WO2005063212A1 - Supports de taille nanometrique a base de lipides a incorporation d'hemisuccinate de cholesteryle et composition de soins cutanes pour application externe en comportant - Google Patents

Supports de taille nanometrique a base de lipides a incorporation d'hemisuccinate de cholesteryle et composition de soins cutanes pour application externe en comportant Download PDF

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WO2005063212A1
WO2005063212A1 PCT/KR2004/003436 KR2004003436W WO2005063212A1 WO 2005063212 A1 WO2005063212 A1 WO 2005063212A1 KR 2004003436 W KR2004003436 W KR 2004003436W WO 2005063212 A1 WO2005063212 A1 WO 2005063212A1
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lipid
skin
scale carrier
based nano
nano
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PCT/KR2004/003436
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English (en)
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Ju Young Park
Hyun Jung Choi
Jong Won Shim
Jae Sung Hwang
Jun Oh Kim
Sang Hoon Han
Ih Seop Chang
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Amorepacific Corporation
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Publication of WO2005063212A1 publication Critical patent/WO2005063212A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • Cholesteryl hemisuccinate incorporated lipid-based nano-carriers and skin-care compositions for external application containing the same
  • the present invention relates to cholesteryl hemisuccinate-incorporated lipid-based nano-scale carriers and to skin-care compositions for external application containing the same. More particularly, the present invention relates to lipid-based nano-scale carriers (hereinafter, "nanocarriers”) that may be liposomes or nanoemulsions prepared by the addition of cholesteryl hemisuccinate or its salts and which have high pH-sensitivity and thereby can release effectively the biologically active substances loaded therein within a cell, so as to enhance the effect as a carrier. Therefore, the skin-care compositions of the present invention containing the nanocarriers can deliver maximally the efficacies of biologically active substances.
  • nanocarriers lipid-based nano-scale carriers
  • biocompatible polymer-incorporated lipid-based liposomes for increasing the circulation time of an active drug in a living body and thereby enhancing the bioavailability thereof; cell-recognition or cell-adhesion molecule-incorporated lipid-based liposomes for specifically delivering giant molecular drugs such as peptides, proteins or genes to a target cell; or liposomes designed to release the active substances loaded therein into a cell by losing the stability thereof in the specific surroundings of cellular organelles have been researched and proposed. In particular, systems designed to release the active substances loaded within liposome in response to the acidic surroundings of cellular organelles have been tried out in various ways.
  • DOPE dioleoylphosphatidylethanolamine
  • vesicles stabilized with pH-sensitive cosurfactants have been extensively studied in acidic solution with a pH range of 4.5 to 6.5 ⁇ F.C. Szoka et al., J. Liposome Res. (1994) 4, 361 ⁇ and were demonstrated to be delivered into cytoplasm of various cells.
  • the early-made liposome formulations had low stability in blood, so they have many limits in direct applications in a living body.
  • most of the liposomes have had unsolved problems in delivery efficiency for production and utilization of carrier materials, as a result of basic researches for gene transfer, and industrial application thereof has not been achieved.
  • the present liposomes or nanoemulsions prepared by the addition of cholesteryl hemisuccinate are pH-sensitive lipid-based nanocarriers to control the release of the active substances loaded therein, so that the nanocarriers of the present invention can deliver active substances, which have comparatively large molecular weight or special chemical structure or insolubility and thereby have a difficulty in transfer into a living body, to a target organ by loading in the inner phase of the nanocarriers, and then can release them by disrupting lipid membranes in response to the specific change of acidic surroundings, resulting in enhancing the effect as a carrier and thereby providing maximally the peculiar efficacies of biologically active substances.
  • the present invention is to provide lipid-based nanocarriers that can control the release of the biologically active substances loaded therein and thereby can enhance the delivery efficiency in a cell. Further, the present invention is to provide lipid-based nanocarriers that can stabilize phospholipid membrane structures and that have sensitivity responsive to acidity change. Therefore, an object of the present invention is to provide pH-sensitive lipid-based nano-scale carriers obtained by the addition of cholesteryl hemisuccinate (CHEMS), and by loading biologically active substances in the inner phase of the nanocarriers. Further, another object of the present invention is to provide skin-care external compositions containing the pH-sensitive lipid-based nano-scale carriers as an active ingredient.
