WO2021101139A1 - 폴리-l-락틱산 필러와 히알루론산 필러 결합체를 함유하는 주사제제 및 그 제조방법 - Google Patents
폴리-l-락틱산 필러와 히알루론산 필러 결합체를 함유하는 주사제제 및 그 제조방법 Download PDFInfo
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- WO2021101139A1 WO2021101139A1 PCT/KR2020/015505 KR2020015505W WO2021101139A1 WO 2021101139 A1 WO2021101139 A1 WO 2021101139A1 KR 2020015505 W KR2020015505 W KR 2020015505W WO 2021101139 A1 WO2021101139 A1 WO 2021101139A1
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- plla
- filler
- microcapsules
- hyaluronic acid
- lactic acid
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- 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
- A61L27/26—Mixtures of macromolecular compounds
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- 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
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/0059—Cosmetic or alloplastic implants
-
- 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
- A61K8/11—Encapsulated compositions
-
- 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
- A61K8/731—Cellulose; Quaternized cellulose derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—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
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- A—HUMAN NECESSITIES
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- 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
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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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
- A61K9/1652—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
- A61L27/20—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
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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- 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
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
- C08J3/122—Pulverisation by spraying
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- 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
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/91—Injection
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- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
- A61L2300/622—Microcapsules
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- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2401/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
- C08J2401/08—Cellulose derivatives
- C08J2401/26—Cellulose ethers
- C08J2401/28—Alkyl ethers
Definitions
- the present invention includes poly-L-lactic acid (hereinafter referred to as "PLLA”) filler and hyaluronic acid (hereinafter referred to as "HA”) conjugate, and contains microcapsules of PLLA-HA It relates to an injection and a method of manufacturing the same.
- PLLA poly-L-lactic acid
- HA hyaluronic acid
- poly-L-lactic acid (“PLLA”) filler is a polymeric synthetic material having biocompatibility and biodegradability as a support for microspheres.
- PLLA poly-L-lactic acid
- HA hyaluronic acid
- HA hyaluronic acid
- the dried PLLA in powder form was freeze-dried in a state in which it was mixed with CMC (carboxy methyl cellulose) and mannitol, and the freeze-dried PLLA was sterilized.
- CMC carboxy methyl cellulose
- mannitol a sugar alcohol
- the prepared suspension is injected into the body. Then, after 3 to 6 months have elapsed, collagen is produced in the body to increase the volume.
- the distilled water component and the CMC component in the injected PLLA suspension are absorbed into the body within a few days, so the volume that occurred immediately after the injection of the PLLA suspension into the body disappears immediately, and the volume increases after a few days after the injection into the body.
- the effect of increasing the volume gradually appeared only after several months (3-6 months) without showing any effect.
- the conventional PLLA filler has a disadvantage in that nodules and granulomas are generated.
- PLLA is injected by diluting with distilled water.
- concentration of the suspension decreases. For this reason, there is also a problem that a long time is required to make a uniform suspension.
- Korean Patent Registration No. 10-1852127 discloses a method for preparing a PLLA and HA conjugate.
- An object of the present invention is to prepare a conjugate of a poly-L-lactic acid filler (PLLA) and a hyaluronic acid filler (HA), and a microcapsule of a uniform particle of a PLLA-HA conjugate in order to solve the above problems. And to provide a method of manufacturing the same.
- PLLA poly-L-lactic acid filler
- HA hyaluronic acid filler
- One aspect of the present invention for solving the above problems is (a) mixing PLLA (poly-L-lactic acid) with CMC (carboxymethylcellulose) and mannitol, freeze-dried, pulverized to a certain size, and sterilized by gamma ray.
- PLLA poly-L-lactic acid
- CMC carboxymethylcellulose
- HA hyaluronic acid
- BDDE butanediol diglycidyl ether
- the "poly-L-lactic acid (also referred to as PLLA, polyL-lactic acid, or polyL-lactic acid)" is approved by the US FDA for facial lipid stiffness in patients infected with human immunodeficiency virus (HIV). As a received filler, it is a component extracted from plants such as sugar cane.
- hyaluronic acid (HA) was first isolated from Vitreous Humor by Meyer and Palmer in 1934 as a polyanionic mucopoly-saccharide, which is widely present in nature. It is a bio-derived polymer material.
- the "hyaluronic acid” is a linear polysaccharide composed of glucuronic acid and acetylglucosamine, and is an extracellular matrix (ECM), synovial fluid of a joint. ), is one of the glycosamino glycans present in the support constituting cartilage.
- ECM extracellular matrix
- Hyaluronic acid also plays an important role as a signaling molecule in cell motility, cell differentiation, wound healing and cancer metastasis.
- the peculiar viscoelastic properties of hyaluronic acid and crosslinked hyaluronic acid add to its importance as a joint synovial fluid.
