Tissue repair injection composition comprising hyaluronic acid gel fused with biodegradable polymer microgranules using eco-friendly solvent, and method for manufacturing same

Abstract

The present invention relates to: a tissue repair injection composition comprising a hyaluronic acid gel fused with biodegradable polymer microgranules in which an eco-friendly solvent is used; and a method for manufacturing same. The tissue repair composition according to the present invention uses an eco-friendly solvent and thus is not harmful to living organisms and the environment, and comprises biodegradable polymer microgranules having a spherical or nearly spherical shape and a rough, bumpy surface and is thus easily absorbed without being phagocytosed by macrophages and can effectively induce the production of collagen. In addition, the tissue repair composition can be used in the form of a hyaluronic acid gel fused with the biodegradable polymer microgranules and thus can be used directly without the need for additional dilution or the like, and exhibits tissue repair effects at the time of injection as well as for a long period of time following injection.

Description

Injectable composition for tissue repair comprising hyaluronic acid gel fused with biodegradable polymer microgranules using an eco-friendly solvent and method for producing the same

[0001] The present invention relates to a tissue repair injection composition comprising a hyaluronic acid gel fused with biodegradable polymer microgranules using an environmentally friendly solvent, and a method for producing the same, and more particularly, to a tissue repair injection composition comprising biodegradable polymer microgranules prepared using an environmentally friendly solvent and hyaluronic acid fused in a gel state, and a method for producing the same.

[0002] With the recent acceleration of population aging and declining birth rates, market demand for senior-friendly and anti-aging industries is rapidly increasing. Furthermore, the desire for youth and beauty is driving the growing popularity of anti-aging industries, including skin treatments, fillers, botulinum toxins, and other cosmetic treatments.

[0003] Human skin can experience soft tissue damage due to external impact, disease, and aging. In these cases, ingredients similar to skin tissue are injected into specific areas to expand soft tissue, improving wrinkles, contouring, and tissue repair. These are commonly referred to as "dermal fillers."

[0004] Filler commercialization is gradually progressing through four generations. First-generation fillers, initially used for cosmetic purposes, are collagen fillers. Due to their animal origin, they are now rarely used. Second-generation hyaluronic acid fillers, with their high biocompatibility and ease of removal, currently hold the majority of the market. Third-generation fillers, including calcium hydroxyapatite (CHA), polymethacrylate (PMMA), and polyacrylamide (PAHG), offer the advantage of semi-permanent results, but are not biodegradable, leading to safety concerns. Fourth-generation fillers are biostimulatory fillers. These biodegradable polymer fillers induce long-term skin regeneration through collagen and elastin production, and their use is currently increasing.

[0005] Hyaluronic acid fillers are suitable for restoring wrinkles and skin volume by injecting cross-linked hyaluronic acid into the skin to supply moisture and restore elasticity. The raw material, hyaluronic acid, has a polysaccharide backbone composed of repeating dimers of N-acetyl-D-glucosaamine and D-glucuronic acid, and is a component that can hold up to 1,000 times its weight in water through hydrogen bonds. On the other hand, it is highly biodegradable (24-48 hours), so filler products are being manufactured by increasing the half-life in the body through cross-linking, and cross-linking agents such as divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), and ethylene glycol diglycidyl ether (EGDGE) are used. Even after cross-linking, hyaluronic acid is rapidly degraded in vivo by enzymes and ROS, limiting its tissue repair effectiveness to approximately 3-12 months. To maintain its effectiveness, reinjections are often required every few months, and regular maintenance is essential. Efforts are ongoing to develop effective cross-linking technologies, such as varying the cross-linking agent and increasing the degree of cross-linking (e.g., Korean Patent Publication No. 10-2022-0099922). However, more proactive alternatives are needed to address the inherent limitations of hyaluronic acid.

[0006] Meanwhile, biocompatible, biodegradable polymers like polylactic acid (PLA) have been used as fourth-generation semi-permanent fillers. These materials biodegrade over time after injection into the skin, stimulating macrophages to gradually promote collagen synthesis, improving overall skin texture and exhibiting anti-aging benefits. While their slow absorption rate allows for a sustained effect of 2-3 years, their lack of immediate post-procedure results is a limitation when used for tissue repair. To address this, practitioners must provide thorough pre-procedure explanations, as insufficient explanations often lead to claims of poor efficacy. Furthermore, the polymer's inherent properties make it difficult to disperse evenly from the aqueous phase to the injectable phase, leading to clumping, which can clog needles and make injections difficult. To address this issue, products formulated with carboxymethylcellulose or uncrosslinked hyaluronic acid have been commercialized. However, these products are typically delivered in powder form, requiring the addition of the injectable or buffer solution prior to treatment and continuous or intermittent shaking for extended periods to disperse the product. Additionally, unlike hyaluronic acid fillers, there is no immediate improvement after injection, and problems such as volume loss and nodule formation often occur within one month after injection.

[0007] Biodegradable polymers do not completely dissolve in aqueous solutions on their own. Therefore, if the suspension process prior to use is not perfect, problems such as needle clogging or unstable injection force, which makes it difficult to control the injection amount, and crystallization may occur in areas where large amounts are injected. To improve this, efforts are being made to provide small devices that automatically stir the solution or to round the shape of the active ingredient to increase the surface area and improve dispersion. Furthermore, because of the need for suspension time, patients undergoing treatment must visit the hospital at the scheduled time, which is inconvenient. Arriving too early means waiting, and even if arriving on time, if the product to be treated is not fully suspended, the patient must wait. This creates inconvenience not only for the practitioner but also for the patient receiving the treatment.

[0008] Furthermore, biodegradable polymers require microparticles for in vivo injection. Conventional methods primarily rely on dissolution in halogenated organic solvents, such as methylene chloride and chloroform. According to the CHEM21 selection guide, these organic solvents are classified as hazardous or highly hazardous, posing toxicity and environmental concerns (Green Chem, 2016, 18, 288-296). Furthermore, production facilities require additional equipment for worker safety, such as explosion-proof and hood systems, and organic solvent dust collection systems. This necessitates high production costs and constant attention to worker safety. Furthermore, the smooth surfaces of conventional biodegradable polymer microparticles hinder macrophage adsorption, negatively impacting the mechanism that stimulates additional collagen production. Therefore, if biodegradable polymers could be micronized with a rough surface structure using eco-friendly solvents, the social and economic implications would be significant.