  • CHEMS cholesteryl hemisuccinate
  • the present invention is characterized in that the lipid-based nanocarriers taking the form of liposome or nanoemulsion comprise cholesteryl hemisuccinate represented by the following chemical formula 1, in addition to a lipid component, for forming lipid-based structures, and loads biologically active substances in the inner phase.
  • cholesteryl hemisuccinate represented by the following chemical formula 1, in addition to a lipid component, for forming lipid-based structures, and loads biologically active substances in the inner phase.
  • the cholesteryl hemisuccinate (hereinafter, "CHEMS”) is a derivative with a carboxyl group at the end of cholesterol.
  • the CHEMS alone; or one selected from salts of CHEMS such as tris salt, tris(hydroxymethyl)aminomethane salt and cyclohexylammonium salt; or a mixture of two or more selected from CHEMS and the salts of CHEMS may be added to a lipid component and can be selected suitably depending on carrier characteristic or processing procedure.
  • the lipid-based nanocarriers according to the present invention may be prepared in the form of liposome or nanoemulsion. In the preparation of liposome or nanoemulsion, the addition of said CHEMS or its salts can stabilize lipid membrane structures.
  • said lipid-based nanocarriers have pH-sensitivity, to destabilize the lipid membrane at pH 6.0 or below and to disrupt the lipid membrane at below this pH, resulting in releasing the biologically active substances loaded in the inner phase. Consequently, said lipid-based nanocarriers can be incorporated in skin-care external compositions. Because said nanocarriers can release effectively the biologically active substances loaded therein into a cell in response to acidity change, the compositions containing the same can provide maximally the efficacies of biologically active substances. Therefore, these skin-care external compositions having said characteristics should be concluded to fall within the sprit and scope of the present invention.
  • the lipid component of the lipid structures for preparing liposomes or nanoemulsions of the present invention may be phospholipids or nitrolipids with a fatty acid chain of 12 to 24 carbon atoms.
  • phospholipids may be more preferable, and specifically: natural phospholipids such as egg lecithin (phosphatidylcholine), soybean lecithin, lysolecithin, sphingomyelin, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, diphosphatidylglycerol, cardiolipin, plasmalogen; hydrogenated products obtained by conventional methods from said phospholipids; and synthetic lipids such as dicetylphosphate, distearoyl-phosphatidylcholine, dioleoyl-phosphatidylethanolamine, dipalmitoyl-phosphatidylcholine, dipalmito
  • Said lipid including phospholipids may be used alone or in combination of two kinds or more.
  • the A mixing ratio depends on the components to be mixed, and the ratio of the minimum component to the maximum component may be preferably 1 :5 or below.
  • phosphatidylcholine : dioleoyl-phosphatidylethanolamine combination may be prepared in diverse molar ratios of 1:1, 2:1, 3:1, 4:1, 5:1, 1:5, 1:4. 1:3, 1:2 in a range of 5:1 to 1:5.
  • phosphatidylcholine : dioleoyl-phosphatidylethanolamine : phosphatidylserine combination may be prepared in diverse molar ratios of 1:1:1, 2:1:1, 3:1:2, 3:2:1. 3:2:2. 4:1:1, 4:2:1. in a range of minimum/maximum component ratio 1:5.
  • the molar ratio of said lipid to CHEMS may be preferably 9:1 to 1:9, for example
  • Said lipid component of the nanocarriers may be used in an amount of 0.001 to 20% and preferably 0.2 to 10% by weight based on the total weight of liposome dispersion or nanoemulsion.
  • phospholipid will be representative of the lipids to be used together with CHEMS.
  • the present invention may comprise further additives such as excipients or stabilizers in addition to cholesteryl hemisuccinate, for stability or handling of liposome preparation.
  • the biologically active substance to be loaded within said nanocarriers may be either water soluble or insoluble and not limited to specific kind, if it may be applied to a living body.
  • it may be one component or extracts from animals or plants or microorganisms, or their mixture containing two kinds or more, depending on purpose or case.
