WO2022124508A1 - Composition injectable pour réparation tissulaire et son procédé de préparation - Google Patents

Composition injectable pour réparation tissulaire et son procédé de préparation Download PDF

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WO2022124508A1
WO2022124508A1 PCT/KR2021/008513 KR2021008513W WO2022124508A1 WO 2022124508 A1 WO2022124508 A1 WO 2022124508A1 KR 2021008513 W KR2021008513 W KR 2021008513W WO 2022124508 A1 WO2022124508 A1 WO 2022124508A1
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tissue repair
microspheres
composition
injectable composition
injection
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PCT/KR2021/008513
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English (en)
Korean (ko)
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김주희
이상노
오현석
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(주)인벤티지랩
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Priority to CN202180006650.5A priority Critical patent/CN114916222B/zh
Publication of WO2022124508A1 publication Critical patent/WO2022124508A1/fr

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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
    • A61L27/26—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
    • A61L27/14—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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • 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
    • 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 an injection composition for tissue repair and a method for preparing the same, and more particularly, to an injection composition for tissue repair and a method for preparing the same .
  • Injectable compositions for tissue repair are generally used for cosmetic purposes, filling or replacement of biological tissues (filling of wrinkles, remodeling of the face, increase of lip volume, etc.), and It has been used for therapeutic purposes to rehydrate the skin by mesotherapy.
  • the hyaluronic acid used as the injection composition for tissue repair, has a problem of insufficient long-term lasting effect because reabsorption in the body occurs very rapidly between 2 weeks and 2 months. Accordingly, as in Korean Patent Application Laid-Open No. 10-2004-0072008, products in which hyaluronic acid and a cross-linking material are cross-linked to each other to extend the resorption period are being sold. However, these cross-linked products have also been reported to have problems due to the toxicity of the cross-linking material.
  • a formulation in which polylactic acid (PLA) having a particle diameter of 20 to 50 ⁇ m is dispersed in an aqueous solution of carboxymethyl cellulose (CMC) or polycaprolactone having a particle diameter of 20 to 50 ⁇ m A formulation in which (Polycaprolactone) (PCL) particles were dispersed in CMC and an aqueous solution of glycerin was used.
  • PLA polylactic acid
  • CMC carboxymethyl cellulose
  • PCL Polycaprolactone
  • the formulation using a polymer that is decomposed in vivo has problems in that the micro-particles are clogged with the needle during injection, and the particles are not uniformly dispersed, so that the uniform tissue repair effect cannot be obtained.
  • the polymer may be injected into the body to induce collagen formation, thereby exhibiting a tissue repair effect, but, like hyaluronic acid, the effect of immediate tissue repair is insignificant.
  • the injection composition for tissue repair when administered by injection, it exhibits an immediate tissue repair effect and at the same time can exhibit a long-term continuous tissue repair effect, reduces discomfort in the procedure, and the particles are uniformly dispersed in a tissue that can be used There is an urgent need to prepare an injection composition for restoration.
  • Patent Document 1 KR10-2004-0072008 A1
  • An object of the present invention is an injection for tissue repair that can be injected into the body to restore skin health damaged by aging and stimulation through improvement of the physiological environment, induce an immediate tissue repair effect and collagen production, and can continuously repair tissue for a long time To provide a composition and a method for preparing the same.
  • Another object of the present invention is an injection composition ready for use without the need to dilute before use when used as an injection, and there is no problem of dosing discomfort in which particles clog the injection needle during injection, and the composition is uniformly dispersed and uniform To provide an injection composition for tissue repair and a method for preparing the same, which exhibits a tissue repair effect.
  • an injection composition for tissue repair according to an embodiment of the present invention, wherein the composition for tissue repair injection comprises: microspheres comprising a biodegradable polymer; and hyaluronic acid (HA), wherein the composition has a value of 3,400 to 3,600 according to Formula 1:
  • G * is the complex shear modulus
  • ⁇ is the phase angle
  • the tissue repair injection composition may further include a polynucleotide (Polynucleotide, PN).
  • PN Polynucleotide
  • the ratio (elastic component/viscous component) of the composition to the elastic component and the viscous component is 6 to 7.
  • the microspheres have a spherical shape with a uniform surface, an average diameter of 35 to 55 ⁇ m, and a standard deviation of 3.0 to 5.5 with respect to the average diameter.