[0009] Accordingly, the inventors of the present invention have sought to develop a new type of filler that does not require a pre-use suspension process and is already uniformly dispersed, enabling immediate use, by solving the problems of conventional biodegradable polymer-containing filler products, such as the need for a long suspension process prior to use and the need for care to ensure uniform dispersion during suspension. In addition, the inventors have sought to develop a new type of filler that resolves the human and environmental harm caused by the use of harmful organic solvents during the manufacturing process, while also roughening the surface structure of the biodegradable polymer to facilitate collagen production stimulation by the biodegradable polymer.

[0010] Accordingly, one object of the present invention is to provide a tissue repair injection composition comprising a hyaluronic acid gel fused with biodegradable polymer microgranules that are already uniformly dispersed and have particle uniformity, and are ready for use without requiring a long-term suspension process before use.

[0011] In addition, another object of the present invention is to provide an injectable composition for tissue repair comprising a hyaluronic acid gel fused with environmentally friendly biodegradable polymer microgranules having reduced harmful effects on the human body and the environment using an environmentally friendly solvent.

[0012] In addition, another object of the present invention is to provide an injectable composition for tissue repair comprising a hyaluronic acid gel fused with rough biodegradable polymer microgranules having a rough surface structure.

[0013] In addition, another object of the present invention is to provide a method for producing an injectable composition for skin repair comprising a hyaluronic acid gel fused with the biodegradable polymer microgranules.

[0014] In one aspect, the present invention provides a method for preparing an injectable composition for tissue repair comprising a hyaluronic acid gel fused with biodegradable polymer microgranules.

[0015] As a specific embodiment, the method for producing the tissue repair injection composition of the present invention is as follows:

[0016] (S10) A step of manufacturing microgranules of a biodegradable polymer using an eco-friendly solvent;

[0017] (S20) A step for preparing a hyaluronic acid gel; and

[0018] (S30) A step of dispersing the biodegradable polymer microgranules of the step (S10) into the hyaluronic acid gel of the step (S20).

[0019] Hereinafter, with reference to FIG. 1, a method for manufacturing a tissue repair injection composition comprising a hyaluronic acid gel fused with biodegradable polymer microgranules of the present invention will be specifically described.

[0020] First, step (S10) is a step of manufacturing microgranules of a biodegradable polymer using an eco-friendly solvent.

[0021] In the present invention, the biodegradable polymer is poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-DL-lactic acid (PDLLA), poly-lactic acid (PLA), polyglycolic acid (PGA), polydioxanone (PDO), polycaprolactone (PCL), poly-α-hydroxy acid (PHA), poly(trimethylene carbonate), poly(alkyl cyanoacrylate), polyhydroxyalkanoates, methoxypolyethylene glycol, It may be at least one selected from the group consisting of hydroxyl polyethylene glycol (PEG), monoalkoxy polyethylene glycol (PEG), polyethylene glycol (PEG), copolymers thereof, and mixtures thereof. Examples of the copolymers thereof may include polylactic acid-glycolic acid copolymer, polydioxanone-caprolactone copolymer, polylactic acid-caprolactone copolymer, etc.

[0022] As a specific example, the biodegradable polymer may be any one of PLA, PLLA, PDLA, PDLLA, PCL, etc., and these are biostable polymer materials because they are decomposed into water, carbon dioxide, and sugar and absorbed in the body.

[0023] The biodegradable polymer included in the present invention may have a weight average molecular weight in the range of 10,000 to 500,000 g / mol, preferably 10,000 to 400,000 g / mol, and more preferably 20,000 to 300,000 g / mol. If the molecular weight is less than 10,000, it is difficult to have persistence in the body and promote collagen production, and if the molecular weight exceeds 500,000, it is difficult to process and is not suitable for producing desired microparticles.

[0024] In the present invention, the environmentally friendly solvent may be a Class 3 solvent, which is the safest category with low toxicity potential and approved for use in pharmaceutical formulations in the United States and other countries, or an environmentally friendly organic solvent, triacetin, or a eutectic solvent known to have low toxicity potential.

[0025] The above Class 3 organic solvents are Dimethyl sulfoxide, Acetic acid, Acetone, Anisole, 1-Butanol, 2-Butanol, Butyl acetate, tert-Butylmethyl ether, Ethanol, Ethyl acetate, Ethyl ether, Ethyl formate, Formic acid, Heptane, Isobutyl acetate, Isopropyl acetate, Methyl acetate, 3-Methyl-1-butanol, Methylethyl ketone, Methylisobutyl ketone, It may be at least one selected from the group consisting of 2-Methyl-1-propanol, Pentane, 1-Pentanol, 1-Propanol, 2-Propanol, Propyl acetate, and mixtures thereof.

[0026] The environmentally friendly organic solvent other than the above Class 3 organic solvent may be at least one selected from the group consisting of dihydrolevoglucosensone, methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate, triethyl phosphate, organic carbonates (e.g., ethylene carbonate, propylene carbonate, butylene carbonate, glycerol carbonate, diethyl carbonate, dimethyl carbonate, etc.), lactate esters (e.g., methyl lactate, ethyl lactate, etc.), tetraglycol, and mixtures thereof.

[0027] As a specific example, the eco-friendly solvent may be at least one selected from the group consisting of Class 3 organic solvents, eco-friendly organic solvents other than Class 3 organic solvents, and mixtures thereof.

[0028] As a specific example, the environmentally friendly organic solvent may be dimethyl sulfoxide. Dimethyl sulfoxide is an environmentally friendly organic solvent belonging to Class 3 solvents, the safest category with low toxicity potential.

[0029] The above triacetin has been approved by the FDA as a food additive generally recognized as safe (GRAS) since 1975 and is a safe, environmentally friendly solvent included in the SCOGS (Select Committee on GRAS substances) database.

[0030] The above eutectic solvent is a mixture of two or more components that are combined through hydrogen bonding, resulting in a lower melting point than each individual component. The two or more components act as hydrogen bond acceptors and hydrogen bond donors for hydrogen bonding. Because they have lower melting points than each individual component, they exist as transparent liquids and form an internal hydrogen bond network, making them environmentally friendly solvents with high solubility.

[0031] The hydrogen bond acceptor of the above eutectic solvent may include at least one selected from the group consisting of choline chloride, betaine, sodium acetate, proline, nicotinamide, L-carnitine, and combinations thereof.

[0032] The hydrogen bond donor of the above eutectic solvent may include at least one selected from the group consisting of polyols, organic acids, fatty acids, amide compounds, sugars, and combinations thereof.

[0033] The above polyol may include, for example, at least one selected from the group consisting of glycerol, erythritol, mannitol, sorbitol, xylitol, lactitol, ethylene glycol, propylene glycol, ribitol, aldonicol, butylene glycol, pentylene glycol, and hexylene glycol.

[0034] The above sugar may include, for example, one or more selected from the group consisting of glucose, fructose, xylose, arabinose, sucrose, lactose, and galactose.

