WO2007078060A1 - Nanocomplexes polymere-liposome et leur procede de preparation, et composition de l'application cutanee externe les contenant - Google Patents

Nanocomplexes polymere-liposome et leur procede de preparation, et composition de l'application cutanee externe les contenant Download PDF

Info

Publication number
WO2007078060A1
WO2007078060A1 PCT/KR2006/005298 KR2006005298W WO2007078060A1 WO 2007078060 A1 WO2007078060 A1 WO 2007078060A1 KR 2006005298 W KR2006005298 W KR 2006005298W WO 2007078060 A1 WO2007078060 A1 WO 2007078060A1
Authority
WO
WIPO (PCT)
Prior art keywords
polymer
liposome
water
liposome complex
lipid
Prior art date
Application number
PCT/KR2006/005298
Other languages
English (en)
Inventor
Eun Chul Cho
Hyung Jun Lim
Jong Won Shim
Ju Young Park
Hwa-Jun Lee
Jun Cheol Cho
Junoh Kim
Original Assignee
Amorepacific Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020050135409A external-priority patent/KR100654102B1/ko
Priority claimed from KR1020050134707A external-priority patent/KR100716802B1/ko
Priority claimed from KR1020060020942A external-priority patent/KR100793824B1/ko
Application filed by Amorepacific Corporation filed Critical Amorepacific Corporation
Publication of WO2007078060A1 publication Critical patent/WO2007078060A1/fr

Links

Classifications

    • 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
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/738—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8105—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • A61K8/8111—Homopolymers or copolymers of aliphatic olefines, e.g. polyethylene, polyisobutene; Compositions of derivatives of such polymers
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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