  • an active substance having whitening efficacy or anti-wrinkle and anti-aging efficacies it ma ' y be preferable to use N-butyldeoxynojirimycin, 1-deoxynojirimycin, castanospermine or the like. It may be loaded in an amount of 0.01 to 30% and preferably 0.1 to 20% by weight based on the total weight of liposome dispersion or nanoemulsion.
  • a method for preparing the bioactive substances-loaded nanocarriers composed of lipid components and CHEMS may be a method which comprises the steps of dissolving said phospholipids and CHEMS in an organic solvent; evaporating and decompressing the solvent, to form a film; adding distilled water thereto; and irradiating with an ultrasonic wave; a method which comprises the steps of dissolving said phospholipids and CHEMS in an organic solvent and then dispersing in an aqueous solution; and irradiating with an ultrasonic wave; a method which comprises the steps of dispersing or dissolving said phospholipids and CHEMS in an organic solvent; and extracting the solvent with excess of distilled water or evaporating the solvent; a method which comprises the steps of dispersing or dissolving said phospholipids and CHEMS in an organic solvent; strongly stirring with homogenizer or high-pressure homogenizer; and then evaporating the solvent; a method which comprises the steps of dispersing or dissolv
  • mechanical force may be added or heating to a temperature of 20 ⁇ 100 ° C, preferably 70 ° C or below, may be carried out.
  • the salts may be dissolved in aqueous phase.
  • the substances may be dissolved in water or aqueous solution and then introduced together in said step of adding aqueous solution or distilled water in the above-mentioned methods, while in the case of water-insoluble active substances, the substances may be dissolved in an organic solvent and then added to the organic solvent containing lipid components, followed by the same procedure as described in said methods.
  • the organic solvent to be used for dissolving said phospholipids and CHEMS or water-insoluble active substances may be one or more selected from the group consisting of acetone, dimethylsulfoxide, dimethylformamide, N-mehtylpyrrolidone, dioxane, tetrahydrofuran, acetic acid, ethyl acetate, acetonitrile, methylethyl ketone, methylene chloride, chloroform, methanol, ethanol, ethyl ether, diethyl ether, hexane and petroleum ether.
  • the nanocarriers of the present invention obtained by said method may have an average particle diameter of 10 to l,000nm, preferably 10 to 500nm depending on the composition of lipid membrane and the method for preparation thereof. Further, they have the sensitivity to acidity change, as demonstrated in experimental examples below, to effectively release the biologically active substances loaded therein within a cell and thereby to enhance the effect as a carrier.
  • the nanocarriers of the present invention can function as a carrier to deliver biologically active substances such as whitening agents, anti-wrinkle agents or anti-aging agents, and to redouble their biological efficacies within a living body.
  • Skin-care external compositions containing the nanocarriers provided by the present invention may be formulated into, but not limited to, cosmetic compositions such as skin softeners, astringents, nutrient toilet water, nutrient creams, massage creams, eye creams, eye essences, essences, cleansing creams, cleansing lotions, cleansing foams, cleansing water, packs, powders, make-up bases, foundations, body lotions, body creams, body oils, body essences, body cleansers, hair dyes, shampoos, rinses, tooth pastes, oral cleaning fluid, hair styling products, hair tonic, lotions, ointments, gels, creams, patches, sprays.
  • cosmetic compositions such as skin softeners, astringents, nutrient toilet water, nutrient creams, massage creams, eye creams, eye essences, essences, cleansing creams, cleansing lotions, cleansing foams, cleansing water, packs, powders, make-up bases, foundations, body lotions, body creams, body oils, body essences,
  • Figure 1 shows the particle-size distributions of the liposomes prepared in Examples 2 to 6.
  • Figure 2 shows the particle-size distributions of the liposomes entrapping N-butyldeoxynojirimycin (NB-DNJ) and 1-deoxynojirimycin (DNJ), prepared in Example 4.
  • Figure 3 shows the particle-size distributions of the liposomes (DOPE:CHEMS (3:2)) prepared in Example 4 and of the liposomes (DOPE:Chol (3:2)) used as a control in Experimental Example 2.