  • the specific surface area of the microspheres is 1.40 to 1.50 m 2 /g.
  • the biodegradable polymer is at least one selected from the group consisting of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, and derivatives thereof.
  • the microspheres can be bioabsorbed within 1 to 3 years after injection into the body.
  • the injectable composition for tissue repair does not need to be diluted before use, and is ready to use.
  • a method for preparing an injection composition for tissue repair comprises the steps of 1) preparing microspheres comprising a biodegradable polymer; 2) preparing a buffer solution; 3) preparing a PN dilution solution by mixing polynucleotide (PN) with the buffer solution of step 2); 4) preparing a mixed dilution solution by mixing sodium hyaluronate gel with the PN dilution solution; 5) mixing and defoaming the microspheres of step 1) with the mixed diluent; and 6) injecting the diluent containing the microspheres of step 5) into the pre-filled syringe.
  • PN polynucleotide
  • the buffer solution may include sodium chloride, di-sodium phosphate, sodium dihydrogen phosphate and water for injection.
  • Step 5) includes: 5-1) mixing the mixed dilution solution in which the microspheres are mixed at a speed ratio of revolution and rotation of 1:1 to 2:1 for 1 to 5 minutes; 5-2) waiting for 1 to 5 minutes after the completion of the mixing; 5-3) repeating steps 5-1) and 5-2) 2 to 4 times; and 5-4) degassing the mixed dilution solution in which the microspheres are mixed at a speed ratio of revolution and rotation of 2:1 to 5:1 for 5 to 20 minutes.
  • Step 6) is to be injected in a ready to use state without the need for dilution before use.
  • An injection composition for tissue repair comprises: microspheres comprising a biodegradable polymer; and hyaluronic acid (HA), wherein the composition has a value of 3,400 to 3,600 according to Formula 1 below:
  • G * is the complex shear modulus
  • ⁇ is the phase angle
  • the existing tissue repair injection composition contains hyaluronic acid as a main component, and the hyaluronic acid is present in joint fluid, cartilage, skin, and the like.
  • the hyaluronic acid is used as an injection composition for tissue repair and injected into the body, the hyaluronic acid attracts water molecules, thereby increasing moisture and skin elasticity in the body.
  • the injection composition for tissue repair containing such hyaluronic acid only has a maintenance period of 6 to 12 months, so there is an inconvenience of having to periodically inject the injection composition into the body.
  • the injectable composition for tissue repair of the present invention comprises: microspheres comprising a biodegradable polymer; and hyaluronic acid (HA), wherein the composition has a value of 3,400 to 3,600 according to Formula 1 below:
  • G * is the complex shear modulus
  • ⁇ is the phase angle
  • the injectable composition for tissue repair of the present invention contains hyaluronic acid and microspheres, and is mainly characterized by exhibiting viscoelastic behavior characteristics, and due to the above characteristics, the uniformly mixed injectable composition is ready for use (Ready to use) can be provided.
  • the viscous and elastic behavior characteristics can be analyzed by measuring the complex shear modulus (G * ) and the phase angle ( ⁇ ).
  • a value that reflects the two characteristics of G * and ⁇ is G * /sin ⁇
  • G * /sin ⁇ is a characteristic value indicating the viscoelastic properties of the composition.
  • a composition with strong elasticity has a high G * /sin ⁇ value and a strong binder. has a low value.
  • Equation 1 in order to provide a uniformly mixed injection composition containing hyaluronic acid and microspheres in a ready to use form, the value according to Equation 1 should be 3,400 to 3,600.
  • the value when the value falls within the above range, it may be provided not only as a uniform injectable composition, but also may be provided in a ready-to-use form, enabling direct administration without a dilution process prior to administration as an injection.
  • the viscosity and elasticity of the injection composition are indicated by hyaluronic acid, and the properties may be affected depending on the content range of hyaluronic acid.
  • the injection composition of the present invention is characterized in that it further contains microspheres and polynucleotides (PN) containing a biodegradable polymer, thereby affecting the viscosity and elasticity of the injection composition.
  • PN polynucleotides
  • the viscosity and elasticity of the injection composition itself are changed under the influence of additional mixing of microspheres and polynucleotides, and the value according to Equation 1 can be expressed by adjusting the content range of the injection composition.
