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WO2008100044A1 - Nanoparticules d'hydrogel d'acide hyaluronique chimiquement réticulé, et procédé d'élaboration correspondant - Google Patents

Nanoparticules d'hydrogel d'acide hyaluronique chimiquement réticulé, et procédé d'élaboration correspondant Download PDF

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WO2008100044A1
WO2008100044A1 PCT/KR2008/000772 KR2008000772W WO2008100044A1 WO 2008100044 A1 WO2008100044 A1 WO 2008100044A1 KR 2008000772 W KR2008000772 W KR 2008000772W WO 2008100044 A1 WO2008100044 A1 WO 2008100044A1
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hyaluronic acid
emulsion
water
dissolved
crosslinking
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Hyung Jun Lim
Eun Chul Cho
Ji Hae Lee
Junoh Kim
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Amorepacific Corp
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Amorepacific Corp
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    • 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
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47K—SANITARY EQUIPMENT NOT OTHERWISE PROVIDED FOR; TOILET ACCESSORIES
    • A47K7/00—Body washing or cleaning implements
    • A47K7/02—Bathing sponges, brushes, gloves, or similar cleaning or rubbing implements
    • A47K7/028—Bathing sponges, brushes, gloves, or similar cleaning or rubbing implements having a rigid handle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/38—Swabs having a stick-type handle, e.g. cotton tips
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • 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
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • 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
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/57—Compounds covalently linked to a(n inert) carrier molecule, e.g. conjugates, pro-fragrances

Definitions

  • the present invention relates to chemically crosslinked hyaluronic acid nanoparticles and a method for preparing the same, and more particularly to chemically crosslinked hyaluronic acid nanoparticles, which are prepared by mixing an oil phase containing a surfactant dissolved therein with a water phase, containing hyaluronic acid and a water-soluble crosslinker, dissolved in an aqueous basic solution, so as to form a w/o emulsion, and crosslinking the hyaluronic acid in the w/o emulsion, are uniformly absorbed and dispersed in the horny layer of the skin, when they are applied on the skin, thus showing improved ability to be absorbed into the skin, and show high water-swelling ratio, when they are dispersed in water.
  • Hyaluronic acid is a straight chain macromolecular mucopolysaccharide composed of repeating units of ⁇ -D-N- acetylglucosamine and ⁇ -D-glucuronic acid.
  • Hyaluronic acid is known to be found not only in mammalian connective tissue, such as subcutaneous tissue or cartilage tissue, but also in the vitreous body of the eye, umbilical cords, and in the capsules of Streptococci, etc.
  • Hyaluronic acid is generally obtainable not only by extraction from cockscombs and umbilical cords, but also as extracted and purified products from the culture broth of streptococci.
  • Natural hyaluronic acid having excellent biocompatibility has no species specificity or tissue or organ specificity and functions to increase skin moisturization, maintain skin elasticity, reduce damage to the lower skin layers when the skin is damaged, and in addition, acts like a lubricant so as to smooth the movement of collagen, the main component of the skin, between cells.
  • natural hyaluronic acid when used intact, it will show poor mechanical properties and is readily degraded and removed by hyaluronidase enzyme in vivo, thus imposing limitations the use thereof in various applications .
  • many studies focused on forming hydrogel through chemical modification or crosslinking with various crosslinkers have been conducted.
  • hydrogel by the chemical modification or crosslinking of hyaluronic acid is generally performed through the alcohol group and carboxylic acid group located at the backbone thereof.
  • the chemical modification of hyaluronic acid is mainly performed by esterification of the carboxylic acid group at the hyaluronic acid backbone is mainly performed by esterification (D. Campoccia et al . , Biomaterials, 19, 1998, 2101-2127)
  • crosslinking for forming hydrogel is performed using dihydrazide (K. P. Vercruysse et al . ,
  • microparticles obtained by preparing micrometer-sized particles from a polymer material and chemically modifying the inside of the particles, have been applied in various fields, including embolization, enzyme immobilization and drug delivery. Since the year 2000, with the development of nanotechnology, studies on the preparation of nanosized particles from water-soluble polymers and the application thereof have been conducted. To date, most studies on hydrogel particles have been focused on the use of biodegradable polymers for application in the fields of new bio-drugs and bio-organs, and on the fabrication of injectable structures for non-invasive surgery. The fields include drug delivery systems, embolization, tissue engineering scaffolds, bulking agents and implants.
