CN1160582A - External-use composite containing cell growth factor - Google Patents
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- CN1160582A CN1160582A CN 96114282 CN96114282A CN1160582A CN 1160582 A CN1160582 A CN 1160582A CN 96114282 CN96114282 CN 96114282 CN 96114282 A CN96114282 A CN 96114282A CN 1160582 A CN1160582 A CN 1160582A
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Abstract
The present invention provides external use composite containing cell growth factor, esp one containing fibroblast growth factor-2 and/or epidermal growth factor, and the composite features that it contains efficient protector and stabilizer for the protein of the said cell growth factor and that it may be in form of hydrogel, aqueous solution, emulsion or liposomes. The active component in the said composite may maintain maximal biological activity and infiltrate into skin to produce its biological effect. On the other hand, the said composite has also excellent skin feeling and remaining property as well as excellent moisture bearing property, permeability and absorption.
Description
The present invention relates to composition for external application, particularly relate to the composition for external application and the production method thereof of the different dosage form that contains cell growth factor.Composition for external application of the present invention has to normal or be subjected to ultraviolet light, and the skin histology of inflammation and/or wound infringement stably discharges the competent cell growth factor peptides, prevents the function of atrophoderma, shriveling with treatment scytitis and/or wound and performance.
As far back as period in time immemorial, the mankind just know and utilize natural plant sap, pigment and various colored mineral powder to make cosmetics.These cosmetics mainly are purpose with the beauty treatment, and some composition may be to the toxic effect of skin.After chemical industry rises and is constantly progressive, the cosmetics emulsifiable, that beauty treatment and skin care effect are arranged have progressively been invented based on hydro carbons, esters, alcohols chemical substance.Since mid-term in this century,, concern and pursuit have also been increased to beauty treatment and skin care along with the continuous improvement of rapid development of economy and people's material life.In recent decades, in some countries of comprising China, Japan and Korea S the many water of Chinese herbal medicine (comprising plant, animal and mineral origin) or cosmetics of alcohol extract of being added with have appearred particularly, these Chinese herbal medicine comprise but are not only limited to Radix Ginseng, Fructus Gleditsia, Radix Angelicae Sinensis, the Radix Angelicae Dahuricae, pollen, Semen Ginkgo, Aloe, Margarita powder etc. (for example referring to Chinese patent application 87150120,87105347,89100708,92109672,93104735,93102038, and the clear 60-23325 of Japanese Patent Application Laid-Open).After the seventies middle and late stage table of discovery skin growth factor (EGF) and fibroblast growth factor cell growth factor such as (FGF); also existing people attempts to add one or more independent cell growth stimulation peptides in conventional cosmetics, and expectation prepares so-called functional cosmetics and external skin protective agent with it as active component.
Polypeptide growth factor is the hormonelike regulator of cell proliferation and differentiation.From various tissues and cell, separated and identified many somatomedin, comprising epidermal growth factor, platelet-derived somatomedin, nerve growth factor, hematopoietic cell growth factor and fibroblast growth factor.
Fibroblast growth factor (FGF) is as BALB/c 3T3 fibroblast being had the factor of growth-promoting activity, isolating from the cattle pituitary tissue (D.Gospodarowicz, Nature 249:123,1974) at first.This molecule is to acid and responsive to temperature, and has high (alkalescence) isoelectric point, IP.Found from brain isolating mitogenic factor afterwards with isolating different from hypophysis cerebri before this, thereby have similar biologic activity based on them and be called acid and basic FGF (being aFGF and bFGF) with different isoelectric point, IPs.AFGF and bFGF are the members of relevant at least 8 kinds of structures, as to have heparin affinity molecule family, they can optionally excite the biologically of the many cell types that comprise mesoblastema and neuroderm cell, and these cells comprise endotheliocyte, smooth muscle cell, adrenal cortical cell, sarcoplast and osteoblast.Cattle bFGF has 154 amino acid whose polypeptide.People bFGF is different from cattle bFGF and is that its 121st amino acids is threonine (Thr) rather than serine (Ser), and the 137th amino acids is serine (Ser) rather than proline (Pro).This description hereinafter is referred to as FGF-2 with the human alkaline fibroblast growth factor analog of the disclosed FGF-2m of being called in cattle and human alkaline fibroblast growth factor and our patent application of awaiting the reply jointly (application number 96114279.0).