Definitions

  • the present invention relates to a polymer-liposome complex using pH-sensitive polymer and the preparation method thereof, and the composition of skin external application containing the same.
  • the polymer-liposome complex comprising the pH-sensitive polymer comprised of methacrylic acid and n-alkyl methacrylate and the lipid bilayer has a sensitive response to pH change, so it improves the effect as a carrier by effectively releasing the hydrophobic bioactive compounds embedded inside the lipid layer or the water-soluble bioactive compounds embedded inside the liposome structure or the hydrophilic bioactive compounds solubilized through hydroxypropyl- ⁇ -cyclodextrin into an organism.
  • the present invention relates to a polymer- lipid based drug carrier and the composition of skin external application containing the same, which can exist structurally stably in the multi-component system such as an emulsion comprised of an aqueous solution, oil, wax and various surfactant.
  • Liposome is one of components being in the spotlight of the way of delivering gene or drug in these days. It is thermodynamically stable in the water-soluble inner nucleus and the lipid vesicle, and it has the lipid bilayer surrounding at least one inner nucleus. In the liposome, the water-soluble drug is included in the continuous lipid bilayer, but the water-insoluble drug is associated with the lipid bilayer itself.
  • the studies which diversify the components of the liposome in order to maximize the efficacy of the active component by delivering the bioactive compounds embedded inside the liposome to cell with a high efficiency are performing actively.
  • the preparation of the liposome comprising the lipid introduced the biocompatible polymer in order to increase the bioavailability of active components by extending the circulation time inside the organism, or the studies about i) the liposome comprising the lipid introduced the cell recognition molecule or the cell adhesion molecule in order to deliver high molecular weight drug such as peptide, protein or gene to target cell or ii) the liposome designed for releasing the bioactive compounds embedded inside the liposome inside the cell due to the decrease in the stability of the liposome by specific condition of small organ inside the cell are proceeding.
  • liposome developed as a drug carrier could not be used as an effective system because of its colloidal and biological instability, but the recent improvement of liposome stability enables the development of anti-bacteria and anticancer liposomal systems.
  • the liposome is also useful in decreasing the toxicity and delivering bioactive compounds for the long run by capturing the compound having the usefulness in itself or having the toxicity not permitted in the therapeutical dosage.
  • DOPE dioleoylphosphatidylethanolamine
  • the research about the polymer-liposome complex having the shape that the liposome is surrounded by the polymer was conducted in order to make the various functions of liposome. That is, the research had an intention to control the release the drug according to the environment of solution by changing the structure of the liposome using the pH-sensitive polymer, and it was started from the early 1980.
  • Early research related to a liposome complex with poly (ethyl acrylic acid) and phospatidylcholine by Tirrell et al . and they developed a system in which polymer chains are adsorbed on the outer wall of liposome, and some parts of structure of this complex change according to pH of solution (Tirrell et al . , Macromolecules, 1984, 17, 1692).
  • lipid bilayer structure of liposome In the preparation of liposome, a certain ratio of the cholesterol is generally added to lipid for stabilizing the lipid bilayer structure of liposome. It was known by numerous studies that structurally and thertnodynamically more stable spherical lipid bilayer structure of liposome can be formed when the cholesterol was embedded in the lipid bilayer structure. Specially, it was confirmed, by analyzing the release rate of fluorescent dye which was captured in the liposome, that the lipid bilayer of liposome embedded with cholesterol was more stable than the lipid bilayer of liposome without cholesterol (Diana Velluto, et al . , Colloids and Surfaces B: Biointerfaces, 40, 2005, 11-18) .
  • the lipid-cholesterol based liposome also does not have the long-term stability in the water, and it is very unstable in the various salts used in bio systems. Further, the stability inside the composition has to be secured in order to use said compositions for the cosmetics and the skin external applications, but its structure is easy to collapse because of the various surfactants inside the composition.
  • drugs or bioactive compounds delivered by using liposome are mostly water-soluble materials hence the drug exists in the lipid vesicle.
  • the water- insoluble drugs have the similar structures with cholesterol derivatives or cholesterol, so they can be embedded in the lipid bilayer of liposome.
  • Triterpenoids naturally driven components having similar structure with cholesterol, are a generic name of pentacyclic compound such as ursolic acid, oleanolic acid, betulin etc. These have been known to have an effect for anti-cancer, liver protection, anti-inflammatory, anti-ulcer, anti-bacterial, anti-hyperlipemia, anti-virus, collagen synthesis in skin, promoting the lipid synthesis in skin, injury healing, etc.
  • the triterpenoid embedded liposome system like a lipid- cholesterol based liposome, is stable in aqueous solution like a lipid-based liposome or a lipid-cholesterol based liposome.
  • the lipid-cholesterol based liposome, in which triterpenoid is embedded is limited in its use because the vesicle structure becomes unstable in aqueous solution containing various salts used in bio systems or in the cosmetics composition having various surfactants.
  • the bioactive compounds can not be effectively embedded in the lipid- cholesterol based liposome. Even though it can be embedded, the stability of the lipid-cholesterol based liposome, in which the bioactive compounds is embedded, was usually not good in aqueous solution.
  • cyclodextrin has a structure that 5-7 glucose molecules form a cyclic ring and has a hydrophobic cavity inside the molecule. Therefore, it has been widely used for solubilizing various water-insoluble drugs. Moreover, there was a research for the effect of promoting the potential transdermal absorption of cyclodextrin.
  • the long-term stability of the liposome should be ensured while maintaining the original liposome structure within the formulation including cyclodextrin or various surfactants as well as within the aqueous solution containing diverse salts, without crystallization of water-soluble or water-insoluble bioactive compounds embedded in the liposome.
  • there is a desperate need to develop a new liposome system that can improve the carrier role by effectively releasing bioactive compounds within the organism through the liposome carrier having the long-term stability, and that can stably exist within various biosystems, cosmetics and compositions of skin external application.
  • the present inventors have been performing researches with the target of development of liposome system having the characteristics of : i) having an efficient delivery of various water-soluble and water- insoluble bioactive compounds and ii) being stable without crystallization of the water-insoluble bioactive compounds under various salts, and in cosmetics and skin external application formulation.
  • the polymer- liposome complex prepared by using the pH-sensitive polymer having the specific composition, and components has the properties of : i) same structure with the lipid or lipid-cholesterol based liposome, ii) increasing the drug delivery efficiency in the body due to the sensitivity to the change in pH, iii) improving the absorption of bioactive compounds into skin, iv) maintaining the long-term stability without crystallization of the water- insoluble bioactive compound in aqueous solution or aqueous solution containing various salts and v) maintaining the structure of liposome stably without crystallization of the bioactive compound in cosmetics and skin external application formulation.
  • the inventors tried the solublization method of the water-insoluble bioactive compounds using hydroxypropyl- ⁇ - cyclodextrin, so that the polymer-liposome complex could deliver the water-insoluble bioactive compounds that were not able to be directly embedded in the lipid bilayer of liposome.
  • the polymer-liposome complex including the water-insoluble bioactive compounds solubilized through hydroxypropyl- ⁇ - cyclodextrin maintained the long-term stability without precipitation/crystallization of the water-insoluble bioactive compounds in aqueous solution, prevented the decrease in the concentration of the water-insoluble compounds due to denaturation and showed an improved skin-absorption in several cases, so the present invention was complete.
  • the present invention is significant in the point that it improved the efficiency of the water-soluble and water- insoluble bioactive compounds by the rapid structural collapse at the specific pH and at the same time it satisfied the requirements of maintaining particle stability without precipitation/crystallization and decrease in the concentration of bioactive compounds under any storing conditions before use, which had not achieved by the precedent technology. It also solves the problem that various water- insoluble bioactive compounds cannot be effectively embedded in the liposome in the lipid or lipid-cholesterol based liposome system.
  • the present invention has usefulness and meanings to supply the polymer- liposome complex having improved stability in various salts and cosmetics composition relative to the lipid-cholesterol based liposome system and enhanced skin-absorption of the water-soluble and the water- insoluble bioactive compounds .
  • An object of the present invention is to provide a polymer-liposome complex comprised of the pH-sensitive random copolymer comprising two monomers of methacrylic acid and n- alkyl methacrylate and the lipid bilayer and the preparation method thereof .
  • Another object of the present invention is to provide a polymer-liposome complex more comprising cholesterol and the preparation method thereof.
  • Another object of the present invention is to provide a polymer-liposome complex which the water-soluble bioactive compound is included inside the lipid bilayer of the liposome of said polymer- liposome complex.
  • Another object of the present invention is to provide a polymer-liposome complex which the water-insoluble bioactive compound is embedded inside the lipid bilayer of the liposome of said polymer-liposome complex.
  • Another object of the present invention is to provide a polymer-liposome complex which the water-soluble bioactive compound or the water-insoluble bioactive compound solubilized through hydroxypropyl- ⁇ -cyclodextrin is included inside the liposome of said polymer-liposome complex.
  • Another object of the present invention is to provide a polymer-liposome complex having the characteristics of : i) having 50 ⁇ 400 nm of particle size depending on the concentration of the polymer and the lipid, the water- soluble/insoluble bioactive compound included/embedded in the lipid bilayer or the water-soluble bioactive compound or the water-insoluble bioactive compound, solubilized through hydroxypropyl- ⁇ -cyclodextrin, included inside the liposome, ii) maintaining the vesicle shape which is same with the lipid comprising no polymer or the lipid-cholesterol based liposome and iii) forming the structure which the hydrophobic part of the polymer is assembled between lipid, lipid-cholesterol or lipid-water-insoluble bioactive compound based lipid bilayer.
  • Another object of the present invention is to provide a polymer-liposome complex comprising the pH-sensitive polymer which maximizes the efficacy of the active component by improving the effect of the carrier caused by responsing to the change in pH of the target organelle in the cell, collapsing its lipid bilayer and releasing the bioactive compound after the bioactive compound stably embedded inside the polymer-liposome complex or inside the lipid bilayer of the polymer-liposome complex is moved to the target site, and improves the skin permeability of the bioactive compound.
  • Another object of the present invention is to provide a polymer-liposome complex comprising the polymer which can maintain stable vesicle structure from cosmetics and the skin external application formulation by keeping the vesicle structure stable from salts or surfactants in aqueous system which cause instability of liposome structure caused by assembling with the lipid or the lipid/cholesterol bilayer, tying the bilayer strongly and protecting the outer wall at the same time.
  • the present invention relates to a polymer- liposome complex using pH-sensitive polymer and the preparation method thereof, and the composition of skin external application containing the same.
