WO2021101353A1 - 조직 수복용 조성물 - Google Patents
조직 수복용 조성물 Download PDFInfo
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- WO2021101353A1 WO2021101353A1 PCT/KR2020/016617 KR2020016617W WO2021101353A1 WO 2021101353 A1 WO2021101353 A1 WO 2021101353A1 KR 2020016617 W KR2020016617 W KR 2020016617W WO 2021101353 A1 WO2021101353 A1 WO 2021101353A1
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- tissue repair
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Images
Classifications
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/60—Materials for use in artificial skin
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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
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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
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
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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
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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
Definitions
- the present invention relates to a composition for tissue repair, and more particularly, to a composition for tissue repair using a polymer.
- the wound covering material can be applied to local wounds or wounds that are not deeply deep, and protects the wound for a period of time until the skin is possible, or protects the wound for 3 to 4 weeks until the self-cultivation skin is completed and cultivated. It serves to facilitate the application of the skin.
- Cultured skin is used in a treatment method to minimize scar tissue in the case of severe skin defects or extensive wounds, and is transplanted for the purpose of permanent engraftment after sufficiently proliferating skin cells using cell culture techniques.
- it is necessary to review a lot of safety through bacteria, fungi, endotoxicity and mycoplasma tests, and various viruses [HIV 1&2, HTLVII&IIII, CMV lgM, B and C hepatitis viruses (Hepatitis B & C), adenovirus]
- viruses HTLVII&IIII, CMV lgM, B and C hepatitis viruses (Hepatitis B & C), adenovirus
- wound coverings there is an advantage that it can be widely applied, handled easily, and can be applied to patients requiring emergency treatment compared to cultured skin.
- the wound covering was used for temporary covering, there is a difficulty in permanent engraftment.
- wound coatings made of natural polymers such as chitin, chitosan, and collagen, the mechanical strength is low, the price is high, and mass production is difficult. It has the disadvantage of lack of adhesion to the site.
- PHA polylactic acid
- CMC carboxymethylcellulose
- PCL polycaprolactone
- a polymer-based tissue repair product has long-term efficacy by avoiding phagocytosis in the body. It is said that it must have a particle diameter of 40um or more in order to exhibit
- the formulation having a particle diameter of 20 ⁇ m or more there is a problem in that the microparticles are clogged in the needle, and there is a problem in that the particles are not uniformly dispersed, so that a uniform tissue repair effect cannot be obtained.
- the present invention was devised to solve the above problem, and to provide a composition for tissue repair using a non-toxic polymer.
- the present invention includes a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, and the copolymer is a colloidal phase tissue repair composition in which water is dispersed, The colloidal phase provides a composition for repairing a tissue that has an increased viscosity by heating the copolymer dispersed in the water.
- the colloidal phase provides a composition for tissue repair, characterized in that the viscosity according to the heating is 20 to 200,000 cP.
- composition provides a composition for tissue repair, characterized in that the range of K value represented by Equation 1 below is 0.01 to 5.
- m 100 is the number of moles of the polymer in 100 g of the aqueous solution
- M h is the molecular weight of the hydrophilic moiety
- M l is the molecular weight of the hydrophobic moiety
- HLB is a value represented by the following equation (2).
- M h is the molecular weight of the hydrophilic moiety
- M is the molecular weight of the entire molecule.
- HLB in Equation 2 provides a composition for tissue repair, characterized in that in the range of 0.1 to 20.
- the hydrophobic biocompatible polymer is any one or more polymers selected from the group consisting of polyglycolic acid, polycaprolactone, polylactic acid, polydioxanone, polytrimethylcarbonate, polyhydroxybutyrate, and copolymers containing the same. It provides a composition for tissue repair, characterized in that.
- hydrophilic biocompatible polymer provides a composition for tissue repair, characterized in that it is any one or more polymers selected from the group consisting of methoxy polyethylene glycol, dihydroxy polyethylene glycol, monoalkoxy polyethylene glycol and polyethylene glycol.
- the bonding structure of the copolymer provides a composition for tissue repair, characterized in that it comprises a structure of the following Formula 1, Formula 2 or Formula 3.