[0035] The organic acid may include, for example, at least one selected from the group consisting of lactic acid, formic acid, acetic acid, propionic acid, malic acid, maleic acid, pyruvic acid, fumaric acid, succinic acid, citric acid, acetic acid, aconitic acid, hyaluronic acid, hydroxycitric acid, levulinic acid, and lactone derivatives.

[0036] The above fatty acid may include, for example, at least one selected from the group consisting of octanoic acid, nonanoic acid, undecylic acid, capric acid, lauric acid, palmitic acid, linolenic acid, and gamma-linolenic acid.

[0037] The above amide compound may include at least one selected from the group consisting of urea, thiourea, acrylamide, acetamide, ceramide, nylon-6, melatonin, and asparagine.

[0038] The hydrogen bond donors, such as the above-mentioned hydrogen chloride choline, betaine, proline, etc., include those selected from amides, sugars, alcohols, organic acids, fatty acids, etc.

[0039] As a specific example, the eutectic solvent can be used by mixing betaine as a hydrogen bond acceptor and glycerin as a hydrogen bond donor with water.

[0040] In the present invention, the biodegradable polymer microgranules are biodegradable polymer particles having a diameter of 20 μm or more that are not phagocytosed by macrophages. If the diameter is less than 20 μm, adverse effects such as granulomas or inflammatory reactions may occur, making them unsuitable (J Drugs Dermatol., 2014, 13, s29-31). In addition, the smaller the diameter of the injection needle, the more effective injection and precise manipulation of the injection solution are possible, and the flow resistance of the fluid is small, which has the advantage of less skin irritation. Therefore, the biodegradable polymer microgranules must be smaller than the diameter of the injection needle to enable injection using the injection according to the purpose of the present invention, and therefore, considering the diameter of the smallest injection needle, it is preferable to have a diameter of 100 μm or less. As a specific example, the biodegradable polymer microgranules according to the present invention have a diameter of 20 to 100 μm.

[0041] In the present invention, the biodegradable polymer microgranules are characterized by having a spherical or nearly spherical shape with an uneven, rough surface (see Fig. 3). Here, the nearly spherical shape refers to a sphericity, i.e., a thickness to diameter ratio of 1:0.7 to 1:1.3, preferably 1:0.8 to 1:1.2. When the biodegradable polymer microgranules have an uneven, rough surface, macrophage adsorption is facilitated, thereby promoting collagen production by fibroblasts and the like through stimulation of macrophages.

[0042] In the present invention, the production of microgranules of a biodegradable polymer using the eco-friendly solvent may include the steps of (A10) mixing a biodegradable polymer in an eco-friendly solvent and stirring to dissolve the biodegradable polymer to produce a biodegradable polymer solution; (A20) freezing the biodegradable polymer solution of step (A10) by spraying it at low temperature; and (A30) removing the solvent from the frozen biodegradable polymer solution of step (A20).

[0043] The above step (A10) is a step of preparing a biodegradable polymer solution by mixing and dissolving a biodegradable polymer in an eco-friendly solvent and stirring. Based on 100 parts by weight of the biodegradable polymer, the eco-friendly solvent may be mixed and dissolved in an amount of 200 to 10,000 parts by weight, preferably 300 to 5,000 parts by weight, and more preferably 500 to 1,000 parts by weight. At this time, the eco-friendly solvent may be the above-described organic solvent, triacetin, or eutectic solvent.

[0044] The above step (A20) is a step of freezing the biodegradable polymer solution of the above step (A10) by spraying it at a low temperature, and the low temperature is performed at a temperature below the freezing point of the solvent and a temperature below the freezing point of the biodegradable polymer, and may vary depending on the type of the solvent and the biodegradable polymer, but for example, -25°C to -5°C, preferably -20°C to -8°C, may be suitable.

[0045] The above spraying refers to applying pressure to a biodegradable polymer solution to spray it to a diameter of 100 um or less, and the sprayed biodegradable polymer solution exists in the form of a frozen solid aerosol due to the low ambient temperature described above during the spraying.

[0046] The above step (A30) is a step of removing a solvent from the frozen biodegradable polymer solution of the above step (A20), and the removal of the solvent can be accomplished by a method such as adsorption, evaporation, or washing, depending on the type of solvent used.

[0047] Meanwhile, the biodegradable polymer microgranules manufactured by removing the solvent can be dried to facilitate the subsequent dispersion process with the hyaluronic acid gel, and the drying can be performed by freeze drying, spray drying, vacuum drying, etc.

[0048] In the present invention, the production of microgranules of a biodegradable polymer using the eco-friendly solvent may be performed by the steps of (B10) mixing the biodegradable polymer and the eco-friendly solvent and dissolving them at high temperature and high pressure to produce a biodegradable polymer solution; (B20) ultrasonically treating the biodegradable polymer melt of step (B10); and (B30) removing the solvent from the melt of step (B20).

[0049] The above step (B10) is a step of mixing a biodegradable polymer and an eco-friendly solvent and dissolving them under high temperature and high pressure to prepare a biodegradable polymer solution. Based on 100 parts by weight of the biodegradable polymer, the eco-friendly solvent may be mixed in an amount of 200 to 10,000 parts by weight, preferably 300 to 5,000 parts by weight, and more preferably 500 to 1,000 parts by weight. At this time, the eco-friendly solvent may be the above-described organic solvent, triacetin, or a eutectic solvent, and preferably, an organic solvent may be used.

[0050] In the above high temperature and high pressure, the high temperature may be 60°C or higher, 60 to 200°C, 70 to 190°C, 120 to 180°C, 80 to 180°C, 90 to 180°C, 100 to 180°C, 120 to 170°C, 140 to 170°C, or 160 to 170°C, and the high pressure may be 0.11 to 20 MPa, 0.11 to 10 MPa, 0.11 to 5 MPa, 0.11 to 2 MPa, 0.11 to 1 MPa, 0.11 to 0.5 MPa, 0.11 to 0.3 MPa, 0.11 to 0.2 MPa, or 0.12 MPa. In addition, the high temperature and high pressure treatment is sufficient for a time period in which the biodegradable polymer is sufficiently dissolved in an environmentally friendly solvent, preferably 10 to 30 minutes, more preferably 15 to 25 minutes, and even more preferably 18 to 22 minutes.

[0051] The above step (B20) is a step of ultrasonically treating the biodegradable polymer melt of the above step (B10), wherein the ultrasonic treatment suppresses further agglomeration of the biodegradable polymer microgranules. The ultrasonic treatment may be performed for 10 to 60 minutes, preferably 20 to 30 minutes.

