Dry preparation for tissue repair

Abstract

The present invention relates to a dry preparation for tissue repair, and more specifically, it discloses a dry preparation for tissue repair that contains a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer and an additive, and that exhibits excellent tissue repair effects when reconstituted in an aqueous medium and injected into the body.

Description

[Technical Field]

[0001] The present invention relates to a dry preparation for tissue repair, and more specifically to a dry preparation for tissue repair that contains a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer and an additive, and that exhibits excellent tissue repair effects after being reconstituted in an aqueous medium and injected into the body. [Background technology]

[0002] In recent years, more and more people are becoming interested in "well-aging," which means aging gracefully from a young age. It is no exaggeration to say that the current beauty market is focusing on "anti-aging," which means aging slowly, beautifully, and healthily. One of the most common signs of aging is loss of volume. In particular, since lack of volume in the face makes people look older and shriveled, interest in fillers to replenish volume is on the rise. As a result, the filler market is growing rapidly every year, and currently accounts for a market worth more than 2 trillion won worldwide.

[0003] Currently, various filler materials are used, and hyaluronic acid fillers account for over 90% of the global filler market. However, they have a very short half-life in the body (1-3 days) and are absorbed very quickly. Therefore, products that extend the absorption period by linking hyaluronic acid with a crosslinking agent are being sold. However, these crosslinked products involve the crosslinking agent BDDE (1,4-butanediol diglycidyl ether), which is a toxic carcinogen. Therefore, these crosslinked products face the problems of increased processing costs due to the removal process, product disposal due to microbial contamination, and product disposal due to the detection of residues.

[0004] For this reason, numerous tissue repair products using biodegradable polymers have been developed. Conventional filler formulations using biocompatible polymers have been developed and used, in which water-insoluble polymers are processed into microparticles and dispersed in a viscous excipient or thickener. For example, formulations in which 20-50 micrometer diameter polylactic acid (PLA) particles are dispersed in a carboxymethylcellulose (CMC) aqueous solution, or 20-50 micrometer diameter polycaprolactone (PCL) particles are dispersed in a CMC and glycerin aqueous solution, have been used. However, these formulations have problems such as surgical inconvenient clogging of needles due to microparticles during injection, and inconsistent particle dispersion, resulting in inconsistent tissue repair effects.

[0005] Therefore, there is an urgent need to develop a tissue repair product and a method for manufacturing the same that can ensure functionality, physical properties, and safety suitable for tissue repair biomaterials without the risk of toxicity due to chemical crosslinking processes, etc. Summary of the Invention [Problem to be solved by the invention]

[0006] The object of the present invention is to provide a tissue repair product that is easy to transport, store and handle as a dry preparation, and that exhibits excellent tissue repair effects after being reconstituted in an aqueous medium and introduced into the body, without the risk of toxicity, and that can ensure functionality, physical properties and safety suitable for a tissue repair biomaterial without the risk of toxicity. [Means for solving the problem]

[0007] One aspect of the present invention provides a dry preparation for tissue repair, comprising a biocompatible copolymer, which is a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, and an additive, wherein when the dry preparation is reconstituted in an aqueous medium, the reconstituted composition exhibits thixotropy, in which the viscosity increases over time.

[0008] Another aspect of the present invention provides a method for producing a dry preparation for tissue repair, comprising: (1) dissolving or dispersing a biocompatible copolymer, which is a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, and an additive in a mixture of an organic solvent and an aqueous medium; and (2) drying the product of step (1); wherein when the product of step (2) is reconstituted in an aqueous medium, the reconstituted composition exhibits thixotropy, i.e., the viscosity of the reconstituted composition increases over time.

[0009] Yet another aspect of the present invention provides an injectable composition for tissue repair, comprising the above-mentioned dry preparation for tissue repair and a pharmaceutically acceptable carrier for injection.

[0010] Yet another aspect of the present invention provides a method for producing an injectable composition for tissue repair, comprising the step of mixing the dry preparation for tissue repair and a pharmaceutically acceptable carrier for injection at room temperature. [Effects of the Invention]

[0011] The dry preparation for tissue repair according to the present invention is easy to transport, store, and handle, and when reconstituted in an aqueous medium, the reconstituted composition exhibits thixotropy, meaning that the viscosity of the reconstituted composition increases over time. As a result, after being introduced into the body, the dry preparation not only exhibits excellent tissue repair effects, but also has no risk of toxicity and can ensure functionality, physical properties, and safety suitable for biomaterials. [Brief explanation of the drawings]

[0012] [Figure 1] The dried preparations produced in Examples 1 to 4 and Comparative Example 2 of the present invention were reconstituted in an aqueous medium, and the results of shear stress measurements were shown for the compositions immediately after reconstitution and at a certain time after reconstitution (X-axis: shear rate (1 / s), Y-axis: shear stress (Pa)). However, in the case of Comparative Example 3, the shear stress of the dispersion preparation produced was measured immediately after production and one hour after production. [Figure 2] 1 shows the results of an animal experiment carried out in Experimental Example 3 of the present invention. [Figure 3]1 shows the criteria for score evaluation carried out in Experimental Example 3 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will now be described in further detail.