  • hydrogel particles are widely used in applications, including the isolation, concentration and stabilization of proteins, immunoassays, bioeactors, sensors, biospecific chromatography and cosmetic fillers.
  • Such hydrogel particles are prepared using physical methods, including emulsification, coacervation, and spray drying, and chemical methods such as heterogeneous polymerization.
  • microcapsules having walls made of polysaccharides can be prepared through crosslinking at the interface in w/o emulsions (M. C. Levy et al., Int. J. Pharm., 62, 1990, 27-35; PCT/FR93/00237) .
  • microcapsules having a size of more than a few micrometers, crosslinked only at the interface are obtained through crosslinking at the interface between the crosslinker- containing organic phase and the polysaccharide-containing aqueous phase in the w/o emulsion.
  • studies focused on preparing hydrogel particles using hyaluronic acid having various advantages have also been conducted, and most of hyaluronic acid hydrogel particles, prepared through chemical crosslinking, have been prepared through w/o emulsions as described by way of example above (V. Dulong et al., Carbohydrate Polymers, 57, 2004, 1-6; Y. H.
  • Hydrogel nanoparticles may have a very high water-swelling ratio, because they have a short diffusion length of water and a large surface area, and in addition, as the particle size thereof become smaller, they can show a significantly improved skin absorption rate compared to that of hydrogel microparticles .
  • the surface of the hyaluronic acid hydrogel nanoparticles showing the above-described characteristics is introduced with reactive groups to allow target factors, physiologically active substances or the like to bind thereto, it is possible to develop functional materials which can very quickly respond to external stimuli.
  • hyaluronic acid nanoparticles were prepared by determining the kind of oil, the oil phase-to-water phase ratio of a w/o emulsion, the kind and concentration of a surfactant, the kind and concentration of a crosslinker, the concentration of hyaluronic acid in the aqueous solution and the like as preparation parameters and controlling such parameters. Also, it was observed through a transmission electron microscope and a scanning electron microscope that the size of the hyaluronic acid hydrogel nanoparticles could be reduced to a few tens of nanometers .
  • hyaluronic acid hydrogel nanoparticles were dispersed in water, the hydrogel nanoparticles were swollen with water, so that the particle size thereof was increased to a few micrometers or larger.
  • a skin absorption test was carried out by dispersing fluorescent-conjugated hyaluronic acid hydrogel nanoparticles in oil, applying the dispersion on the skin obtained from albino guinea pigs, and measuring the skin absorption of the hydrogel nanoparticles using a Franz-cell system.
  • a confocal laser scanning microscope it was observed through a confocal laser scanning microscope that the hyaluronic acid hydrogel nanoparticles were uniformly absorbed and dispersed in the horny layer of the skin tissue, thereby completing the present invention.
  • the present invention provides a method of preparing hyaluronic acid hydrogel nanoparticles by crosslinking hyaluronic acid, the method comprising: mixing i) an oil phase containing a surfactant dissolved therein with ii) a water phase, containing hyaluronic acid and a water-soluble crosslinker, dissolved in an aqueous basic solution, so as to a form a w/o emulsion, and crosslinking the hyaluronic acid in the w/o emulsion.
  • the present invention provides hyaluronic acid hydrogel nanoparticles, prepared by crosslinking hyaluronic acid in a mixture of i) an oil phase containing a surfactant dissolved therein and ii) a water phase, containing hyaluronic acid and a water-soluble crosslinker, dissolved in an aqueous basic solution.
  • the present invention relates to a method for preparing chemically crosslinked hyaluronic acid hydrogel nanoparticles, the method comprising mixing i) an oil phase containing a surfactant dissolved therein with ii) a water phase, containing hyaluronic acid and a water-soluble crosslinker, dissolved in an aqueous basic solution, so as to a form a w/o emulsion, and crosslinking the hyaluronic acid in the w/o emulsion.
  • the mixing ratio between the oil phase containing the surfactant dissolved therein and the water phase, containing the hyaluronic acid and the water- soluble crosslinker, dissolved in the aqueous basic solution, which are used to form the w/o emulsion is preferably 1:1 to 7:3 (oil phase: water phase) by weight.
  • the water phase-to-oil phase ratio influences the particle size and stability of the w/o emulsion, and if the ratio of the water phase to the oil phase is excessively high, a large and unstable w/o emulsion will be formed, and thus the size of the resulting dried particles will be increased.
