WO2021154038A1 - Structure métal-organique type à libération prolongée utilisant de la cyclodextrine et son procédé de fabrication - Google Patents

Structure métal-organique type à libération prolongée utilisant de la cyclodextrine et son procédé de fabrication Download PDF

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WO2021154038A1
WO2021154038A1 PCT/KR2021/001223 KR2021001223W WO2021154038A1 WO 2021154038 A1 WO2021154038 A1 WO 2021154038A1 KR 2021001223 W KR2021001223 W KR 2021001223W WO 2021154038 A1 WO2021154038 A1 WO 2021154038A1
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active material
mof
metal
cyclodextrin
producing
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PCT/KR2021/001223
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English (en)
Korean (ko)
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최경민
이현신
장수인
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숙명여자대학교 산학협력단
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Publication of WO2021154038A1 publication Critical patent/WO2021154038A1/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • 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
    • 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
    • A61K8/84—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
    • A61K8/85—Polyesters
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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 metal-organic framework comprising a cyclodextrin (CD)-based metal-organic framework (MOF) and a biodegradable polymer such as polycaprolactone, and a method for manufacturing the same will be.
  • CD cyclodextrin
  • MOF metal-organic framework
  • biodegradable polymer such as polycaprolactone
  • MOF is a crystalline nanopore structure in which a metal ion and an organic linker (organic linker or organic ligand) are linked by a coordination bond to form a three-dimensional structure.
  • MOF is a porous material with a wide surface area, so chemical reactions occur actively, and the pore size, pore shape, and structure can be adjusted depending on the type of metal ion and organic linker used in the MOF. It has the advantage that it can be easily synthesized.
  • Cyclodextrin (CD) is a representative biodegradable and biodegradable material, has low toxicity, and has characteristics of enhancing drug safety, bioavailability, and solubility in water-soluble substances. Therefore, MOF using cyclodextrin has been studied.
  • Cyclodextrin-based MOF has excellent properties compared to conventional porous crystals such as zeolite or porous carbon by combining the porous characteristics of MOF with the encapsulation ability of cyclodextrin by placing cyclodextrin as a ligand. Also, studies have been reported that CD-MOF can overcome the physicochemical and biochemical limitations of drugs.
  • U.S. Patent Publication No. 2017-0028383 discloses a cyclodextrin-based metalloorganic framework and a method of using the same
  • US Patent Publication 2017-0274097 discloses an active substance release as a composition comprising a cyclodextrin-based metalloorganic framework It is effective in, and it is disclosed that it can be used for cosmetic or therapeutic purposes.
  • EP 3374402 discloses that the cyclodextrin-based metalorganic framework is water-soluble and non-toxic so that it can be used in oral pharmaceutical formulations.
  • PCL Polycaprolactone
  • Korean Patent Application Laid-Open No. 10-2017-0123099 discloses that, when a filler composition for skin containing PCL as a main component and hyaluronic acid gel as a carrier is used, not only high biocompatibility, immediate treatment effect, and skin moisture but also particles It is disclosed that it can be homogeneous to provide a natural and soft texture.
  • PCL can be coated on a porous tricalcium phosphate scaffold to control and inhibit the release rate of proteins (Journal of biomedical materials research. Part B, Applied biomaterials v.91B no.2, 2009, 831-838), and to Lovastatin. It is known that the coating can control the release of lovastatin through hydrophilic-hydrophobic and hydrophobic-hydrophobic interactions (Materials science & engineering. C, Materials for biological applications v.33 no.6, 2013, 3121-3128).
  • Japanese Patent No. 6,080,172 discloses that substituted polycaprolactone functions to serve as drug storage and drug release, and thus can be used as a coating agent in medical devices such as stents.
  • the conventional cyclodextrin (CD)-based metal-organic frameworks (MOF) do not control the release rate of the active material, are decomposed in an aqueous environment, and may be harmful to the human body.
  • CD-MOF metal-organic frameworks
  • CD-metal-organic frameworks (MOF) on which an active material is supported by mixing cyclodextrin (CD), a metal compound, and an active material;
  • the cyclodextrin may be ⁇ -cyclodextrin.