  • the polymer-liposome complex comprises the pH-sensitive polymer comprising two monomers of methacrylic acid and n-alkyl methacrylate as shown in formula 1 and the liposome structure comprising lipid bilayer, and the water-soluble/water-insoluble bioactive compounds can be included/embedded in the lipid bilayer and the water-soluble bioactive compounds or the water-insoluble bioactive compounds solubilized through hydroxypropyl- ⁇ - cyclodextrin can be embedded inside the liposome structure .
  • the polymer comprising two monomers of methacrylic acid and stearyl methacrylate as shown in formula 2 can be more comprised in poly (methacrylic acid- co-n-alkyl methacrylate) random copolymer of formula 1.
  • n 0.85 ⁇ 0.6
  • m 0.15 ⁇ 0.4.
  • the polymer used in the polymer-liposome complex of the present invention is the pH-sensitive polymer comprising methacrylic acid monomer introduced for the pH-sensitivity and n-alkyl methacrylate monomer introduced for the assembly with a lipid bilayer of liposome.
  • the polymer-liposome complex comprising said polymer shows a response to pH, so the structural stability is decreased in the range below pH 5.0, and the embedded bioactive compound is released by the collapse of the structure in the lower pH.
  • said polymer- liposome complex can be used for skin external application.
  • the polymer prepared by using methacrylic acid changes its structure according to the pH change in aqueous solution, and the range and the degree of the pH-sensitivity depend on the number of alkyl chain present in monomer, the molecular weight of the polymer and the polydispersity index showing the molecular weight distribution of the polymer .
  • the polymer comprising said methacrylic acid monomer and n-alkyl methacrylate monomer is polymerized by the general free radical thermal initiation method, and anionic or cationic polymerization can be used to control the molecular weight distribution.
  • the mixing ratio of methacrylic acid (or acrylic acid, x of formula 1) and n-alkyl methacrylate (or methacrylate substituted with cholesterol, y of formula 1) used in said polymerization is 90 : 10 ⁇ 50 : 50 in mole ratio, preferably, 85 : 15 ⁇ 60 : 40.
  • n-alkyl methacrylate is less than 10% in mole ratio, there is a possibility that a part of polymer is present independently in aqueous solution and it acts as a surfactant. If n-alkyl methacrylate exceeds 50%, a hydrophobic part of polymer increases, so it can lead to instability in the structure of liposome in the preparation of the polymer-liposome complex.
  • the molecular weight of the polymer comprising said methacrylic acid monomer and n-alkyl methacrylate monomer affects the vesicle size of the polymer-liposome complex and the stability of the polymer-liposome complex, specially, the long-term structural stability.
  • the range of the molecular weight can be used in the polymer-liposome complex is 5,000 ⁇ 200,000 in the number average molecular weight, preferably, 10,000 ⁇ 50,000.
  • Stearyl methacrylate introduced for the assembly with a lipid bilayer of liposome in the present invention can be assembled with the lipid bilayer according to the kind of lipid assembled. According to the purposes, the monomer containing cholesterol component in place of stearyl chain can be introduced.
  • phospholipids or nitrolipids which have a fatty acid chain of 12 ⁇ 24 carbons, can be used as the component of lipid bilayer in the preparation of the polymer-liposome complex of the present invention.
  • the phospholipids are preferable.
  • one or more than two mixture selected from the group consisting of derivatives of the synthetic lipids and fatty acid mixtures obtained by hydrolysis of the synthetic lipids such as dicetylphosphate, distearoylphosphatidylcholine, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylcholine , dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylserine , eleostearoylphosphatidylcholine , eleostearoylphosphatidylethanolamine and eleostearoylphosphatidylserine, which are the hydrogenation products of natural phospholipids selected from egg yolk lecithin (phosphatidylcholine) , soybean lecithin, lysolecithin, sphingomyelin, phosphatidic acid, phosphatidylserine, phosphatidylglycerol , phosphatidyl
  • the composition such as phosphatidylcholine : phosphatidylethanolamine, phosphatidylcholine : phosphatidylglycerol, phosphatidylcholine : phosphatidylinositol, phosphatidylcholine : phosphatidic acid or phosphatidylcholine : dioleoylphosphatidylethanolamine can be used.
  • the mixing ratio changes according to the components, but the mixing ratio of maximum component compared to minimum component is preferably less than 1: 5.
  • phosphatidylcholine dioleoylphosphatidylethanolamine
  • the range of mole ratio is 5 : 1 - 1 : 5. Therefore, various ratios such as 1 : 1, 2 : 1, 3 : 1, 4 : 1, 5 : 1, 1 : 5, 1 : 4, 1 : 3 or 1 : 2 can be used.
  • phosphatidylcholine: dioleoylphosphatidylethanolamine : phosphatidylserine can be used in various ratios such as 1:1:1, 2:1:1, 3:1:2, 3:2:1, 3:2:2, 4:1:1 or 4:2:1 within the range of 1 : 5 mole ratio.
  • Cholesterol can be more mixed according to need of the polymer-liposome complex of the present invention.
  • the addition of cholesterol disturbs self-assembly of lipid- polymer bilayer, but it helps the formation of a stable spherical liposome by improving the curvature of liposome.
  • the ratio of poly (methacrylic acid-co-n-alkyl methacrylate) random copolymer, which is pH-sensitive polymer used for having the pH-sensitivity and maintaining the structural stability in the polymer-liposome complex of the present invention, and lipid is as follows.
  • 1 ⁇ 50 wt%, preferably 5 ⁇ 30 wt% of poly (methacrylic acid-co-n- alkyl methacrylate) random copolymer is used, and 50 ⁇ 99 wt%, preferably 50 ⁇ 90 wt% of lipid is used of total weight of the vesicle components.
  • 1 - 50 wt% of cholesterol of total weight of the vesicle components can be more comprised.
  • the content of pH-sensitive polymer and lipid used in the polymer-liposome complex is 0.001 ⁇ 15 wt%, preferably 1 - 10 wt% compared to polymer-liposome complex aqueous solution.
  • the water-soluble bioactive compounds or the water- insoluble bioactive compounds solubilized through hydroxypropyl- ⁇ -cyclodextrin are embedded inside the polymer- liposome complex.
  • Said water-soluble bioactive compounds are one or more than two whitening, anti-oxidation and anti- wrinkle materials selected from the group consisting of N- butyldeoxynoj irimycin which is known as whitening materials, 1-deoxynoj irimycin, castanospermin, streptomyces culture extract (SCE) , calcium pentatheine sulfonate, arbutin, vitamin C (ascorbic acid) , ethylascorbyl ether, vitamin C derivative such as sodium ascorbyl phosphate, a-ketoglutaric acid which is known as anti-wrinkle materials and epigallocatechin gallate (EGCG) .
  • the amount of said water-soluble bioactive compounds is 0.001 ⁇ 10 wt%, preferably 0.01 ⁇ 5
  • said water-insoluble bioactive compounds solubilized through hydroxypropyl- ⁇ -cyclodextrin are selected from the group consisting of rhubarb extract which has an anti-oxidation, skin-stabilizing and whitening effect, rhaponticin which is an indicator ingredient of rhubarb extract and undecylenoyl phenylalanine which is known as whitening materials.
  • the amount of said water-insoluble bioactive compounds is 0.001 ⁇ 10 wt%, preferably 0.1 - 2 wt% compared to polymer-liposome complex aqueous solution.
  • the amount of hydroxypropyl- ⁇ -cyclodextrin used for solubilizing the water-insoluble bioactive compounds embedded inside the polymer-liposome complex of the present invention is 3 ⁇ 15 times, preferably 5 - 10 times of the content of water-insoluble bioactive compounds.
  • bioactive compounds embedded in the lipid bilayer of the polymer-liposome complex of the present invention are water-insoluble, it is one selected from the group consisting of triterpenoid of ursolic acid, oleanolic acid, betulinic acid, betulin and b-boswellic acid having a similar structure with cholesterol, flavonoid of diosmetin, quercetin and genestein, phloretin and drabae semen extract.
  • the amount of said water-insoluble bioactive compounds is 0.001 ⁇ 5 wt%, preferably 0.1 ⁇ 2 wt% compared to total polymer-liposome complex.
  • Liposome is generally prepared by using ultrasonic or high pressure homogenizer.
  • the polymer-liposome complex according to the present invention is prepared using high pressure homogenizer by the steps of : a) mixing poly (methacrylic acid-co-n-alkyl methacrylate) copolymer of formula 1 and lipidto organic solvent which is miscible with water, and heating and dissolving the mixture at 50 ⁇ 70 ° C; b) mixing said a) mixture and water heated to 50 ⁇ 70 °Q and first dispersing the mixture using homogenizer ; and c) obtaining the vesicles from said b) mixture using high pressure homogenizer.
  • the organic solvent which is miscible with water is not limited, but it is preferable to be selected from ethanol, methanol, isopropyl alcohol, acetone and tetrahydrofuran .
  • the water- insoluble bioactive compound can be mixed in a) step.
  • a-1) mixing hydroxy-propyl- ⁇ -cyclodextrin and water-insoluble bioactive compound to water, and heating and solubilizing water-insoluble bioactive compound using homogenizer at 60 ⁇ 70 ° C ; and a-2) controlling pH of said b) solution more than 7 using acid or base ; can be more comprised.
  • the water-soluble bioactive compound in b) step, can be comprised in heated water.
  • high pressure homogenizer is used in c) step. Its pressure can be controlled to 100 ⁇ 1000 bar depending on particle size and dispersity of product, and 500 ⁇ 1000 bar is preferable.
  • step to control the concentration of polymer-liposome complex by removing the remaining organic solvent and water using rotary evaporator can be more comprised depending on the used organic solvent.
  • the polymer-liposome complex of the present invention obtained by said preparation method has the particle size of 50 ⁇ 400 nm depending on the concentration of polymer and lipid, the concentration of water-insoluble bioactive compound embedded in lipid bilayer of liposome or the concentration of water-soluble bioactive compound embedded inside the liposome or the concentration of water-insoluble bioactive compound solubilized through hydroxypropyl- ⁇ -cyclodextrin, and maintain same structure and particle form with lipid not comprising polymer or lipid-cholesterol based liposome.
  • the polymer-liposome complex can improve the effect as a carrier by effectively releasing the bioactive compound embedded inside the lipid layer within the cells because it not only has structure which hydrophobic part of polymer is assembled between lipid or lipid/cholesterol based bilayer but also is sensitive response to pH change.
  • the polymer-liposome complex in which the water-insoluble bioactive compound is embedded as shown in FIG. 2, can improve the effect as a carrier by effectively releasing the water-insoluble bioactive compound embedded inside the lipid bilayer within the cells because it not only has structure which hydrophobic part of polymer is assembled between lipid- water- insoluble bioactive compound based lipid bilayer but also is sensitive response to pH change. Also, as shown in FIG.
  • polymer is assembled with lipid-water- insoluble bioactive compound based lipid bilayer, and keeps the liposome structure stable, by tying the lipid bilayer strongly and protecting the outer wall of liposome at the same time, from salts or surfactants in aqueous solution which cause instability of liposome structure. In addition, it helps so that the water- insoluble bioactive compounds embedded in the lipid bilayer do not form the crystal in aqueous solution.
  • the water-insoluble bioactive compound solubilized through hydroxypropyl- ⁇ - cyclodextrin is embedded in the polymer-liposome complex.
  • the polymer is assembled with lipid-cholesterol based lipid bilayer, and keeps the liposome structure stable from salts or surfactants in aqueous solution which cause instability of liposome structure by tying the lipid bilayer strongly and protecting the outer wall of liposome.
  • composition of skin external application comprising polymer-liposome complex of the present invention is not limited in its formulation, and it can be formulated to skin softener, astringent, astringent lotion, nutritious cream, massage cream, eye cream, eye essence, essence, cleansing cream, cleansing lotion, cleansing foam, cleansing water, pack, powder, makeup base, foundation, body lotion, body cream, body oil, body essence, body cleanser, hair dye, shampoo, rinse, toothpaste, mouth wash solution, hair setting agent, hair tonic, lotion, ointment, gel, cream, patch and spray etc.
  • polymer-liposome complex using pH- sensitive polymer according to the present invention is designed to be capable of controlled release of drugs depending on the change in pH of solution by using the characteristic of changing its structure depending on pH of aqueous solution.
  • polymer-liposome complex of the present invention has a much improved delivery of active components to the body with better efficacy, by effectively releasing bioactive compounds, which are embedded in polymer-liposome complex, within cells since its stability deteriorates rapidly at a particular pH, and shows excellent skin absorption.
  • polymer-liposome complex using pH-sensitive polymer according to the present invention has much improved stability in regard to various salts and cosmetics formulation compared to the well-known lipid-cholesterol based liposome system. It has the effect not only to prevent titer decrease of bioactive compounds that are embedded in it but also to improve great skin absorption.
