Tissue repair composition comprising copolymer of hydrophilic biocompatible polymer and hydrophobic biocompatible polymer

Abstract

The present invention relates to a composition for tissue repair comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, which has rapid biodegradability in the body, excellent biocompatibility and collagen regeneration effect, and thus can be used as a composition for tissue repair. And has excellent in-vivo injectable properties, and thus can be used as an injection.

Description

Technical Field

[0001] The present invention relates to a tissue repair composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer. Specifically, the composition of the present invention has temperature sensitivity, in vivo injectability and collagen regeneration effect, and can be used as an excellent tissue repair injection. Background Art

[0002] For most people, wrinkles occur when the ability to produce collagen is insufficient due to aging. When skin inflammation is severe, due to damage to the dermis, fibroblasts produce insufficient collagen, causing the dermis to deform and become concave or pierced with an awl.

[0003] The sunken shape leaves scars.

[0004] When the loss of dermal tissue leads to insufficient collagen production, wrinkles or scars are often left. In order to improve wrinkles or scars caused by damaged dermal tissue, tissue repair injections can be used. In order to restore dermal tissue, biocompatible tissue repair injections are used.

[0005] The main tissue repair injectables currently under development include products using hyaluronic acid gel for facial plastic surgery, which are widely used due to their excellent biocompatibility and reabsorption.

[0006] However, hyaluronic acid gel does not stimulate collagen production in the dermis, and has the characteristics of large particle size and high viscosity. Due to these characteristics, when directly injected into the dermis of narrow and deep skin scars, there is a risk of bulging of the surrounding skin, so it is not suitable. In addition, when side effects such as filler agglomeration occur, hyaluronidase needs to be injected into the filler surgery site and surgery to decompose the existing hyaluronic acid is required, resulting in bruises or swelling at the filler surgery site.

[0007] On the other hand, when administering conventional tissue repair injections using polycaprolactone or polylactic acid, which are synthetic polymers for facial plastic surgery, side effects such as agglomeration and non-inflammatory nodules are feared, so it is recommended to inject them into the subcutaneous layer of deep wrinkles, and there is a problem that if side effects occur, surgical removal is required. In addition, conventional tissue repair injections using polycaprolactone or polylactic acid have a characteristic of a biodegradation period of 12 to 24 months in the body. Due to this characteristic, when the polycaprolactone or polylactic acid is applied subcutaneously, a continuous tissue repair effect is exhibited, but when applied intradermally, there is a problem of granuloma formation.

[0008] Regarding the tissue repair composition or injection based on the polycaprolactone, Korean Patent Publication No. 10-2020-0158100 proposes a tissue repair composition in which a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer is made into microparticles, but reports a dosage form in which the viscosity increases with increasing temperature. Korean Patent Publication No. 10-2015-0053181 proposes a temperature-sensitive tissue repair composition in which a polymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer is made into microparticles. The composition has the characteristics of being in a gel form below 30°C, but increasing viscosity and being in a sol form at a temperature above 30°C. Therefore, when injected into the skin at the site of dermal loss, there is a great risk of side effects such as the formation of nodules or filler agglomerations, and is therefore not suitable. In addition, Korean Patent Publication No. 10-2016-0122111 proposes a tissue repair composition in which a polymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer is made into microparticles, but only reports that it exists in the form of a suspension at 20 to 35°C, and there is no report on the change of properties with the use temperature. Korean Patent Publication No. 10-2015-0010464 proposes a tissue repair composition in which a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer is made into microparticles in the absence of a solubilizer, but there is no report on the change of properties with the use temperature, so there is no temperature sensitivity feature. When injected into the skin of an experimental rat (SD rat), a tumor-like morphology can be confirmed in the tissue after 6 weeks, so it is not suitable for tissue repair.

[0009] Furthermore, the particles of existing tissue repair injections focus on physical tissue repair and are made to have relatively high viscosity and elasticity. Therefore, injection needles above 30G (gauge) require a large injection force, causing surgical inconveniences such as needle clogging. In order to reduce this inconvenience, 18-27G injection needles are used, but this causes great pain to patients during surgery.

[0010] In order to solve such above-mentioned problems, the present inventors invented a composition for tissue repair, the viscosity of which decreases as the temperature increases and which has a small particle size and can therefore be easily used as an injection, and completed the present invention.