Except stimulating cellular growth, FGF also can stimulate the cell of many types in non-mitosis mode different reactions to take place, for example promote cell to injury migration (chemotactic factor activity), new angiogenesis, adjusting nerve degeneration and viability (neurotrophic activity), endocrine regulation function and stimulation or the (Baird such as inhibition specific cell protein expression, extracellular matrix generation and cell survival of promotion, A.and Bohler, P., Handbook of Exp.Pharmacol., 95 (1): 369-418,1990).The FGF preparation is used for that accelerating wound healing, nervous tissue are repaired to these character in order to use, the medicine of prevention and treatment brain and myocardial ischaemia (collateral blood vessels generation) is laid a good foundation.Moreover, only with regard to effect, be the mesoderm that subcutaneous tissue all derives from the embryo because the second layer of skin histology is dermal tissue and the 3rd layer, so skin histology is the main target site of FGF just to skin histology.Existing many research work confirm, FGF can promote the differentiation and the propagation of corium and subcutaneous tissue inner cell, the acceleration cell upgrades, more collagen fiber of justacrine and elastic fiber and substrate (Sprugel K.H., et al., Effect of growthfactor in vivo.l.cell ingrowth into porous supcutaneouschambers.Am.J.Pathol.129:601-613,1987), thus play the effect of delaying decrepitude of skin.Particularly, FGF can by " dose-effect effect " in other words " cascade amplification " promote the differentiation and the propagation of cell, it acts on than hormone more trickle (the Schweigere L.et al. of the influence of airframe systems, Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their owngrowth, Nature 325:257-259,1987).FGF is different from other hormonelike peptide class somatomedin and is that it mainly acts on the deep tissues and the cell of skin, and the aging basic reason of skin aging, shrinkage just of skin corium and subcutaneous tissue.
The growth factor polypeptide that epidermal growth factor (EGF is also referred to as urogastrone) is made up of 53 or 52 aminoacid.Found that EGF has short mitotic activity to the polytype cell that comprises epidermis and Interstitial cell and fibroblast, thereby can be used for accelerating wound healing and treat digestive tract ulcer (Knauer, D.J.et al., Relationship betweenepidermal growth factor receptor occupaney and mitogenic response, J.Biol.Chem.259 (9): 5623-5631,1984; Okeef, E.et al., Invest.Dermatol., 78:482-485,1982 and United States Patent (USP) 4,820,690).Topical application with regard to this somatomedin, disclose and used the EGF (β-urogastrone) that from urine, extracts to mix mutually with conventional cosmetic base, made the composition for external application or the cosmetics (seeing clear 61-15810 of Japanese patent application and Chinese patent application CN1063410A) of the multiple dosage form that comprises astringent, ointment, emulsion and lipstick as active component.
As everyone knows, the polypeptide growth factor that comprises epidermal growth factor (EGF) and fibroblast growth factor (FGF), platelet-derived somatomedin (PDGF) has all showed unstability, promptly be easy to inactivation at normal temperatures with in the water-bearing media, meet difficulty thereby cause in actual applications.The inventor finds utilizing the human fibroblastic growth factor (hFGF-2) produced with the DNA recombinant technique or its analog to prepare in the research process of local topical preparation that remedy for external use and preparation FGF-2 are the primary activity composition or cosmetic composition; in conventional carrier and excipient, add one or more sulfated polysaccharide class materials and be selected from Polyethylene Glycol; the material of polyacrylic acid and hydroxypropyl cellulose etc. is as stabilizing agent or activity protecting agent; can improve the stability of FGF-2 greatly; make the half life significant prolongation of this reactive protein in water-bearing media or gel, and have preferably anti-low pH ability and temperature tolerance preferably.
Therefore, an object of the present invention is to provide the composition for external application that contains the cell growth factor polypeptide, said composition contains at least a cell growth factor as active component, the stabilizing agent of at least a said active polypeptide, and acceptable substrate or excipient on the external preparation for skin.
According to one embodiment of the invention, wherein said cell growth factor is selected from fibroblast growth factor, epidermal growth factor, insulin like growth factor, platelet-derived somatomedin, and nerve growth factor and brain derived nerve growth factor.According to a preferred embodiment of the invention, wherein said cell growth factor is fibroblast growth factor and/or epidermal growth factor or their analog, and said cell growth factor can be extract from natural origin or produce with the DNA recombinant technique.
According to a preferred embodiment of the invention, wherein said substrate is the aqueous gel substrate that contains water solublity wetting agent, hydrophilic gel and pH regulator agent.According to this embodiment of the present invention, wherein said water solublity wetting agent component is selected from propylene glycol, 1,3-butanediol, glycerol, glycerol glycol, hyaluronic acid and sodium salt thereof or its cross-linked ester or by it isolating macromole hyaluronic acid element, or chitosan; Said hydrophilic gel is selected from carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, gelatin, xanthan gum, silicon cave natural gum, guar gum and alginic acid and sodium salt thereof.
According to one embodiment of the invention, wherein said reactive protein stabilizing agent is optional from sulfated polysaccharide for example carageen polysaccharide, heparin, heparin sulfate, dextran sulfate, sulphuric acid mannan, polyphosphoric acid pentosan, sulphuric acid ring mush, CSSO3, methylol aminopolysaccharide, hydroxy methocel, sucrose octasulfate and polyglycine, Polyethylene Glycol and polypropylene glycol.