[0014] The dry preparation for tissue repair of the present invention comprises a biocompatible copolymer, which is a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, and an additive.

[0015] In the present invention, the term "dried preparation" includes all preparations in a dried state, and there are no particular limitations on the form thereof, nor on the drying method used in producing the preparation. For example, the preparation may be dried to a powder form by freeze-drying, vacuum drying, or other drying methods (e.g., spin drying, spray drying), but is not limited thereto. In one embodiment, the dry tissue repair formulation of the present invention may be in the form of, but is not limited to, a powder, a sponge, a plug (rod), or a bead.

[0016] In one embodiment, the hydrophilic biocompatible polymer may be selected from the group consisting of polyethylene glycol or a derivative thereof (e.g., alkoxy- or hydroxy-polyethylene glycol), polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, and combinations thereof, more specifically, polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), and combinations thereof.

[0017] In one embodiment, the hydrophobic biocompatible polymer may be a polymer of a monomer derived from an α-hydroxy acid, more specifically selected from the group consisting of polylactide, polyglycolide, poly(lactic-glycolide), polymandelic acid, polycaprolactone, polydioxan-2-one, polyamino acids, polyorthoesters, polyanhydrides, polycarbonate, polytrimethylcarbonate, poly-β-polyhydroxybutyrate, polyhydroxyvalerate, and combinations thereof, more specifically selected from the group consisting of polylactide, polyglycolide, poly(lactic-glycolide), and combinations thereof.

[0018] Specifically, the number average molecular weight (Mn1) (unit: g / mol) of the hydrophilic biocompatible polymer measured by GPC may be 1,000 or more, 2,000 or more, 3,000 or more, 4,000 or more, 5,000 or more, 6,000 or more, 7,000 or more, 8,000 or more, or 9,000 or more, or may be 30,000 or less, 29,000 or less, 28,000 or less, 27,000 or less, 26,000 or less, 25,000 or less, 24,000 or less, 23,000 or less, 22,000 or less, or 21,000 or less, but is not limited to these.

[0019] Specifically, the number average molecular weight (Mn2) (unit: g / mol) of the hydrophobic biocompatible polymer measured by GPC may be 500 or more, 1,000 or more, 2,000 or more, 3,000 or more, 4,000 or more, or 5,000 or more, or may be 20,000 or less, 19,000 or less, 18,000 or less, 17,000 or less, 16,000 or less, 15,000 or less, 14,000 or less, 13,000 or less, 12,000 or less, or 11,000 or less, but is not limited to these.

[0020] Specifically, the total number average molecular weight of the biocompatible copolymer by GPC may be 1,500 or more, 2,000 or more, 5,000 or more, 7,000 or more, 9,000 or more, 10,000 or more, 12,000 or more, or 14,000 or more, and may be 50,000 or less, 48,000 or less, 45,000 or less, 42,000 or less, 40,000 or less, 38,000 or less, 35,000 or less, or 32,000 or less, but is not limited to these.

[0021] In one embodiment, the ratio (Mn1 / Mn2) of the number average molecular weight (Mn1) of the hydrophilic biocompatible polymer to the number average molecular weight (Mn2) of the hydrophobic biocompatible polymer in the biocompatible copolymer may be 2.5 or less. Specifically, the ratio of the number average molecular weights of the hydrophilic and hydrophobic biocompatible polymers (Mn1 / Mn2) may be 2.5 or less, 2.4 or less, 2.3 or less, or 2.2 or less, or may be 0.6 or more, 0.7 or more, 0.8 or more, or 0.9 or more, but is not limited to these. The number average molecular weights of the hydrophilic and hydrophobic biocompatible polymers may be measured, for example, by gel permeation chromatography (GPC).

[0022] Gel permeation chromatography (GPC) employs a physical elution mechanism in which larger components are eluted first and smaller components are eluted later depending on the size of the hydrodynamic volume of the components to be analyzed. Therefore, large molecules cannot enter the pores of the porous gel and pass through quickly, while small molecules enter the pores of the gel, remain there, and pass through slowly. This method analyzes the molecular weight of the molecules passing through the column in the order of speed.