[0052] The step of removing the solvent from the melt of the above step (B30) is a step of removing the solvent from the melt of the above step (B20). The removal of the solvent can be accomplished by a method such as adsorption, evaporation, or washing, depending on the type of solvent used.

[0053] Meanwhile, the biodegradable polymer microgranules manufactured by removing the solvent can be dried to facilitate the subsequent dispersion process with the hyaluronic acid gel, and the drying can be performed by freeze drying, spray drying, vacuum drying, etc.

[0054] The above step (S20) is a step for manufacturing a hyaluronic acid gel.

[0055] In the present invention, the hyaluronic acid gel refers to a hydrogel in a hydrated state in which a cross-linking agent is added to a hyaluronic acid aqueous solution to cross-link hyaluronic acid.

[0056] In the present invention, hyaluronic acid is used to mean not only hyaluronic acid itself but also its salts and derivatives. Therefore, the term "hyaluronic acid aqueous solution" as used herein encompasses aqueous solutions of hyaluronic acid, aqueous solutions of hyaluronic acid salts, aqueous solutions of hyaluronic acid derivatives, and aqueous solutions of mixtures thereof.

[0057] The above hyaluronic acid may have an average molecular weight of, for example, 50,000, 60,000, 100,000, 200,000, 500,000, 800,000, 1,000,000, 1,200,000, 1,500,000, 1,800,000, 2,000,000, 2,200,000, 2,500,000, 2,800,000, 2,900,000, or 3,000,000. The average molecular weight may be within the range of any two values ​​exemplified herein. Considering the crosslinked gel of hyaluronic acid, it is preferably 1,000,000 or more, and preferably 1,500,000 or more.

[0058] The above hyaluronic acid aqueous solution is hyaluronic acid dissolved in an alkaline solution, and the alkaline solution has a pH of 11 to 13, preferably 11.5 to 12.5, and examples thereof include sodium hydroxide solution, magnesium hydroxide solution, calcium hydroxide solution, etc.

[0059] The crosslinking agent is preferably a substance that has excellent biocompatibility and can crosslink hyaluronic acid, and examples thereof include 1,4-butandiol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), divinyl sulfone (DVS), polyethylene glycol (PEG), polyethylene glycol diglycidyl ether, bis ethyl carbodiimide (BCDI), 1,6-hexanediol diglycidyl ether, N-hydroxysuccinimide (NHS), and 1-ethyl-3(3-dimethylaminopropyl) carbodiimide. (1-ethyl-3(3-dimethylaminopropyl)carboiimide, EDC), hexamethylenediamine (HMDA), 1,2,7,8-diepoxyoctane (DEO), citric acid, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether,There are compounds such as glycerol polyglycidylether, trimethylpropane polyglycidyl ether, bisepoxypropoxyethylene (1,2-(bis(2,3-epoxypropoxy)ethylene), pentaerythritol polyglycidyl ether, and sorbitol polyglycidyl ether. Preferably, BDDE, EGDGE, DVS BCEDI, etc. can be used.

[0060] The crosslinking method of hyaluronic acid using the above crosslinking agent can utilize any known technology and is not limited to the crosslinking method. As a specific example, the hyaluronic acid gel can be manufactured by dissolving hyaluronic acid in a sodium hydroxide solution at pH 12, adding a crosslinking agent, mixing, and then maturing at room temperature under nitrogen conditions.

[0061] Meanwhile, after manufacturing the hyaluronic acid gel, it is desirable to remove the cross-linking agent as much as possible for biostability. The removal of the cross-linking agent may be performed after manufacturing the hyaluronic acid gel in step (S20) and before step (S30) below, or may be performed after step (S30) below. At this time, the removal of the cross-linking agent may be performed using various methods known in the art, such as those disclosed in Korean Patent No. 10-1922711 and Korean Patent No. 10-1044339, and a specific example includes a dialysis method.

[0062] The above step (S30) is a step of dispersing the biodegradable polymer microgranules of the above step (S10) into the hyaluronic acid gel of the above step (S20).

[0063] The hyaluronic acid gel of step (S20) used in the above step (S30) may be a hyaluronic acid gel in a hydrated state manufactured in step (S20) and from which the crosslinking agent is removed or not as described above.

[0064] The above dispersion can be achieved by stirring at a weight ratio of hyaluronic acid and biodegradable polymer microgranules of 1:0.5 to 5, preferably 1:0.5 to 4, more preferably 1:0.5 to 3, and even more preferably 1:0.5 to 2.5. When the weight ratio of the biodegradable polymer microgranules is less than 0.5 weight ratio with respect to the hyaluronic acid, the tissue repair ability of the final manufactured restorative composition is excellent at the initial stage of administration, but the restorative ability decreases over time, and there is a problem that continuous tissue repair due to the expected collagen production ability is insufficient compared to the existing hyaluronic acid filler. In addition, when the weight ratio of the biodegradable polymer microgranules exceeds 5 weight ratio with respect to the hyaluronic acid, a stable hyaluronic acid fusion gel is not formed due to the excess of the biodegradable polymer, and there is a possibility of inflammation occurring biologically.

[0065] In addition, in order to control the content of hyaluronic acid gel and biodegradable polymer microgranules contained in the final composition manufactured during the dispersion process or to provide additional uses, at least one of purified water, a physiologically active substance, and a local anesthetic may be additionally included.

[0066] The content of hyaluronic acid contained in the final composition may be 1 to 5 wt% based on the weight% of the entire composition. If the content is less than 1 wt%, the effect of tissue repair is minimal. If it exceeds 5 wt%, the hyaluronic acid gel is very hard and does not have the injection force that can be injected with a syringe. In addition, the content of biodegradable polymer microgranules contained in the final composition may be 1 to 10 wt% based on the weight% of the entire composition. If the content is less than 1 wt%, the effect of tissue repair is minimal. If it exceeds 10 wt%, the pH of the composition becomes less than 6.0, which increases the acidity, making it unsuitable as a composition for tissue repair.

[0067] The above-mentioned physiologically active substance may be a component useful for biocompatibility and skin tissue repair, and examples thereof include, but are not necessarily limited to, mannitol, inositol, allantoin, matrine, phytic acid, niacinamide, vitamin C and its derivatives, ectoine, ergothioneine, glutathione, nicotinamide, nicotinamide riboside, nicotinamide mononucleotide, peptides, amino acids, carnosine, exosomes, and the like. The above-mentioned physiologically active substance may be included in an amount of 0.01 to 3.0 wt%, preferably 0.05 to 2.5 wt%, and more preferably 0.05 to 2.0 wt%, based on the weight% of the total composition. If the content of the above-mentioned physiologically active substance is less than 0.01 wt%, the physiologically active effect due to the addition of the physiologically active substance may be minimal, and if the content of the physiologically active substance exceeds 3.0 wt%, there is a problem that the hyaluronic acid gel in which the biodegradable polymer microgranules of the composition are fused may be decomposed by the physiologically active substance, which is not preferable.