- hyaluronic acid is a biomaterial with excellent biocompatibility that can be used in tissue engineering and drug delivery systems because hyaluronic acid does not have any problems.
- Hyaluronic acid and hyaluronic acid oligosaccharides have a three-dimensional structure in solution, which induces a wide range of internal hydrogen bonds, limited fluidity of polymer chains, and unique helical and coiled coil reactions. do.
- Hyaluronic acid generally has a molecular weight of about 1,000 to 10,000,000 Da and, as mentioned above, has unique physicochemical properties and unique biological functions.
- Hyaluronic acid plays a major role in the homeostasis of cellular tissues and lubrication of joints, and it specifically binds to a specific protein on the cell surface, thereby playing a very important role in cell fluidity, growth factor action, and inflammatory response. It has been developed and used as a medical component for domestic and overseas tissue repair (replacement and reconstruction of human tissues), and is widely used in skin care and cosmetic fields.
- the CMC (carboxymethylcellulose) is used as a carrier, and the carrier of the present invention is not limited to CMC, and carboxy methyl cellulose, sodium carboxy methyl cellulose, sodium alginate (Sodium alginate), Gelatin, Albumin, Collagen, Sodium Hyaluronic Acid, Dextran, Hydroxyethyl cellulose, Hydroxypropyl methyl cellulose), glycerin (Glycerin), sorbitol (Sorbitol), and propylene glycol (Propylene Glycol) may be at least one selected from the group consisting of.
- mannitol was used in the present invention, it is not limited thereto, and as excipients and diluents that can be generally used, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used, but are limited thereto. It is not.
- the BDDE butanediol diglycidyl ether
- DVS divinyl sulfone
- BCDI bis ethyl carbodiimide
- PEG polyethylene Glycol
- the PLLA-HA microcapsule-containing filler of the present invention is freeze-dried in step (a) is an initial freeze-drying step of 12 to 24 hours at -60 to 100 degrees Celsius, and 5 to 10 days at 15 to 25 degrees It is composed of a late drying step of drying during, and the size of the pulverized particles may be in the range of 30 um to 100 um, but is not limited thereto.
- the PLLA-HA microcapsule-containing filler of the present invention is to use 30 to 80 liters per 100 grams of HA in the phosphate buffer solution of step (b), and uniform particles are obtained by passing through the size of 80 to 120 mesh. It may be one, but is not limited thereto.
- the PLLA-HA microcapsule-containing filler of the present invention is prepared by mixing 15 to 25 ml of distilled water per 10 mg of microcapsules when preparing a filler for face after step (f) above, and preparing a filler for body. In this case, it may be prepared by mixing 25 to 35 cc of distilled water per 10 mg of microcapsules.
- the PLLA-HA conjugate according to the present invention is prepared by applying a microcapsule manufacturing method using PLLA and HA, and because PLLA-HA is evenly distributed in the suspension in the form of an emulsion of microparticles, PLLA does not clump in one place, thus preventing granuloma formation. There is an effect of lessening.
- a preferred embodiment of the method for manufacturing sustained-release microparticles comprising a poly-L-lactic acid filler and a hyaluronic acid filler conjugate according to the present invention configured as described above will be described as follows.
- a detailed description of a related known function or configuration may unnecessarily obscure the subject matter of the present invention, a detailed description thereof will be omitted.
- terms to be described later are terms defined in consideration of functions in the present invention, which may vary according to the intentions or precedents of users or operators, and accordingly, the meaning of each term should be interpreted based on the contents throughout the present specification. will be.
- PLLA poly-L-lactic acid filler
- HA hyaluronic acid filler
- poly-L-lactic acid also referred to as PLLA, polyL-lactic acid or polyL-lactic acid
- PLLA poly-L-lactic acid
- polyL-lactic acid is a filler approved by the US FDA for facial lipid stiffness in patients infected with human immunodeficiency virus (HIV).
- HBV human immunodeficiency virus
- HA hyaluronic acid
- Vitreous Humor by Meyer and Palmer in 1934 as a polyanionic mucopoly-saccharide, which is widely present in nature. It is a bio-derived polymer material.
- Hyaluronic acid is distributed in almost all tissues such as animal skin, muscles, skeleton, blood, lymph, placenta, eyes, cartilage, synovial fluid, etc. with various molecular weights (1-10 million Daltons), and among them, is most widely distributed in skin tissues. .
- Hyaluronic acid has been developed and used as a medical component for tissue repair (replacement and reconstruction of human tissues) at home and abroad, and is widely used in skin care and cosmetic fields.
- the meaning of'conjugate' described in the present invention is a simple mixture of a poly-L-lactic acid filler and a hyaluronic acid filler, and not a specific type of physical or chemical combination.