  • the metal compound is composed of metal acetate, metal acrylate, metal carboxylate, metal sulfate, metal hydroxide, metal nitrate, metal oxynitrate, metal oxide, metal oxychloride and metal chloride. may be selected from the group.
  • the metal compound is Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Cd, La, W, Os, Ir, Pt, Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb, Cs, Mg, It may include one or more metal elements or ions selected from the group consisting of Ca, Sr, and Ba. More specifically, the metal compound may be potassium hydroxide.
  • the metal compound may be 10 to 35 wt% based on the total weight of the cyclodextrin, the metal compound and the active material. More specifically, the metal compound may be 23 to 30 wt% based on the total weight of the cyclodextrin, the metal compound, and the active material.
  • the active material may be selected from the group consisting of organic acids, drugs, metal ions, oxides and gases. More specifically, it may be lactic acid or a derivative thereof.
  • the active material may be 1 to 10 wt% based on the total weight of the cyclodextrin, the metal compound, and the active material. More specifically, the active material may be 2 to 5 wt% based on the total weight of the cyclodextrin, the metal compound, and the active material.
  • cetyl trimethyl ammonium bromide may be additionally mixed in step 1).
  • cetyltrimethylammonium bromide may be 1 to 10 wt% based on the total weight of the cyclodextrin, metal compound, active material, and cetyltrimethylammonium bromide. More specifically, the amount of cetyltrimethylammonium bromide may be 2 to 5 wt% based on the total weight of the cyclodextrin, metal compound, active material, and cetyltrimethylammonium bromide.
  • the biodegradable polymer is gelatin, collagen, fibrin, elastin, alginate, hyaluronic acid, polyetherimide; PEI ), polycaprolactone (PCL), polylactic acid (PLA), chitosan (chitosan), polyglycolic acid (PGA), and derivatives thereof. More specifically, it may be polycaprolactone (PCL) or a derivative thereof.
  • the mixing weight ratio of the biodegradable polymer in step 2) and the CD-MOF on which the active material is supported may be 2 to 10: 1. More specifically, the mixing weight ratio of the biodegradable polymer and the CD-MOF on which the active material is supported may be 2 to 4 : 1.
  • the active material may be lactic acid or a derivative thereof
  • the biodegradable polymer may be polycaprolactone or a derivative thereof.
  • the CD-MOF composition on which the active material is supported may have sustained-release properties.
  • a CD-MOF composition which is a metal-organic framework comprising a coordination bond of a repeating unit comprising cyclodextrin and a metal, wherein the metal-organic framework is coated with a biodegradable polymer.
  • the cyclodextrin may comprise ⁇ -cyclodextrin.
  • the metal may be potassium.
  • the active material may be selected from the group consisting of organic acids, drugs, metal ions, oxides and gases, but is not limited thereto. More specifically, it may be lactic acid or a derivative thereof.
  • the biodegradable polymer may be polycaprolactone (PCL) or a derivative thereof.
  • the active material may be lactic acid or a derivative thereof
  • the biodegradable polymer may be polycaprolactone or a derivative thereof.
  • the CD-MOF composition according to the present invention has a release amount of the active substance of 20% or less for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 1 It can be maintained for more than a week, more than 2 weeks, more than 3 weeks, more than 4 weeks, more than 5 weeks. More specifically, the release amount of the active substance is not less than 5% and not more than 20% for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 1 week or more, 2 weeks or more, 3 weeks or more. or more, 4 weeks or more, 5 weeks or more.
  • the CD-MOF composition according to the present invention is any one or more of the group consisting of fillers, drug carriers, pharmaceuticals, quasi-drugs, cosmetics, dermatological medical devices, wound dressings, ointments, lotions, and microneedles. can be used, and more specifically, it can be used as a filler.
  • the present invention relates to a metal-organic framework composition prepared by mixing cyclodextrin (CD)-based metal-organic frameworks (MOF) with a biodegradable polymer such as polycaprolactone, and a method for preparing the same
  • the composition of the present invention can control the release of the active substance in the CD-MOF to be gradually progressed through a biodegradable polymer such as polycaprolatone, and is stabilized by preventing hydrolysis of cyclodextrin, and is biodegradable. It has the advantage that it can be used for many purposes without harm to the human body due to the sex polymer.