According to this embodiment of the present invention, the wherein said content that is added in the cell growth factor in the water-setting gelatinous matrix is 0.1-1000ppm (weight), is preferably 1-100ppm; The content of water solublity wetting agent is 0.5-30% (weight): be preferably about 5-20% (weight); The content of hydrophilic gel is about 0.05-20% (weight), is preferably about 0.1-5% (weight); And the active polypeptide stabiliser content in the water-setting gum base is about 0.1-1000ppm, better is about 1-100ppm.
According to another embodiment of the invention, wherein said substrate is the Emulsion of being made by water, water solublity wetting agent, lipid and emulsifying agent.Wherein said emulsifying agent can be the lipophilic emulsifier of the Isosorbide Dinitrate of, two or the triglyceride that are selected from the saturated or unsaturated fatty acid of long-chain, saturated or unsaturated fatty acid; Be selected from phosphatidyl glycerol diacyl ester, the phospholipid of phosphatidylcholine diacyl ester, lecithin, phosphatidylcholine two myristoyl esters, phosphatidyl glycerol two myristoyl esters and be selected from the monostearate of polyethenoxy sorbitan, the amphoteric ion type emulsifying agent of monoleate.
According to the present invention, can add the free radical scavenger that one or more are selected from a-tocopherol, ascorbic acid, glutathion or derivatives thereof in the said aqueous gel type composition for external application that contains cell growth factor; One or more are selected from the vitamin of vitamin A, ascorbic acid, vitamin B, biotin, pantothenic acid, vitamin D, vitamin E; One or more are selected from methyl hydroxybenzoate, ethyl ester, propyl ester and butyl ester, and the waterborne-type preservation of phenoxypropanol.Can also contain the anti-wrinkle of skin that is selected from N-acetyl-L-cysteine and derivant thereof in addition forms agent and is selected from salicylic acid and the keratolytic of derivant, and the lubricant that is selected from polymethyl acid glyceride and derivant thereof, and the skin penetrant that is selected from lauric soap and dimethyl sulfoxine.
According to one embodiment of the invention, wherein can in said aqueous gel, add appropriate amount oleaginous base and emulsifying agent, make Emulsion according to a conventional method.
According to another embodiment of the present invention, wherein can utilize the combination of above-mentioned suitable composition or composition, make high sticking high gel or ointment according to a conventional method.
According to another embodiment of the present invention, wherein can utilize the combination of above-mentioned suitable composition or composition, make according to a conventional method cell growth factor is enclosed in liposome composition in the liposome.
According to another embodiment of the present invention, wherein can utilize the combination of above-mentioned proper composition or composition, make pre-adding according to a conventional method or use before the interim cell growth factor polypeptide that adds, contain the skin care liquid of one or more skin protectant in addition.
According to this embodiment of the present invention, wherein said skin protectant comprises but is not only limited to glycerol, hyaluronic acid, vitamin E, lecithin, amino acid complex, natural plants or animal extracts and native protein or polysaccharide hydrolysis thing.
The present invention further provides the method for preparing the aqueous gel type skin care compositions that contains cell growth factor, this method comprises the freeze-dried product for preparing the cell growth factor of extracting from natural origin or produce with the DNA recombinant technique respectively, with by the water solublity wetting agent, hydrophilic gel, the aqueous gel substrate that acceptable auxiliary element is formed on reactive protein stabilizing agent and other external preparation for skin, and under proper temperature that does not contain the biologic activity of destroying growth factor activity protein and pH condition, add said cell growth factor and fully mixing it.
According to a preferred embodiment of the invention, wherein the freeze-dried preparation of said cell growth factor is joined in the said aqueous gel substrate before use temporarily.
The present invention relates to comprise the aqueous gel type composition for external application of cell growth factor, said composition is by being selected from fibroblast growth factor, epidermal growth factor, insulin like growth factor, platelet-derived somatomedin, nerve growth factor, one or more active polypeptide of brain derived nerve growth factor and aqueous gel substrate are formed, wherein said cell growth factor can be when producing said composition for external application, joins in the said aqueous gel substrate under temperature that is unlikely to biologically active polypeptides is damaged or makes it inactivation and pH condition and uniform mixing with it; Perhaps also can prepare and pack the aqueous gel substrate of skin care compositions of the present invention and the freeze-dried preparation of cell growth factor respectively, join the freeze-dried powder of cytokine in the aqueous gel substrate according to the ratio of regulation before using temporarily and fully mixing it.
According to aqueous gel composition for external application of the present invention, wherein cell growth factor better is fibroblast growth factor and/or epidermal growth factor, and fibroblast growth factor-2 (FGF-2) preferably.Said FGF-2 can prepare by natural origin or with the DNA recombinant technique.