  • the injection composition of the present invention has a viscosity of 75 to 85 Pa, a measured elasticity of 500 to 550 Pa, and an elastic component and viscous
  • the ratio (elastic component / viscous component) to the component) is characterized in that 6 to 7.
  • the elastic and viscous properties of the composition are included within the scope of the present invention, it is possible to provide a uniform injectable composition, and the hyaluronic acid, microspheres and polynucleotides maintain a uniform state even within the skin tissue after administration. Therefore, there is no difference in effect according to the site.
  • microparticles containing biodegradable polymers are used as an injection composition for tissue repair, there is a problem in that the particle diameter of the microparticles is not uniform, so that the tissue repair effect does not appear evenly when injected into the body.
  • microspheres comprising a biodegradable polymer according to an embodiment of the present invention, and it can be seen that the surface exhibits a uniform spherical shape.
  • FIG. 2 is an SEM measurement photograph of biodegradable polymer particles used as a composition for tissue repair in other products, and it can be seen that they exhibit an irregular shape rather than a spherical shape.
  • FIG. 3 is an SEM measurement photograph of biodegradable polymer particles used as a composition for tissue repair in other products. Although the spherical shape is the same as in the present invention, it can be confirmed that the surface of the particles is not uniform.
  • the conventional injectable composition for tissue repair has a problem in that the shape of the microspheres is not constant, the particle diameters are different from each other, or the surface is not uniform, so that the tissue repair effect does not appear evenly when injected into the body.
  • the shape of the microspheres does not show a constant size or if the surface is not uniform, there is a difference in the rate of decomposition when injected into the body, thereby causing a problem in that the tissue repair effect in the skin is different.
  • the microspheres have an average diameter of 35 to 55 ⁇ m, a standard deviation of the average diameter of 3.0 to 5.5, and a specific surface area of 1.40 to 1.50 m 2 /g.
  • the main feature is that the dispersion of the average diameter is small, which means that the diameter range of the microspheres included in the composition is very narrowly distributed, and the surface is uniformly formed to represent a large specific surface area value. .
  • microspheres are distributed in a uniform size, exhibit a large specific surface area value, and can be absorbed into the body within 1 to 3 years after injection into the body.
  • the composition for tissue repair of the present invention contains microspheres including hyaluronic acid and biodegradable polymer at the same time as described above, and can induce collagen production by hyaluronic acid and microspheres, resulting in a short-term tissue repair effect is shown by hyaluronic acid, and even if the tissue repair effect by hyaluronic acid is reduced, it can exhibit a tissue repair effect for a long time by the microspheres containing the biodegradable polymer.
  • the biodegradable polymer may be any one or more selected from the group consisting of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, and derivatives thereof.
  • a method for preparing an injection composition for tissue repair comprises the steps of 1) preparing microspheres comprising a biodegradable polymer; 2) preparing a buffer solution; 3) preparing a PN dilution solution by mixing polynucleotide (PN) with the buffer solution of step 2); 4) preparing a mixed dilution solution by mixing a sodium hyaluronate dilution solution with the PN dilution solution; 5) mixing and defoaming the microspheres of step 1) with the mixed diluent; and 6) injecting the diluent containing the microspheres of step 5) into the pre-filled syringe.
  • PN polynucleotide
  • Step 1) is a step of preparing microspheres containing a biodegradable polymer.
  • step may include a) preparing a first mixture; b) preparing a second mixture; c) injecting the first mixture into the microchannel in a straight direction; d) injecting the second mixture into microchannels on both sides or on one side; e) collecting microspheres; f) agitating the collected microspheres; and g) washing and drying the microspheres.
  • Step a) is a step of preparing a first mixture, dissolving a biodegradable polymer in an organic solvent to prepare a first mixture, wherein the biodegradable polymer is polylactic acid, polylactide, polylactic-co-glycolic acid , polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate , polylactic acid, polyamino acids, and combinations thereof, preferably polylactic acid (PLLA), but is not limited to the above examples.
  • the biodegradable polymer is polylactic acid, polylactide, polylactic-co-glycolic acid , polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalate, poly
  • the organic solvent is immiscible with water, for example, any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof, preferably dichloromethane, It is not limited to, an organic solvent capable of dissolving a biodegradable polymer, and is not limited to the above examples, and any organic solvent that can be easily selected by a person skilled in the art can be used.
  • the biodegradable polymer in the first mixture contains 1 to 10% by weight, preferably 3 to 7% by weight, but is not limited to the above example.