  • the inventive method for preparing the chemically crosslinked hyaluronic acid hydrogel nanoparticles comprises the steps of: a) dissolving a surfactant in an oil component; b) dissolving hyaluronic acid and a water-soluble crosslinker in an aqueous basic solution; c) adding the solution of step b) to the solution of step a) to form a w/o emulsion; d) heating the w/o emulsion of step c) at 60 ° C while crosslinking the hyaluronic acid with the crosslinker in the aqueous solution; e) maintaining the temperature of the w/o emulsion of step d) at room temperature and, at the same time, neutralizing the aqueous solution with an acid and completing the crosslinking between the crosslinker and the hyaluronic acid; and f) collecting hyaluronic acid hydrogel nanoparticles from the w/o emulsion of step e
  • the collection of the hyaluronic acid hydrogel nanoparticles in the step f) is carried out by washing the w/o emulsion of step e) with an organic solvent to obtain a hyaluronic acid hydrogel nanoparticle solution and drying the obtained nanoparticle solution in a vacuum at a temperature of 70-90 ° C to removing the remaining organic solvent .
  • the molecular weight of the hyaluronic acid which is used to prepare the hyaluronic acid hydrogel nanoparticles of the present invention, influences the viscosity of the w/o emulsion.
  • the molecular weight of the hyaluronic acid that is used in the present invention is 300,000-10,000,000
  • the oil phase that is used to the hyaluronic acid hydrogel nanoparticles of the present invention may be at least one selected from among vegetable oil, mineral oil, silicone oil and synthetic oil. Preferably, it is cetyl ethylhexanoate (CEH), dodecane or heptane.
  • CEH cetyl ethylhexanoate
  • dodecane dodecane or heptane.
  • the surfactant that is used to prepare the hyaluronic acid hydrogel nanoparticles may be at least one selected from surfactants which can stabilize the w/o emulsion.
  • the surfactant may be cetyl PEG/PPG-10/1 dimethicone (ABIL EM-90) , sorbitan sesquioleate (ARLACEL 83) , or polyethylene glycol (30) dipolyhydroxy stearate (ARLACEL P135) .
  • the water-soluble crosslinker that is used to prepare the hyaluronic acid hydrogel nanoparticles of the present invention may be at least one selected from crosslinkers which form crosslinkes with natural polymer saccharides.
  • crosslinkers which form crosslinkes with natural polymer saccharides.
  • ester linkages other than ester linkages, which were frequently formed through esterfication in the prior art, will be formed.
  • PEG chain as a backbone in order for the components of the crosslinked structure to have a higher affinity for water when the crosslinked structure is dispersed in water.
  • BDG buthylene glycol diglycidyl ether
  • PEGDG polyethylene glycol diglycidyl ether
  • the inventive method for preparing the hyaluronic acid hydrogel nanoparticles in order to carry out the crosslinking of the hyaluronic acid with the crosslinker in the aqueous solution, it is required to increase the pH of the aqueous basic solution, containing the hyaluronic acid and the crosslinker, dissolved therein, to a pH of 12-14 using a base, such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate or ammonia, so as to increase the reactivity of the hydroxyl group of the hyaluronic acid.
  • a base such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate or ammonia
  • the reaction temperature be lowered to room temperature and that the aqueous basic solution be neutralized with an acid, such as acetic acid, hydrochloric acid, sulfuric acid, nitric acid or citric acid.
  • the amount of the hyaluronic acid that is used to the hyaluronic acid hydrogel nanoparticles of the present invention is 1-10 wt%, and preferably 2-5 wt%, based on the weight of the aqueous basic solution.
  • the concentration of the hyaluronic acid in the aqueous solution is lower than the lower limit of the above-specified range, entanglement between polymer chains will be reduced, and thus crosslinking in the same chain rather than crosslinking between different chains will occur, so that a three-dimensional network structure comprising several hyaluronic acid backbones cannot be obtained.
  • the concentration of the hyaluronic acid in the aqueous solution exceeds the upper limit of the above- specified range, the viscosity thereof in the aqueous solution will be excessively increased, making it difficult to form small and stable w/o emulsion particles.
  • the concentration of hyaluronic acid is 2-5 wt% based on the weight of the aqueous solution in order to provide the desired results.
  • the amount of the surfactant that is required to prepare the hyaluronic acid hydrogel nanoparticles and functions to stably maintain the w/o emulsion is 1-10 wt%, and preferably 2-6 wt%, based on the weight of the mixture of the oil phase and the aqueous phase in the w/o emulsion.