[0023] In one embodiment, the biocompatible copolymer may be prepared by a method including, but not limited to, the steps of: polymerizing the monomer for the hydrophobic biocompatible polymer in the presence of the hydrophilic biocompatible polymer to prepare a copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer; and drying the prepared copolymer.

[0024] The step of polymerizing the monomer for the hydrophobic biocompatible polymer in the presence of the hydrophilic biocompatible polymer can be carried out according to known methods and conditions. Specifically, the biocompatible copolymer can be dried by freeze-drying or other drying methods (e.g., spin-drying, etc.), more specifically, but not limited to, freeze-drying. The freeze-drying of the biocompatible copolymer can be performed in the presence of a freeze-drying aid such as those described above, but is not limited to this.

[0025] In one embodiment, the additive is selected from the group consisting of a buffering agent, a lyophilization aid, a tonicity agent, or a combination thereof.

[0026] In one embodiment, the buffering agent is selected from the group consisting of monobasic sodium phosphate (NaH2PO4), dibasic sodium phosphate (Na2HPO4), monobasic potassium phosphate (KH2PO4), dibasic potassium phosphate (K2HPO4), sodium citrate, sodium acetate, sodium bicarbonate, sodium carbonate, or a combination thereof. The buffering agent includes its hydrates. For example, the term "dibasic sodium phosphate" includes hydrates of dibasic sodium phosphate (e.g., dihydrate, heptahydrate, etc.). In one embodiment, the buffer comprises a combination of dibasic sodium phosphate and monobasic sodium phosphate.

[0027] In one embodiment, when the buffer contains a combination of dibasic sodium phosphate (or dibasic potassium phosphate) and monobasic sodium phosphate (or monobasic potassium phosphate), the molar ratio of dibasic sodium phosphate (or dibasic potassium phosphate):monobasic sodium phosphate (or monobasic potassium phosphate) may be, but is not limited to, 6-8:4-2, more specifically 6.5-7.5:3.5-2.5, and even more specifically 6.8-7.2:3.2-2.8.

[0028] In one embodiment, the phosphate buffer can be used in an appropriate amount, for example, but not limited to, 5 mg to 100 mg per 1 g of the biocompatible copolymer. In one embodiment, the lyophilization aid (also called a lyophilization agent) may be one or more selected from the group consisting of lactose, maltose, sucrose, trehalose, mannitol, sorbitol, maltitol, xylitol, and lactitol.

[0029] In one embodiment, the lyophilization aid can be used in an amount of, but not limited to, 0.1% to 20% by weight, more specifically, 0.5 to 10% by weight. In one embodiment, the tonicity agent is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, glucose, boric acid, or a combination thereof. In one embodiment, the tonicity agent can be used in an amount of, but not limited to, 0.1% to 20% by weight, more specifically, 0.5 to 10% by weight.

[0030] In one embodiment, the dry formulation for tissue repair of the present invention further comprises a local anesthetic. Specifically, the local anesthetic may be ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, or butoxycaine. toxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dicyclonine, ecgonidine, ecgonine, ethyl chloride chloride), etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloridechloride), myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, pyridocaine, polidocanol , pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

[0031] In one embodiment, the dry preparation for tissue repair of the present invention further comprises one or more components selected from the group consisting of a polynucleotide fraction, a polynucleotide fragment, a biocompatible polymer, or a combination thereof.

[0032] Specifically, the polynucleotide fraction or fragment refers to a polymer consisting of nucleotide units, preferably including nucleotide units including adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). The units may also be modified, and modified nucleotide units include 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 2-O-methylcytidine, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylamino-methyluridine, dihydrouridine, 2-O-chiropseudouridine, 2-O-methylguanosine, inosine, N6-isopentyladenosine, 1-methyladenosine, 1-chiropseudouridine, 1-methylguanosine, 1-methylinosine, 2,2-dimethylguanosine, 2-methyladenosine, 2-methylguanosine, 3-methylcytidine, 5-methylcytidine, N6-methyladenosine, 7-methylguanosine, 5-methylaminomethyl Examples of suitable uridine include, but are not limited to, uridine, 5-methoxyaminomethyl-2-thiouridine, 5-methoxyuridine, 5-methoxycarbonylmethyl-2-thiouridine, 5-methoxycarbonylmethyluridine, 2-methylthio-N6-isopentyladenosine, uridine-5-oxyacetic acid-methyl ester, uridine-5-oxyacetic acid, wybutoxosine, wybutosine, pseudouridine, queuosine, 2-thiocytidine, 5-methyl-2-thiouridine, 2-thiouridine, 4-thiouridine, 5-methyluridine, 2-O-methyl-5-methyluridine, or 2-O-methyluridine, and the like.