According to composition for external application of the present invention, wherein the water solublity wetting agent as one of hydrogel matrix composition can be the glycerol or derivatives thereof, for example propoxylated glycerol and ethoxylated glycerol, perhaps can be propylene glycol, ethylene glycol, polyvinylpyrrolidone, hyaluronic acid or its high molecular weight component, for example the hyaluronan of molecular weight more than 30kD (Hyalectin, HAC).Hyaluronic acid is as skin moisturizing regulator commonly used in the Cosmetic Manufacture, owing to be the one group of mixture that the heterogeneity molecular weight is arranged that extracts from natural origin, wherein molecular weight has the stronger anaphylaxis that causes less than the component of 30kD to skin, so the wetting agent that preferred use is made up of glycerol and hyaluronan in aqueous gel compositions of the present invention.Experiment shows, this wetting agent has fabulous hygroscopicity and releases moist, but the i.e. moisture content in its absorbing environmental under the environment of higher temperature, and discharge moisture content at the next skin that can promote of the environment of big humidity, thereby make local skin keep suitable humidity, promptly can promote the comfort of skin, help the abundant reservation of EGF in the present composition and FGF again and bring into play its biologic activity.Can be according to United States Patent (USP) 5,166, the method described in 331 is by hyaluronic acid preparation and purification hyaluronan.
According to the aqueous gel type skin care compositions that contains cell growth factor of the present invention, wherein the content of water solublity wetting agent account for composition total weight at about 0.1%-40%.Be preferably 1%-30%, preferably account for 5%-20%.
The aqueous gels that is used for the present composition can be cellulose ether, polyvinylpyrrolidone, polyvinyl alcohol, collagen hydrolysate, silicone natural gum, gelatin or xanthan gum of being selected from hydroxy methocel, hydroxyethyl-cellulose, methylcellulose and hydroxypropyl cellulose and composition thereof.Other aqueous gels that are suitable for are chain alkyl acrylate, for example better are the octadecyl acrylic acid methyl ester .s.Yet from helping protecting the angle of the biologically active polypeptides that will add the present composition, better being to use with the hydroxypropyl cellulose is the cellulose ether of representative and the mixture of collagen hydrolysate.The content of aqueous gels generally accounts for the 0.01%-10% of composition weight in the present composition, is preferably 0.1-3%, is preferably 0.5%-1%.
Under the situation for preparing the composition for external application that is added with cell growth factor in advance, the viscosity of aqueous gels better is about 400 to 4000Cps in the present composition.On the contrary, under the situation of the composition for external application of interim interpolation cell growth factor dried frozen aquatic products, aqueous gels viscosity better is about 200-1000Cps in the present composition before preparation is used.
As previously mentioned, because polypeptide cytokineses such as EGF and FGF are all relative unstable in room temperature and aqueous solution, be subjected to various Effect of Environmental and the degeneration inactivation than being easier to, therefore when preparation the present invention contains the composition for external application of cell growth factor, a primary aspect is to keep the stability of these biologic activity peptides in water-bearing media as much as possible, prolongs its activity and holds time.For this purpose, we use this laboratory with DNA recombinant technique preparation have the active polypeptide of human fibroblastic growth factor and its analog primary activity material as composition for external application of the present invention, and utilize the various protein stabilizing agent that is added in the aqueous gel substrate to carry out lot of experiments.Found that, particularly with the people of this prepared in laboratory recombinate FGF or its analog (rhFGF-Arg
78, Arg
96. be FGF-2m) under the situation as active component, in gel-type vehicle of the present invention (glycerol adds the 0.9%NaCl solution of CMC), add be selected from Polyethylene Glycol, hydroxypropyl cellulose, sulfated polysaccharide and glutathion one or more materials as stabilizing agent, can make in this skin care compositions rhFGF-2 or rhFGF-2m improve nearly 10% (seeing EXPERIMENTAL EXAMPLE) in 6 months stability of room temperature preservation.The wherein said sulfated polysaccharide class material that is suitable for use as stabilizing agent comprises salt, polyglycine and the trimethyl glycine of PEG400, carageen polysaccharide, heparin, heparin sulfate, dextran sulfate, many sulphuric acid pentosan, sulphuric acid mannan, sulphuric acid cyclodextrin, methylol chitin, sucrose octasulfate.
Can prepare above-mentioned aqueous gel skin care compositions according to conventional method well known to those skilled in the art.
Though one object of the present invention mainly relates to contain FGF and/or EGF and the aqueous gel compositions of other cell growth factor that may add, the present invention has more than the compositions that is limited to the aqueous gel dosage form.It will be appreciated by those skilled in the art that: at conventional lipid skin moistening material low gel content, that add appropriate amount in the low viscous water-bearing media, for example glyceride, plant or mineral oil, alkenyl ester, ethoxylation lipidol and add suitable emulsifying agent or have the phospholipid of emulsification function or polymer-modified, for example non-ionic polyacrylamide can be made Emulsion or liposome composition with compositions of the present invention.