  • FIG. 1 is a diagram illustrating a method for preparing a sustained-release metal-organic framework.
  • FIG. 2 is a diagram confirming the crystal form of CD-MOF prepared by using cyclodextrin and a metal compound through SEM.
  • FIG 3 is a diagram illustrating the crystal form of the CD-MOF supported with lactic acid, an active material, through SEM.
  • 5 to 7 are diagrams confirming the change according to the adjustment of the mixing ratio of polycaprolactone and lactic acid-supported CD-MOF through SEM.
  • FIGS. 8 to 10 are diagrams confirming the crystallinity of CD-MOF, lactic acid-supported CD-MOF, and polycaprolactone-coated lactic acid-supported CD-MOF through PXRD.
  • FIG. 11 is a view confirming the sustained-release property of polycaprolactone-coated lactic acid-supported CD-MOF in Di water by HPLC.
  • FIG. 12 is a view confirming sustained release of polycaprolactone-coated lactic acid-supported CD-MOF in PBS by HPLC.
  • the active substance is lactic acid or a derivative thereof
  • the biodegradable polymer is polycaprolactone or a derivative thereof.
  • CD-metal-organic frameworks (MOF) on which an active material is supported by mixing cyclodextrin (CD), a metal compound, and an active material;
  • It relates to a method for producing a CD-MOF composition carrying an active material, comprising the step of mixing the CD-MOF of step 1) with a biodegradable polymer to obtain a mixture.
  • the present invention also relates to a CD-MOF composition prepared by the above method.
  • the present invention is a metal-organic framework (MOF) comprising a coordination bond of a repeating unit containing cyclodextrin (CD) and a metal, the metal-organic framework is coated with a biodegradable polymer CD-MOF composition.
  • MOF metal-organic framework
  • the CD-MOF is a crystalline material having a skeletal structure formed by connecting metal ions and an organic linker, and includes metal clusters.
  • various free linker structures increase the distance between the clusters.
  • the clusters are linked together in a periodic manner by organic linkers.
  • the micropore size present in the CD-MOF through various combinations between the metal (ion) and the organic linker, it facilitates the selective absorption and release of the active material.
  • the absorption and release amount of CD-MOF can be controlled by changing the absorption and release distance of the active material by controlling the particle size of the CD-MOF having micropores.
  • the organic linker used in the present invention basically refers to a cyclodextrin composed of several glucose, and the cyclodextrin refers to ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the organic linker includes cross-linking of other organic molecules to the cyclodextrin, and may form empty regions, that is, pores in the resulting structure by forming a gap between metals (ions), and control their size.
  • ⁇ -cyclodextrin has the largest inner radius, so it has the best ability to trap active substances.
  • the metal compound is composed of metal acetate, metal acrylate, metal carboxylate, metal sulfate, metal hydroxide, metal nitrate, metal oxynitrate, metal oxide, metal oxychloride and metal chloride. may be selected from the group.
  • the metal compound is Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Cd, La, W, Os, Ir, Pt, Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb, Cs, Mg, It may include one or more elements or metal ions selected from the group consisting of Ca, Sr, and Ba.
  • Metal compounds constituting the CD-MOF of a metal ion type, and metal ion may be to control the particle size of the CD-MOF to vary in size depending on their kind, and when the metal ion is K + CD-MOF the organic acid size By having a particle size suitable for contrast, the absorption *?* emission ability is excellent.
  • a plurality of metal clusters and a plurality of cyclodextrins are combined to form a skeleton structure of CD-MOF, and a space is created between the metal cluster and the metal cluster by the cyclodextrin, and an active material in the space This can be accepted.
  • the CD-MOF on which the active material is supported may be prepared by adjusting the reaction ratio of the cyclodextrin, the metal compound, and the active material. More specifically, a CD-MOF composition carrying an active material may be prepared by mixing 55 to 89 wt% of cyclodextrin, 10 to 35 wt% of a metal compound, and 1 to 10 wt% of the active material. More specifically, 65 to 75 wt% of the cyclodextrin, 23 to 30 wt% of the metal compound, and 2 to 5 wt% of the active substance may be mixed.