[0068] The above local anesthetic may additionally include ingredients such as local anesthetics such as lidocaine, mepivacaine, levobupivacaine, and prilocaine. The content of the local anesthetic may be appropriately adjusted by a person skilled in the art, but may preferably be contained in an amount of 0.1 to 0.5 wt% based on the weight% of the total composition.

[0069] The hyaluronic acid gel fused with biodegradable polymer microgranules manufactured by the above method is in the form of a turbid gel that does not separate over time and maintains its dispersed state. Since the pH is neutral at 6.5 to 7.5, there is no problem in administering it to skin tissue.

[0070] Therefore, the hyaluronic acid gel fused with the biodegradable polymer microgranules manufactured above can be provided as a tissue repair composition, and the composition can be used as is, but preferably, it can be used after being packed in a prefilled syringe and then sealed.

[0071] As a specific example, a hyaluronic acid gel fused with the biodegradable polymer microgranules manufactured above was packed in a prefilled syringe and then injected into skin tissue at a uniform pressure of 40 N or less.

[0072] Therefore, the hyaluronic acid gel fused with biodegradable polymer microgranules manufactured by the above method is characterized by having a syringe pressure of 40 N or less when measured at an injection speed of 5 to 15 mm / min with a 27G (ID 0.210 mm) syringe.

[0073] In another aspect, the present invention provides an injectable composition for tissue repair comprising a hyaluronic acid gel fused with biodegradable polymer microgranules.

[0074] In the present invention, tissue repair may mean temporarily or semi-permanently improving or restoring wrinkles on the face or body, improving contours, creating volume in tissue, or regenerating tissue to heal scars, etc., by injecting the composition. The tissue may refer to a part of the face or body.

[0075] The above tissue repair injection composition may be filled into a syringe, preferably a pre-filled syringe, and injected into the skin layer. In addition, the tissue repair composition may also be described herein as a filler or dermal filler, unless otherwise specified.

[0076] In addition, since the tissue repair composition contains a hyaluronic acid gel fused with biodegradable polymer microgranules, not only does the tissue repair effect appear immediately upon injection of the composition into the tissue, but the tissue repair effect by the biodegradable polymer microgranules is maintained even after a long period of time, thereby increasing satisfaction with tissue repair.

[0077] In addition, since the tissue repair composition contains a hyaluronic acid gel fused with biodegradable polymer microgranules, and the gel has a syringe pressure of 40 N or less when measured at an injection speed of 5 to 15 mm / min with a syringe of 27G (ID 0.210 mm), the composition is easy to inject into tissue and the pain of the person receiving the injection is reduced.

[0078] In the skin repair composition of the present invention, the biodegradable polymer microgranules are biodegradable polymer particles having a spherical or nearly spherical shape with a rough, uneven surface, and a diameter of 20 um to 100 um, obtained by using an eco-friendly solvent.

[0079] These biodegradable polymer microgranules can be manufactured by the method described in the above-described manufacturing method, and since they are manufactured using an eco-friendly solvent, biodegradable polymer microgranules with reduced harm to the human body and the environment can be provided.

[0080] The above biodegradable polymer microgranules may be present in an amount of 1 to 10% by weight of the total composition. If the content is less than 1% by weight, the effect of tissue repair is minimal, and if it exceeds 10% by weight, the pH of the composition becomes less than 6.0, which increases acidity and makes it unsuitable as a composition for tissue repair.

[0081] In the skin repair composition of the present invention, the hyaluronic acid gel in which the biodegradable polymer microgranules are fused can be manufactured by the method described in the manufacturing method described above, and the hyaluronic acid and crosslinking agent, etc. are as described above.

[0082] The above hyaluronic acid may be 1 to 5 wt% based on the weight% of the entire composition. If the content is less than 1 wt%, the effect of tissue repair is minimal, and if it exceeds 5 wt%, the hyaluronic acid gel is excessively hard, which causes a problem in that it cannot be injected with a syringe.

[0083] The hyaluronic acid gel in which the biodegradable polymer microgranules are fused may be composed of hyaluronic acid and biodegradable polymer microgranules in a weight ratio of 1:0.5 to 5, preferably 1:0.5 to 4, more preferably 1:0.5 to 3, and even more preferably 1:0.5 to 2.5. When the weight ratio of the biodegradable polymer microgranules is less than 0.5 weight ratio with respect to hyaluronic acid, the tissue repair ability of the final manufactured repair composition is excellent at the initial stage of injection, but there is a problem that the repair ability decreases over time, and the continuous tissue repair due to the expected collagen production ability is insufficient compared to the existing hyaluronic acid filler, and when the weight ratio of the biodegradable polymer microgranules is more than 5 weight ratio with respect to the weight of hyaluronic acid, a stable hyaluronic acid fusion gel is not formed due to the excess of the biodegradable polymer, and biologically, there is a possibility that inflammation may occur.

[0084] In the skin repair injection composition of the present invention, in order to adjust the content of the hyaluronic acid gel and the biodegradable polymer microgranules to the above-described content or to provide an additional use, at least one of purified water, a physiologically active substance, and a local anesthetic may be additionally included.

[0085] The above-mentioned physiologically active substance may be a component useful for biocompatibility and skin tissue repair, and examples thereof include, but are not necessarily limited to, mannitol, inositol, allantoin, matrine, phytic acid, niacinamide, vitamin C and its derivatives, ectoine, ergothioneine, glutathione, nicotinamide, nicotinamide riboside, nicotinamide mononucleotide, peptides, amino acids, carnosine, exosomes, and the like. The above-mentioned physiologically active substance may be included in an amount of 0.01 to 3.0 wt%, preferably 0.05 to 2.5 wt%, and more preferably 0.05 to 2.0 wt%, based on the weight% of the total composition. If the content of the above-mentioned physiologically active substance is less than 0.01 wt%, the physiologically active effect due to the addition of the physiologically active substance may be minimal, and if the content of the physiologically active substance exceeds 3.0 wt%, there is a problem that the hyaluronic acid gel in which the biodegradable polymer microgranules of the composition are fused may be decomposed by the physiologically active substance, which is not preferable.

[0086] The above local anesthetic may additionally include ingredients such as local anesthetics such as lidocaine, mepivacaine, levobupivacaine, and prilocaine. The content of the local anesthetic may be appropriately adjusted by a person skilled in the art, but may preferably be contained in an amount of 0.1 to 0.5 wt% based on the weight% of the total composition.