  • polymer- liposome complex of the present invention could stably embed water-insoluble bioactive compounds, which could be embedded in lipid-cholesterol based liposome, as well as the other water-insoluble bioactive compounds, which could not be embedded, in the lipid bilayer of polymer-liposome complex. It could embed water-insoluble bioactive compounds in the lipid bilayer, excluding triterpenoid, which could not be embedded in lipid-cholesterol based liposome.
  • polymer-liposome complex of the present invention could include various water- insoluble bioactive compounds, which were impossible to be embedded in the lipid bilayer of lipid-cholesterol based liposome, by being solubilized through hydroxypropyl- ⁇ -cyclodextrin. Regarding various cyclodextrins, it was verified that its structure was relatively stable compared to that of the lipid-cholesterol based liposome, which indicates its high value of practical use.
  • FIG. 1 shows the schematic diagram of polymer-liposome complex .
  • FIG. 2 shows the schematic diagram of polymer-liposome complex, in which the water-insoluble bioactive compounds are embedded .
  • FIG. 3 shows the schematic diagram of polymer-liposome complex, in which the water-insoluble bioactive compounds solubilized through hydroxypropyl- ⁇ -cyclodextrin are comprised.
  • FIG. 4 shows the photograph of crystal of betulin in aqueous solution using polarizing microscope.
  • FIG. 5 shows the photograph of polymer- liposome complex (Example 24), in which the betulin in aqueous solution is embedded, using polarizing microscope.
  • FIG. 6 shows the photograph of crystal of oleanolic acid in aqueous solution using polarizing microscope.
  • FIG. 7 shows the photograph of polymer-liposome complex (Example 28) , in which the oleanolic acid in aqueous solution is embedded, using polarizing microscope.
  • FIG. 8 shows the photograph of crystal of diosmetin in aqueous solution using polarizing microscope.
  • FIG. 9 shows the photograph of lipid-cholesterol based liposome (Comparative Example 9) , in which the diosmetin in aqueous solution is not embedded effectively, using polarizing microscope.
  • FIG. 10 shows the photograph of polymer-liposome complex (Example 30) , in which the diosmetin in aqueous solution is embedded, using polarizing microscope.
  • FIG. 11 shows the initial particle size distributions of lipid-cholesterol based liposome comprising the cyclodextrin ( (a) Comparative Example 12 : vesicle-only, (b) Comparative Example 13 : HP- ⁇ -CD, (c) Comparative Example 14 : ⁇ -CD, (d) Comparative Example 15 : M- ⁇ -CD, (e) Comparative Example 16 : DM- ⁇ -CD, (f) Comparative Example 17 : TM- ⁇ -CD, (g) Comparative Example 18 : ⁇ -CD) .
  • FIG. 12 shows the initial particle size distributions of polymer- liposome complex comprising the cyclodextrin ( (a)
  • Example 34 vesicle-only, (b) Example 35 : HP- ⁇ -CD, (c) Example 36 : ⁇ -CD, (d) Example 37 : M- ⁇ -CD, (e) Example 38 : DM- ⁇ -CD, (f) Example 39 : TM- ⁇ -CD, (g) Example 40 : ⁇ -CD) .
  • FIG. 13 shows the particle size distributions at 4 weeks after preparation of lipid-cholesterol based liposome comprising the cyclodextrin
  • (a) Comparative Example 12 vesicle-only,
  • Comparative Example 13 HP- ⁇ -CD,
  • Comparative Example 14 ⁇ -CD,
  • Comparative Example 15 M- ⁇ -CD,
  • Comparative Example 16 DM- ⁇ -CD,
  • Comparative Example 17 TM- ⁇ -CD
  • Comparative Example 18 : ⁇ -CD
  • FIG. 14 shows the particle size distributions at 4 weeks after preparation of polymer-liposome complex comprising the cyclodextrin
  • Example 34 vesicle-only
  • Example 35 HP- ⁇ -CD
  • Example 36 ⁇ -CD
  • Example 37 M- ⁇ -CD
  • Example 38 DM- ⁇ -CD
  • Example 39 TM- ⁇ -CD
  • Example 40 ⁇ -CD
  • FIG. 15 shows the heat capacity vs temperature of polymer-liposome complex (Example 5) according to the present invention in aqueous solution.
  • FIG. 16 shows the heat flow vs temperature when the former lipid-cholesterol based liposome (Comparative Example 2) dispersion is mixed to nanoemulsion composition.
  • FIG. 17 shows the heat flow vs temperature when the polymer-liposome complex (Example 4) dispersion according to the present invention is mixed to nanoemulsion composition.
  • FIG. 18 shows the particle size distribution of nanoemulsion of Experimental Example 4.
  • FIG. 19 shows the particle size distribution of polymer- liposome complex (Example 25) , in which the betulin is embedded, of Experimental Example 4.
  • FIG. 20 shows the particle size distribution of lipid- cholesterol based liposome (Comparative Example 6) , in which the betulin is embedded, of Experimental Example 4.
  • FIG. 21 shows the particle size distribution of nanoemulsion composition comprising polymer-liposome complex, in which the betulin is embedded, of Experimental Example 4.
  • FIG. 22 shows the particle size distribution of nanoemulsion composition comprising lipid-cholesterol based liposome of Experimental Example 4.
  • FIG. 23 shows the photo of structure change vs pH of the former lipid-cholesterol based liposome (Comparative Example 2) and polymer-liposome complex (Example 1 and 4) according to the present invention in aqueous solution of Experimental
  • FIG. 24 shows the photo of structure change vs pH of the former lipid-cholesterol based liposome (Comparative Example 6) and polymer- liposome complex (Example 25) , in which the betulin is embedded, according to the present invention in aqueous solution of Experimental Example 5.
  • FIG. 25 shows the skin permeability of arbutin using
  • FIG. 26 shows the skin permeability of arbutin using
  • FIG. 27 shows the skin permeability of rhaponticin using Franz-Cell of Example 42 and Comparative Example 28 of the present invention.
  • FIG. 28 shows the skin permeability of rhaponticin of polymer-liposome complex and nanoemulsion, in which the rhubarb extract solubilized through hydroxypropy1- ⁇ - cyclodextrin is comprised, prepared in Example 44 and Comparative Example 31 respectively.
  • Example 1 Preparation of polymer-liposome complex using the pH-sensitive polymer.
  • the polymer-liposome complex using the pH-sensitive polymer was prepared by the steps of: i) heating and dissolving poly (methacrylic acid-co-n-alkyl methacrylate) copolymer, 100% hydrated oleoyl-palmitoyl/oleoyl-stearyl phosphatidylcholine mixture (Lipoid S100-3) and cholesterol to ethanol (60 ° C), ii) adding said mixture to water (60 ° C), iii) preparing the first dispersed polymer-liposome complex by agitating said mixture using homogenizer at 5000 rpm for 5 minutes, iv) obtaining the nanoparticles from said mixture using high pressure homogenizer (1000 bar, 3 cycle) and v) removing the remaining ethanol solution using rotary evaporator.
  • Table 1 shows the compositions (weight basis) of said components .
  • Table 2 The components and the compositions used in polymer-liposome complex comprising the water-soluble bioactive compound.
  • Table 3 shows the weight compositions of said components .
  • the liposome comprised of lipid-cholesterol was prepared by the steps of: i) heating and dissolving 100% hydrated oleoyl-palmitoyl/oleoyl-stearyl phosphatidylcholine mixture (Lipoid S100-3) , cholesterol, ii) adding said mixture to water (60 ° C) or bioactive compound aqueous solution (60 ° C), iii) obtaining the nanoparticles from said mixture using high pressure homogenizer (1000 bar, 3 cycle) after agitating said mixture using homogenizer at 5000 rpm for 5 minutes and iv) removing the remaining ethanol solution using rotary evaporator.
  • Table 6 shows the weight compositions of said components .
  • the lipid-cholesterol based liposome, in which the water- insoluble bioactive compound is embedded was prepared by the steps of: i) heating and dissolving 100% hydrated oleoyl- palmitoyl/oleoyl-stearyl phosphatidylcholine mixture (Lipoid S100-3) , water-insoluble bioactive compound and cholesterol to organic solvent (60°C), ii) adding said mixture to water (60 ° C), iii) preparing the first dispersed lipid-cholesterol based liposome, in which the water-insoluble bioactive compound is embedded, by agitating said mixture using homogenizer at 5000 rpm for 5 minutes, iv) obtaining the nanoparticles from said mixture using high pressure homogenizer (1000 bar, 3 cycle) , v) removing the remaining organic solvent using rotary evaporator and vi) removing some water by distillation to control the concentration of the water-insoluble bioactive compound and the lipid-cholesterol based
  • Table 7 The components and the compositions used in lipid-cholesterol based liposome, in which the water-insoluble bioactive compound is embedded.
  • the lipid-cholesterol based liposome comprising the various cyclodextrins was prepared by the steps of: i) dissolving cyclodextrin to purified water and heating it to 60 ° C, ii) heating and dissolving cholesterol and 100% hydrated oleoyl-palmitoyl/oleoyl-stearyl phosphatidylcholine mixture (Lipoid S100-3) to organic solvent (60 ° C), iii) adding said mixture to cyclodextrin aqueous solution and heating it to 60 ° C, iv) preparing the lipid-cholesterol based liposome comprising the cyclodextrin by agitating said mixture using homogenizer at 5000 rpm for 5 minutes, v) obtaining the nanoparticles from said mixture using high pressure homogenizer (1000 bar, 3 cycle) , vi) removing the remaining organic solvent using rotary evaporator and vii) removing some water by distillation
  • the lipid-cholesterol based liposome in which the water- insoluble bioactive compound solubilized through hydroxypropyl- ⁇ -cyclodextrin is comprised, was prepared by the steps of: i) adding hydroxypropyl- ⁇ -cyclodextrin, water- insoluble bioactive compound and acidic or basic compound to purified water and heating it to 60 ° C, ii) solubilizing the water-insoluble bioactive compound by agitating said mixture using homogenizer at 7000 rpm for 10 minutes, iii) heating and dissolving cholesterol and 100% hydrated oleoyl- palmitoyl/oleoyl-stearyl phosphatidylcholine mixture (Lipoid S100-3) to organic solvent (60 ° C), iv) adding said mixture to water-insoluble bioactive compound aqueous solution and heating it to 60 ° C, v) preparing the lipid-cholesterol based liposome comprising the water-insoluble bioactive
  • the water-insoluble bioactive compound aqueous solution was prepared by the steps of : i) adding hydroxypropyl- ⁇ - cyclodextrin, water-insoluble bioactive compound and acidic or basic compound to purified water and heating it to 60 ° C and ii) solubilizing the water-insoluble bioactive compound by agitating said mixture using homogenizer at 7000 rpm for 10 minutes.
  • Table 11 shows the weight compositions of said components .
  • the nanoemulsion, in which 1 wt% of the rhubarb extract is comprised, was prepared as shown in Table 12 in order to compare the titer decrease and the skin permeability of polymer- liposome complex and lipid-cholesterol based liposome comprising 1 wt% of the rhubarb extract prepared according to Example 44 and Comparative Example 29.
  • polymer-liposome complex using the pH-sensitive polymer (Example 1 ⁇ 17) , polymer-liposome complex comprising the water-soluble bioactive compound (Example 18 ⁇ 23), polymer-liposome complex comprising the water-insoluble bioactive compound (Example 24 ⁇ 33) , polymer-liposome complex comprising various cyclodextrins (Example 34 ⁇ 40) , polymer- liposome complex, in which the water-insoluble bioactive compound solubilized through hydroxypropyl- ⁇ -cyclodextrin is comprised (Example 41 ⁇ 45) , lipid and lipid-cholesterol based liposome (Comparative Example 1 ⁇ 5) , lipid-cholesterol based liposome comprising the water-insoluble bioactive compound (Comparative Example 6 ⁇ 11) , lipid-cholesterol
  • Example 1 ⁇ 23 the particle size polymer-liposome complex comprising the pH-sensitive polymer (Example 1 ⁇ 23) was larger than that of liposome not comprising the pH-sensitive polymer (Comparative Example 1 ⁇ 5) . Also, in polymer-liposome complex of Example 1 - 23, when the amount of polymer was increased, its particle size was increased. From the particle sizes (150 nm & 80 nm) of polymer-liposome complex (Example 6 and 7) , it was found that the particle size depended on the concentration of lipid, cholesterol and polymer contained in ethanol .
  • Comparative Example 1 failed to prepare the liposome due to the precipitation while trying to prepare the liposome only with phosphatidylcholine.
  • the particles were successfully formed with the aid of polymer such as Example 3 even when vesicle was prepared with only phosphatidylcholine . It is presumed that said result was because the polymer played a good role in forming spherical bilayer of lipid.
  • Example 15 - 17 which formed particles from polymer-liposome complex comprising different mole ratio of methacrylic acid and stearyl methacrylate, it was verified that among complexes consisted of methacrylic acid and stearyl methacrylate, the mole ratio of stearyl methacrylate was between 10% and 50%.
  • Example 18 - 23 In the polymer-liposome complexes comprising the water- soluble active compounds (Example 18 - 23) , the change in particle sizes depending on the kind of active compounds was not nearly observed in the same composition and they showed almost the same particle sizes with the polymer-liposome complex of Example 1 ⁇ 17, which did not comprise active compounds .