  • Figure 4 shows, as results of Experimental Example 2, the transparency of the liposome dispersion and the characteristic change of the liposomes in response to acidity change.
  • Figure 4(a) shows the absorbance of the DOPE:Chol liposomes used as a control
  • Figure 4(b) shows the absorbance of the liposomes prepared in Example 4.
  • Figure 5 shows, as further results of Experimental Example 2, the turbidities of the DOPE:CHEMS liposomes of Example 4 and of the DOPE:Chol liposomes used as a control, in response to acidity change, which were evaluated by means of the absorbance at 550nm.
  • Figure 6 shows results of Experimental Example 3.
  • Figure 6(a) show the Western blotting results showing N-glycosylation-inhibiting effects of N-butyldeoxynojirimycin (NB-DNJ) loaded in the liposomes (LiJ of Example 4 (lines 4 to 8: respective concentrations are 200, 100, 50, 5 and l ⁇ M), depending on the concentrations thereof, compared with the effects of unloaded N-butyldeoxynojirimycin as a control (lines 1 to 3: respective concentrations are 0, 200 and 50 ⁇ M).
  • Figure 6(b) shows the melanin contents produced by the cells of test groups and of control groups in the Western blotting. The items in the horizontal axis correspond to those of lines 1 to 8 in Figure
  • Figure 7 shows further results of Experimental Example 3.
  • Figure 7(a) shows the Western blotting results showing N-glycosylation-inhibiting effects of N-butyldeoxynojirimycin (NB-DNJ) (lines 3 and 4: respective concentrations are 100 and 50 ⁇ M) and of 1-deoxynojirimycin (DNJ) (lines 6 to 8 : respective concentrations are 100, 50 and 5 ⁇ M) independently loaded in the liposomes (I ⁇ ) of Example 4, depending on the concentrations thereof, compared with the effects of unloaded N-butyldeoxynojirimycin (lines 1 and 2: respective concentrations are 0 and lOO ⁇ M) and of unloaded 1-deoxynojirimycin (line 5: concentration is lOO ⁇ M) as controls.
  • NB-DNJ N-butyldeoxynojirimycin
  • DNJ 1-deoxynojirimycin
  • Figure 7(b) shows the melanin contents produced by the cells of test groups and of control groups in said Western blotting.
  • the items in the horizontal axis correspond to those of lines 1 to 8 in Figure 7(a).
  • Figure 8 shows further results of Experimental Example 3.
  • Figure 8(a) shows the Western blotting results showing N-glycosylation-inhibiting effects of unloaded N-butyldeoxynojirimycin (NB-DNJ) in phosphate buffered saline (PBS) (lines 1 and 2: respective concentrations are 0 and 120 ⁇ M); of N-butyldeoxynojirimycin (NB-DNJ) loaded in the liposomes (L 2 ) of Example 7 (lines 3 and 4: respective concentrations are 0 and 120 ⁇ M); and of N-butyldeoxynojirimycin (NB-DNJ) loaded in the liposomes (L 3 ) of Example 8 (lines 5 and 6: respective concentrations are 0 and 120 ⁇ M), depending on the concentrations thereof.
  • Figure 8(b) shows the melanin contents produced by the cells with 0 and 120 ⁇ M N-butyldeoxynojirimycin loaded in the liposomes (Li) of Example 4 (the items 7 and 8 respectively in the horizontal axis); and by the cells of test groups and of control groups in said Western blotting shown in Figure 8(a) (the items 1 to 6 in the horizontal axis corresponding to those of lines 1 to 6 in Figure 8(a)).
  • Figure 9 shows, as results of Experimental Example 4, the dextran-rhodamine B-loading efficiencies of the liposomes of Example 4 and of the DOPE:PEG-5 rapeseed sterol liposomes as a control, each labeled with 1% fluorescein-DHPE.
  • Figure 10 shows further results of Experimental Example 4, the confocal laser scanning microscopy images showing the behavior within a cell of the liposomes labeled with 1% fluorescein-DHPE and entrapping dextran-rhodamine B therein, after a 1-hour incubation, wherein b, d and fare images showing the behavior of the liposomes of Example 4 and a, c and e are of the DOPE:PEG-5 rapeseed sterol liposomes as a control, a and b are images under fluorescein filter only; c and d are images under rhodamine filter only; e is a composite obtained by superimposing a, c and UN-filter image; and f is by superimposing b, d and UV-filter images.