- X is a hydrophilic biocompatible polymer
- Y is a hydrophobic biocompatible polymer
- hydrophilic biocompatible polymer provides a composition for tissue repair, characterized in that 100 to 50,000 g/mol.
- hydrophobic biocompatible polymer provides a composition for tissue repair, characterized in that 500 to 70,000 g/mol.
- the copolymer provides a composition for tissue repair, characterized in that 600 to 120,000g / mol.
- composition for tissue repair characterized in that the concentration in the colloidal solution of the copolymer is 10 to 50% by weight.
- a colloidal tissue repair composition that is safe because it is not toxic when injected in vivo, and can be used for emergency patients, including a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized.
- FIG. 1 is a photograph of a colloidal aqueous solution according to the present invention with a DSLR (D3000, NIcon, Japan),
- Figure 3 is a photograph taken with a DSLR (D3000, Nicon, Japan) whether the sample leaks after injecting PBS and colloidal aqueous solution,
- Figure 4 is a photograph taken through an optical microscope of the skin thickness over time after injecting the colloidal aqueous solution
- the present inventors studied biocompatible polymers to make a safe tissue repair composition that can be used for emergency patients, can be manufactured at a relatively inexpensive price, and is non-toxic, as a result of polymerizing a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer. It was discovered that the coalescence can safely repair tissues without toxicity in vivo and can be applied to emergency patients, and the present invention has been reached.
- the present invention discloses a composition for repairing a tissue in a colloidal phase in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, and the copolymer is dispersed in water.
- the colloid refers to a state in which fine particles larger than molecules or ions are dispersed in a gas or liquid, and the entire colloidal state is referred to as a colloid.
- the particle size of the colloidal phase cannot be identified with the naked eye, and the insoluble foreign matter does not exist, and the insoluble foreign matter refers to the United States Pharmacopoeia (USP). It refers to an insoluble foreign matter that is easily detected when the solution formulation is placed in a container that has been cleaned according to the general test method for insoluble particulate matter and observed with the naked eye at a location of about 2750 to 3000 lx brightness, just under a white light source.
- USP United States Pharmacopoeia
- the particle size is invisible to the naked eye, and when the composition is injected into the body, a matrix structure is formed by binding between polymers, so that phagocytosis does not occur, and a long-term tissue repair effect can be exhibited in the skin.
- the colloidal phase may be heated to increase the viscosity.
- a colloid having an increased viscosity is formed by heating at a temperature between the melting point of the copolymer and the boiling point of water.
- the colloidal phase in which the copolymer is dispersed in water has a very low viscosity because the composition is not made as the copolymer is simply dispersed in water, but the colloidal phase according to the present invention has a small amount of organic material after dispersing the copolymer in water. It can be prepared into a composition by causing a reaction between the copolymers through various preparation methods such as addition of a solvent, and preferably by applying heat to cause a reaction.
- the particle size cannot be identified with the naked eye, and insoluble foreign matter does not exist, the viscosity of the colloidal phase increases as compared to before causing the reaction, and the increased viscosity. Does not decrease even when the temperature decreases.
- the viscosity of the colloidal phase having increased viscosity by causing a reaction between copolymers through the preparation method may be 20 to 200,000 cP (centipoise), preferably 25 to 190,000 cP (centipoise).
- the range of the K value represented by Equation 1 below may be 0.01 to 5, preferably 0.3 to 1.8, and more preferably 0.4 to 1.5. If the K value is less than 0.01 or exceeds 5, the efficacy of the formulation may be lowered.
- Equation 1 m 100 is the number of moles of the polymer in 100 g of the aqueous solution, M h is the molecular weight of the hydrophilic moiety, M 1 is the molecular weight of the hydrophobic moiety, and HLB is a value represented by the following equation.
- Equation 2 M h is the molecular weight of the hydrophilic moiety, and M is the molecular weight of the entire molecule.
- the number of moles of the copolymer dissolved in 100 g of the aqueous solution is the molecular weight of the hydrophobic biocompatible polymer, the molecular weight of the hydrophilic biocompatible polymer, and Since it does not have a certain value according to the mixing ratio, the range of the tissue repair efficacy of the composition for tissue repair of the present invention could not be set.