[0033] The polynucleotides may also be naturally occurring nucleic acids, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and may be single-stranded or double-stranded. Furthermore, they may contain nucleic acid analogs, which include unnatural bases, nucleotides with linkages to other nucleotides other than natural phosphodiester bonds, or nucleotides containing bases linked via linkages other than phosphodiester bonds. Examples of nucleotide analogs include, but are not limited to, phosphorothioates, phosphorodithioates, phosphorotriesters, phosphoramidates, boranophosphates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, or peptide-nucleic acids (PNAs). The polynucleotides may also contain synthetic or modified nucleotides. Various types of modifications to oligonucleotides are known in the art.

[0034] Specifically, the biocompatible polymer may be hyaluronic acid.The hyaluronic acid refers to hyaluronic acid itself, its salts and derivatives, and may include an aqueous solution of hyaluronic acid, an aqueous solution of a hyaluronate salt, and an aqueous solution of a mixture thereof.The hyaluronate salt may be one or more selected from the group consisting of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and tetrabutylammonium hyaluronate.

[0035] The dry preparation for tissue repair of the present invention can be produced by dissolving or dispersing the biocompatible copolymer in an appropriate solvent and drying it, but is not limited thereto. Specifically, according to another aspect of the present invention, there is provided a method for producing a dry preparation for tissue repair, comprising: (1) a step of dissolving or dispersing a biocompatible copolymer, which is a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, and an additive in a mixture of an organic solvent and an aqueous medium; and (2) a step of drying the product of step (1); wherein, when the product of step (2) is reconstituted in an aqueous medium, the reconstituted composition exhibits thixotropy, i.e., the viscosity of the reconstituted composition increases over time.

[0036] According to one embodiment, in the method for producing the dry preparation for tissue repair, the biocompatible copolymer, which is a copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer, can be dissolved or dispersed in an aqueous medium containing an organic solvent and an additive (e.g., a buffer), and then the resulting solution can be freeze-dried.

[0037] In one embodiment, the organic solvent may be at least one selected from the group consisting of ketone solvents, alcohol solvents, sulfone solvents, nitrile solvents, ether solvents, amide solvents, alkane solvents, and combinations thereof, more specifically, may be a ketone solvent or a mixed solvent containing the same, but is not limited to these.

[0038] In one embodiment, the ketone solvent may consist of or include one or more of a substituted or unsubstituted linear or cyclic aliphatic ketone, more specifically a linear or cyclic aliphatic ketone having a total of 3 to 10 carbon atoms, even more specifically a linear or cyclic aliphatic ketone having a total of 3 to 7 carbon atoms, and even more specifically a linear aliphatic ketone having a total of 3 to 5 carbon atoms. For example, the ketone solvent may be, but is not limited to, acetone, methyl ethyl ketone, diethyl ketone, dipropyl ketone, cyclohexanone, 4-hydroxy-4-methyl-2-pentanone, methyl-n-propyl ketone, methyl-n-butyl ketone, methyl-i-butyl ketone, methyl-n-amyl ketone (or 2-heptanol), or a combination thereof.

[0039] In one embodiment, the alcohol-based solvent may consist of or include one or more aliphatic alcohols having a total carbon number of 1 to 6, more specifically, one or more aliphatic alcohols having a total carbon number of 1 to 4. For example, the alcohol-based solvent may be, but is not limited to, ethanol, methanol, t-butanol, isopropanol, or a combination thereof.

[0040] In one embodiment, the sulfone-based solvent may be composed of or contain one or more sulfoxides having a total carbon number of 2 to 6, more specifically, sulfoxides having a total carbon number of 2 to 4. For example, the sulfone-based solvent may be, but is not limited to, dimethyl sulfoxide, diethyl sulfoxide, or a combination thereof.

[0041] In one embodiment, the nitrile solvent may be composed of or contain one or more nitriles having a total carbon number of 2 to 8, more specifically, one or more nitriles having a total carbon number of 2 to 6. For example, the nitrile solvent may be, but is not limited to, acetonitrile.