  • Figure 11 shows, as the result of Experimental Example 5, the fluorescence intensity of HM3KO cells analyzed by FACS (Flow Activated Cell Sorter), wherein the cells treated with CHEMS-incorporated pH-sensitive lipid-based nanocarriers exhibited relatively high fluorescence intensity in both fluorescein (a) and calcein (b), compared with a non-treated group and with a control group treated with non-pH-sensitive lipid-based nanocarriers.
  • FACS Flow Activated Cell Sorter
  • Figure 12 shows, as results of Experimental Example 6, the skin penetration evaluated in the 18-hour Frantz-diffusion cell system using the abdominal skins of Albino Hartley guinea pigs, and increased by CHEMS-incorporated pH-sensitive lipid-based nanocarriers entrapping (a) 0.4% and (b) 0.2% deoxynojirimycin, compared with the liposomes of a control group.
  • Figure 13 shows, as a further result of Experimental Example 6, the skin penetration evaluated in the 18-hour Frantz-diffusion cell system using the abdominal skins of SKHl hairless mice, wherein (a) shows the penetration rate after 18 hours, increased by CHEMS-incorporated pH-sensitive lipid-based nanocarriers entrapping deoxynojirimycin therein, and (b) shows the quantities of the drug penetrated and accumulated for 1, 3, 6, 12 and 18 hours, compared with the liposomes of the control group.
  • Figure 14 shows, as a result of Experimental Example 7, the pigmentation degree, i.e.
  • Figure 15 shows, as a further result of Experimental Example 7, photographs showing the pigmentation degree of the UN-irradiated back skins of guinea pigs, 4 weeks before and after treatment (a) with 2% hydroquinone, as a positive control; (b) with the empty liposomes of control group; (c) with 1% deoxynojirimycin; (d) with 0% deoxynojirimycin; (e) with CHEMS-incorporated pH-sensitive lipid-based nanocarriers entrapping 0.5% deoxynojirimycin therein; (f) with empty CHEMS-incorporated pH-sensitive lipid-based nanocarriers; (g) and with the liposomes of control group entrapping 0.5% deoxynojirimycin therein.
  • Examples 1 to 9 1.75mg of phosphatidylethanolamine (phospholipid) and 0.75mg of CHEMS were dissolved in 1.25m£ of chloroform:methanol (95:5, v/v), and then the solvent was evaporated under reduced pressure to form a film. 750/zg of N-butyldeoxynojirimycin was dissolved in distilled water and 1.25m was added to said film, which was then irradiated with an ultrasonic wave to give liposome dispersion. In detail, the liposome dispersions were prepared according to the ratios shown in Table 1. In these examples, N-butyldeoxynojirimycin was firstly used as a biologically active substance, to give said nanocarriers.
  • Saturated lecithin obtained by extracting soybean and then hydrogenating, PEG-5 rapeseed sterol (Generol R E 51), ethyl hexanediol, and ethanol or propylene glycol were mixed according to the ratios shown in Table 2 and then heated to 60 °C, to be dissolved.
  • the size distributions of the liposomes prepared in Examples 2 to 6 are shown in Figure 1. Further, the size distributions of the liposomes entrapping N-butyldeoxynojirimycin (NB-DNJ) therein, prepared in Example 4, and of the liposomes entrapping 1-deoxynojirimycin (DNJ) therein, prepared by the same procedure as described in Example 4, are shown in Figure 2. Further the size distributions of the liposomes of Example 4 and of the dioleoyl-phosphatidylethanolamine:cholesterol liposomes (DOPE:Chol (3:2)) used as a control in Experimental Example 2, are shown in Figure 3.