  • Example 2 where the water-insoluble bioactive compounds are embedded had more stable form of liposome with a fixed particle size compared to the lipid-cholesterol based liposome (Comparative Example) where the water-insoluble bioactive compounds are embedded.
  • the polymer-liposome complexes comprising triterpenoid such as betulin, ursolic acid, oleanolic acid, etc. (Example 24 ⁇ 29) and lipid-cholesterol based liposome (Comparative Example 6 - 8) had formed stable liposome with particle sizes, because triterpenoid, different from other water-insoluble bioactive compounds, has similar molecular shape to cholesterol and is embedded in the lipid bilayer of liposome as shown in FIG. 2, so that it helps the formation of structurally and thermodynamically more stable spherical lipid bilayer structure of liposome .
  • the particle size of polymer-liposome complex comprising pH-sensitive polymer was larger than that of lipid-cholesterol based liposome not comprising the pH-sensitive polymer (Comparative Example) .
  • the polymer-liposome complexes of Example 30 ⁇ 33 in which the water-insoluble bioactive compounds such as diosmetin, phloretin, drabae semen extract except triterpenoid are embedded, had fixed particle sizes and made the stable form of liposome.
  • the lipid-cholesterol based liposome of Comparative Example 9 - 11 had a precipitation phenomenon and the liposome comprising the water-insoluble bioactive compound was not formed.
  • the pH-sensitive polymer comprised in polymer-liposome complex of the present invention played a supporting role in keeping the lipid bilayer stable, not alone with a pH-sensitivity to the lipid bilayer of liposome as shown in FIG. 2.
  • FIG. 4 - 10 shows the photographs of betulin crystal in aqueous solution, Example 24, oleanolic acid crystal in aqueous solution, Example 28, diosmetin crystal in aqueous solution, Comparative Example 9 and Example 30 using polarizing microscope. From FIG. 4 - 10, it was observed that betulin, oleanolic acid and diosmetin remained as crystals in aqueous solution and the polymer-liposome complex where betulin, oleanolic acid, and diosmetin were embedded (Example 24, 28 and 30) did not form the crystals of the above betulin, oleanolic acid and diosmetin in aqueous solution.
  • FIG. 4 - 10 shows that the water-insoluble bioactive compounds embedded in the polymer-liposome complex were well dispersed in the bilayer without crystallization. Accordingly, it was found that water-insoluble bioactive compounds were stably collected in the lipid bilayer of polymer- liposome complex .
  • Example 34 ⁇ 40 In comparison of the size between the polymer-liposome complex comprising various cyclodextrins in Example 34 ⁇ 40 and the lipid-cholesterol based liposome comprising various cyclodextrins in Comparative Example 12 ⁇ 18, it was observed that the polymer-liposome complex comprising various cyclodextrins in Example 34 ⁇ 40 had larger particles than the lipid-cholesterol based liposome in Comparative Example 12 ⁇ 18, just as the polymer-liposome complex not comprising cyclodextrin.
  • FIG. 11 and FIG. 12 show the particle size distributions of the as-prepared lipid-cholesterol based liposome of Comparative Example 12 ⁇ 18 and the polymer-liposome complex of Example 34 ⁇ 40.
  • FIG. 12 (a) ⁇ (g) shows the particle size distributions of the as-prepared lipid-cholesterol based liposome of Comparative Example 12 ⁇ 18 and the polymer-liposome complex of Example 34 ⁇ 40.
  • FIG. 12 (a) ⁇ (g) shows that stable vesicles were formed in polymer- liposome complex
  • FIG. 11 (a) ⁇ (d) , (f) and (g) show the particle size distributions at 4 weeks after preparation of lipid- cholesterol based liposome of Comparative Example 12 ⁇ 18 and polymer-liposome complex of Example 34 ⁇ 40.
  • lipid-cholesterol based liposome (Comparative Example 14, 16 and 18) comprising some cyclodextrin ( ⁇ -CD, DM- ⁇ -CD and ⁇ -CD) had started to have unstable structure, and then their particle sizes became larger or their particles were precipitated.
  • the polymer-liposome complex had formed and kept long-term stable structure regarding all cyclodextrins . Accordingly, it was found that in case of vesicle comprising cyclodextrin, the vesicle prepared by using polymer-liposome complex had much greater structural stability than lipid- cholesterol based vesicle.
  • FIG. 15 shows the thermal property, which was measured by microcalorimetry, on polymer-liposome complex of Example 5 and liposome of Comparative Example 4.
  • Liposome of Comparative Example 4 showed the transition point of gel to liquid crystal at around 50 ° Q but polymer-liposome complex of Example 5 showed it at around 43 ° C Having the transition point of gel to liquid crystal in polymer-liposome complex indicates that the self-assembly structure is being kept, which is the characteristics of bilayer. That means the aliphatic chain of stearyl methacrylate, a component of pH-sensitive polymer of polymer-liposome complex prepared according to the present invention, is self-assembled with lipid components. Thus, as shown in FIG. 1, it was found that the pH-sensitive polymer used in polymer-liposome complex keeps liposome's unique property by assembling with lipid-cholesterol and covers the wall of bilayers.
  • the polymer-liposome complex of Example 41 ⁇ 45 could obtain the stable vesicle aqueous solution with the particle sizes of 115 ⁇ 195 nm.
  • the polymer-liposome complex of Comparative Example 19 ⁇ 21 shown in Table 13 could not obtain the polymer-liposome complex aqueous solution, and the polymer-liposome complex itself was not well formed along with the crystal formation of the water-insoluble bioactive compound.
  • the particle size of polymer-liposome complex changed depending on the kind of water-insoluble bioactive compounds, which were solubilized through hydroxypropyl- ⁇ -cyclodextrin, and the concentration of the components of polymer-liposome complex.
  • polymers kept the liposome structure stable from various elements that made the liposome structure unstable in aqueous solution by assembling with the lipid-cholesterol based lipid bilayer, tying the lipid bilayer strongly and protecting the outer wall of liposome.
  • Table 15 shows the change in particle sizes of the solutions by the time, using dynamic light scattering, Zetasizer 3000HSa Malvern Instruments.
  • the solutions were kept at low temperature (2 ° C ) and at room temperature (25 ° C ) respectively in order to observe the long-term stability of polymer-liposome complex of Example 1, 4, 10, 11 and 19 and lipid-cholesterol based liposome in Comparative Example 2 and 3.
  • Table 15 shows the change in particle sizes of the solutions by the time, using dynamic light scattering, Zetasizer 3000HSa Malvern Instruments.
  • the solutions were kept at low temperature (2°C ), at room temperature (25 ° C ) and at high temperature (40 "C ) respectively in order to observe the long-term stability of polymer- liposome complex, in which the water-insoluble bioactive compounds were embedded (Example 24, 25, 30 and 31) , polymer-liposome complex, in which the water- insoluble bioactive compounds solubilized through hydroxypropyl- ⁇ -cyclodextrin were embedded (Example 41 ⁇ 44) and lipid-cholesterol based liposome, in which the water- insoluble bioactive compounds were embedded (Comparative Example 6) .
  • Comparative Example 3 In comparison of stability between lipid-cholesterol based liposome comprising streptomyces extract (Comparative Example 3) and polymer-liposome complex (Example 19) , Comparative Example 3 had the gradually increased particle size at low and room temperature as the storage time got longer. It formed some precipitation after eight weeks, but Example 19 with the same amount of streptomyces extract had the nearly unchanged particle size after eight weeks. Thus, it was observed that polymer-liposome complex of the present invention, when it included active components, kept more stable structure in the long run than lipid-cholesterol based liposome .
  • polymer-liposome complex in Example 24, 25, 30 and 31 and lipid-cholesterol based liposome in Comparative Example 6, which were kept in aqueous solution at 40 ° C had relatively increased particle sizes compared to any other temperatures. This might be resulted from the volume expansion of liposome by loosening of self-assembly of lipid bilayer of vesicles at high temperature of 40°C compared to low temperature (2 "C) and room temperature (25 "C).
  • polymer in polymer-liposome complex plays a supporting role in tying the lipid bilayer of liposome strongly so that the stable and bilayer structure of liposome can be kept even with cyclodextrin compared to lipid-cholesterol based liposome.
  • Table 16 shows the result of the long-term stability according to salt addition to polymer-liposome complex of Example 4 and 25, and to lipid-cholesterol based liposome of Comparative Example 2 and 6 in the sodium phosphate buffer solution and HEPES (N-2-hydroxyethyl-piperazine-N 1 -2-ethan sulfonate) buffer solution.
  • polydispersity indicates the size distribution of particles. Small value of polydispersity indicates the narrower distribution of particles.
  • the polymer-liposome complex of Example 4 according to the present invention did not show big difference in particle sizes and polydispersity in the long time regardless of storing at distilled water and the buffer solution with salt.
  • the particle size became larger, polydispersity increased, and the structure went unstable when it was kept in the sodium phosphate buffer solution added with sodium phosphate and sodium chloride (NaCl) , because the buffer solution with salt influenced the particle size and polydispersity.
  • polymer-liposome complex comprising betulin of Exmaple 25 did not show much of a difference in the particle size and polydispersity when it was kept in the buffer solution without salt or with salt, but in case of lipid- cholesterol based liposome comprising betulin of Comparative Example 6, it was observed that the particle size became larger and polydispersity increased, and the structure went unstable in the sodium phosphate buffer solution added with sodium phosphate and sodium chloride (NaCl) . When it was kept in the HEPES buffer solution, the structure collapsed and the precipitation is formed after one week.
  • polymer-liposome complex of the present invention had kept more stable structure in the existence of water-soluble bioactive compounds and other salts than lipid-cholesterol based liposome. Also, the polymer-liposome complex, in which the water-insoluble bioactive compounds are embedded, had a more stable structure in aqueous solution with salt, which was used in biosystems, than lipid-cholesterol based liposome, in which the water-insoluble bioactive compounds were embedded.
  • Comparative Example 2 were put into the nanoemulsion formulation with the average droplet size of 137 nm, which was formulated by the compositions and contents of Table 17, with 10 wt%, 30 wt% and 50 wt% of vesicle solutions at 60 ° C Then, they were stirred for five minutes at 7200 rpm through the homogenizer, and after the cooling and degassing process, the formulation comprising vesicle was prepared. The thermal behaviors of these prepared formulation-vesicle mixture was observed by using the differential scanning calorimetry, DSC QlOOO, TA Instruments. The results are shown in FIG. 16 and FIG. 17.
  • Table 17 The compositions and contents of nanoemulsion formulation to compare the stability of polymer-liposome complex with lipid-cholesterol based liposome in nanoemulsion formulation.
  • FIG. 16 shows the thermograms for the mixtures of nanoemulsion and lipid-cholesterol based liposome of Comparative Example 2 for various contents of vesicles.
  • Liposome showed the transition point of gel to liquid crystal at around 51 ° C and nanoemulsion showed the transition point of emulsion droplet at around 62 ° C.
  • each transition point was disappeared, but a single transition point appeared. It was also found that the transition point above changed as the composition changed. If vesicle and nanoemulsion droplet exist independently and stably within the mixture, the transition point of vesicle solution and nanoemulsion formulation should be appeared at each transition point with different peak intensity. From FIG.
  • FIG. 17 shows the thermograms of polymer-liposome complex of Example 4, which showed the transition point of gel to liquid crystal at 45°C.
  • polymer-liposome complex and nanoemulsion were mixed together, as also shown in FIG. 17, two transition points co-exist, which is characteristics of the transition point of gel to liquid crystal of polymer- liposome complex and droplet of nanoemulsion. Different from the case of liposome-nanoemulsion, this is because each polymer-liposome complex and nanoemulsion kept its own structure and stayed uniformly when polymer-liposome complex and nanoemulsion were mixed and stirred.
  • polymer-liposome complex of the present invention solved the problem of storage stability, which the current lipid-cholesterol liposome has.
  • the present invention also has a very stable structure in cosmetics formulation comprising water-soluble active compound, salt and surfactant compared to the lipid-cholesterol based liposome.