  • Step b) is a step of preparing a second mixture, and a second mixture is prepared by dissolving a surfactant in water.
  • the surfactant can be used without limitation as long as the biodegradable polymer solution can help form a stable emulsion.
  • nonionic surfactants it is at least one selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof, and more specifically, methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol , polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, ester amine, linear diamine, pattiamine, and any one or more selected from the group consisting of mixtures thereof, preferably Although it is polyvinyl alcohol, it is not limited to an example.
  • the second mixture is a surfactant dissolved in water, and the surfactant may be included in an amount of 0.1 to 5% by weight, preferably 0.1 to 0.5% by weight, but is not limited thereto.
  • Steps c) and d) are steps of injecting the first mixture and the second mixture into the microchannel formed on the wafer to flow.
  • the microchannel may be formed on a material selected from the group consisting of a silicon wafer or a polymer film, but examples of the material are not limited to the above example, and any material capable of forming a microchannel may be used.
  • the polymer film is polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone ( Polysulfone) and mixtures thereof may be selected from the group consisting of, but not limited to the above examples.
  • microchannel is prepared.
  • the microchannel has an average diameter of 80 to 120 ⁇ m, preferably 100 ⁇ m, but is not limited thereto.
  • the average diameter of the microchannel can be changed according to the range of the injection pressure.
  • the second mixture may be injected at a pressure of 1,500 to 2,500 mbar, and the first mixture may be injected at a pressure of 300 to 700 mbar.
  • the average diameter of the microchannel is closely related to the average diameter of the particles, but is also closely related to the injection pressure of the first mixture and the second mixture, so it is not limited to the above example, and the average diameter of the particles to be prepared or when injected It can be changed according to the pressure conditions.
  • step c) the first mixture is injected into the microchannel in the linear direction to flow, and in step d), the microchannel on both sides or one side is formed to form an intersection point with the microchannel in the linear direction. to flow by injecting
  • the first mixture flows along the linear microchannel
  • the second mixture flows along the microchannel forming an intersection with the linear microchannel on both sides or one side based on the linear microchannel, encounter with the flow of the first mixture.
  • the first mixture when the first mixture is injected into the microchannel in a straight direction, it is injected under a constant pressure condition and flows at a constant flow rate, and the pressure condition at this time is 300 to 700 mbar, preferably 500 mbar, but it is not limited to examples.
  • the second mixture when the second mixture is injected into the microchannels of both sides or one side, it is injected under a constant pressure condition and flows at a constant flow rate, and the pressure condition at this time is 1500 to 2500 mbar, preferably 2000 mbar, but not limited to examples does not
  • the second mixture is flowed under a higher pressure condition.
  • the flow of the first mixture and the second mixture are relatively more
  • the second mixture having a high flow rate compresses the first mixture, and at this time, the biodegradable polymer in the first mixture produces spherical microspheres due to the repulsive force of the first mixture and the second mixture.
  • Step e) is a step of collecting microspheres, and the microspheres are collected in a water tank containing the second mixture to prevent aggregation between initially generated microspheres.
  • step e the second mixture prepared in step b), that is, a mixed solution of a surfactant and water, is used.
  • a part is injected into the microchannel, and the other part is injected into the microchannel. is used to prevent agglomeration between the collected microspheres by moving them to the water bath of step e).
  • Step f) is a step of stirring the collected microspheres in a water bath, and the microspheres are stirred at a constant temperature condition and agitation speed, and the organic solvent present on the surface of the sustained-release particles is evaporated and removed.
  • the stirring conditions include the steps of primary stirring at a speed of 150 to 650 rpm for 0.5 to 1.5 hours at 10 to 15 °C; And after the first stirring step, it proceeds in the order of the second stirring step at a speed of 500 to 1,500 rpm for 2.0 to 4.0 hours at 50 to 70 °C.
  • the stirring speed proceeds with a different stirring speed in the first and second stirring steps, and the stirring process is performed using a faster speed in the second stirring step than in the first stirring step.
  • the temperature conditions are also characterized by stirring by increasing the temperature in the secondary stirring process compared to the primary stirring process, and as the temperature is increased stepwise, the organic solvent present on the surface of the microspheres
  • the evaporation rate can be controlled. That is, by slowly evaporating the organic solvent present on the surface of the microsphere, microspheres having a smooth surface can be prepared.