Emulsion, particularly oil-in-water emulsion are the systems that the most generally uses that so far functional skin care formulation is used for skin.Therefore, can use conventional method that compositions of the present invention is made Emulsion.In order to help being included in the dispersion and the absorption of Emulsion aqueous phase active polypeptide, better use mineral oil, for example silicone oil uses the isotonic sodium chlorrde solution that is dissolved with Polyethylene Glycol and emulsion and polypropylene cellulose as water as oil phase, and uses (C
10-22) alkyl acrylate, for example lauryl acrylate or stearyl acrylate acid esters are as primary emulsion and surfactant.In addition, can also use suitable alkali nertralizer or citrate buffer that the pH value of gained Emulsion is maintained in the scope of about neutrality or meta-alkalescence.
Can before the preparation emulsion, in above-mentioned host material, add FGF-2 and or the EGF polypeptide, and active polypeptide protective agent or stabilizing agent add the pH regulator agent in case of necessity.Perhaps also can be after making Emulsion, adding active polypeptide and stabilizing agent or protective agent before using, and with above-mentioned substrate mixing after be coated on skin surface.
The emulsifying agent that is suitable for can be the lipophilic emulsifier of the Isosorbide Dinitrate of, two or the triglyceride that are selected from the saturated or unsaturated fatty acid of long-chain, saturated or unsaturated fatty acid; Be selected from the phospholipid of phosphatidyl glycerol diacyl ester, phosphatidylcholine diacyl ester, lecithin, phosphatidylcholine two myristinates, phosphatidyl glycerol two myristinates; And be selected from the monostearate of polyethenoxy sorbitan, the amphoteric ion type emulsifying agent of monoleate.
According to another embodiment of the invention, can also be by thin layer hydration known in the art, anti-phase evaporation (for example referring to Szoka, F.et al., Proc.Natl.Acad.Sci, USA, 75:4194-4197,1978), and solvent injection method, compositions of the present invention is made the high-viscosity gel or the paste composition for external application of FGF-2/ or EGF/ liposome.In FGF-2/ liposome of the present invention, the content of neutral phospholipid and electronegative phospholipid accounts for the 20-50% of gross weight respectively.Employed neutral phospholipid can be selected from the phospholipid of or chemosynthesis isolating from natural origin with known method, for example can be by the phosphatidyl glycerol ester or the phosphatidyl inositide that extract in the yolk.In addition, in lipid components, can add cholesterol, so as to the stability of raising liposome bilayer, thus FGF that substantially extension body is outer (or in body) discharges and/or the half life of EGF.Moreover, in this liposome composition, can also contain other and be used to improve liposome stability and stability and the favourable composition of release characteristic, for example alpha-tocopherol of alpha-tocopherol or polyethoxylated of active polypeptide.
In order to prepare FGF-2/ lipidosome gel compositions of the present invention, vesicle can be generated fat and be dissolved in the suitable organic solvent, and dry to form thin lipid film under vacuum.Under strong agitation, make this film water and about 30 minutes then, to obtain vesicle.This vesicle is scattered in the aforementioned gel-type vehicle, so that the FGF-2 liposome accounts for the 5-20% of composition total weight.The hydration that above-mentioned vesicle forms fat contains more fortunately in the low electric conductivity water-bearing media of zwitterionic compound and carries out.The liposome aqueous gel compositions that so obtains is gelatinous, and has low relatively lipid concentration.
In addition, also can at first the ampholyte chemical compound that is not in isoelectric point, IP be joined in the lipid film to form liposome, the pH with water-bearing media is transferred to the isoelectric point, IP of this medium to reach required gel state then.FGF-2 can be dissolved in suitable concentration in the preparation and be used for forming in the water-bearing media of liposome composition.The suspension of making by this way comprises microencapsulated encapsulate, liposome absorption and free F GF-2 or FGF-2m.As mentioned above, can after liposome is made, FGF-2 be added in the established liposome, to produce the FGF-2/ liposome composition that has only adsorbed FGF-2.
The fluidic FGF-2 of the containing liposome composition that makes as stated above can be mixed to make the paste composition of higher liposome concentration with the neutral fat plastid of sky, perhaps there is the aqueous gel compositions of viscosity higher to mix with aforementioned the said FGF-2 of containing liposome composition, to obtain the paste composition of low lipid concentration.The FGF-2/ liposome composition of so making has the high viscosity of about 1000-10000Cps.
The invention provides and contain cell growth factor; the composition for external application of fibroblast growth factor-2 and/or epidermal growth factor particularly; be characterised in that said composition contains on the cosmetics and the pharmaceutically FGF-2 of effective dose and/or protein protectant or the stabilizing agent of EGF, and said composition can be aqueous gel or Emulsion or liposome composition form.According to compositions of the present invention, wherein bigger biologic activity can be kept and keep to active component on the one hand, and infiltrate skin and bring into play its inherent biological action; Said composition also has advantages of good skin sensation and persistence characteristic on the other hand, and good wettability, permeability and absorbability.