- the present invention is to derive the range of the tissue repair efficacy of the tissue repair composition, in a colloidal aqueous solution in which the hydrophobic biocompatible polymer and the hydrophilic biocompatible polymer are polymerized and dissolved in water, the above air dissolved in 100 g of the aqueous solution.
- a constant value was confirmed and determined as the K value.
- the K value is the number of moles of the polymer dissolved in 100 g of an aqueous solution measured on a colloid in which a hydrophobic biocompatible polymer and a copolymer of a hydrophilic biocompatible polymer are dispersed, the molecular weight of the hydrophobic biocompatible polymer, and the hydrophilic biocompatible polymer. It is a value showing the relationship between the molecular weight of and HLB value.
- the K value in the colloidal phase represents a constant value depending on the number of moles of the polymer dissolved in 100 g of the aqueous solution, the molecular weight of the hydrophobic biocompatible polymer, the molecular weight of the hydrophilic biocompatible polymer, and the HLB.
- the efficacy of the above formulation means that the hydrophilic polymer plays a large role in the copolymer before it is introduced into the body to form a colloidal phase evenly and stably dispersed in the aqueous solution without insoluble foreign matters that can be visually identifiable due to the interaction between the solvent and the polymer.
- the hydrophobic polymer plays a large role due to the influence of the internal environment, and the structure in which the polymer is stably dispersed in the aqueous solution collapses, and the matrix structure formed by the binding between the polymers induces collagen to repair the tissue.
- tissue repair refers to a mechanism that attempts to return the tissue to its original state when necrosis or defect occurs in the tissue due to trauma or inflammation such as skin tissue.
- the high molecular weight refers to the number average molecular weight (Mn).
- Mn number average molecular weight
- the number average molecular weight refers to an average molecular weight obtained by averaging the molecular weights of component molecular species of a polymer compound having a molecular weight distribution by a moisture content or a molar fraction.
- the value of HLB according to Equation 2 may be in the range of 0.1 to 20, preferably in the range of 1 to 14, more preferably in the range of 2 to 12, and even more preferably in the range of 2.5 to 10. It can be in the range of. If the value of HLB is less than 0.1, the polymerized polymer may not be dissolved in water, and if it exceeds 20, it may be absorbed into the body when injected into the body, and thus there may be no efficacy as a formulation.
- the HLB value (Hydrophile-Lipophile Balance) is a value indicating the degree of affinity of an amphiphilic polymer to water and oil. A large HLB indicates a high proportion of a hydrophilic polymer, and a small indicates a low proportion of a hydrophilic polymer.
- the hydrophobic biocompatible polymer is polyglycolic acid, polycaprolactone, polylactic acid, polydioxanone, and polytrimethyl so as to meet the K value according to Equation 1 above. It may be any one or more polymers selected from the group consisting of carbonate (polythree methyl carbonate), polyhydroxybutyrate, and copolymers including the same, and preferably polycaprolactone.
- the hydrophilic biocompatible polymer is methoxy polyethylene glycol, dihydroxy polyethylene glycol, monoalkoxy polyethylene glycol, and It may be any one or more polymers selected from the group consisting of polyethylene glycol, preferably methoxypolyethylene glycol.
- the bonding structure of the copolymer may be represented by the following Formula 1, Formula 2, or Formula 3, but is not limited thereto.
- X is a hydrophilic biocompatible polymer
- Y is a hydrophobic biocompatible polymer
- the molecular weight of the hydrophilic biocompatible polymer may be 100 to 50,000 g/mol, preferably 300 to 20,000 g/mol, more preferably 700 to 15,000, so as to meet the K value according to Equation 1 above. It may be g/mol, and even more preferably 1,000 to 10,000 g/mol.
- the molecular weight of the hydrophobic biocompatible polymer may be 500 to 70,000 g/mol, preferably 1,000 to 30,000 g/mol, and more preferably 1,500 to 27,500 so as to meet the K value according to Equation 1 above. It may be g/mol, and even more preferably 2,000 to 25,000 g/mol.
- the molecular weight of the copolymer may be 600 to 120,000 g/mol, preferably 1,300 to 50,000 g/mol, more preferably 2,200 to 42,500 g/mol, so as to meet the K value according to Equation 1 mol, and even more preferably 3,000 to 35,000 g/mol.