  • the temperature at which the first mixture and the second mixture flow through the microchannel is also 15 to 20°C, preferably 15°C. That is, after flowing through the microchannel and forming an intersection to generate microspheres, the temperature is constantly maintained at 15 to 20° C. until the collected microspheres are first stirred. It is possible to manufacture and maintain spherical particles only by maintaining a low temperature in the manufacturing process of the microspheres. That is, when it is not a low-temperature condition, it is difficult to manufacture particles having a constant spherical shape.
  • step g) is a step of washing and drying the sustained-release particles, and the microspheres from which all organic solvents have been removed on the surface by stirring are washed several times with sterilized filtered purified water to remove the surfactant remaining in the microspheres, , then freeze-dried.
  • the freeze-drying conditions include: freezing at -45 to -40°C for 1 to 15 hours; After the freezing step, the first drying step for 1 to 15 hours by raising the temperature to -30 to -20 °C under 150 to 250 ⁇ bar conditions; After the first drying step, the second drying step for 1 to 15 hours by raising the temperature to 1 to 5 °C; and raising the temperature to 20 to 40° C. after the second drying step and performing a third drying step for 1 to 25 hours.
  • the surface of the particles is not prepared evenly as shown in FIG. 2 by manufacturing differently from the above conditions, the decomposition rate of the microspheres increases, and thus a problem may occur in which the tissue repair effect cannot be exhibited for a long time as in the present invention.
  • Step 2) is a step of preparing a buffer solution.
  • the buffer solution contains sodium chloride, dibasic sodium phosphate, sodium dihydrogen phosphate and water for injection.
  • sodium chloride, dibasic sodium phosphate and sodium dihydrogen phosphate are dissolved in water for injection in a weight ratio of 1:0.1:0.03 to 1:0.2:0.1, and the pH of the prepared buffer is 6 to 8.
  • Step 3) is a step of preparing a PN dilution solution by mixing polynucleotide (PN) with the buffer solution of step 2), and 10 to 30 parts by weight of the polynucleotide is mixed with respect to 100 parts by weight of the buffer solution.
  • the PN dilution solution is then stirred for 10 to 50 minutes at a speed of 50 to 150 rpm in order to be uniformly mixed.
  • Step 4) is to prepare a mixed dilution solution by mixing sodium hyaluronate gel with the PN dilution solution. After the mixing, the stirring process was performed for 5 to 20 minutes at a speed of 50 to 150 rpm.
  • step 1) Mixing and defoaming the microspheres of step 1) with the mixed dilution solution, specifically, 5-1) the mixing dilution solution in which the microspheres are mixed, and the speed ratio of revolution and rotation is 1:1 to 2:1 mixing for 1 to 5 minutes with a furnace; 5-2) waiting for 1 to 5 minutes after the completion of the mixing; 5-3) repeating steps 5-1) and 5-2) 2 to 4 times; and 5-4) degassing the mixed dilution solution in which the microspheres are mixed at a speed ratio of revolution and rotation of 2:1 to 5:1 for 5 to 20 minutes.
  • the mixed dilution solution specifically, 5-1 the mixing dilution solution in which the microspheres are mixed, and the speed ratio of revolution and rotation is 1:1 to 2:1 mixing for 1 to 5 minutes with a furnace; 5-2) waiting for 1 to 5 minutes after the completion of the mixing; 5-3) repeating steps 5-1) and 5-2) 2 to 4 times; and 5-4) degassing the mixed dilution solution in which the microspheres are mixed at a speed
  • the microspheres, polynucleotides and hyaluronic acid in the composition can be uniformly mixed, and then by adjusting the revolution and rotation rate ratio in step 5-4), It is possible to proceed with the optimal defoaming process.
  • the composition of the present invention can be provided as a ready-to-use formulation, and then, in step 6), injecting the diluent into the prefilled syringe proceed with
  • the present invention is put into the body, it can restore the skin health damaged by aging and stimulation through improvement of the physiological environment, induces an immediate tissue repair effect and collagen production, and enables continuous tissue repair for a long time.
  • Figure 2 is an SEM measurement of the biodegradable polymer particles according to an embodiment of the present invention.
  • FIG 3 is an SEM measurement photograph of biodegradable polymer particles according to an embodiment of the present invention.