Using FGF-2; particularly use the FGF-2 analog (FGF-2m) (referring to the patent application № .96114279.0 that awaits the reply jointly) of this Laboratory Production to do under the situation of active component of composition for external application of the present invention; because we utilize side-directed mutagenesis that the 78th and 96 cysteine that is exposed to molecular surface in the FGF-2 aminoacid sequence three-D space structure changed over arginine rather than the serine that has amino group; thereby more help said amino group and can add in the compositions as the formation of the oh group in protectant peg molecule covalent bond; so as to preventing the FGF-2 molecule aggregation, thereby improved the stability of reactive protein greatly.In addition, because composition for external application of the present invention mainly is not contain lipid or only contain the aqueous gel form of seldom measuring lipid, so no matter wherein contain or do not contain cutaneous permeable agent, all can make said reactive protein be able to absorption maximum, and have the characteristic that postpones release at agents area in the part.
Also answer lay special stress on to be pointed out that at last, though in order to keep the biologic activity of cell growth factor to greatest extent, skin protection substrate of the present invention and cell growth factor polypeptide can be separated to pack also to mix also by user before use temporarily and use it in the time limit at the appointed time, but also can in the substrate of the present composition, directly sneak into these peptide materials in process of production fully, its biologic activity obviously be reduced and be unlikely.
Below by implementing the present invention is described for example further, but these embodiment limit the scope of the invention by any way.
EXPERIMENTAL EXAMPLE
In the present embodiment, use the l cell of cultivating as target cell, with
3The H-thymidine (
3H-TdR) method of mixing detect in composition for external application of the present invention, add heparin sulfate or dextran sulfate and Polyethylene Glycol to substrate in the influence of biologic activity of contained hbFGF-2m.
1. the preparation of sample and storage: the aqueous gel substrate that is used for this experiment according to prescription described in the embodiment 1 and compound method preparation.The amount of these substrate with every pipe 4ml is added on respectively in 4 groups of 12 sterile test tube (20ml volume).The 1st group of gel adds 10mM (1ml) PBS as negative control; The 2nd group of dextran sulfate solution that adds 0.1ug/ml; The 3rd group of Polyethylene Glycol (each 0.5ml) that adds 1ug/ml heparin sulfate and 0.2ug/ml; The 4th group adds the gel-type vehicle that the 1ug/ml hydroxypropyl cellulose that is dissolved in 10mM PBS (1ml) obtains viscosity higher.In above-mentioned 2,3,4 groups of samples, add hFGF-2m with the heavy dose of of 1ug/ml respectively then.Use be added with same amount hFGF-2m but do not add stabilizing agent gel-type vehicle (with the 1st group than the low viscosity gel-type vehicle) as positive control, and be decided to be the 5th group.After preparation is finished above-mentioned all samples being contained in aseptic vial with cover, to be built in room temperature (20-25 ℃) under placement 6 months standby.
2. preparation of target cell and detection: briefly, at first with about 10
6Individual BALB/c3T3 cell (being provided by institute of Materia Medica,Chinese Academy of Medical Sciences) is inoculated in 3ml and contains in the DMEM culture medium of 10% hyclone.In 37 ℃ at 5%CO
2Cultivate in the incubator after 24 hours,, make the final concentration of serum become 1% with fresh DMEM culture medium dilution culture.Continue to cultivate after 2 days, in culture, add and as above prepare and store 6 months test specimen and control sample (2ml/10
5Individual cell).And add
3H-TdR (final concentration is 2uCi/ml).37 ℃ are continued insulation after 24 hours, wash cell 3 times with cold saline.Centrifugal back adds 10% trichloroacetic acid with precipitating proteins in the cell precipitation thing.Wash 2 times with normal saline once more, and the adding alcohol-ether is washed once.Be added on mensuration radiation counting in the 4ml scintillation vial with getting 0.1ml behind the formic acid digestion precipitate.
Calculate FGF-2m to the synthetic stimulation index of 3T3 cell DNA and obtain result as shown in table 1 by following formula.The mean+SD of data represented three mensuration shown in the table.
The stable group of table 1 FGF in aqueous gel compositions handled cell
3H-TdR incorporation (CPM) stimulation index p value 1 negative control (no FGF) 16,065 1.00-2 gels+heparin+FGF 24,576 1.52＜0.053 gel+heparin+25,387 1.58＜0.05
Polyethylene Glycol+FGF4 high-viscosity gel+FGF 23,875 1.48＜0.055 gels+FGF 23,064 1.43＜0.05
(positive control)
From the result shown in the last table as can be seen, have the polypeptide (FGF-2m) of fibroblastic growth stimulating activity in the skin care compositions of the present invention, in aqueous gel substrate, after storing 6 months under the room temperature, still remain with higher biologic activity.In addition, in compositions of the present invention, add the material that PEG400, emulsion and polypropylene cellulose and sulfated polysaccharide etc. have FGF-2 stabilisation function, can protect the biologic activity of this polypeptide effectively.In this experimental system, and do not add stabilizing agent or protectant sample is compared, add these stabilizing agents and can make protein active exceed about 11%.