  • the concentration of the surfactant influences the particle size and stability of the w/o emulsion, and thus, if it is lower than the lower limit of the above-specified range, the size and of the particles will be increased and the stability of the particles will be reduced.
  • the surfactant will stabilize the w/o emulsion particles, but it becomes an unnecessary impurity component in the resulting particles, and thus is preferably used in small amounts in view of purity.
  • the surfactant is preferably used in an amount of 2-6 wt%.
  • a water-miscible organic solvent which is used to collect crosslinked hyaluronic acid hydrogel nanoparticles from the w/o emulsion and wash the nanoparticles, is not specifically limited, but is selected from among ethanol, methanol, isopropylalcohol, acetone and tetrahydrofuran .
  • the inventive preparation method may further comprise a step of making an aqueous solution of the washed hyaluronic acid hydrogel nanoparticles and washing the aqueous solution with an organic solvent .
  • the inventive chemically crosslinked hyaluronic acid hydrogel nanoparticles obtained through the above- described preparation method, may have a particle size ranging from a few tens to a few hundreds of nanometers in a dried state by controlling preparation parameters, including the concentration of hyaluronic acid in the aqueous phase of the w/o emulsion, the kind of crosslinker, the water phase-to-oil phase ratio of the w/o emulsion, the kind of oil in the w/o emulsion, and the kind and concentration of surfactant in the w/o emulsion.
  • the hyaluronic acid hydrogel nanoparticles are characterized in that, when they are swollen with water, the particle size thereof will increase to a few micrometers or larger within a short time.
  • the preparation parameters are not suitably controlled, the w/o emulsion will become unstable, or the particle size of the w/o emulsion will increase, and in addition, the particle size of the resulting chemically crosslinked hyaluronic acid hydrogel particles will increase, so that the particles will hardly have a size of nanometer scale in a dried state .
  • the present invention provides hyaluronic acid hydrogel nanoparticles, prepared by crosslinking hyaluronic acid in a w/o emulsion consisting of a mixture of i) an oil phase containing a surfactant dissolved therein and ii) a water phase, containing hyaluronic acid and a water-soluble crosslinker, dissolved in an aqueous basic solution.
  • the mixing ratio between the oil phase containing the surfactant dissolved therein and the water phase, containing the hyaluronic acid and the water-soluble crosslinker, dissolved in the aqueous basic solution, which are used to form the w/o emulsion is preferably 1:1-7:3 (oil phase: water phase) by weight.
  • the water-soluble crosslinker is preferably a bisepoxide, such as butylene glycol diglycidyl ether (BDG) or polyethylene glycol diglycidyl ether (PEGDG) .
  • BDG butylene glycol diglycidyl ether
  • PEGDG polyethylene glycol diglycidyl ether
  • the chemically crosslinked hyaluronic acid hydrogel nanoparticles according to the present invention may have a particle size much smaller than that of hyaluronic acid hydrogel microparticles, prepared through the prior general w/o emulsion, as a result of controlling various preparation parameters. Also, because the particle size thereof was reduced to the nanometer scale, it was observed that the hyaluronic acid hydrogel nanoparticles showed an improved ability to be absorbed into skin tissue, and in addition, the safety of the hyaluronic acid hydrogel nanoparticles could be confirmed through primary skin irritation tests. Also, when the HA hydrogel nanoparticles are dispersed in water, they show high water-swelling ratio, suggesting that they can be used in various applications. [Description of Drawings]
  • FIG. 1 is an optical micrograph of a w/o emulsion, containing hyaluronic acid and a crosslinker in a water phase.
  • A Example 12; B: Example 13; C: Comparative Example 5; and D: Comparative Example 6.
  • FIG. 2 is a scanning electron micrograph of dried hyaluronic acid hydrogel nanoparticles.
  • A Example 13; and B: Comparative Example 5.
  • FIG. 3 is a scanning electron micrograph of dried hyaluronic acid hydrogel particles (Example 11) .
  • FIG. 4 is a transmission electron micrograph of dried hyaluronic acid hydrogel particles (Example 11) .
  • FIG. 5 is an optical micrograph of swollen hyaluronic acid hydrogel particles in an aqueous solution.
  • A Example 12; B: Example 13; C: Comparative Example 5; and D: Comparative Example 6.