[0042] In one embodiment, the ether solvent may be composed of or contain one or more linear or cyclic aliphatic ethers having a total carbon number of 2 to 8, more specifically, linear or cyclic aliphatic ethers having a total carbon number of 2 to 6. For example, the ether solvent may be, but is not limited to, 1,4-dioxane.

[0043] In one embodiment, the amide solvent may be one or more amides having a total of 2 to 8 carbon atoms, more specifically, one or more amides having a total of 2 to 6 carbon atoms. For example, the amide solvent may be, but is not limited to, dimethylacetamide.

[0044] In one embodiment, the alkane solvent may be composed of or may include one or more linear or cyclic alkanes having a total carbon number of 4 to 10, more specifically, linear or cyclic alkanes having a total carbon number of 4 to 8. For example, the alkane solvent may be, but is not limited to, cyclohexane.

[0045] The amount of the organic solvent used is not particularly limited as long as it can dissolve the entire biocompatible copolymer. In one embodiment, the amount of the organic solvent used may be, but is not limited to, 1 mL to 10 mL, more specifically, 1 mL to 5 mL per gram of the biocompatible copolymer.

[0046] In one embodiment, the aqueous medium may be, but is not limited to, distilled water, purified water, deionized water, ultrapure water, saline solution, or a combination thereof. In one embodiment, the aqueous medium containing the additive (e.g., buffer) may be, but is not limited to, a phosphate buffer. In one embodiment, the aqueous medium may be used in an amount of 2 mL to 40 mL, more specifically 4 mL to 20 mL, per 1 g of the biocompatible copolymer, but is not limited thereto.

[0047] In one embodiment, the concentration of the biocompatible copolymer in the biocompatible copolymer dispersion may be, but is not limited to, 0.1 to 50% by weight, more specifically, 1 to 30% by weight. According to one embodiment, a lyophilization aid can be added to the copolymer solution or dispersion prepared using organic solvents and aqueous media prior to lyophilization. In one embodiment, the freeze-drying may be carried out at a temperature of -45°C to -15°C, more specifically at a temperature of -40°C to -20°C.

[0048] The dry preparation for tissue repair of the present invention is easily dissolved in an aqueous medium at room temperature to form polymer particles. After being introduced into the body, the particles self-assemble to form large structures due to the hydrophobic aggregation of the hydrophobic polymers under the influence of the internal environment, and induce collagen without being phagocytosed by macrophages, thereby demonstrating excellent tissue repair effects. Furthermore, when the dry preparation for tissue repair of the present invention is reconstituted with an aqueous medium, the reconstituted composition exhibits thixotropy, in which shear stress (i.e., viscosity) increases over time, and therefore can exert excellent tissue repair effects when injected into the human body.

[0049] In one embodiment, when the dry preparation for tissue repair of the present invention is reconstituted with an aqueous medium, the reconstituted composition may have a shear stress measured 1 hour after reconstitution that is 1.5 times or more the shear stress measured immediately after reconstitution under the same conditions.

[0050] More specifically, a composition obtained by reconstituting the dry tissue repair preparation of the present invention in an aqueous medium (e.g., 25°C) at a concentration of 12.5 wt% (hereinafter referred to as a 12.5 wt% reconstituted composition) may have a shear stress measured at a shear rate of 10 / s 1 hour after reconstitution (hereinafter referred to as "shear stress (1 hour)") that is 1.5 times or more the shear stress measured under the same conditions immediately after reconstitution (hereinafter referred to as "shear stress (initial)").

[0051] More specifically, the shear stress (1 hour) of the 12.5 wt% reconstituted composition may be, but is not limited to, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2 times or more, 2.1 times or more, 2.2 times or more, 2.3 times or more, 2.4 times or more, 2.5 times or more, 2.6 times or more, 2.7 times or more, 2.8 times or more, 2.9 times or more, or 3 times or more of the initial shear stress. Furthermore, the shear stress (1 hour) of the 12.5 wt% reconstituted composition may be, but is not limited to, 6 times or less, 5.5 times or less, 5 times or less, 4.5 times or less, or 4 times or less of the initial shear stress.

[0052] In one embodiment, when the dry preparation for tissue repair of the present invention is reconstituted in an aqueous medium, the reconstituted composition may have a shear stress measured 6 hours after reconstitution that is at least twice the shear stress measured under the same conditions immediately after reconstitution. More specifically, a 12.5 wt% reconstituted composition of the dry tissue repair preparation of the present invention may have a shear stress measured at a shear rate of 10 / s 6 hours after reconstitution (hereinafter referred to as "shear stress (6 hours)") that is at least twice the shear stress (initial).