Embodiment 1: contain aqueous gel and the preparation thereof of FGF-2m
Use conventional hybrid technology to mix following (A) aqueous gel substrate and (B) contain the aqueous solution of FGF-2 and stabilizing agent thereof:
Composition percentage by weight A. glycerol 20.0
PEG400 2.0
Hydroxypropyl cellulose 2.0
Methyl parahydroxybenzoate 0.2
Polymethyl glyceride 0.6B. reorganization FGF-2 10ppm
Dextran sulfate 0.05
Hyaluronan 0.05
Distilled water adds to 100.0
Above-mentioned raw materials A after 55 ℃ of dissolvings and fully mixing, is cooled to 40 ℃, adds the aqueous solution of raw material B and with the further mix homogeneously of agitator, the 0.1M NaOH solution that adds appropriate amount then is transferred to the pH of gained gel about 6.5.The aqueous gel that so makes has less viscosity, can keep the biologic activity of FGF-2m by stabilizing agent effectively.In addition, this gel has the advantages of good skin sensation when being applied to skin surface, and fabulous wettability and permeability are arranged.
Embodiment 2: the preparation of aqueous solution substrate and use
Use conventional hybrid technology to mix following component, be used as the aqueous solution substrate of skin lotion with preparation:
The composition percentage by weight
Glycerol 20.0
Dextran sulfate 0.02
Normal saline adds to 100.0
The so mixed aqueous solution that gets is preserved separately, extract cold-dry powder that (2ml) this aqueous solution in a small amount places the FGF-2 in another sterile chamber in order to dissolving not by user during use, treat to refill after the fully dissolving in the said aqueous solution fully mixing and dosage according to the rules and use as early as possible.Embodiment 3: the oil-in-water emulsion and the substrate preparation that contain FGF-2 use conventional mixing and emulsifying technology preparation to contain the emulsion composition of following ingredients:
Composition percentage by weight A. polyoxyethylene (20)
Arlacel-60 2.0
Hydrogenated lanolin 5.0
Squalene 10.0
Cera Flava 4.0
Glycerol 10.0
Silicone oil 0.5
Vitamin E 0.1
Propylene glycol 2.0
Polyethylene Glycol 0.5B. FGF-2 5ppm
Heparin sulfate 0.1
Hyaluronate sodium 0.05
Distilled water adds to 100.0
The oil phase substrate raw material A is heated to 75 ℃ of thawings, mixing and be cooled to 40 ℃ after add aqueous phase B solution, fully stir and be cooled to room temperature then.The emulsion that so makes has good stable, and with contact skin after rapid breakdown of emulsion and can impel the FGF-2 that is contained in aqueous phase to infiltrate skin as early as possible.This Emulsion also has good water retention property and scrubbing effect in addition.
Embodiment 4: contain oil-in-water emulsion and the preparation thereof of FGF-2
Use conventional mixing and emulsifying technology preparation to contain the emulsion composition of following ingredients:
Composition percentage by weight A. lecithin 4.0
Glycerol monostearate 3.0
Lanolin alcohol 3.0
Disodiumedetate 0.05
Glycerol 3.0
Carboxymethyl cellulose 0.2
Isopropyl myristate 5.0
Methyl parahydroxybenzoate 0.1
An amount of B. FGF-2 of citrate buffer 5ppm
CSSO3 0.1
Vitamin C 0.01
Distilled water adds to 100.0
Place 80 ℃ to melt down raw material A, stir companion's mixing and be cooled to 50 ℃.Further use ultrasonic emulsator emulsifying then, add the aqueous solution of raw material B simultaneously, obtain uniform cream sample preparation.Said preparation has viscosity higher, more helps keeping the biologic activity of FGF-2 in the presence of protective agents such as heparin.
Embodiment 5: contain the preparation of the liposome composition of FGF-2
With contain lecithality phosphatldylcholine/yolk phosphatidyl glycerol/cholesterol/alpha-tocopherol (1: 1: 0.5: dehydration lipid mixture 0.02 weight ratio), with the legal preparation liposome of conventional pellicular water.At first, the lipid material dissolution in chloroform/methanol (2: 1 weight ratios), and is poured into gained solution at the bottom of the garden in the flask.Form the thin layer lipid film behind the vacuum drying.On this film, pour the hydration buffer of 2.5% (weight/volume) glycine (a kind of zwitterionic compound) of 10 times of volume/weight into.Eddy current stirs down, and hydration obtains tremelloid liposome material after 1.5 hours.Can use the lipid and the aqueous solution of bactericidal device, filtration sterilization, this liposome vesicle material of preparation in sterilizing room is to reduce microbial contamination as much as possible.Use Brookfield DV-II viscometer, the average viscosity that records this liposome composition after adding 0.1%NaCL (weight) is 1.5 * 103Cps.