  • FIG. 6 is a confocal laser scanning micrograph showing the skin absorption rate of fluorescent-conjugated hyaluronic acid hydrogel particles. [Best Mode]
  • HA hyaluronic acid
  • CEH cetyl ethylhexanoate
  • ARLACEL 83 A-83
  • ARLACEL P135 A-P135
  • ABIL EM- 90 AE- 90
  • BDG butylene glycol diglycidyl ether
  • PEGDG polyethylene glycol diglycidyl ether
  • LYD lucifer yellow dextran
  • Examples 1 to 6 HA hydrogel particles prepared using dodecane as oil phase of w/o emulsion
  • a surfactant A- 83 or A-P135 was dissolved in dodecane using a stirrer, while HA (having a number-average molecular weight of 1,500,000) and a crosslinker BDG or PEGDG were dissolved in an aqueous solution of 0.1 N sodium hydroxide using a stirrer. While the 0. IN sodium hydroxide solution, containing HA and the crosslinker dissolved therein, was added slowly to the dodecane containing the surfactant dissolved therein, the mixture was mixed with an emulsifier for 10 minutes with stirring at a speed of 7000 rptn to prepare a w/o emulsion.
  • the emulsion was transferred into a reactor, and it was heated at 60 ° C and subjected to an initial crosslinking reaction, while it was stirred such that the w/o emulsion was kept. While the mixture was continued to be stirred, the temperature of the reactor was controlled to room temperature, an acetic acid was added to the w/o emulsion in order to neutralize the aqueous phase of the w/o emulsion, and the w/o emulsion was subjected to a crosslinking reaction at room temperature for 2 days with stirring.
  • Examples 7 to 13 Hyaluronic acid hydrogel particles prepared using heptane as oil phase of w/o emulsion
  • a surfactant A- P135 was dissolved in heptane using a stirrer, while HA (having a number-average molecular weight of 1,500,000) and a crosslinker PEGDG were dissolved in an aqueous solution of 0.1 N sodium hydroxide using a stirrer. While the 0.
  • Example 14 according to the weight composition ratios shown in Table 3 below, a surfactant A-P135 was dissolved in heptane using a stirrer, while HA (having a number-average molecular weight of 1,500,000), a crosslinker PEGDG and a fluorescent LYD were dissolved in an aqueous solution of 0.1 N sodium hydroxide using a stirrer. While the 0. IN sodium hydroxide solution, containing HA, PEGDC and LYD dissolved therein, was added slowly to the heptane containing A-P135 dissolved therein, the mixture was mixed with an emulsifier for 10 minutes with stirring at a speed of 7000 rpm to prepare a w/o emulsion.
  • the emulsion was transferred into a reactor, and it was heated at 60 ° C and subjected to an initial crosslinking reaction, while it was stirred such that the w/o emulsion was kept. While the mixture was continued to be stirred, the temperature of the reactor was controlled to room temperature, an acetic acid was added to the w/o emulsion in order to neutralize the aqueous phase of the w/o emulsion, and the w/o emulsion was subjected to a crosslinking reaction at room temperature for 2 days with stirring.
  • Comparative Examples 1 and 2 HA hydrogel particles prepared using CEH as oil phase of w/o emulsion
  • a surfactant AE- 90 was dissolved in CEH using a stirrer, while HA (having a number-average molecular weight of 1,500,000) and a crosslinker BDG were dissolved in an aqueous solution of 0.1 N sodium hydroxide using a stirrer. While the 0. IN sodium hydroxide solution, containing HA and BDG dissolved therein, was added slowly to the CEH containing AE- 90 dissolved therein, the mixture was mixed with an emulsifier for 10 minutes with stirring at a speed of 7000 rpm to prepare a w/o emulsion.
  • the emulsion was transferred into a reactor, and it was heated at 60 ° C and subjected to an initial crosslinking reaction, while it was stirred such that the w/o emulsion was kept. While the mixture was continued to be stirred, the temperature of the reactor was controlled to room temperature, an acetic acid was added to the w/o emulsion in order to neutralize the aqueous phase of the w/o emulsion, and the w/o emulsion was subjected to a crosslinking reaction at room temperature for 2 days with stirring.
  • Comparative Examples 3 to 7 Hydrogel particles prepared using heptane as oil phase of w/o emulsion
  • a surfactant A-135 was dissolved in heptane using a stirrer, while HA (having a number-average molecular weight of 1,500,000) and a crosslinker PEGDG were dissolved in an aqueous solution of 0.1 N sodium hydroxide using a stirrer. While the 0.