- PLLA poly-L-lactic acid
- CMC carboxymethylcellulose
- mannitol a poly-L-lactic acid
- the freeze-drying was performed in an initial freeze-drying step of 12 to 24 hours at -60 to 100 degrees Celsius and a late drying step of drying for 5 to 10 days at 15 to 25 degrees Celsius.
- the lyophilized PLLA mixture was pulverized to a size in the range of 30 um to 100 um (appropriately 50 um) using an overhead steer, and gamma ray sterilization was performed to prepare a PLLA mixture powder.
- Example 1 In order to prepare an oil-in-water (O/W) emulsion, the PLLA mixture prepared in Example 1 was mixed with medium chain triglyceride (MCT) oil and an emulsifier PGPR (polyglycerol polyricinoleate). ; An oil phase (O) was prepared by stirring with a mixture of polyglycerol polyricinoleate) to make it transparent.
- MCT medium chain triglyceride
- PGPR polyglycerol polyricinoleate
- the water phase (W) for covering the oil phase was prepared as follows.
- HA having a molecular weight of about 2 million Kda was mixed with a crosslinking agent, BDDE (butanediol diglycidyl ether) at a certain ratio, and gelled, and the gelled HA was washed with a phosphate buffer.
- Phosphoric acid buffer was used 30 to 80 liters (appropriately 50 liters) per 100 grams of HA.
- the HA after washing was passed through a mesh having a uniform size of 80 to 120 mesh to obtain a crosslinked HA of uniform particles.
- the optimal mesh hole size may be 100 mesh.
- the oil phase (O) and the aqueous phase (W) were mixed and stirred for 5 minutes at 400 rpm in a stirrer, and this was homogenized (5 minutes, 20,000 rpm) using a homogenizer to prepare an O/W emulsion.
- the O/W emulsion prepared in Example 2 was prepared in powder form microcapsules using a spray dryer (Eyela spray-dryer SD-1000, Eyela, Tokyo, Japan).
- the specific inlet air temperature was 130 ⁇ 5°C
- the discharge air temperature was 80 ⁇ 5°C
- the rotary sprayer was 10 ⁇ 10 kPa
- the blower speed was 0.80 m 3 /min
- the pump speed was adjusted to 1.0 mL/min.
- microcapsules prepared through the above process were injected into a vial and then gamma-ray sterilized once more and stored frozen at -20°C.
- It is characterized in that it can be used immediately by injecting water for injection into the microencapsulated PLLA-HA O/W emulsion.
- a filler for face 15 to 25 ml of distilled water per 10 mg of microcapsules are mixed, and When manufacturing a filler, it can be prepared by mixing 25 to 35 cc of distilled water per 10 mg of microcapsules.
- microencapsulated PLLA-HA O/W emulsion has been micronized and homogenized during the manufacturing process, and the problem of having to be used after mixing and suspending the water for injection before use, which existed in the prior art, and leaving it for 2 hours or more, and inside the injection composition
- the problem of agglomeration of particles such as PLLA has been solved.
- the present invention shortens the time until initial volume formation during injection, which is a disadvantage of conventional PLLA filler products (e.g., products such as Scultra), by 6 to 8 weeks or more, and reduces granuloma formation, which is another disadvantage of existing PLLA fillers.
- conventional PLLA filler products e.g., products such as Scultra
- granuloma formation which is another disadvantage of existing PLLA fillers.
- it is based on a form in which cross-linked hyaluronic acid is combined, but furthermore in this invention, the aggregated shape of PLLA is significantly reduced even after insufficient mixing time or long-term storage by making them microparticles.
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Abstract
Description
Claims (4)
- (a) PLLA(폴리-L-락틱산)에 CMC(카르복시메틸셀룰로스)와 마니톨을 섞은 후 동결 건조시키고, 일정한 크기로 분쇄한 후 감마레이 멸균을 실시하여 PLLA 혼합물을 제조하는 PLLA 혼합물 제조단계;(b) HA(히알루론산)를 BDDE(부탄디올 디글리시딜 에테르) 가교제와 섞은 후 젤화시키고, 인산완충액으로 세척한 다음, 균일한 입자의 가교 HA를 얻은 후 메쉬를 통과시켜 균일한 입자의 가교 HA를 수득하는 HA 혼합물 제조단계;(c) 상기 PLLA 혼합물을 유기용매에 녹여 오일상(O)을 수득하는 단계;(d) 상기 가교 HA에 증류수를 첨가하여 수상(W)을 수득하는 단계;(e) 상기 오일상(O) 및 수상(W)을 혼합하여 PLLA-HA 에멀젼을 수득하는 단계; 및(f) 상기 (e) 단계의 PLLA-HA에멀젼을 분무건조하여 미세캡슐을 제조하는 단계;를 포함하는 PLLA-HA 미세캡슐 함유 필러의 제조방법.