  • Example 4 The stability evaluation of polymer- liposome complex comprising betulin and lipid-cholesterol based liposome in nanoemulsion cosmetics formulation.
  • the solutions prepared in Example 25 and Comparative Example 6 were mixed with the nanoemulsion formulation with the average particle size of 137 nm, which was formulated by the compositions and contents of Table 17, with 10 wt% ratio of vesicle solutions.
  • nanoemulsion formulations comprising polymer-liposome complex comprising betulin and lipid-cholesterol based liposome respectively were produced.
  • FIG. 18-22 show the graph of the particle size using dynamic light scattering, Zetasizer 3000HSa Malvern Instruments, after storing the nanoemulsion above, polymer- liposome complex comprising betulin (Example 25) , lipid- cholesterol based liposome (Comparative Example 6) , nanoemulsion formulation comprising polymer- liposome complex comprising betulin and nanoemulsion formulation comprising lipid-cholesterol based liposome each for four weeks at room temperature .
  • FIG. 18 shows the particle size distribution of the nanoemulsion prepared from the composition of Table 17
  • FIG. 19 shows the particle size distribution of polymer-liposome complex comprising betulin (Example 25)
  • FIG. 20 shows the particle size distribution of lipid-cholesterol based liposome comprising betulin (Comparative Example 6)
  • FIG. 21 shows the particle size distribution of nanoemulsion formulation comprising polymer-liposome complex comprising betulin
  • FIG. 22 shows the particle size distribution of nanoemulsion formulation comprising lipid-cholesterol based liposome comprising betulin. From FIG.
  • nanoemulsion formulation comprising polymer-liposome complex comprising betulin had much better structural stability in the formulation than nanoemulsion formulation comprising lipid- cholesterol based liposome comprising betulin. It was also found that lipid-cholesterol based liposome comprising betulin failed to keep the stable liposome structure and collapsed when it got mixed within nanoemulsion formulation.
  • FIG. 23 shows the photographs of the solution after diluting the concentrations of polymer-liposome complex in Example 1 and Example 4 and liposome in Comparative Example 2 to 0.1 wt% by- using sodium phosphate buffer solution in which the pH of the solution was adjusted to 3 , 4, 5, 6 and 7.4 with hydrochloric acid solution.
  • Table 18 shows the change in particle sizes depending on pH of the solution.
  • FIG. 24 shows the photographs of the solution after diluting polymer-liposome complex comprising betulin as water- insoluble bioactive compound of Example 25 and lipid- cholesterol based liposome of Comparative Example 6 to 0.1 wt% by using sodium phosphate buffer solution, in which the pH of the solution was adjusted to 3, 4, 5, 6 and 7.4 with hydrochloric acid solution.
  • Table 18 shows the change in particle sizes depending on pH of the solution.
  • polymer-liposome complex of the present invention stably keeps its particle form at more than pH 5, but its stability deteriorates rapidly at less than pH 5, so that it can effectively release the bioactive compounds inside the cell and promote the delivery effect as a carrier.
  • polymer-liposome complex comprising betulin of Example 25 kept stable particle form at more than pH 5, but failed to keep it at lower pH and showed rapid structural collapse. This is because the pH-sensitive polymer has dramatic change in its form and destructs the structure of complex at less than pH 5.
  • polydispersity indicates the size distribution of particles. Small value of polydispersity indicates the narrower distribution of particles.
  • water-soluble bioactive compounds In order to promote the efficiency of water-soluble bioactive compounds within cells, they should have the function to promote the delivery efficiency of bioactive compounds within cells using a carrier, which also has to release the drug at a certain environment within cells at the same time.
  • the surroundings of ribosome within cells keep lower pH (pH 4.5 ⁇ 5.5) than the physiological condition.
  • the delivery efficiency can be promoted within cells of water-soluble bioactive compounds. Therefore, the following experiment was conducted to observe whether the water-soluble drug released selectively depending on pH of aqueous solution comprising polymer-liposome complex of the present invention.
  • 200 ⁇ l of polymer-liposome complex comprising HPTS-DPX and lipid-cholesterol based liposome were respectively put in 20 ml of 20 mM HEPES buffer solution (pH 7.1, includes 144 mM sodium chloride) and 20 ml of 100 mM MES buffer solution (pH 3.45, includes 144 mM sodium chloride) and then dispersed.
  • the 2 ml of this solution was sealed in the dialysis tube, and it was put into 30 ml of isotonic solution (pH 7.1 and 3.45 respectively) , which was controlled to have the same pH, and the amount of HPTS-DPX released was detected with time from the solution under contstant stirring and temperature .
  • Table 19 shows the amount of HPTS-DPX in the detected solution through fluorescence spectroscopy (Hitachi 4500) .
  • the total amount of HPTS-DPX in isotonic solution was detected through fluorescence spectroscopy (Hitachi 4500) after its structure was completely collapsed by putting polymer-liposome complex and liposome into 10% Triton X-100 solution.
  • polymer-liposome complex of the present invention changes dramatically its structure depending on pH changes and is able to control and release drugs depending on pH change.
  • the skin permeability of the arbutin solution collected by polymer- liposome complex as a carrier the arbutin solution collected by lipid-cholesterol based liposome and the arbutin aqueous solution without vesicle were measured.
  • the aqueous solution of polymer-liposome complex and lipid-cholesterol based liposome comprising 2 wt% of arbutin (Example 21 and Comparative Example 5) and 2 wt% of arbutin aqueous solution were prepared respectively.
  • the skin extracted from the Guinea pig was installed in Franz- cell (Hanson Research) , experiment equipment for skin permeability, and the upper side of the skin was filled with the aqueous solution of polymer-liposome complex comprising arbutin, the aqueous solution of lipid-cholesterol based liposome comprising arbutin and the arbutin aqueous solution respectively. Then, the solution released through the skin was withdrawed every six hour.
  • 25 shows quantified concentration of arbutin (Skin permeability, P (mg/cm 2 ) ) regarding how much arbutin molecules from the aqueous solution of polymer- liposome complex comprising arbutin, the aqueous solution of lipid-cholesterol based liposome comprising arbutin and the arbutin aqueous solution was permeated through the skin, using high performance liquid chromatography (Hewlett Packard) .
  • P skin permeability
  • polymer- liposome complex for promoting skin permeability improves when polymer- liposome complex exists in emulsion formulation, compared to lipid-cholesterol based liposome and the aqueous solution comprising arbutin.
  • FIG. 26 shows the result of skin permeability of said mixture using the same method above . From FIG. 26, different from FIG.
  • polymer-liposome complex has excellent skin permeability not only in vesicle itself but also in multi- component systems including salt, oil, wax, etc.
  • lipid-cholesterol based liposome has lost the skin permeability that vesicle itself has and showed the almost same skin permeability ability with the emulsion formation without vesicle. This is considered to be quite related to structural stability inside the emulsion system of vesicle as described above.
  • Example 44 The titer stability of rhubarb extract was observed in polymer-liposome complex, in which rhubarb extracts solubilized through hydroxypropyl- ⁇ -cyclodextrin was embedded, (Example 44) and nanoemulsion comprising rhubarb extract (Comparative Example 31) .
  • Table 20 shows the measurement result of rhaponticin concentration, an indicative component of rhubarb extract, using high performance liquid chromatography, with time while the samples of Example 44 and Comparative Example 31 were kept at room temperature and 40 ° C respectively.
  • Rhaponticin the indicative component of rhubarb extract, is a water- insoluble bioactive compound that is inclined to decrease its concentration by light or temperature. According to the result of Table 20 above, rhubarb extract comprised in polymer-liposome complex, after it is solubilized by hydroxypropyl- ⁇ -cyclodextrin, has better titer stability compared to rhubarb extract comprised in the nanoemulsion.
  • the skin absorption of rhaponticin was compared between polymer-liposome complex comprising rhaponticin solubilized through hydroxypropyl- ⁇ -cyclodextrin and the aqueous solution where rhaponticin solubilized through hydroxypropy1- ⁇ - cyclodextrin was dispersed prepared in Example 42 and Comparative Example 28 respectively.
  • FIG. 27 and FIG. 28 show the result of rhaponticin concentration that was permeated into the skin, using high performance liquid chromatography, in order to compare the skin absorption of rhaponticin.
  • FIG. 27 is the comparison result of skin absorption of rhaponticin between polymer-liposome complex comprising rhaponticin solubilized through hydroxypropyl- ⁇ -cyclodextrin (Example 42) and the aqueous solution, in which rhaponticin solubilized through hydroxypropyl- ⁇ -cyclodextrin was dispersed (Comparative Example 28).
  • Rhaponticin solubilized through hydroxypropyl- ⁇ -cyclodextrin showed quite good skin permeation, but polymer-liposome complex of Example 42 had 162% higher skin permeation of rhaponticin compared to the aqueous solution of Comparative Example 28.
  • FIG. 28 is the comparison result of skin absorption of rhaponticin, the indicative component of rhubarb extract, between polymer-liposome complex comprising rhubarb extract solubilized through hydroxypropyl- ⁇ -cyclodextrin (Example 44) and nanoemulsion comprising rhubarb extract (Comparative Example 31) .
  • rhubarb extracts in polymer-liposome complex had 842% higher skin absorption effect of rhaponticin. This is much higher skin absorption effect of rhaponticin than the current formulation and it can be a great help for various formulation prescription of water-insoluble bioactive compounds through hydroxypropyl- ⁇ -cyclodextrin and polymer-liposome complex with excellent stability.
  • streptomyces extract was used, which is known to have the ability to inhibit melanin formation.
  • Polymer-liposome complex comprising the ⁇ streptomyces extracts (Example 19) and streptomyces extract aqueous solution were inserted into cell culture medium in order to keep the concentration of all streptomyces extracts in the medium cultivating human melanoma HM3KO cells as noted in Table 21. After the culture medium including the cells above was incubated for 24 hours, the cells were removed and the remaining solution was collected after centrifugal separation of the cells. Table 21 shows the ratio of amount of melanin from the intensity of absorbance peak that was produced at 490 nm using UV-vis spectroscopy.
  • Polymer-liposome complex using pH-sensitive polymer according to the present invention is designed to be capable of controlling and releasing drugs depending on the change in pH of solution by using the characteristics of changing its structure depending on pH of aqueous solution.
  • polymer- liposome complex of the present invention could stably embed water-insoluble bioactive compounds, which could be embedded in lipid-cholesterol based liposome, as well as the other water-insoluble bioactive compounds, which could not be embedded in lipid-cholesterol based liposome, in the lipid bilayer of polymer-liposome complex. It could embed water- insoluble bioactive compounds in the lipid bilayer, excluding triterpenoid, which could not be embedded in lipid-cholesterol based liposome.
  • polymer-liposome complex of the present invention could include/embed various water-insoluble bioactive compounds, which were impossible to be included/embedded in the lipid bilayer of general lipid-cholesterol based liposome, inside the liposome after being solubilized through hydroxypropyl- ⁇ -cyclodextrin. Regarding various cyclodextrins, it was verified that its structure was relatively stable compared to that of the general lipid-cholesterol based liposome .
  • polymer-liposome complex of the present invention has a much improved delivery efficiecy of active components to the body and better efficacy, by effectively releasing bioactive components, which are embedded in polymer- liposome complex, within cells since its stability deteriorates rapidly at a particular pH, and shows excellent skin permeation.
  • polymer-liposome complex using pH-sensitive polymer according to the present invention has much improved stability in regard to various salts and cosmetics formulation compared to the well-known lipid- cholesterol based liposome system. It has the effect not only to prevent titer decrease of bioactive components that are embedded in it but also to improve great skin permeation, which indicates its high value of practical use.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Birds (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