  • Comparative Example I 1 crosslinked HA hydrogel particles were prepared in the same manner as in Comparative Examples 3-6, except that the process of neutralization with acetic acid was not carried out. [Table 5]
  • Test Example 1 Optical microscopic observation of size of w/o emulsion, containing HA and crosslinker in water phase The size and shape of the w/o emulsions, obtained in Examples 1-14 and Comparative Examples 1-7 and containing the HA and crosslinker in the water phase, were measured using an optical microscope.
  • FIG. 1 is an optical micrograph of the w/o emulsion particles obtained in Examples 12-13 and Comparative Examples 5-6. As can be seen in FIG.
  • factors determining the stability and emulsion particle size of the w/o emulsions include the kinds of oil and surfactant, the ratio of the water phase to the oil phase, the concentration of the surfactant, etc. It could be observed that, when the used oil was dodecane or heptane, the w/o emulsion had a relatively small particle size and a clear interface, and the increase in the ratio of the aqueous phase to the oil phase led to an increase in the particle size of the w/o emulsion.
  • A-83 or A-P135 was used as the surfactant, a more stable w/o emulsion could be obtained, and when the surfactant was used in an amount of more than 3 wt% based on the total weight of the oil and aqueous sodium hydroxide of the w/o emulsion, a small and stable w/o emulsion could be obtained.
  • the reason why the stable particle shape and shape of the w/o emulsion are important is that the emulsion greatly influences the swollen particle shape and particle size of the resulting HA hydrogel particles in the aqueous solution and that the smaller particle size of the w/o emulsion is advantageous for obtaining dried HA hydrogel nanoparticles .
  • Test Example 2 Observation of size of dried HA hydrogel particles using scanning electron microscope and transmission electron microscope
  • FIG. 2 is a scanning electron micrograph of the dried HA hydrogel particles, obtained in Example 13 and Comparative Example 5. As can be seen in FIG.
  • FIGS . 3 and 4 are a scanning electron micrograph and transmission electron micrograph of the dried HA hydrogel particles prepared in Example 11. As can be seen in FIGS. 3 and 4, the dried hydrogel particles had a particle size of 20-400 nm. Based on the above result, it can be seen that factors determining the size of the dried HA hydrogel particles include, in addition to factors influencing the size of the w/o emulsion in crosslinking occurs, the degree of crosslinking, the concentration of HA in the water phase of the w/o emulsion, the presence or absence of the neutralization process, etc. From the results of the scanning electron microscopic and transmission electron microscopic observations of the particle sizes, it is thought that the particle size of the w/o emulsions is the most important factor determining the particle size of the finally dried HA hydrogel particles.
  • Test Example 3 Observation of size of optical microscopic observation of swollen HA hydrogel particles
  • FIG. 5 shows optical micrographs of the swollen HA hydrogel particles prepared in Examples 12-13 and Comparative Examples 5-6.
  • the results in FIG. 5 are because the crosslinking of HA hydrogel particles occurs in the w/o emulsion as described above, and thus the biggest factor determining the size of the swollen HA hyrogel particles is the particle size of the w/o emulsion.
  • the degree of crosslinking with the crosslinker and the kind of crosslinker can also influence the size of swollen HA hydrogel particles.
  • Test Example 4 Skin absorption test of fluorescent- conjugated HA hydrogel particles through Franz-cell system
  • a skin absorption test of the fluorescent-conjugated HA hydrogel particles prepared in Example 14 was carried out.
  • the skin absorption test was carried out on the skin, obtained from albino guinea pigs, for 3 hours and 6 hours using the Franz-cell system.
  • the dried HA hydrogel particles were dispersed in CEH at a concentration of 1 wt% using an emulsifier, and then a given amount of the dispersion was applied on the skin tissue.
  • the skin tissue applied with the LYD- conjugated hydrogel particles for each of 3 hr and 6 hr, was separated from the Franz-cell to prepare samples for microscopic observation.
  • the fluorescent LYD in the samples was observed using a confocal laser scanning microscope, and thus determining the skin absorption of the HA hydrogel particles as a function of time.
  • FIG. 6 shows the fluorescent intensity of LYD, observed with a confocal laser scanning microscope to measure the skin absorption with time of the fluorescent LYD-conjugated HA hydrogel particles obtained in Example 14.