[0011] Prior art literature

[0012] Patent Literature

[0013] Patent Document 0001: Korean Patent Publication No. 10-2020-0158100

[0014] Patent document 0002: Korean Publication Patent No. 10-2015-0053181

[0015] Patent Document 0003: Korean Publication Patent No. 10-2016-0122111

[0016] Patent Document 0004: Korean Publication Patent No. 10-2015-0010464 Summary of the invention

[0017] Technical issues

[0018] The object of the present invention is to provide a composition for tissue repair, which comprises a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer and has excellent effects and physicochemical properties.

[0019] Furthermore, an object of the present invention is to provide a method for preparing the composition for tissue repair.

[0020] Technical Solution

[0021] The present invention provides a tissue repair composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, characterized in that the weight ratio of the hydrophilic biocompatible polymer to the hydrophobic biocompatible polymer contained in the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is 1:1 to 15:1, and the molecular weight of the copolymer is 1000 g / mol to 10000 g / mol.

[0022] The weight ratio of the hydrophilic biocompatible polymer to the hydrophobic biocompatible polymer in the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer may be preferably 2:1 to 8:1, more preferably 2:1 to 4:1.

[0023] The molecular weight of the copolymer may preferably be 3000 g / mol to 9000 g / mol.

[0024] The concentration of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer in the composition may be 1 weight percent to 50 weight percent, and may be preferably 5 weight percent to 40 weight percent.

[0025] The particle size of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer may be 10 μm or less, preferably 5 μm or less, and more preferably 1 μm or less.

[0026] The viscosity of the tissue repair composition comprising the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer may decrease as the temperature increases.

[0027] The hydrophilic biocompatible polymer may be at least one selected from the group consisting of methoxy polyethylene glycol, dihydroxy polyethylene glycol, monoalkoxy polyethylene glycol, monoacyl polyethylene glycol and polyethylene glycol.

[0028] The hydrophobic biocompatible polymer may be one or more selected from the group consisting of polycaprolactone, polyglycolic acid, and copolymers thereof.

[0029] The tissue repair composition comprising the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer may be in the form of an injection, and the injection force of the injection may be 15N or less.

[0030] The tissue repair composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer can be biodegraded within 12 weeks after intradermal injection, preferably within 10 weeks, and more preferably between 2 weeks and 8 weeks.

[0031] The copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer of the present invention may preferably be a methoxypolyethylene glycol-polycaprolactone copolymer.

[0032] Effects of the Invention

[0033] The composition of the present invention has excellent biocompatibility and collagen regeneration effect, and can be used as a composition for tissue repair. In addition, the composition has temperature sensitivity that viscosity decreases as temperature increases and excellent in vivo injectability, and can be used as an injection dosage form without worrying about side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The following is a method for calculating the polymerization ratio of a methoxypolyethylene glycol-polycaprolactone copolymer (provided that n and m each represent an integer) and a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer by nuclear magnetic resonance spectroscopy.

[0035] Figure 2 It shows whether the composition prepared according to Example 1 produces a precipitate.

[0036] Figure 3 The properties of the composition prepared according to Example 5 at different concentrations are shown.

[0037] Figure 4 An injection preparation containing the composition of the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2 is shown.

[0038] Figure 5The following graph shows changes in the skin over time after the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2 was injected into experimental rats.

[0039] Figure 6 The results of Hemato & Eosin staining of skin tissues are shown after the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2 was injected into experimental rats for 4 weeks.

[0040] Figure 7 The results of Masson's Trichrome staining of skin tissues are shown after the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2 was injected into experimental rats for 4 weeks.

[0041] Figure 8 The results of measuring the skin thickness after injecting the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2 into experimental rats are shown.

[0042] Fig. 9 The following are the results of hematoxilin-eosin staining of skin tissues of experimental rats after the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Example 1 was injected into the experimental rats for 1 week, 2 weeks, and 8 weeks.

[0043] Fig.10 To show the results of hematoxilin-eosin staining of skin tissues of experimental rats after the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Example 2 was injected into the experimental rats for 1 week, 2 weeks, and 8 weeks.

[0044] Fig.11 The following are the results of Hemato & Eosin staining of skin tissues after the polycaprolactone tissue repair composition of Comparative Example 3 was injected into experimental rats for 1 week, 2 weeks, and 8 weeks. DETAILED DESCRIPTION

[0045] Hereinafter, the embodiments and examples of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily implement the present invention. However, the present invention can be implemented in various forms and is not limited to the embodiments and examples described herein.

[0046] Throughout the specification of the present invention, when a certain part is described as “comprising” a certain structural element, unless there is a special description to the contrary, it means that other structural elements may also be included, rather than excluding other structural elements.