L'invention concerne un complexe polymère-liposome utilisant un polymère sensible au pH et son procédé de préparation, ainsi que la composition de l'application cutanée externe contenant ce complexe. L'invention concerne également un vecteur de médicaments à base de polymère-lipide et la composition de l'application cutanée externe conçue pour être présente de manière stable dans une solution aqueuse, une solution aqueuse contenant divers sels et une formulation cosmétique en comparaison avec un liposome à base de lipides.
PCT/KR2006/005298 2005-12-30 2006-12-07 Nanocomplexes polymere-liposome et leur procede de preparation, et composition de l'application cutanee externe les contenant WO2007078060A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR1020050135409A KR100654102B1 (ko) 2005-12-30 2005-12-30 유용성 생리활성성분이 함입된 안정도가 우수한 산성도민감성 고분자-리포좀 나노복합체의 제조 및 이를 함유하는화장품 조성물
KR10-2005-0135409 2005-12-30
KR10-2005-0134707 2005-12-30
KR1020050134707A KR100716802B1 (ko) 2005-12-30 2005-12-30 산성도 민감성 고분자를 포함한 고분자-리포좀 나노복합체제조 및 이를 함유하는 피부 외용제 조성물
KR10-2006-0020942 2006-03-06
KR1020060020942A KR100793824B1 (ko) 2006-03-06 2006-03-06 하이드록시프로필-베타사이클로 덱스트린을 이용하여가용화된 유용성 생리활성성분을 담지하는 고분자-리포좀나노복합체