- the concentration in the colloidal solution of the copolymer may be 10 to 50% by weight so as to meet the K value according to Equation 1. If it exceeds 50%, the colloidal aqueous solution may have a gel with a very high viscosity, making it very difficult to inject through a syringe, and if it is less than 10%, it may not be effective as a formulation.
- the colloidal phase does not change or increases in turbidity when water is added.
- the turbidity decreases, but the turbidity of the colloidal phase of the present invention does not decrease.
- the polymer dispersed in a colloidal phase forms a structure in which a hydrophilic biopolymer and a hydrophobic biopolymer can be dissolved in water together.
- the solubilized structure formed by the hydrophilic biopolymer and the hydrophobic biopolymer is broken. Therefore, when water is added as described above, bonds between the hydrophobic biopolymers are formed so that turbidity does not change or rather increases.
- the present invention provides a method of preparing the composition for tissue repair.
- the manufacturing method includes preparing a copolymer by polymerizing a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer, and adding the copolymer to water to obtain a colloidal solution.
- the tissue repair composition prepared by the above manufacturing method exhibits a tissue repair effect of forming collagen when injected into the skin.
- a copolymer (mPEG2000-PCL2000) was prepared by polymerizing a polycaprolactone monomer having a molecular weight of 2,000 g/mol as a hydrophobic biocompatible polymer under a catalyst to methoxypolyethleneglycol having a molecular weight of 2,000 g/mol as a hydrophilic biocompatible polymer.
- mPEG2000-PCL2000 was prepared by polymerizing a polycaprolactone monomer having a molecular weight of 2,000 g/mol as a hydrophobic biocompatible polymer under a catalyst to methoxypolyethleneglycol having a molecular weight of 2,000 g/mol as a hydrophilic biocompatible polymer.
- Preparation Example 1 it was prepared in the same manner as in Preparation Example 1, except for polymerization with polycaprolactone having a molecular weight of 4,000 g/mol instead of polycaprolactone having a molecular weight of 2,000 g/mol.
- Preparation Example 1 it was prepared in the same manner as in Preparation Example 1, except for polymerization with polycaprolactone having a molecular weight of 5,000 g/mol instead of polycaprolactone having a molecular weight of 2,000 g/mol.
- Preparation Example 1 it was prepared in the same manner as in Preparation Example 1, except for polymerization with polycaprolactone having a molecular weight of 7,500 g/mol instead of polycaprolactone having a molecular weight of 2,000 g/mol.
- Preparation Example 1 it was prepared in the same manner as in Preparation Example 1, except for polymerization with polycaprolactone having a molecular weight of 10,000 g/mol instead of polycaprolactone having a molecular weight of 2,000 g/mol.
- Preparation Example 1 it was prepared in the same manner as in Preparation Example 1, except for polymerization with polycaprolactone having a molecular weight of 12,500 g/mol instead of polycaprolactone having a molecular weight of 2,000 g/mol.
- Preparation Example 1 it was prepared in the same manner as in Preparation Example 1, except for polymerization with polycaprolactone having a molecular weight of 15,000 g/mol instead of polycaprolactone having a molecular weight of 2,000 g/mol.
- a copolymer (mPEG5000-PCL5000) is prepared by polymerizing a polycaprolactone monomer having a molecular weight of 5,000 g/mol as a hydrophobic biocompatible polymer under a catalyst and methoxypolyethleneglycol having a molecular weight of 5,000 g/mol as a hydrophilic biocompatible polymer.
- mPEG5000-PCL5000 is prepared by polymerizing a polycaprolactone monomer having a molecular weight of 5,000 g/mol as a hydrophobic biocompatible polymer under a catalyst and methoxypolyethleneglycol having a molecular weight of 5,000 g/mol as a hydrophilic biocompatible polymer.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except that polymerization was performed with polycaprolactone having a molecular weight of 7,500 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except that polymerization was performed with polycaprolactone having a molecular weight of 10,000 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except for polymerization with polycaprolactone having a molecular weight of 12,500 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except that polymerization was performed with polycaprolactone having a molecular weight of 15,000 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except that polymerization was performed with polycaprolactone having a molecular weight of 17,500 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except for polymerization with polycaprolactone having a molecular weight of 20,000 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- Preparation Example 8 it was prepared in the same manner as in Preparation Example 8, except for polymerization with polycaprolactone having a molecular weight of 25,000 g/mol instead of polycaprolactone having a molecular weight of 5,000 g/mol.