  • the fluorescent intensity of LYD was evenly dispersed in the horny layer of the skin tissue with the passage of time, suggesting that the HA hydrogel nanoparticles dispersed in oil could be absorbed at least into the horny layer.
  • Example 5 Primary skin irritation test of HA hydrogel particles A primary skin irritation test of the HA hydrogel particles prepared in Example 11 was carried out on two male New Zealand White rabbits (Hallym experimental animal center, Korea) at a concentration of 5% according to the Draize test method. The results of skin responses were evaluated according to "evaluation standards of skin responses" provided in toxicity test standards of Korea Food and Drug Administration Notification No 2005-60, and whether the test material would be used was determined by the primary irritation index (P.I.I) . As a result, the P.I.I value of the test material was 0, suggesting that abnormal skin symptoms, including erythema, edema and clusts, could not be observed, [industrial Applicability]
  • the chemically crosslinked hyaluronic acid hydrogel nanoparticles according to the present invention are uniformly absorbed and dispersed in the horny layer of the skin, when they are applied on the skin, thus showing improved ability to be absorbed into the skin. Also, when the chemically crosslinked hyaluronic acid hydrogel nanoparticles are dispersed in water, they show high water-swelling ratio.

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Abstract

La présente invention concerne des nanoparticules d'hydrogel d'acide hyaluronique chimiquement réticulé, et un procédé d'élaboration correspondant. En l'occurrence, pour obtenir les nanoparticules d'acide hyaluronique chimiquement réticulé, on prend une phase huileuse contenant un tensioactif en solution, et on la mélange à une phase aqueuse. Celle-ci contient de l'acide hyaluronique et un réticulant hydrosoluble dissout dans une solution aqueuse basique. Après obtention de l'émulsion eau dans huile, on procède à la réticulation de l'acide hyaluronique dans ladite émulsion. En application cutanée, ces nanoparticules sont absorbées et dispersées de façon uniforme dans la couche cornée de la peau, faisant ainsi preuve d'une meilleure aptitude à l'absorption dans la peau, et d'une importante aptitude à se gonfler d'eau quand elles sont dispersées dans l'eau.
PCT/KR2008/000772 2007-02-15 2008-02-11 Nanoparticules d'hydrogel d'acide hyaluronique chimiquement réticulé, et procédé d'élaboration correspondant Ceased WO2008100044A1 (fr)

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RU2425694C1 (ru) * 2010-04-14 2011-08-10 Государственное образовательное учреждение высшего профессионального образования "Оренбургский государственный университет" Наноструктурированный биопластический материал
ITRM20110008A1 (it) * 2011-01-12 2012-07-13 Alfonso Barbarisi Procedimento per la partecipazione di nanoparticelle reticolate a base di estere benzilico dell'acido ialuronico da utilizzare come vettori per il rilascio controllato di principi attivi
RU2481127C1 (ru) * 2012-02-21 2013-05-10 Общество с ограниченной ответственностью Научно-производственное предприятие "Наносинтез" Микронаноструктурированный биопластический материал
EP2883605A4 (fr) * 2012-08-08 2016-01-27 Sekisui Chemical Co Ltd Procédé de fabrication de microcapsules et microcapsules ainsi obtenues
JPWO2014024971A1 (ja) * 2012-08-08 2016-07-25 積水化学工業株式会社 マイクロカプセルの製造方法、及び、マイクロカプセル
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WO2017177265A1 (fr) * 2016-04-12 2017-10-19 Capsular Technologies Pty Ltd Composition injectable pour l'administration d'un agent biologiquement actif
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EP4268812A3 (fr) * 2017-10-12 2023-12-27 SolyPlus GmbH Procédé de traitement de biopolymères utilisant des combinaisons de solvants
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WO2019073363A1 (fr) * 2017-10-12 2019-04-18 Solyplus Berlin Gmbh Procédé de traitement de biopolymères utilisant des combinaisons de solvants
US20210038492A1 (en) * 2019-08-08 2021-02-11 Amorepacific Corporation Composition of freeze-dried formulation, cosmetic kit for external use on skin including the same, and method for skin moisturizing including applying the same onto the skin
JPWO2022172790A1 (fr) * 2021-02-10 2022-08-18
WO2022172790A1 (fr) * 2021-02-10 2022-08-18 株式会社 資生堂 Préparation cosmétique
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