[0087] The tissue repair composition according to the present invention contains a hyaluronic acid gel fused with biodegradable polymer microgranules, and thus has the effect of simultaneously and for a long time expressing the tissue repair effect of hyaluronic acid and the biodegradable polymer. In addition, the biodegradable polymer microgranules included in the composition of the present invention are manufactured using an eco-friendly solvent, and therefore are less harmful to the body and the environment. In addition, they have a spherical or nearly spherical shape with an uneven and rough surface and a diameter of 20 um to 100 um, so that they are easy to inject into tissues, and after injection, they are not phagocytosed by macrophages but are well adsorbed, so that they can effectively induce collagen production.

[0088] In addition, the hyaluronic acid gel fused with biodegradable polymer microgranules included in the composition of the present invention has a syringe pressure of 40 N or less when measured at an injection speed of 5 to 15 mm / min with a 27G (ID 0.210 mm) syringe, so that the composition of the present invention including it can be easily injected into tissue and has the effect of reducing pain for the person receiving the injection. In addition, since the composition of the present invention exists in a gel form, a separate dilution or stirring process is unnecessary before injection into tissue, and the problem of unevenness occurring in the dilution or stirring process does not occur, so that not only can it be injected right away, but also has the effect of reducing pain for the person receiving the injection.

[0089] FIG. 1 is a drawing illustrating a method for manufacturing an injectable composition for tissue repair according to one embodiment of the present invention.

[0090] FIG. 2 is a drawing showing a state in which a tissue repair injection composition (Example 3) according to one embodiment of the present invention is packed in a prefilled syringe.

[0091] FIG. 3 is a picture showing the fine surface structure of an injectable composition for tissue repair (Example 3) according to one embodiment of the present invention, confirmed and photographed using SEM.

[0092] FIG. 4 is a picture taken by SEM to confirm the fine surface structure of Comparative Example 3 for comparison with the tissue repair injection composition according to one embodiment of the present invention.

[0093] The present invention will be described in detail below. However, these examples are provided to illustrate the present invention and the scope of the present invention is not limited to these examples.

[0094] <Example 1>

[0095] 5% (w / w) of poly-L-lactic acid (PLLA) having a weight-average molecular weight of 200,000 g / mol or less was dissolved in dimethyl sulfoxide at room temperature, spray-frozen at -10°C at a rate of 5 mL / min, washed with ethanol, and freeze-dried to prepare polymer microgranules. Meanwhile, 10% (w / w) of hyaluronic acid was dissolved by stirring in an alkaline aqueous solution in which 0.04 g of NaOH was dissolved in 100 g of purified water, and 2% (w / w) of the freeze-dried polymer microgranules and 1% (w / w) of BDDE were added, stirring was stopped, and the mixture was aged at room temperature for 24 hours to prepare a crosslinked gel. The cross-linked gel was dialyzed against 1X PBS buffer for 3-14 days until the cross-linker disappeared, and then 0.3% (w / w) of lidocaine hydrochloride was added to adjust the hyaluronic acid concentration to a final concentration of 2% (w / w). The final fusion gel was ground to 100 μm, packed into prefilled syringes, and sterilized.

[0096] <Example 2>

[0097] 15% (w / w) of PLLA with a weight-average molecular weight of less than 200,000 g / mol was added to a eutectic solvent of betaine / glycerin / water, autoclaved (160°C, 0.12 MPa, 20 min), and sonicated while lowering the temperature to obtain microgranules, which were washed and freeze-dried. Meanwhile, 10% hyaluronic acid was dissolved by stirring under alkaline conditions where 0.04 g of NaOH was dissolved in 100 g of purified water, and 1% BDDE was added and mixed, and aged for 24 hours at room temperature under nitrogen conditions to make a cross-linked gel. The cross-linked gel was dialyzed against 1X PBS buffer for 3-14 days until the cross-linker disappeared, and the drug of microgranule polymer (2%) and lidocaine hydrochloride (0.3%) was added to hydrate the cross-linked gel, and the final concentration of hyaluronic acid was adjusted to 2%. The polymer-fused hyaluronic acid gel was ground to 100 μm, packed into a prefilled syringe, and sterilized.

[0098] <Example 3>

[0099] 15% (w / w) of PLLA having a weight average molecular weight of 200,000 g / mol or less was added to triacetin, autoclaved (170°C, 0.12 Mpa, 20 min), and sonicated while gradually lowering the temperature to obtain microgranules, which were washed and freeze-dried. Afterwards, a hyaluronic acid gel fused with 2% microgranule polymer was manufactured through the same process as in Example 2, and then packed and sterilized in a prefilled syringe. The final appearance is as shown in Fig. 2.

[0100] <Example 4>

[0101] It was manufactured using the same process as Example 3, except that the concentration of biodegradable polymer microgranules was mixed at 12%.

[0102] <Example 5>

[0103] The same process as Example 3 was performed except that the concentration of biodegradable polymer microgranules was mixed at 5%.

[0104] <Example 6>

[0105] The same process as Example 3 was performed except that the concentration of biodegradable polymer microgranules was mixed at 1%.

[0106] <Comparative Example 1>

[0107] We purchased and used Scultra (a freeze-dried product made from a mixture of polylactic acid and carboxymethyl cellulose) that was already on sale.

[0108] Comparative Example 2

[0109] 10% hyaluronic acid was dissolved by stirring under alkaline conditions (pH 12), 1% BDDE was added, stirring was stopped, and the mixture was aged at room temperature for 24 hours to create a cross-linked gel. The cross-linked gel was dialyzed against 1X PBS buffer for 3-14 days until the cross-linking agent disappeared, and lidocaine hydrochloride (0.3%) was added to adjust the hyaluronic acid concentration to a final concentration of 2.4%. Afterwards, it was ground to 100 μm, packed in a pre-filled syringe, and sterilized.

[0110] <Comparative Example 3>

[0111] 5% (w / w) of PCL having a weight average molecular weight of 50,000 g / mol or less was dissolved in methylene chloride, a halogenated organic solvent, and passed through a 30 μm pore SPG membrane column to be injected into a 1% PVA (polyvinylalcohol) aqueous solution containing a surfactant to prepare a microemulsion, which was washed and freeze-dried to prepare microparticles.

[0112] Comparative Example 4

[0113] The same process as in Comparative Example 3 was performed except that 5% (w / w) of PLLA having a weight average molecular weight of 200,000 g / mol or less was used.

[0114] Experimental Example 1. Confirmation of the microgranule particle size of biodegradable polymers.