  • the present invention provides an injection composition for tissue repair, the composition comprising: microspheres comprising a biodegradable polymer; And hyaluronic acid (Hyaluronic acid, HA), wherein the composition relates to an injection composition for tissue repair having a value of 3,400 to 3,600 according to Formula 1:
  • G * is the complex shear modulus
  • ⁇ is the phase angle
  • Polylactic acid (PLLA) was dissolved in dichloromethane to prepare a first mixture.
  • polylactic acid (PLLA) in the first mixture was included in a proportion of 5% by weight.
  • Polyvinyl alcohol as a surfactant was mixed with water to prepare a second mixture containing 0.25 wt% of polyvinyl alcohol.
  • the first mixture and the second mixture were injected into microchannels formed on a silicon wafer to flow.
  • the first mixture was flowed under a pressure condition of 500 mbar
  • the second mixture was flowed under a pressure condition of 2,000 mbar.
  • the temperature condition was maintained at 15°C.
  • microspheres formed at the intersection where the flow of the first mixture and the flow of the second mixture meet were collected in a water bath containing the second mixture.
  • microspheres collected in the water bath were first stirred at 15° C. at a rate of 200 to 400 rpm for 1 hour, and then the temperature was raised to 60° C., followed by second stirring at a speed of 800 to 1,200 rpm for 3 hours.
  • microspheres were washed several times with sterile filtered purified water, and freeze-dried to prepare microspheres.
  • the prepared buffer solution has a pH of 6 to 7.
  • a PN dilution solution was prepared by mixing 20 parts by weight of polynucleotide with respect to 150 parts by weight of the buffer solution and stirring at 100 rpm for 30 minutes. 800 parts by weight of sodium hyaluronate gel was mixed with 150 parts by weight of the PN diluted solution, and stirred at a speed of 100 rpm for 10 minutes.
  • microspheres prepared in Preparation Example 1 were mixed, and the revolving and rotating speed ratio was 1.2:1, mixed for 1 to 5 minutes, and after waiting for 2 minutes, the mixing process was performed again. Thereafter, the defoaming process was performed for 10 minutes at a speed ratio of 3:1 for revolution and rotation.
  • composition after the mixing and defoaming process was completed was prepared in a ready-to-use form by filling a syringe.
  • Preparation Example 1 Freezing at -40°C for 15 hours; After the freezing step, the first drying step for 15 hours by raising the temperature to -25 °C under 150 to 250 ⁇ bar conditions; After the first drying step, the second drying step for 15 hours by raising the temperature to 4 °C; and raising the temperature to 25° C. after the second drying step and drying the third for 25 hours. Comparative Example 1 After freeze-drying in Preparation Example 1, the temperature was increased to 25° C. and dried for 55 hours. Comparative Example 2 In Preparation Example 1, the freeze-drying process was not performed, and drying was performed in the first to third drying steps. Comparative Example 3 In Preparation Example 1, the third drying step was increased to 45° C. and dried.
  • the surface When pores are formed on the surface, the surface is non-uniform and the decomposition rate is fast when injected into the body, which may cause a problem in that the tissue repair effect cannot be exhibited for a long period of time.
  • microspheres with a uniform surface as shown in FIG. 1 can be prepared, but under other conditions, microspheres with a non-uniform surface are prepared as shown in FIG. 3 Confirmed.
  • the elasticity (Storage modulus, elastic modulus), viscosity (Loss modulus, viscous modulus), complex viscosity, and phase angle of the injection composition were measured.
  • the resistance to a given force was measured by injecting a sample between a balanced plate and a microscopically vibrating and rotating geometry.
  • the shear strain was determined in the amplitude sweep evaluation, and the viscoelasticity characteristics were confirmed through the frequency sweep evaluation. Measurement conditions were shear strain: 0.15 %, temperature: 25 °C, frequency gap: 0.5 mm, and the corresponding frequency (0.1 ⁇ 10 Hz) was measured and the measured value was confirmed at 1 Hz.
  • Equation 1 the values of Equation 1 below were derived, and the ratios for elasticity and viscosity were calculated:
  • G * is the complex shear modulus
  • ⁇ is the phase angle
  • the injection composition of the present invention can confirm that the value of Formula 1 is included within the scope of the present invention, measured only for hyaluronic acid, or for tissue repair injection compositions on the market When measured, it was confirmed that the shear modulus value was not measured, so that the value of Equation 1 as in the present invention was not derived.