[0053] More specifically, the shear stress (6 hours) of the 12.5 wt% reconstituted composition may be, but is not limited to, 2 times or more, 2.1 times or more, 2.2 times or more, 2.3 times or more, 2.4 times or more, 2.5 times or more, 2.6 times or more, 2.7 times or more, 2.8 times or more, 2.9 times or more, 3 times or more, 3.1 times or more, 3.2 times or more, 3.3 times or more, 3.4 times or more, 3.5 times or more, 3.6 times or more, 3.7 times or more, 3.8 times or more, 3.9 times or more, or 4 times or more of the initial shear stress. Furthermore, the shear stress (6 hours) of the 12.5 wt% reconstituted composition may be, but is not limited to, 8 times or less, 7.5 times or less, 7 times or less, 6.5 times or less, 6 times or less, 5.5 times or less, or 5 times or less of the initial shear stress.

[0054] In the present invention, the tissue repair effect refers to the effect of restoring skin tissue to its original state when necrosis or loss occurs in the skin tissue due to trauma, inflammation, aging, or the like. Therefore, another aspect of the present invention provides an injectable composition for tissue repair, comprising the dry preparation for tissue repair of the present invention; and a pharmaceutically acceptable carrier for injection.

[0055] The pharmaceutically acceptable injectable carrier contained in the injectable composition for tissue repair may be any conventional carrier, and may be selected from the group consisting of, for example, distilled water for injection, saline, 5% glucose, a buffer solution (e.g., phosphate buffer solution (PBS)), a hyaluronic acid solution, and combinations thereof, but is not limited thereto.

[0056] In addition to the above components, the injectable composition for tissue repair may further contain one or more conventional additives that can be used in injectable preparations.

[0057] In yet another aspect, the present invention provides a method for producing an injectable composition for tissue repair, which comprises mixing (preferably at room temperature) the dry preparation for tissue repair of the present invention and a pharmaceutically acceptable carrier for injection, where "room temperature" means 1 to 30°C, 20 to 30°C, 22 to 28°C, or more specifically 24 to 26°C (e.g., 25°C).

[0058] Conventional polymeric tissue repair products require heating (e.g., the temperature must be raised between the melting point of the polymer and the boiling point of water) to be prepared in the form of an aqueous solution. However, the dry tissue repair preparation prepared by the method of the present invention is easily soluble in an aqueous medium even at room temperature, so that an injectable composition in the form of an aqueous solution can be easily prepared and used at room temperature.

[0059] The present invention will be described in more detail below with reference to examples and comparative examples, but the scope of the present invention is not limited to these examples. [Example]

[0060] Example 1 To obtain a biocompatible copolymer with a target number-average molecular weight (Mn) of 15,000 g / mol, D,L-lactide monomer was polymerized in the presence of a catalyst in the presence of methoxypolyethylene glycol (mPEG) with a number-average molecular weight (Mn1) of 9,850 g / mol (measured by GPC). The resulting polymer was then dried to obtain a copolymer. GPC analysis revealed that the number-average molecular weight (Mn) of the mPEG-poly(D,L-lactide) copolymer was 15,500 g / mol. The molecular weight of the hydrophobic polymer was calculated by subtracting the molecular weight of the hydrophilic polymer from the molecular weight of the copolymer. The ratio of the number-average molecular weight (Mn1) of mPEG (the hydrophilic polymer in the copolymer) to the number-average molecular weight (Mn2) of poly(D,L-lactide) (the hydrophobic polymer in the copolymer), Mn1 / Mn2, was 1.74. A dispersion of the copolymer was prepared using a linear aliphatic ketone solvent with a total carbon number of 4 and a phosphate buffer solution. 10 wt% of D-mannitol was added to the prepared dispersion as a freeze-drying aid to prepare a mixture for freeze-drying, which was then freeze-dried to produce a powdered dry formulation for tissue repair.

[0061] Example 2 A powder formulation was produced in the same manner as in Example 1, except that the target number-average molecular weight (Mn) of the biocompatible copolymer was set to 17,000 g / mol. GPC measurement revealed that the number-average molecular weight (Mn) of the produced mPEG-poly(D,L-lactide) copolymer was 17,100 g / mol, and the hydrophobic polymer molecular weight was calculated by subtracting the hydrophilic polymer molecular weight from the measured molecular weight of the copolymer. The ratio (Mn1 / Mn2) of the number-average molecular weight (Mn2) of mPEG (the hydrophilic polymer in the copolymer) to the number-average molecular weight (Mn1) of poly(D,L-lactide) (the hydrophobic polymer in the copolymer) was 1.36. Using the polymer thus produced, a powdered dry preparation for tissue repair was produced in the same manner as in Example 1.