[0115] The biodegradable polymer microgranules manufactured in Examples 1 to 3 were mixed with purified water at a concentration of 0.5%, vortexed for 10 seconds, dispersed by sonication (1 minute), and then observed under an optical microscope, and the particle sizes thereof were measured. In addition, the microparticles manufactured in Comparative Examples 3 and 4 were observed using the same method, and the particle sizes thereof were measured.

[0116] Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 size (um) 20-40 40-70 50-100 20-40 20-50

[0117] As can be seen from Table 1 above, Examples 1 to 3 manufactured based on eco-friendly solvents confirmed that microparticles were formed, similar to Comparative Examples 3 and 4 using a conventional halogenated organic solvent and surfactant.

[0118] Experimental Example 2. Surface verification of biodegradable polymer microgranules

[0119] The microsurface structure of the biodegradable polymer microgranules manufactured in Example 3 and the surface structure of the microparticles of Comparative Example 3 were confirmed by scanning electron microscopy (SEM) and are shown in FIGS. 3 and 4. As a result, it was confirmed that the microgranules of Example 3 had a bumpy surface (see FIG. 3), whereas those of Comparative Example 3 had a smooth, sphere-type surface (see FIG. 4). When the surface of the biodegradable polymer microgranules of the present invention was modified to be bumpy, the dispersion stability in the aqueous hydrogel was increased, facilitating the formation of a stable fusion filler. In contrast, when the surface of the particles was smooth, as in Comparative Example 3, when hydrophobic biodegradable polymer particles were dispersed in a hyaluronic acid hydrogel and then wet-sterilized, the generation of voids between the oil phase and the aqueous phase increased, facilitating the formation of bubbles, which is a problem that makes it unsuitable for the manufacture of a stable, commercially viable fusion filler.

[0120] Experimental Example 3. pH and property stability of hyaluronic acid filler fused with biodegradable polymer

[0121] The pH of the fillers of Examples 1 to 3 and Comparative Examples 1 to 3 manufactured above was measured with a pH meter (Thermo scientific, Orion star A211), and the stability of the properties was observed at one-week intervals after storage at room temperature for two weeks. Since Comparative Examples 1 and 3 are powder properties, the properties were compared by dispersing them in purified water at a concentration of 4% (w / v) corresponding to the combined weight of the hyaluronic acid and microgranules of Examples 1 to 3.

[0122] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 40 Day pH 7.29 Turbid gel pH 7.15 Turbid gel pH 6.93 Turbid gel pH 6.51 Precipitated liquid pH 7.23 Clear gel pH 6.70 Precipitated liquid pH 7.19 Precipitated liquid Week 1 pH 7.46 Maintained pH 7.22 Maintained pH 7.01 Maintained pH 6.50 Precipitated liquid pH 7.24 Maintained pH 6.67 Precipitated liquid pH 7.14 Precipitated liquid Week 2 pH 7.38 Maintained pH 7.18 Maintained pH 6.95 Maintained pH 6.49 Precipitated liquid pH 7.23, maintained properties pH 6.65, precipitated liquid pH 7.00, precipitated liquid

[0123] As can be seen from Table 2 above, it was confirmed that the hyaluronic acid fillers (Examples 1 to 3) fused with biodegradable polymers were stable in pH and properties. On the other hand, in the case of Comparative Examples 1 and 3 and 4, the microparticles were not homogeneous and precipitated within a few minutes, which was confirmed to be a property that caused inconvenience to the practitioner when used as an injection solution.

[0124] Experimental Example 4. Injection stability of hyaluronic acid filler fused with biodegradable polymer

[0125] An injection force stability test was conducted on the fillers of Examples 1 to 3 and Comparative Examples 1 to 3 manufactured above. It was determined whether the pressure required to inject the contents of the syringe during filler injection was 40 N or less and whether the pressure was uniform, and this was used for the product specifications (AND, MCT-2150). Comparative Examples 1 and 3 were dispersed in purified water at a concentration of 4% (w / w), the same as the combined weight of the hyaluronic acid and microgranules of Examples 1 to 3, and then placed in a pre-filled syringe for comparison. When the injection force (N) was measured at a speed of 10 mm / m using a 1 mL syringe and a 27 G injection needle, the standard deviation of the average injection force for 20 to 60 seconds after injection was expressed as <5%: +++, <15%: ++, <25%: +.

[0126] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 40 Days++++++++++++++++1 Week++++++++++++++++2 Week++++++++++++++++

[0127] As can be seen from Table 3 above, the hyaluronic acid fillers fused with biodegradable polymers (Examples 1, 2, and 3) exhibited stable injection force, indicating a uniform phase, and it was determined that there would be no problems such as clogging of the injection needle. In addition, it was confirmed that the formulation provided convenience for the procedure as it could be injected immediately without the need to separately prepare and suspend the injection water during the procedure, and hyaluronic acid and biodegradable polymer were injected in a single procedure. In contrast, Comparative Examples 1, 3, and 4, excluding Comparative Example 2, did not exhibit stable injection force, indicating an uneven phase, and it was expected that problems such as clogging of the injection needle could occur. In addition, Comparative Example 2, a filler composed only of a general hyaluronic acid gel, exhibited stable injection force, indicating that it was a uniform phase. However, it was confirmed that the hyaluronic acid filler fused with the biodegradable polymer microgranules of the present invention had a stable injection force, similar to the general hyaluronic acid gel filler of Comparative Example 2, despite the biodegradable polymer microgranules being fused thereto.

[0128] Experimental Example 5. pH of hyaluronic acid filler fused with biodegradable polymer

[0129] The pH of Examples 3 to 6 was measured using the same method as Experimental Example 2 above.

[0130] Example 3 Example 4 Example 5 Example 6 Comparative Example 2 pH 6.9 3 5.5 0 7.0 1 7.1 5 7.23

[0131] From the results in Table 4, it was confirmed that increasing the biodegradable polymer ratio compared to Example 3 (Example 4) resulted in increased acidity and was not suitable for injection, and in the case of Comparative Example 2, it was confirmed that the pH was neutral like the existing hyaluronic acid filler because there was no biodegradable polymer.

[0132] Experimental Example 6. Efficacy Test of Polymer-Fused Hyaluronic Acid Filler

[0133] After injecting 200 uL of Examples 1 to 3 and Comparative Example 1 into the back of hairless mice, the volume change was measured, and the results are shown in Table 5 below. As a result, Examples 1 to 3 and Examples 5 and 6 showed a significant reduction in the initial volume decrease after 1 month, which was observed when treating with a simple mixture formulation of polylactic acid and carboxymethyl cellulose (Comparative Example 1), and showed a continuous volume maintenance effect after 3 months, unlike Comparative Example 1.