  • NB-DNJ N-butyldeoxynojirimycin
  • DOPE:Chol (3:2) dioleoyl-phosphatidylethanolamine:cholesterol liposomes
  • the CHEMS-incorporated lipid-based nanocarriers provided by the present invention can destabilize lipid structures in specific response to an acidic surroundings, for example, cellular organelles such as endosome having a general pH range of 6.0 to 5.0, to effectively release the biologically active substances loaded therein within a cell and thereby to enhance the delivery efficiency as a carrier.
  • an acidic surroundings for example, cellular organelles such as endosome having a general pH range of 6.0 to 5.0
  • N-butyldeoxynojirimycin and nojirimycin as whitening agents, are inhibitors for N-glycosylation required in pigment production of tyrosinase.
  • Tyrosinase is a key enzyme in melanin biosynthesis. Accordingly, for the evaluation, the cultured cells were collected and treated with endoglycosidase H (EndoH) and protein-N-glycosidase F (PNGase F), followed by electrophoresis and Western blotting, resulting in examining N-glycosylation of tyrosinase.
  • EndoH endoglycosidase H
  • PNGase F protein-N-glycosidase F
  • the CHEMS-incorporated lipid-based nanocarriers provided by the present invention regardless of the kind of phospholipids (dioleoyl-phosphatidylethanolamine, phosphatidylcholine or combination of two kinds or more), shown in Figure 8, can enhance an N-glycosylation-inhibiting effect and melanin biosynthesis-inhibiting effect by 4-fold or more, considering the efficacy of the active substances loaded therein as a concentrating effect of active ingredients.
  • CLSM confocal laser scanning microscopy
  • Figure 10 shows the behavior within a cell of the liposomes after a 1-hour incubation, observed by confocal laser scanning microscopy, wherein b, d and f are images showing the behavior of the liposomes of Example 4 and a, c and e are of the DOPE:PEG-5 rapeseed sterol liposomes as a control, a and b are images under fluorescein filter only; c and d are images under rhodamine filter only; e is a composite obtained by superimposing a, c and UN-filter images; and f is by superimposing b, d and UN-filter images.
  • the results indicate that the CHEMS-incorporated lipid-based nanocarriers provided by the present invention can be effectively delivered into the human melanoma cell line and can effectively release active substances loaded therein.
  • calcein-loaded pH-sensitive nanocarriers composed of phosphatidylethanolamine and CHEMS were prepared by the same procedure as described in Example 1, using fluorescent calcein in distilled water. As described above, HM3KO cells were incubated with said nanocarriers for 1 hour. Calcein-loaded non-pH-sensitive structures composed of phosphatidylcholine and CHEMS, prepared by using the same amount of calcein in distilled water, were used as a control.
  • HM3KO cells incubated with the fluorescein-labeled pH-sensitive lipid-based nanocarriers exhibited higher fluorescence intensity compared with the control group, i.e. the cells with the non-pH-sensitive lipid-based nanocarriers.
  • calcein which cannot permeate cellular membrane by itself, was delivered into the cell with entrapped in the pH-sensitive lipid-based nanocarriers and the quantity delivered was more than that of the control group delivered with entrapped in the non-pH-sensitive lipid-based nanocarriers. Consequently, FACS analysis demonstrated quantitatively that the pH-sensitive lipid-based nanocarriers provided by the present invention have excellent delivery efficiency into a cell, compared with non-pH-sensitive lipid-based nanocarriers.
  • the penetration of the nanocarriers entrapping 0.4% deoxynojirimycin therein was compared with that of the non-pH-sensitive liposomes composed of dioleoyl-phosphatidylcholine and cholesterol, used as a control 1.
  • the penetration of the nanocarriers entrapping 0.2% deoxynojirimycin therein was compared with that of the non-pH-sensitive liposomes composed of phosphatidylcholine and CHEMS, used as a control 2.
  • a certain amount of PBS maintained at 37 ° C was supplied continuously to the lower part of Franz-diffusion cells.
  • Plastic plates having a 1cm diameter circular window were put on the skins, which were then exposed to UN radiation with a Waldmann UN 800 (Herbert Waldmann GmbH&E, Philis TL/12 lamp emitting 280 ⁇ 305nm).
  • the UN intensity was 500mJ/cm 2 , applied once a week for three consecutive weeks, and the total energy dose was l,500mJ/cnf.