[0062] Example 3 A powder formulation was produced in the same manner as in Example 1, except that the target number-average molecular weight (Mn) of the biocompatible copolymer was set to 20,000 g / mol. GPC measurement revealed that the number-average molecular weight (Mn) of the produced mPEG-poly(D,L-lactide) copolymer was 20,200 g / mol. The hydrophobic polymer molecular weight was calculated by subtracting the hydrophilic polymer molecular weight from the measured molecular weight of the copolymer. The ratio (Mn1 / Mn2) of the number-average molecular weight (Mn2) of mPEG (the hydrophilic polymer in the copolymer) to the number-average molecular weight (Mn1) of poly(D,L-lactide) (the hydrophobic polymer in the copolymer) was 0.95. Using the polymer thus produced, a powdered dry preparation for tissue repair was produced in the same manner as in Example 1.

[0063] Example 4 A powdered dry preparation for tissue repair was prepared in the same manner as in Example 1 using the biocompatible copolymer prepared in Example 1, except that a linear aliphatic ketone solvent having a total carbon number of 3 was used.

[0064] Comparative Example 1 As Comparative Example 1, Miracle L, a commercially available liquid product known to produce collagen, was used.

[0065] Comparative Example 2 A powdered dry preparation for tissue repair was prepared in the same manner as in Example 1 using the biocompatible copolymer prepared in Example 1, except that no organic solvent was used when preparing the polymer dispersion, and only phosphate buffer solution was used.

[0066] Comparative Example 3 A dispersion was prepared in the same manner as in Example 1 using the biocompatible copolymer prepared in Example 1, except that only a phosphate buffer solution was used without using an organic solvent. D-mannitol, a lyophilization aid, was added to the prepared dispersion at 10 wt%. The concentration of the dispersion was the same as that of the dispersion reconstituted in Experimental Example 2.

[0067] Experimental Example 1: Analysis of polymer molecular weight The number average molecular weights (Mn) of the copolymers produced in Examples 1 to 3 were measured by gel permeation chromatography (GPC) under the conditions shown in the table below. [Table 1]

[0068] Experimental Example 2: Measurement of shear stress The dry preparations for tissue repair of Examples 1 to 4 and Comparative Example 2 were reconstituted with water for injection to form 12.5 wt% aqueous compositions, and shear stress was measured using a rheometer immediately after reconstitution, 1 hour after reconstitution, and 6 hours after reconstitution, while increasing the shear rate from 0.1 / s to 10 / s. For Comparative Example 3, shear stress was measured immediately after production and 1 hour after production. The measurement results are shown in Table 1 below and Figure 2. Rheometer (MCR102e, Anton Paar) parameter settings Temperature: 25℃ Shear rate: 0.1 to 10 / s (ramp linear) Loading volume: 500 μL Plate diameter: 25mm Distance between plate and glass: 0.8mm Results: Relationship between shear rate and shear stress [Table 2]

[0069] Experimental Example 3: Verification of effectiveness as a tissue repair preparation through animal experiments The effectiveness of the powdered dry preparation of the present invention on tissue repair was verified by animal experiments, which were carried out using 5-week-old SD rats (purchased from Orient Bio). In the animal experiments, 5-week-old SD rats were administered saline and test substances bilaterally. During the experiment, the rats were kept in a temperature of 24±2°C, a relative humidity of 50±10%, and a 12-hour lighting period. Food was available ad libitum.

[0070] Physiological saline was used as a control, and 100 μL of the reconstituted compositions (12.5 wt% concentration) prepared by dissolving each of the dry preparations prepared in Examples 1 to 4 and Comparative Example 2 in water for injection as test substances, as well as the preparations of Comparative Example 1 (a commercially available liquid product, Miracle L) and Comparative Example 3 (dispersions) were continuously injected. After 4 weeks, the experimental animals were sacrificed, and the skin tissue at the sample injection site (the area indicated by the arrow in the upper part of Figure 3) was stained with Masson's trichrome (MT) to observe collagen formation within the tissue and evaluate the ability of new collagen biosynthesis. The results are shown in Figure 3 (lower part of Figure 3). The areas where new collagen was produced were scored according to the following criteria, and the results are shown in Table 2 below. [Table 3] [Table 4]

[0071] The thickness of the area where new collagen was produced was measured and compared with the thickness of the control group for relative evaluation. The results are shown in Table 3 below. [Table 5] From the results of Figure 3 and Tables 2 and 3, it was confirmed that the reconstituted composition of the dried preparation of the example showed superior collagen formation compared to the comparative example, and in particular, a large number of collagen fibers were formed that were significantly thicker than those of Miracle L of Comparative Example 1. In other words, the dried preparation according to the present invention has the advantages of being easier to transport, store and handle, and being more easily dissolved in aqueous media at room temperature, compared to the commercially available product (Miracle L) of Comparative Example 1, and it was confirmed that when introduced into the body, it induces better collagen formation and exerts better tissue repair effects.