  • cetyl trimethyl ammonium bromide may be additionally mixed during the preparation of the CD-MOF composition carrying the active material. More specifically, 45 to 88 wt% of cyclodextrin, 10 to 35 wt% of a metal compound, 1 to 10 wt% of an active substance, and cetyltrimethylammonium bromide (CTAB) may be mixed in a ratio of 1 to 10 wt%.
  • CTAB cetyltrimethylammonium bromide
  • the active material is supported in the metal-organic framework of step 1), and examples of the active material are selected from the group consisting of organic acids, drugs, metal ions, oxides and gases. It may be any one, but various materials may be supported depending on the field of application.
  • the size of the metal-organic framework may vary depending on the type of cyclodextrin, and the size may be controlled for significant sustained release of the active material of the CD-MOF composition.
  • the biodegradable polymer is gelatin, collagen, fibrin, elastin, alginate, hyaluronic acid, polyetherimide; PEI), polycaprolactone (PCL), polylactic acid (PLA), chitosan (chitosan), polyglycolic acid (PGA), poly- ⁇ -caprolactone-lactic acid copolymer (PCLA), Poly- ⁇ -caprolactone-glycolic acid copolymer (PCGA), polylactic acid-glycolic acid copolymer (PLGA), polyethylene glycol (PEG), polydioxanone (PDO), polytrimethylene carbonate ( polytrimethylene carbonate); PTMC), polyamino acid, polyanhydride, polyorthoester, polyphosphazene, polyiminocarbonate, polyphosphoester, poly hydroxyvalerate, derivatives thereof and mixtures thereof. More specifically, it may be polycaprolactone (PCL) or a derivative thereof, and in
  • the active material may be lactic acid or a derivative thereof
  • the biodegradable polymer may be polycaprolactone or a derivative thereof.
  • the mixing weight ratio of polycaprolactone and the CD-MOF on which the active material is supported may be 2 to 10: 1. More specifically, the mixing weight ratio of polycaprolactone and CD-MOF may be 2 to 4: 1, in which case the sustained release property is the best, and when the mixing weight ratio is lower than 2:1, polycaprolactone is CD -Due to not being sufficiently coated on the MOF, the release amount of the active material may be small due to an uneven surface. there is. However, if a small amount of release is desired, the sustained-release property may be exhibited by adjusting the weight mixing ratio, and in this case, the sustained-release property may be exhibited even if the weight mixing ratio is not 2 to 4:1.
  • the CD-MOF composition on which the active material is supported may have sustained-release properties. More specifically, the release amount of the active substance is 20% or less for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 1 week or more, 3 weeks or more, 4 weeks or more, 5 It can last longer than a week. More specifically, the release amount of the active substance may be maintained at 5% or more and 20% or less for 5 weeks or more.
  • the release amount of the active substance is not less than 5% and not more than 20% for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 1 week or more, 3 weeks or more, 4 weeks or more. It can be maintained for more than 5 weeks. It can be released slowly by specifying the mixing ratio of the biodegradable polymer, cyclodextrin, metal compound and active substance.
  • mixing can be mixed through sonication, but is not limited thereto, and any mixing method is possible. Any method for removing the solvent to obtain a mixture is possible.
  • CD-MOF is primarily released by biodegradation of a biodegradable polymer in a biodegradable environment, and secondarily, in the CD-MOF by a hydrophilic environment (eg, water). It is characterized in that the active material is released, and may have a characteristic of being released slowly due to the coating of the biodegradable polymer.
  • the CD-MOF composition in which the active material is supported is slowly released, the material can be effectively delivered when used in a drug-releasing filler, but is not limited thereto. It can be used for medical and cosmetic purposes such as scar treatment and whitening effect. Therefore, the CD-MOF composition carrying the active material can be used in any one or more of the group consisting of fillers, drug carriers, pharmaceuticals, quasi-drugs, cosmetics, dermatological medical devices, wound dressings, ointments, lotions, and microneedles. there is.
  • the CD-MOF composition loaded with the active material of the present invention exhibits the effect of slowly releasing the active material in the CD-MOF through mixing with a biodegradable polymer such as polycaprolatone, safety and stabilization of the human body. can have advantages.