  • the test sample was applied at a dose of 5 ⁇ & per hyperpigmented site.
  • cosmetic compositions containing the liposome dispersions or nanoemulsions of the present invention were provided as the following formulations.
  • the CHEMS-incorporated lipid-based nanocarriers such as liposomes and nanoemulsion, provided by the present invention can destabilize lipid membrane structures in specific response to an acidic surroundings, for example, cellular organelles such as endosome having a general pH range of 6.0 to 5.0, and thereby can effectively release the biologically active substances loaded therein within a cell and can increase skin penetration, so as to enhance the effect as a carrier.
  • the nanocarriers of the present invention can function as a carrier to deliver biologically active substances such as whitening agents or anti-wrinkle and anti-aging agents and to redouble their biological efficacies within a living body.

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Abstract

La présente invention a trait à des supports de taille nanométrique à base de lipides à incorporation d'hemisuccinate de cholestéryle et composition de soins cutanés pour application externe en comportant. Les supports de taille nanométrique de la présente invention peuvent accroître la pénétration cutanée de substances biologiquement actives, et présentent une sensibilité élevée au pH et peuvent donc assurer une libération efficace des substances biologiquement actives qui y sont chargées au sein d'une cellule, afin d'améliorer l'effet de support. En outre les compositions de soins cutanés de l'invention contenant lesdits supports de taille nanométrique peuvent assurer une administration maximale des effets bénéfiques des substances biologiquement actives.
PCT/KR2004/003436 2003-12-31 2004-12-24 Supports de taille nanometrique a base de lipides a incorporation d'hemisuccinate de cholesteryle et composition de soins cutanes pour application externe en comportant WO2005063212A1 (fr)

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WO2011031849A2 (fr) * 2009-09-10 2011-03-17 The Board Of Regents Of The University Of Oklahoma Lipides anioniques et nanostructures lipidiques et leurs procédés de fabrication et d'utilisation
WO2010105842A3 (fr) * 2009-03-19 2011-05-26 Bubbles And Beyond Gmbh Préparation pour utilisation extérieure
EP2692334A1 (fr) * 2011-03-31 2014-02-05 Kao Corporation Composition de vésicule
WO2015152422A1 (fr) * 2014-04-01 2015-10-08 L'oreal Composition sous la forme de nano- ou de micro-émulsion

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KR100799657B1 (ko) * 2005-06-30 2008-01-30 김진석 ｐＨ에 민감한 면역리포좀
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WO2010105842A3 (fr) * 2009-03-19 2011-05-26 Bubbles And Beyond Gmbh Préparation pour utilisation extérieure
CN102387787A (zh) * 2009-03-19 2012-03-21 泡沫&超越有限公司 外用制剂
DE102009013469B4 (de) * 2009-03-19 2014-04-17 Bubbles And Beyond Gmbh Zubereitung zur äußerlichen Anwendung
WO2011031849A2 (fr) * 2009-09-10 2011-03-17 The Board Of Regents Of The University Of Oklahoma Lipides anioniques et nanostructures lipidiques et leurs procédés de fabrication et d'utilisation
WO2011031849A3 (fr) * 2009-09-10 2011-08-11 The Board Of Regents Of The University Of Oklahoma Lipides anioniques et nanostructures lipidiques et leurs procédés de fabrication et d'utilisation
US8420118B2 (en) 2009-09-10 2013-04-16 The Board Of Regents Of The University Of Oklahoma Anionic lipids and lipid nano-structures and methods of producing and using same
US9173839B2 (en) 2009-09-10 2015-11-03 The Board Of Regents Of The University Of Oklahoma Anionic lipids and lipid nano-structures and methods of producing and using same
EP2692334A1 (fr) * 2011-03-31 2014-02-05 Kao Corporation Composition de vésicule
EP2692334A4 (fr) * 2011-03-31 2014-11-19 Kao Corp Composition de vésicule
US9694076B2 (en) 2011-03-31 2017-07-04 Kao Corporation Vesicle composition
WO2015152422A1 (fr) * 2014-04-01 2015-10-08 L'oreal Composition sous la forme de nano- ou de micro-émulsion

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