Publications (1)

Publication Number Publication Date
WO2007078060A1 true WO2007078060A1 (fr) 2007-07-12

Family

ID=38228380

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/005298 WO2007078060A1 (fr) 2005-12-30 2006-12-07 Nanocomplexes polymere-liposome et leur procede de preparation, et composition de l'application cutanee externe les contenant

Country Status (1)

Country Link
WO (1) WO2007078060A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120189689A1 (en) * 2009-06-08 2012-07-26 Epitarget As Acoustically sensitive drug delivery particles comprising non-lamellar forming phosphatidylcholine
JP2012206948A (ja) * 2011-03-29 2012-10-25 Kose Corp リポソーム組成物、並びにそれを用いた化粧料、皮膚外用剤及びその製造方法
CN102844021A (zh) * 2010-04-13 2012-12-26 株式会社爱茉莉太平洋 用于经皮吸收的聚合物/脂质体纳米复合材料组合物及其制备方法
CN102871848A (zh) * 2012-10-15 2013-01-16 西安雅芝生物科技有限公司 五环三萜类化合物环糊精包合物前体脂质体及其制备方法
CN103221028A (zh) * 2010-11-22 2013-07-24 株式会社爱茉莉太平洋 含有齐墩果酸的化妆品组合物
WO2015167402A1 (fr) * 2014-05-02 2015-11-05 Agency For Science, Technology And Research Masque facial de traitement dermique
CN105521494A (zh) * 2014-10-15 2016-04-27 株式会社爱茉莉太平洋 含有大分子的、引入有细胞穿透肽的药物输送载体
WO2016065444A1 (fr) * 2014-10-31 2016-05-06 Universidade Estadual De Campinas - Unicamp Procédé d'obtention de transporteurs lipidiques nanostructurés en copolymère tribloc, transporteurs lipidiques nanostructurés ainsi obtenus et leurs utilisations
CN106432612A (zh) * 2016-11-05 2017-02-22 上海碳威新材料科技有限公司 一种环糊精囊泡及其制备方法和应用
CN108969444A (zh) * 2018-09-19 2018-12-11 陈洁珍 一种去黑眼圈、抗皱紧肤修护眼霜及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011757A1 (fr) * 1991-12-10 1993-06-24 Orion-Yhtymä Oy Compositions de medicaments pour usage parenteral
US6379697B1 (en) * 1994-06-03 2002-04-30 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Orthern Ireland Stabilization of photosensitive materials

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011757A1 (fr) * 1991-12-10 1993-06-24 Orion-Yhtymä Oy Compositions de medicaments pour usage parenteral
US6379697B1 (en) * 1994-06-03 2002-04-30 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Orthern Ireland Stabilization of photosensitive materials

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8906409B2 (en) * 2009-06-08 2014-12-09 Epitarget As Acoustically sensitive drug delivery particles comprising non-lamellar forming phosphatidylcholine
US20120189689A1 (en) * 2009-06-08 2012-07-26 Epitarget As Acoustically sensitive drug delivery particles comprising non-lamellar forming phosphatidylcholine
CN102844021A (zh) * 2010-04-13 2012-12-26 株式会社爱茉莉太平洋 用于经皮吸收的聚合物/脂质体纳米复合材料组合物及其制备方法
US9572769B2 (en) 2010-04-13 2017-02-21 Amorepacific Corporation Polymer-liposome nanocomposite composition for percutaneous absorption, and method for preparing same
JP2016222694A (ja) * 2010-11-22 2016-12-28 株式会社アモーレパシフィックＡｍｏｒｅｐａｃｉｆｉｃ Ｃｏｒｐｏｒａｔｉｏｎ オレアノール酸が捕集された化粧料用ナノリポソームの製造方法
CN103221028A (zh) * 2010-11-22 2013-07-24 株式会社爱茉莉太平洋 含有齐墩果酸的化妆品组合物
JP2013542984A (ja) * 2010-11-22 2013-11-28 株式會社アモーレパシフィック オレアノール酸を含有する化粧料組成物
JP2012206948A (ja) * 2011-03-29 2012-10-25 Kose Corp リポソーム組成物、並びにそれを用いた化粧料、皮膚外用剤及びその製造方法
CN102871848A (zh) * 2012-10-15 2013-01-16 西安雅芝生物科技有限公司 五环三萜类化合物环糊精包合物前体脂质体及其制备方法
WO2015167402A1 (fr) * 2014-05-02 2015-11-05 Agency For Science, Technology And Research Masque facial de traitement dermique
CN105521494A (zh) * 2014-10-15 2016-04-27 株式会社爱茉莉太平洋 含有大分子的、引入有细胞穿透肽的药物输送载体
CN105521494B (zh) * 2014-10-15 2021-06-29 株式会社爱茉莉太平洋 含有大分子的、引入有细胞穿透肽的药物输送载体
WO2016065444A1 (fr) * 2014-10-31 2016-05-06 Universidade Estadual De Campinas - Unicamp Procédé d'obtention de transporteurs lipidiques nanostructurés en copolymère tribloc, transporteurs lipidiques nanostructurés ainsi obtenus et leurs utilisations
CN106432612A (zh) * 2016-11-05 2017-02-22 上海碳威新材料科技有限公司 一种环糊精囊泡及其制备方法和应用
CN108969444A (zh) * 2018-09-19 2018-12-11 陈洁珍 一种去黑眼圈、抗皱紧肤修护眼霜及其制备方法
CN108969444B (zh) * 2018-09-19 2021-02-02 青岛生康盛生物科技有限公司 一种去黑眼圈、抗皱紧肤修护眼霜及其制备方法

Similar Documents

Publication Publication Date Title
WO2007078060A1 (fr) Nanocomplexes polymere-liposome et leur procede de preparation, et composition de l'application cutanee externe les contenant
Verma et al. Self assembled materials: design strategies and drug delivery perspectives
Elnaggar et al. Lecithin-based nanostructured gels for skin delivery: an update on state of art and recent applications
Wang et al. Preparation and evaluation of lidocaine hydrochloride-loaded TAT-conjugated polymeric liposomes for transdermal delivery
Cai et al. Micelles of different morphologies—advantages of worm-like filomicelles of PEO-PCL in paclitaxel delivery
Tsai et al. Liposomal microencapsulation using the conventional methods and novel supercritical fluid processes
Dhawan et al. Catanionic systems in nanotherapeutics–Biophysical aspects and novel trends in drug delivery applications
US5962015A (en) Stabilized liposomes
US20200345651A1 (en) Nanocapsule for delivery of lipophilic compound and process of preparation thereof
US20080181939A1 (en) Polymersomes and related encapsulating membranes
Pinto et al. Niosomes as nano-delivery systems in the pharmaceutical field
JP5856144B2 (ja) 経皮吸収用高分子‐リポソームナノ複合体組成物及びその製造方法
US11826474B2 (en) Nano-lipid carrier for encapsulation of bioactive material, and method for producing same
Hong et al. Role of zein incorporation on hydrophobic drug-loading capacity and colloidal stability of phospholipid nanoparticles
Kuznetsova et al. Cationic liposomes mediated transdermal delivery of meloxicam and ketoprofen: Optimization of the composition, in vitro and in vivo assessment of efficiency
Umbarkar Niosome as a Novel Pharmaceutical Drug Delivery: A Brief Review Highlighting Formulation, Types, Composition and Application.
Kapare et al. Micellar drug delivery system: a review
US20100143424A1 (en) Casein nanoparticle
US20230017661A1 (en) Compositions and modular nano- and microparticles for the delivery of various agents and use thereof
KR100716802B1 (ko) 산성도 민감성 고분자를 포함한 고분자-리포좀 나노복합체제조 및 이를 함유하는 피부 외용제 조성물
CN104667286B (zh) 一种尺寸单分散性聚合物纳米囊泡及其制备方法和应用
Pippa et al. Preparation, development and in vitro release evaluation of amphotericin B–loaded amphiphilic block copolymer vectors
KR100654102B1 (ko) 유용성 생리활성성분이 함입된 안정도가 우수한 산성도민감성 고분자-리포좀 나노복합체의 제조 및 이를 함유하는화장품 조성물
Patel et al. Cubosomes: novel nanocarriers for drug delivery
KR100793824B1 (ko) 하이드록시프로필-베타사이클로 덱스트린을 이용하여가용화된 유용성 생리활성성분을 담지하는 고분자-리포좀나노복합체

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06824005

Country of ref document: EP

Kind code of ref document: A1