The concentration that wherein is used to form the interior contained FGF-2 of water-bearing media (above-mentioned buffer) of liposome composition can be decided according to application target and gel coating part, generally accounts for the 0.1-100ppm of total composition.Can when adding FGF-2, add protective agent or the stabilizing agent that is selected from Polyethylene Glycol, hydroxypropyl cellulose and sulfated polysaccharide in the lump.Can comprise that be wrapped, that be adsorbed and free F GF-2 in the formed liposome suspension.Also can form the back and add FGF-2 with suitable concentration at liposome.
The Liposomal formulation that so obtains can use separately, also can mix the back by proper proportion at the gel-type vehicle that makes with embodiment 1 and use.Said preparation can further keep the biologic activity of FGF-2 effectively, and can reach the purpose that delays to discharge active polypeptide in the part.
Claims (18)
1. the composition for external application that contains cell growth factor, said composition contain at least a cell growth factor polypeptide, the stabilizing agent of at least a said polypeptide, and acceptable substrate on the external preparation for skin.
2. according to the compositions of claim 1, wherein said cell growth factor polypeptide is selected from fibroblast growth factor, epithelical cell growth factor, insulin like growth factor, platelet-derived somatomedin and nerve growth factor and brain derived nerve growth factor polypeptide.
3. according to the compositions of claim 2, wherein said cell growth factor polypeptide is fibroblast growth factor-2 and epithelical cell growth factor.
4. according to any one compositions in the claim 1 to 3, wherein said cell growth factor polypeptide be extract from natural origin or produce with the DNA recombinant technique.
5. according to any one compositions in the claim 1 to 3, the stabilizing agent of wherein said cell growth factor polypeptide is selected from Polyethylene Glycol, POLYPROPYLENE GLYCOL, methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, heparin, heparin sulfate, CSSO3, dermatan sulfate, methylol aminopolysaccharide, many sulphuric acid pentose, sulphuric acid mannan, dextran sulfate, carageen polysaccharide, sulphuric acid cyclodextrin, methylol chitin, hyaluronan, hyaluronic acid, sucrose octasulfate, polyglycine, trimethyl glycine and glutathion and half amic acid.
6. according to the compositions of claim 1, wherein said substrate is aqueous gel substrate.
7. according to the compositions of claim 6, wherein said aqueous gel substrate contains water-soluble fluidity wetting agent, hydrophilic gel and pH regulator agent.
8. according to the compositions of claim 7, wherein said water solublity wetting agent is selected from glycerol, glycerol glycol, propylene glycol, 1,3 butylene glycol, hyaluronic acid and sodium salt thereof or its cross-linked ester or by it isolating macromole hyaluronan, or chitosan; And wherein said hydrophilic gel is selected from hydroxy methocel, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidine cave, gelatin, xanthan gum, silicone natural gum, guar gum and alginic acid and sodium salt thereof.
9. according to the compositions of claim 1, wherein said substrate is the aqueous solution that contains one or more emollient and polypeptide stabilizing agent.
10. according to the compositions of claim 1, wherein said substrate is oil-in-water type or water-in-oil emulsion.
11. according to the compositions of claim 1, wherein said substrate is liposome or its compositions.
12. according to any one compositions in claim 1 or 6 to 11, wherein said cell growth factor polypeptide is to add in the said substrate of preparation, or forms independent placement and interim adding the before using with its lyophilizing.
13. according to any one compositions in the claim 6 to 11, wherein said cell growth factor is fibroblast growth factor-2 and/or epidermal growth factor.
14. according to the compositions of claim 13, wherein said fibroblast growth factor and/or the content of epidermal growth factor in said compositions are about 1-100ppm.
15., also contain penetrating dose of one or more skins in the said substrate according to any one compositions in the claim 1 to 11.
16., also contain one or more vitamin in the said substrate according to any one compositions in the claim 1 to 11.
17., also have one or more antioxidants in the said substrate according to any one compositions in the claim 1 to 11.
18., also contain one or more free radical scavengers in the wherein said substrate according to any one compositions in the claim 1 to 11.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96114282 CN1160582A (en) | 1996-12-27 | 1996-12-27 | External-use composite containing cell growth factor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96114282 CN1160582A (en) | 1996-12-27 | 1996-12-27 | External-use composite containing cell growth factor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1160582A true CN1160582A (en) | 1997-10-01 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96114282 Pending CN1160582A (en) | 1996-12-27 | 1996-12-27 | External-use composite containing cell growth factor |
Country Status (1)
| Country | Link |
|---|---|
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-
1996
- 1996-12-27 CN CN 96114282 patent/CN1160582A/en active Pending
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