mol)-2-octyl group lauryl ether	3.0	3.0	3.0	3.0	3.0	3.0
Tocopherol acetas	0.05	0.05	0.05	0.05	0.05	0.05
							Propyl p-hydroxybenzoate	0.3	0.3	0.3	0.3	0.3	0.3
Macrogol 4000	5.0	5.0	5.0	5.0	5.0	5.0
							Glycerol	7.0	7.0	7.0	7.0	7.0	7.0
Spice	In right amount	In right amount	In right amount	In right amount	In right amount	In right amount
							Distilled water	To 100	To 100	To 100	To 100	To 100	To 100
Embodiment 48	5	-	-	-	-	-
							Embodiment 51	-	5	-	-	-	-
Embodiment 52	-	-	5	-	-	-
							Embodiment 53	-	-	-	5	-	-
Embodiment 55					5
							Embodiment 57						5

[preparation 53-58] analeptic

O/W emulsion composition, described compositions contain embodiment 1,4-6,8,10 nano-particle, and be shown in table 32.

[table 32]

Component	Preparation 53	Preparation 54	Preparation 55	Preparation 56	Preparation 57	Preparation 58
							Ethanol	55.0	55.0	55.0	55.0	55.0	55.0
Oleum Ricini	5.0	5.0	5.0	5.0	5.0	5.0
							Glycerol	3.0	3.0	3.0	3.0	3.0	3.0
Burnt octanone amine	0.1	0.1	0.1	0.1	0.1	0.1
							Spice, pigment	In right amount	In right amount	In right amount	In right amount	In right amount	In right amount
Distilled water	To 100	To 100	To 100	To 100	To 100	To 100
							Embodiment 1	2
Embodiment 4		2
							Embodiment 5			2
Embodiment 6				2
							Embodiment 8					2
Embodiment 10						2

Claims (16)

1, a kind of self aggregation polymer nano granules, this nano-particle contains amphipathic polymer and physiologically active ingredient, wherein, amphipathic polymer contain polycaprolactone as hydrophobic block and Polyethylene Glycol as hydrophilic block, and amphipathic polymer embedding physiologically active ingredient.

2, according to the self aggregation polymer nano granules of claim 1, wherein, the size of nano-particle is the 1-1000 nanometer.

3, according to the self aggregation polymer nano granules of claim 1, wherein, be benchmark with the gross weight of nano-particle, the content of physiologically active ingredient is 0.1-50 weight %.

4, according to the self aggregation polymer nano granules of claim 1, wherein, amphipathic polymer is the copolymer of polycaprolactone and Polyethylene Glycol, and the weight ratio of polycaprolactone and Polyethylene Glycol is 1: 9-9: 1.

5, according to the self aggregation polymer nano granules of claim 1, wherein, the molecular weight of polycaprolactone is 500 to 100000 dalton.

6, according to the self aggregation polymer nano granules of claim 1, wherein, the molecular weight of Polyethylene Glycol is 500 to 100000 dalton.

7, self aggregation polymer nano granules according to claim 1, wherein, physiologically active ingredient is selected from by rheum rhabarbarum, genistein, Tangeretin, hesperidin, catechin, isoflavone, danazol, haloperidol, furosemide, sorbide nitrate, chloromycetin, sulfamoxole, caffeine, cimetidine, diclofenac sodium, coenzyme Q10, vitamin E and its derivant, vitamin A and its derivant, provitamin D3 and its derivant, ursolic acid, oleanolic acid, rosmarinic acid, 18 β-enoxolone, glabridin, aleuritic acid, polyphenol, Esculin, (-) epigallocatechin gallate (EGCG), turmeric acid, the ginsenoside, tetrahydrocurcumin, Herba Centellae, beta-carotene, asiaticoside, farnesol, cupreol, linoleic acid, acid and gamma-linolenic, resveratrol, Fructus Vitis viniferae phenol, Semen Ginkgo, triclosan, minoxidil, natural oil, ceramide, sphingol, the thuja leaf extract, Radix Polygoni Multiflori extract, Radix Glycyrrhizae extract, Semen Coicis extract and Fei Nasi carry in the group of being formed.

8, according to the self aggregation polymer nano granules of claim 1, wherein, physiologically active ingredient is water insoluble.

9, self aggregation polymer nano granules according to Claim 8, wherein, physiologically active ingredient is selected from by ginsenoside, coenzyme Q10 and natural on-off cycles of hair growth component or hair and grows in the group that component forms.

10, self aggregation polymer nano granules according to claim 9, wherein, physiologically active ingredient is selected from by Fei Nasi and carries, minoxidil, the thuja leaf extract, Radix Polygoni Multiflori extract, Radix Glycyrrhizae extract, the Semen Coicis extract, isoflavone, genistein, Tangeretin, hesperidin, catechin, vitamin E and its derivant, vitamin A and its derivant, provitamin D3 and its derivant, ursolic acid, oleanolic acid, rosmarinic acid, 18-β-enoxolone, farnesol, β-sitoesterol, linoleic acid, gamma-Linolenic acid, resveratrol, ceramide, in the group that sphingol and ginsenoside are formed.

11, a kind of composition for external application, said composition contain each described nano-particle of claim 1-10.

12, according to the composition for external application of claim 11, described compositions is following preparation: hair care agent, hair care water, dandruff therapeutic agent, send out frost, hair jelly, hair spray, shampoo, Rinsing, demineralized water, skin soft agent, nutritive water, nourishing cream, massage cream, the element of refining, eye cream, eye refine element, cleansing cream, cleaning foam, clean water, facial film, powder, cosmetic base material, foundation cream, profit precursor emulsion, profit body frost, profit body oil, moisten body refine element, hair dye, lotion, ointment, gel, cream, paster or spray.

13, a kind of preparation method of self aggregation polymer nano granules, this method comprises the steps:

By making as the polycaprolactone of hydrophobic block with as the Polyethylene Glycol copolymerization of hydrophilic block, preparation amphipathic polymer;

Above-mentioned amphipathic polymer and physiologically active components dissolved are also stirred the preparation solution mixture in organic solvent;

In the solution mixture of above-mentioned preparation, add aqueous solution and carry out emulsifying; And

Remove organic solvent, obtain the granule of nano-scale.

14, according to the method for claim 13, wherein, amphipathic polymer is the copolymer of polycaprolactone and Polyethylene Glycol, and the weight ratio of polycaprolactone and Polyethylene Glycol is 1: 9-9: 1.

15, according to the method for claim 13, wherein, the physiologically active component is water insoluble.

16, according to the method for claim 13, wherein, the physiologically active component is selected from by ginsenoside, coenzyme Q10 and natural on-off cycles of hair growth component or hair and grows in the group that component forms.

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