  • the value of Formula 1 corresponds to a value measured only when provided as an injection composition for tissue repair such as the present invention.
  • the composition of Preparation Example 2 is on the left side, and the control example (the chaeum sub-) on the right side. Q) was injected subcutaneously.
  • mice A total of 60 mice were used, and 0.15 mL was constantly injected subcutaneously, and the tissue repair power and persistence of the administered samples were confirmed according to the lapse of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and 24 weeks immediately after injection. .
  • composition of Preparation Example 2 maintained the injected form as compared to the Control Example, while the Control Example did not gradually maintain the shape during the test period and spread to the surrounding tissues.
  • composition of Preparation Example 1 has better stability against foreign body reactions and the effectiveness of maintaining the injected form compared to the control example.
  • the present invention relates to an injection composition for tissue repair and a method for preparing the same, and more particularly, to an injection composition for tissue repair and a method for preparing the same .

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition injectable pour la réparation tissulaire et son procédé de préparation, ladite composition pouvant fournir un effet de réparation tissulaire à court terme et un effet de réparation tissulaire à long terme en induisant la production de collagène, et la santé de la peau endommagée par le vieillissement et l'irritation peut être restaurée. La présente invention concerne également : une composition injectable pour la réparation tissulaire, qui est une composition injectable prête à l'emploi sans besoin de dilution avant l'utilisation, qui peut donc être immédiatement utilisée, et qui est uniformément dispersée, présentant ainsi un effet uniforme de réparation tissulaire ; un procédé pour la préparer.
PCT/KR2021/008513 2020-12-10 2021-07-05 Composition injectable pour réparation tissulaire et son procédé de préparation WO2022124508A1 (fr)

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Citations (6)

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WO2007126048A1 (fr) * 2006-04-28 2007-11-08 Daiichi Sankyo Company, Limited Procede de production de suspension homogene et stable et appareil associe
KR20170027090A (ko) * 2015-09-01 2017-03-09 (주)시지바이오 히알루론산 조성물 및 그의 제조방법
KR20170093829A (ko) * 2014-12-12 2017-08-16 주식회사 모테조 피하 주사용제 및 피하 주사용제를 함유하는 주사기의 제조 방법
KR20170123099A (ko) * 2016-04-28 2017-11-07 주식회사 한국비엔씨 폴리카프로락톤 및 히알루론산을 포함하는 피부용 필러 조성물
KR20190027274A (ko) * 2017-09-06 2019-03-14 (주)인벤티지랩 조직 수복용 주사제 조성물 및 이의 제조 방법
KR20190102967A (ko) * 2018-02-26 2019-09-04 주식회사 뉴트라팜텍 조직 수복용 히알루론산 피부 충진제 조성물

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KR100481514B1 (ko) 2003-02-07 2005-04-07 삼성전자주식회사 입력신호레벨 제어장치 및 제어방법
EP3381438B1 (fr) * 2015-11-24 2023-06-07 BMI Korea Co. Ltd Composition pour l'injection d'acide hyaluronique, contenant un dérivé de l'acide hyaluronique et une fraction adn, et utilisation de cette dernière
AU2019231273A1 (en) * 2018-03-06 2020-09-24 Epibone, Inc. Injectable off-the- shelf cartilage, tendon, and ligament repair compositions and methods of use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007126048A1 (fr) * 2006-04-28 2007-11-08 Daiichi Sankyo Company, Limited Procede de production de suspension homogene et stable et appareil associe
KR20170093829A (ko) * 2014-12-12 2017-08-16 주식회사 모테조 피하 주사용제 및 피하 주사용제를 함유하는 주사기의 제조 방법
KR20170027090A (ko) * 2015-09-01 2017-03-09 (주)시지바이오 히알루론산 조성물 및 그의 제조방법
KR20170123099A (ko) * 2016-04-28 2017-11-07 주식회사 한국비엔씨 폴리카프로락톤 및 히알루론산을 포함하는 피부용 필러 조성물
KR20190027274A (ko) * 2017-09-06 2019-03-14 (주)인벤티지랩 조직 수복용 주사제 조성물 및 이의 제조 방법
KR20190102967A (ko) * 2018-02-26 2019-09-04 주식회사 뉴트라팜텍 조직 수복용 히알루론산 피부 충진제 조성물

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