- a copolymer (mPEG10000-PCL10000) is prepared by polymerizing a polycaprolactone monomer having a molecular weight of 10,000 g/mol as a hydrophobic biocompatible polymer with a methoxypolyethleneglycol having a molecular weight of 10,000 g/mol under a catalyst.
- mPEG10000-PCL10000 a copolymer having a molecular weight of 10,000 g/mol as a hydrophobic biocompatible polymer with a methoxypolyethleneglycol having a molecular weight of 10,000 g/mol under a catalyst.
- Preparation Example 16 it was prepared in the same manner as in Preparation Example 16, except for polymerization with polycaprolactone having a molecular weight of 12,500 g/mol instead of polycaprolactone having a molecular weight of 10,000 g/mol.
- Preparation Example 16 it was prepared in the same manner as in Preparation Example 16, except for polymerization with polycaprolactone having a molecular weight of 15,000 g/mol instead of polycaprolactone having a molecular weight of 10,000 g/mol.
- Preparation Example 16 it was prepared in the same manner as in Preparation Example 16, except for polymerization with polycaprolactone having a molecular weight of 17,500 g/mol instead of polycaprolactone having a molecular weight of 10,000 g/mol.
- Preparation Example 16 it was prepared in the same manner as in Preparation Example 16, except for polymerization with polycaprolactone having a molecular weight of 20,000 g/mol instead of polycaprolactone having a molecular weight of 10,000 g/mol.
- Preparation Example 16 it was prepared in the same manner as in Preparation Example 16, except for polymerization with polycaprolactone having a molecular weight of 25,000 g/mol instead of polycaprolactone having a molecular weight of 10,000 g/mol.
- Preparation Example 16 it was prepared in the same manner as in Preparation Example 16, except for polymerization with polycaprolactone having a molecular weight of 30,000 g/mol instead of polycaprolactone having a molecular weight of 10,000 g/mol.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 10% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 15% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 20% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 25% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 30% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 35% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 40% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 45% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 50% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that an aqueous colloidal solution of 55% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that a colloidal aqueous solution of 60% by weight of a polymer was prepared in Example 1.
- a colloidal aqueous solution was prepared in the same manner as in Example 1, except that an aqueous colloidal solution of 65% by weight of a polymer was prepared in Example 1.
- the number of moles of the polymer in 100 g of aqueous solution was measured, and the K value according to Equation 1 below was measured. Accordingly, the efficacy of the formulation was evaluated (highlight treatment of the portion having the efficacy of the formulation), and the results are shown in Tables 1 and 2 below.
- Equation 1 m 100 is the number of moles of the polymer in 100 g of the aqueous solution, M h is the molecular weight of the hydrophilic moiety, M 1 is the molecular weight of the hydrophobic moiety, and HLB is a value represented by the following equation.
- Equation 2 M h is the molecular weight of the hydrophilic moiety, and M is the molecular weight of the entire molecule.
- the number of moles of the polymer dissolved in 100 g of the aqueous solution can be known, and it can be seen that the lower the HLB value at a certain concentration, the lower the number of moles.
- the concentration exceeds 45% by weight, the viscosity of the colloidal aqueous solution becomes strong, making it difficult to inject by injection, and if it is less than 15% by weight, it is absorbed into the body during intracorporeal injection, and the formulation has no efficacy.
- the proportion of the hydrophobic biocompatible polymer is high, so that when water is added, the polymer is not dissolved, and if it exceeds 10, it is absorbed into the body when injected into the body, and the formulation has no efficacy.
- the relationship between the molecular weight of the hydrophilic biopolymer and the hydrophobic biopolymer and the value of HLB can be understood. If the molecular weight of the hydrophilic biopolymer is the same, the higher the molecular weight of the hydrophobic biopolymer increases. The K value decreases. This is the same even when judging by the ratio of the hydrophilic biopolymer and the hydrophobic biopolymer. In addition, even if the molecular weight of the hydrophilic biopolymer is different, it can be seen that the K value has very similar values when the ratio of the hydrophilic biopolymer and the hydrophobic biopolymer is the same.