  • Potassium hydroxide, methanol, ethanol and ⁇ -cyclodextrin were prepared from Sigma Aldrich. After dissolving 56.11 mg (1 mmol) of potassium hydroxide in 5.0 ml of water, 5.0 ml of potassium hydroxide (KOH) solution, 162 mg (0.125 mmol) of ⁇ -cyclodextrin, and 0.5 ml of ethanol were added to a 10 ml vial. . Thereafter, it was filtered using a syringe filter having a pore size of 0.45 ⁇ m. After preparing a separate 135 ml wide-mouth bottle, 20 ml of methanol was added. After adding 10 ml of the filtered solution to a 135 ml wide-mouth bottle, the lid for the wide-mouth bottle was closed and reacted in an oven at 50° C. for 12 to 24 hours.
  • KOH potassium hydroxide
  • CTAB Cetyl Trimethyl Ammonium Bromide
  • lactic acid ((L)-lacitc acid)
  • EtOH ethanol
  • Polycaprolactone (PCL) was dissolved in 3 ml of acetone. Thereafter, the metal-organic framework prepared in Example ⁇ 1-2> was introduced and sonication was performed, followed by rotational concentration. At this time, the amount of acetone used is constant, and the mixing ratio of polycaprolactone and the carrier prepared in Example ⁇ 1-2> is 0.5:1, 1:1, 2:1, 4:1, 6:1, respectively. , was prepared in a mass ratio of 9:1.
  • the crystal form of the metal-organic framework, the support, and the polycaprolactone-coated support was confirmed through a scanning electron microscope (SEM), and the results are shown in FIGS. 2 to 4 .
  • the crystal form of the polycaprolactone-coated support according to the mixing ratio of the reactants was confirmed through SEM, and the results are shown in FIGS. 5 to 7 .
  • the lactic acid content of the support was analyzed through High Performance Liquid Chromatography (HPLC).
  • HPLC High Performance Liquid Chromatography
  • An Agilent 1200 model was used for analytical HPLC, a column for Phenomenex Luna C18 HPLC was used, and phosphoric acid aqueous solution (H 3 PO 4 0.1%, pH 2) and acetonitrile (acetonitrile, 100%) were used as the mobile phase, respectively. Analysis was performed using a flow rate of 0.6 ml/min and UV 210 nm. As a result of the analysis, it was confirmed that 0.114 ⁇ mol/mg of lactic acid corresponding to about 29% of the input amount of lactic acid was contained in 1 mg/ml of the polycaprolactone-coated support.
  • Example 1 the polycaprolactone-coated carrier 200 in which the mass ratio of polycaprolactone and the carrier was 0.5:1, 1:1, 2:1, 4:1, 6:1, 9:1, respectively. mg was added to 45 ml of DI water or PBS (Phosphate buffered saline, pH 7.4). After sampling by time without a separate stirring process, 1 ml was added and analyzed by HPLC (High Performance Liquid Chromatography). For HPLC, an Agilent 1200 model was used, and a Phenomenex Luna C18 HPLC column was used for the column. As the mobile phase, aqueous phosphoric acid solution (H 3 PO 4 0.1%, pH 2) and acetonitrile (acetonitrile, 100%) were used, respectively. Analysis was performed using 0.6 ml/min and UV 210 nm. The analysis results are shown in Tables 1 and 2 and FIGS. 11 and 12 .
  • the release amount was calculated based on the lactic acid content in the initial polycaprolactone-coated support, and when the mixing ratio of polycaprolactone and the support was 2:1 and 4:1, the release amount was 13.62 ⁇ 16.89% in Di water, respectively. (2:1), 13.31-14.41% (4:1), respectively, in PBS, 8.55-9.77% (2:1) and 10.51-11.69%, which was confirmed to have high sustained-release properties.
  • the present invention can be used in industrial fields requiring sustained release of active substances such as organic acids.

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Abstract

La présente invention se rapporte à une composition à structure métal-organique (MOF) et son procédé de fabrication, la composition ayant un taux de libération pouvant être régulé et étant stable à travers le mélange des structures métal-organique à base de cyclodextrine (CD) supportant une substance active ayant un polymère biodégradable tel que de la polycaprolactone.
PCT/KR2021/001223 2020-01-29 2021-01-29 Structure métal-organique type à libération prolongée utilisant de la cyclodextrine et son procédé de fabrication WO2021154038A1 (fr)

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