[0134] Example 1 Example 2 Example 3 Example 5 Example 6 Comparative Example 1 Volume immediately after treatment 100% 100% 100% 100% 100% 1 month later Volume 80% 86% 80% 85% 90% 30% 3 months later Volume 75% 79% 78% 80% 87% 35%

Claims

1. A method for producing an injectable composition for tissue repair comprising a hyaluronic acid gel fused with biodegradable polymer microgranules using an eco-friendly solvent, (S10) A step of producing microgranules of a biodegradable polymer using an eco-friendly solvent; (S20) a step of manufacturing a hyaluronic acid gel; and (S30) a step of dispersing the biodegradable polymer microgranules of step (S10) into the hyaluronic acid gel of step (S20); The above step (S10) is: (A10) a step of preparing a biodegradable polymer solution by stirring and dissolving a biodegradable polymer in an eco-friendly solvent; (A20) a step of freezing the biodegradable polymer solution of step (A10) by spraying it at a low temperature; and (A30) a step of removing the solvent from the frozen biodegradable polymer solution of step (A20); or (B10) A manufacturing method comprising a step of mixing a biodegradable polymer and an eco-friendly solvent and dissolving them at high temperature and high pressure to produce a biodegradable polymer solution; (B20) a step of ultrasonically treating the biodegradable polymer melt of step (B10); and (B30) a step of removing the solvent from the melt of step (B20).

2. A manufacturing method according to claim 1, characterized in that the biodegradable polymer is at least one selected from the group consisting of poly-L-lactic acid, poly-D-lactic acid, poly-DL-lactic acid, polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, polyalphahydroxysides, poly(trimethylene carbonate), poly(alkylcyanoacrylates), polyhydroxyalkanoates, methoxypolyethylene glycol, hydroxylpolyethylene glycol, monoalkoxypolyethylene glycol, polyethylene glycol, copolymers thereof, and mixtures thereof.

3. In the first paragraph, the eco-friendly solvent is dimethyl sulfoxide, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutylacetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, dihydrolevoglucocenone, methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate, triethyl phosphate, ethylene carbonate, propylene carbonate, butylene carbonate glycerol carbonate, A manufacturing method characterized in that it is at least one organic solvent selected from the group consisting of diethyl carbonate, dimethyl carbonate, methyl lactate, ethyl lactate, tetraglycol, and mixtures thereof, triacetin, or a eutectic solvent.

4. A manufacturing method according to claim 3, characterized in that the eutectic solvent is a mixture comprising at least one hydrogen bond acceptor selected from the group consisting of choline chloride, betaine, sodium acetate, proline, nicotinamide, L-carnitine, and combinations thereof, and at least one hydrogen bond donor selected from the group consisting of polyols, organic acids, fatty acids, amide compounds, sugars, and combinations thereof.

5. A manufacturing method according to claim 1, wherein the biodegradable polymer microgranules have a spherical or nearly spherical shape with a rough surface and a diameter of 20 to 100 um.

6. A manufacturing method according to claim 1, characterized in that the step (A10) or the step (B10) mixes 200 to 10,000 parts by weight of an eco-friendly solvent based on 100 parts by weight of a biodegradable polymer.

7. A manufacturing method according to claim 1, characterized in that the low temperature of step (A20) is -25 to -5°C.

8. A manufacturing method according to claim 1, characterized in that the dispersion in step (S30) comprises hyaluronic acid and biodegradable polymer microgranules in a weight ratio of 1:0.5 to 5.

9. A manufacturing method according to claim 1, characterized in that the dispersion in step (S30) further comprises at least one selected from the group consisting of purified water, a physiologically active substance, and a local anesthetic in addition to the hyaluronic acid gel and biodegradable polymer microgranules.

10. An injectable composition for tissue repair comprising a hyaluronic acid gel fused with microgranules of a biodegradable polymer manufactured using an eco-friendly solvent, The above hyaluronic acid is 1 to 5 wt% of the total content of the composition, The microgranules of the above biodegradable polymer are 1 to 10 wt% of the total content, The microgranules of the biodegradable polymer are prepared by a method including: (A10) a step of stirring and dissolving the biodegradable polymer in an eco-friendly solvent to prepare a biodegradable polymer solution; (A20) a step of spraying and freezing the biodegradable polymer solution of step (A10) at a low temperature; and (A30) a step of removing the solvent from the frozen biodegradable polymer solution of step (A20); or (B10) a step of mixing the biodegradable polymer and an eco-friendly solvent and dissolving them at a high temperature and high pressure to prepare a biodegradable polymer solution; (B20) a step of ultrasonicating the biodegradable polymer melt of step (B10); and (B30) a step of removing the solvent from the melt of step (B20).

11. A tissue repair injection composition according to claim 10, wherein the biodegradable polymer microgranules have a spherical or nearly spherical shape with an uneven surface and a diameter of 20 um to 100 um.

12. A tissue repair injection composition according to claim 10, characterized in that the hyaluronic acid and biodegradable polymer microgranules are contained in a weight ratio of 1:0.5 to 5.

13. A tissue repair injection composition according to claim 10, wherein the biodegradable polymer is at least one selected from the group consisting of poly-L-lactic acid, poly-D-lactic acid, poly-DL-lactic acid, polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, polyalphahydroxysides, poly(trimethylene carbonate), poly(alkylcyanoacrylates), polyhydroxyalkanoates, methoxypolyethylene glycol, hydroxylpolyethylene glycol, monoalkoxypolyethylene glycol, polyethylene glycol, copolymers thereof, and mixtures thereof.

14. In the 10th paragraph, the eco-friendly solvent is dimethyl sulfoxide, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutylacetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, dihydrolevoglucocenone, methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate, triethyl phosphate, ethylene carbonate, propylene carbonate, butylene carbonate glycerol carbonate, A tissue repair injection composition characterized by comprising at least one organic solvent selected from the group consisting of diethyl carbonate, dimethyl carbonate, methyl lactate, ethyl lactate, tetraglycol, and mixtures thereof, triacetin, or a eutectic solvent.

15. A tissue repair injection composition according to claim 14, wherein the eutectic solvent is a mixture comprising at least one hydrogen bond acceptor selected from the group consisting of choline chloride, betaine, sodium acetate, proline, nicotinamide, L-carnitine, and combinations thereof, and at least one hydrogen bond donor selected from the group consisting of polyols, organic acids, fatty acids, amide compounds, sugars, and combinations thereof.

16. In the 10th paragraph, the dispersion of the step (S30) is characterized in that it further comprises at least one of purified water, a physiologically active substance, and a local anesthetic in addition to the hyaluronic acid gel and the biodegradable polymer microgranules.

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