- the K value has a constant value within a certain concentration range to be described later, and the efficacy of the formulation can be confirmed within this range.
- the K value is converted to about 0.12 to 3.26, and the effective portion of the formulation is in the range of 0.4 to 1.5.
- the concentration in the colloidal aqueous solution is 15 to 45% by weight, HLB 2.5 to 10, and K values are effective as a formulation at 0.4 to 1.5.
- composition for tissue repair according to the present invention a colloidal phase prepared using Preparation Example 3 was used to measure turbidity according to the following method, and the results are shown in FIG. 9.
- a formazin turbidity standard of 4000 NTU was used as the turbidity standard solution.
- a standard solution and a colloidal phase prepared using Preparation Example 3 were diluted 2, 5, 10 and 20 times, respectively, and put in a vial to prepare a sample for comparison, and the turbidity of the diluted standard solution Are 4000, 2000, 800, 400 and 200 NTU respectively.
- the turbidity is not lowered even when diluted from left to right, but rather, it is possible to visually confirm the case that it is thicker than the undiluted solution.
- Example 1 the heated colloidal aqueous solution (Example 1) has increased viscosity without precipitation and foreign matters as compared with a non-heated mixture (Comparative Example).
- the viscosity of the heated colloidal aqueous solution is in the range of 26.4 to 188404.6 cP, and as the polymer concentration in the aqueous solution increases, the viscosity tends to increase. It can be seen that the viscosity is increased to 190,000 times as much.
- the experiment was subdivided into 3 groups of 10 rats by designating 8 places per 6-week-old SD rat individual, one side with phosphate buffered saline (PBS) and the other side as the test material group.
- PBS phosphate buffered saline
- the breeding environment was set at 24 ⁇ 2°C, 50 ⁇ 10% relative humidity, and 12 hours lighting time, and food was allowed to eat freely.
- PBS was injected as a negative control in the left subcutaneous layer centering on the midline of each rat, and a colloidal aqueous solution prepared by dissolving the polymer prepared in Preparation Example 3 in water in the right subcutaneous layer (concentration 25%, HLB 5.7, K value 0.8864) 250 ⁇ l of each was constantly injected to observe whether the sample leaked immediately after injection, and the results are shown in FIG. 3.
- FIG. 3 is a photograph taken with a DSLR (D3000, Nicon, Japan) to determine whether a sample leaks after injecting PBS and an aqueous colloidal solution
- FIG. 4 is an optical microscope to measure skin thickness over time after injecting an aqueous colloidal solution. It is a picture taken through
- FIG. 5 is a picture taken through an optical microscope of collagen over time after injecting a colloidal aqueous solution.
- Figure 6 is a photograph taken through an optical microscope of the skin thickness over time after injecting PBS
- Figure 7 is a photograph taken through an optical microscope of collagen over time after injecting PBS
- 8 is a graph showing the skin thickness over time after injecting PBS and colloidal aqueous solution.
- the thickness of the subcutaneous layer also increases with time up to 6 weeks according to the injection of the colloidal aqueous solution in the tissue subcutaneous layer injected with the colloidal aqueous solution. , It can be seen that the increase width accordingly was significantly improved compared to FIG. 6 in which PBS was injected.
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Abstract
Description
본 발명에 따른 조직 수복용 조성물에 대하여 하기 방법에 따라 탁도를 측정하기 위해 제조예 3을 이용하여 제조된 콜로이드 상을 사용하였고, 이에 대한 결과를 도 9에 나타내었다. 탁도 표준액으로 4000NTU의 formazin turbidity standard를 사용하였다.
[삭제]
도 9를 검토하면, 표준액의 경우 왼쪽에서 오른쪽으로, 희석이 될수록 탁도가 낮아지는 것을 알 수 있다.
Claims (12)
- 소수성 생체적합성 고분자 및 친수성 생체적합성 고분자가 중합된 공중합체를 포함하고, 상기 공중합체가 물에 분산된 콜로이드 상(phase)의 조직 수복용 조성물로서,상기 콜로이드 상은 상기 물에 분산된 공중합체를 가열하여 점도가 증가된 상인 조직 수복용 조성물.