- 청구항 1에 있어서,상기 (a) 단계의 동결건조는 영하 60~100도에서 12 내지 24시간의 초기 동결건조 단계와, 15~25도에서 5일~10일 동안 건조하는 후기 건조단계로 구성되고, 분쇄한 입자의 크기는 30um~100um의 범위가 되도록 하는 것을 특징으로 하는, PLLA-HA 미세캡슐 함유 필러의 제조방법.
- 청구항 1에 있어서,상기 (b) 단계의 인산완충액은 HA 100gram 당 30~80리터를 사용하도록 하고, 균일한 입자는 80~120메쉬의 크기를 통과시켜 수득한 것을 특징으로 하는, PLLA-HA 미세캡슐 함유 필러의 제조방법.
- 청구항 1에 있어서,상기 (f) 단계 이후에, 페이스용의 필러를 제조할 경우 미세캡슐 10mg당 증류수 15~25ml를 혼합하고, 바디용의 필러를 제조할 경우 미세캡슐 10mg당 증류수 25~35cc를 혼합하는 것을 특징으로 하는, PLLA-HA 미세캡슐 함유 필러의 제조방법.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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BR112021013133-7A BR112021013133A2 (pt) | 2019-11-22 | 2020-11-06 | Formulação de injeção contendo um conjugado de preenchimento de ácido poli-l-láctico e de preenchimento de ácido hialurônico, e método para prepará-la |
US17/057,781 US11400182B2 (en) | 2019-11-22 | 2020-11-06 | Injectable formulation containing a poly l lactic acid filler and a hyaluronic acid filler conjugate and a method for preparing the same |
ES20806918T ES2953848T3 (es) | 2019-11-22 | 2020-11-06 | Formulación de inyección que contiene relleno de ácido poli-l-láctico y conjugado de relleno de ácido hialurónico, y procedimiento de preparación de la misma |
EP20806918.7A EP3851130B1 (en) | 2019-11-22 | 2020-11-06 | Injection formulation containing poly-l-lactic acid filler and hyaluronic acid filler conjugate, and method for preparing same |
Applications Claiming Priority (2)
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KR10-2019-0151389 | 2019-11-22 | ||
KR1020190151389A KR102183941B1 (ko) | 2019-11-22 | 2019-11-22 | 폴리-l-락틱산 필러와 히알루론산 필러 결합체를 함유하는 주사제제 및 그 제조방법 |
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WO2021101139A1 true WO2021101139A1 (ko) | 2021-05-27 |
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PCT/KR2020/015505 WO2021101139A1 (ko) | 2019-11-22 | 2020-11-06 | 폴리-l-락틱산 필러와 히알루론산 필러 결합체를 함유하는 주사제제 및 그 제조방법 |
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US (1) | US11400182B2 (ko) |
EP (1) | EP3851130B1 (ko) |
KR (5) | KR102183941B1 (ko) |
BR (1) | BR112021013133A2 (ko) |
ES (1) | ES2953848T3 (ko) |
PT (1) | PT3851130T (ko) |
WO (1) | WO2021101139A1 (ko) |
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KR102183845B1 (ko) * | 2019-11-22 | 2020-11-30 | 주식회사 지씨에스 | 폴리-l-락틱산 필러와 히알루론산 필러 결합체를 함유하는 서방성 주사제제 및 그 제조방법 |
KR102483759B1 (ko) * | 2022-01-18 | 2022-12-30 | 박민규 | 필러 조성물의 제조 방법 |
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- 2020-11-06 US US17/057,781 patent/US11400182B2/en active Active
- 2020-11-06 ES ES20806918T patent/ES2953848T3/es active Active
- 2020-11-06 WO PCT/KR2020/015505 patent/WO2021101139A1/ko unknown
- 2020-11-06 EP EP20806918.7A patent/EP3851130B1/en active Active
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- 2020-11-23 KR KR1020200157471A patent/KR102385210B1/ko active IP Right Grant
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Also Published As
Publication number | Publication date |
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KR20210063265A (ko) | 2021-06-01 |
KR102183941B1 (ko) | 2020-11-27 |
KR20210063264A (ko) | 2021-06-01 |
KR102385287B1 (ko) | 2022-04-12 |
KR20210063266A (ko) | 2021-06-01 |
KR102385223B1 (ko) | 2022-04-12 |
BR112021013133A2 (pt) | 2021-09-28 |
PT3851130T (pt) | 2023-07-31 |
US11400182B2 (en) | 2022-08-02 |
KR102385241B1 (ko) | 2022-04-12 |
EP3851130A1 (en) | 2021-07-21 |
EP3851130B1 (en) | 2023-05-31 |
ES2953848T3 (es) | 2023-11-16 |
KR20210063263A (ko) | 2021-06-01 |
US20210379244A1 (en) | 2021-12-09 |
EP3851130A4 (en) | 2022-05-04 |
KR102385210B1 (ko) | 2022-04-12 |
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