Claims

1. A dry preparation for tissue repair, comprising: The present invention includes a biocompatible copolymer, which is a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, and an additive; A dry preparation for tissue repair, wherein when the dry preparation is reconstituted in an aqueous medium, the composition obtained by the reconstitution exhibits thixotropy, that is, the viscosity of the composition increases over time.

2. 2. The dry preparation for tissue repair according to claim 1, wherein the hydrophilic biocompatible polymer is selected from the group consisting of polyethylene glycol or a derivative thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, and combinations thereof.

3. 2. The dry preparation for tissue repair according to claim 1, wherein the hydrophobic biocompatible polymer is selected from the group consisting of polylactide, polyglycolide, poly(lactic-glycolide), polycaprolactone, polydioxan-2-one, polyamino acid, polyorthoester, polyanhydride, polycarbonate, and combinations thereof.

4. the hydrophilic biocompatible polymer is selected from the group consisting of polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), and combinations thereof; 2. The dry preparation for tissue repair according to claim 1, wherein the hydrophobic biocompatible polymer is selected from the group consisting of polylactide, polyglycolide, poly(lactic-glycolide), and combinations thereof.

5. 2. The dry preparation for tissue repair according to claim 1, wherein the additive is selected from the group consisting of a buffering agent, a freeze-drying aid, an isotonicity agent, or a combination thereof.

6. The buffer is sodium phosphate monobasic (NaH 2 P.O. 4 ), dibasic sodium phosphate (Na 2 HPO 4 ), monobasic potassium phosphate (KH 2 P.O. 4 ), dibasic potassium phosphate (K 2 HPO 4 6. The dry preparation for tissue repair according to claim 5, wherein the dry preparation is selected from the group consisting of sodium citrate, sodium acetate, sodium bicarbonate, sodium carbonate, or a combination thereof.

7. 6. The dry preparation for tissue repair according to claim 5, wherein the freeze-drying aid is one or more selected from the group consisting of lactose, maltose, sucrose, trehalose, mannitol, sorbitol, maltitol, xylitol and lactitol.

8. 6. The dry preparation for tissue repair according to claim 5, wherein the isotonicity agent is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, glucose, boric acid, or a combination thereof.

9. A dry preparation for tissue repair as described in claim 1, wherein when the dry preparation is reconstituted in an aqueous medium, the reconstituted composition has a shear stress measured 1 hour after reconstitution that is 1.5 times or more the shear stress measured immediately after reconstitution under the same conditions.

10. A dry preparation for tissue repair as described in claim 1, wherein when the dry preparation is reconstituted in an aqueous medium, the reconstituted composition has a shear stress measured 6 hours after reconstitution that is at least twice the shear stress measured under the same conditions.

11. A method for producing a dry preparation for tissue repair, comprising: (1) a step of dissolving or dispersing a biocompatible copolymer, which is a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, and an additive in a mixture of an organic solvent and an aqueous medium; and (2) drying the product of step (1); Including, A method for producing a dry preparation for tissue repair, wherein when the product of step (2) is reconstituted in an aqueous medium, the reconstituted composition exhibits thixotropy, that is, viscosity increases over time.

12. The method for producing a dry preparation for tissue repair according to claim 11, wherein the organic solvent is at least one selected from the group consisting of ketone solvents, alcohol solvents, sulfone solvents, nitrile solvents, ether solvents, amide solvents, alkane solvents, and combinations thereof.

13. The dry preparation for tissue repair according to any one of claims 1 to 10; and a pharmaceutically acceptable injectable carrier; An injectable composition for tissue repair comprising:

14. The injectable composition for tissue repair according to claim 13, wherein the dry preparation for tissue repair or the injectable carrier contains a local anesthetic.

15. The injectable composition for tissue repair according to claim 13, further comprising one or more components selected from the group consisting of polynucleotide fragments, polynucleotide fractions, biocompatible polymers, or combinations thereof.

16. A method for producing an injectable composition for tissue repair, comprising a step of mixing the dry preparation for tissue repair according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier for injection.

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