- 제1항에 있어서,상기 콜로이드 상은 상기 가열에 따른 점도가 20 내지 200,000 cP인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 조성물은 하기 수학식 1로 나타내는 K값의 범위가 0.01 내지 5인 것을 특징으로 하는 조직 수복용 조성물:<수학식 1>K=(m100*Mh 2*10)/(Ml*HLB2)여기서, m100은 수용액 100g중 중합체의 몰수이고, Mh는 친수성 부분의 분자량이고, Ml는 소수성 부분의 분자량이고, HLB는 하기 수학식2로 나타낸 값이다.<수학식 2>HLB=20*Mh/M여기서, Mh는 친수성 부분의 분자량이고, M은 분자 전체의 분자량이다.
- 제1항에 있어서,상기 수학식 2에서 HLB의 값은 0.1 내지 20의 범위인 것을 특징으로 하는 조직수복용 조성물.
- 제1항에 있어서,상기 소수성 생체적합성 고분자는 폴리글리콜산, 폴리카프로락톤, 폴리락트산, 폴리디옥사논, 폴리트리메틸카르보네이트, 폴리하이드록시부틸레이트 및 이를 포함하는 공중합체로 이루어진 군으로부터 선택되는 어느 하나 이상의 고분자인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 친수성 생체적합성 고분자는 메톡시폴리에틸렌글리콜, 디히드록시폴리에틸렌글리콜, 모노알콕시폴리에틸렌글리콜 및 폴리에틸렌글리콜로 이루어진 군으로부터 선택된 어느 하나 이상의 고분자인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 공중합체의 결합 구조는 하기 화학식 1, 화학식 2 또는 화학식 3의 구조를 포함하는 것을 특징으로 하는 조직 수복용 조성물:[화학식 1]X-Y[화학식 2]Y-X-Y[화학식 3]X-Y-X여기서, X는 친수성 생체적합성 고분자이고, Y는 소수성 생체적합성 고분자이다.
- 제1항에 있어서,상기 친수성 생체적합성 고분자는 100 내지 50,000g/mol인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 소수성 생체적합성 고분자는 500 내지 70,000g/mol인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 공중합체는 600 내지 120,000g/mol인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 공중합체의 콜로이드 용액 내의 농도는 10 내지 50중량%인 것을 특징으로 하는 조직 수복용 조성물.
- 제1항에 있어서,상기 콜로이드 상은 탁도가 물을 첨가하는 경우 변화가 없거나 증가하는 것을 특징으로 하는 조직 수복용 조성물.
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US17/777,225 US20220401628A1 (en) | 2019-11-22 | 2020-11-23 | Tissue restoration composition |
CA3157909A CA3157909A1 (en) | 2019-11-22 | 2020-11-23 | Tissue restoration composition |
CN202080080552.1A CN114728099A (zh) | 2019-11-22 | 2020-11-23 | 组织修复组合物 |
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BR112022009700A BR112022009700A2 (pt) | 2019-11-22 | 2020-11-23 | Composição de restauração de tecido |
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- 2020-11-23 WO PCT/KR2020/016617 patent/WO2021101353A1/ko active Application Filing
- 2020-11-23 JP JP2022526692A patent/JP2023501468A/ja active Pending
- 2020-11-23 CN CN202080080552.1A patent/CN114728099A/zh active Pending
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- 2020-11-23 BR BR112022009700A patent/BR112022009700A2/pt unknown
- 2020-11-23 KR KR1020200158100A patent/KR20210063274A/ko not_active Application Discontinuation
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EP4043044A1 (en) | 2022-08-17 |
MX2022005829A (es) | 2022-06-08 |
AU2020387490A1 (en) | 2022-06-16 |
BR112022009700A2 (pt) | 2022-08-09 |
EP4043044A4 (en) | 2023-11-01 |
KR20210063274A (ko) | 2021-06-01 |
CN114728099A (zh) | 2022-07-08 |
CA3157909A1 (en) | 2021-05-27 |
JP2023501468A (ja) | 2023-01-18 |
US20220401628A1 (en) | 2022-12-22 |
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