[0047] The present invention provides a tissue repair composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, wherein the viscosity of the composition decreases as the temperature increases.

[0048] In the present invention, "tissue repair" refers to the mechanism of regenerating tissue when tissue necrosis and defects occur due to trauma, inflammation, aging, etc., in order to restore the tissue to its original state, or to improve facial or body wrinkles, improve contours, form a sense of tissue volume, or heal scars.

[0049] The tissue repair composition may be an aqueous solution or a hydrogel.

[0050] In the present invention, "hydrophilic biocompatible polymer" refers to a polymer that has affinity and biocompatibility for water-soluble solvents. It refers to a general term for all biocompatible polymers that can be added to biologically active substances such as natural or synthetic polymers and are useful to the human body. It is mainly used to improve the solubility and biocompatibility of drugs, but is not limited to this.

[0051] The hydrophilic biocompatible polymer includes methoxy polyethylene glycol, dihydroxy polyethylene glycol, monoalkoxy polyethylene glycol, monoacyl polyethylene glycol and polyethylene glycol, and is preferably methoxy polyethylene glycol.

[0052] In the present invention, "hydrophobic biocompatible polymer" refers to a polymer having affinity and biocompatibility for non-water-soluble solvents, and is used for preparing non-water-soluble drug media or hydrophobic medical materials, but is not limited thereto.

[0053] The hydrophobic biocompatible polymer includes polycaprolactone, polyglycolic acid and copolymers thereof, and is preferably polycaprolactone.

[0054] In the present invention, the methoxypolyethylene glycol-polycaprolactone copolymer refers to a copolymer having the following structure.

[0055] Chemical formula 1:

[0056]

[0057] (Provided that n and m each represent an integer.)

[0058] The methoxy polyethylene glycol-polycaprolactone copolymer is a linear amphiphilic copolymer formed by the association of a hydrophilic substance methoxy polyethylene glycol and a hydrophobic component polycaprolactone polymer mPEG-PCL. In addition, the present invention provides a method for preparing a tissue repair composition comprising the copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer.

[0059] The preparation method comprises: a step of preparing a copolymer by polymerizing the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer; and a step of obtaining an aqueous solution by adding the copolymer into physiological saline.

[0060] Hereinafter, the present invention will be described in more detail by way of examples. However, the following examples are only for illustrative purposes and are not intended to limit the scope of the present invention.

[0061] Preparation Example 1

[0062] Methoxy polyethylene glycol-polycaprolactone copolymer 3875g / mol

[0063] A catalyst was added to 230 g of polyethylene glycol monomethyl ether (2000 g / mol) and 114 g of monomer caprolactone (molecular weight: 114 g / mol), and polymerization was performed at 120° C. for 18 hours to prepare a methoxy polyethylene glycol-polycaprolactone copolymer having a molecular weight of 3875 g / mol. The molecular weight was measured by gel permeation chromatography (GPC).

[0064] Preparation Example 2

[0065] Methoxy polyethylene glycol-polycaprolactone copolymer 3316g / mol

[0066] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 220 g of polyethylene glycol monomethyl ether (2000 g / mol) and 72 g of caprolactone monomer.

[0067] Preparation Example 3

[0068] Methoxy polyethylene glycol-polycaprolactone copolymer 3349g / mol

[0069] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 290 g of polyethylene glycol monomethyl ether (2000 g / mol) and 72 g of caprolactone monomer.

[0070] Preparation Example 4

[0071] Methoxy polyethylene glycol-polycaprolactone copolymer 7569g / mol

[0072] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 230 g of polyethylene glycol monomethyl ether (4000 g / mol) and 114 g of caprolactone monomer.

[0073] Preparation Example 5

[0074] Methoxy polyethylene glycol-polycaprolactone copolymer 8464g / mol

[0075] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 220 g of polyethylene glycol monomethyl ether (4000 g / mol) and 72 g of caprolactone monomer.

[0076] Preparation Example 6

[0077] Methoxy polyethylene glycol-polycaprolactone copolymer 6426g / mol

[0078] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 290 g of polyethylene glycol monomethyl ether (4000 g / mol) and 72 g of caprolactone monomer.

[0079] Preparation Example 7

[0080] Methoxy polyethylene glycol-polycaprolactone copolymer 7721g / mol

[0081] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 230 g of polyethylene glycol monomethyl ether (5000 g / mol) and 114 g of caprolactone monomer.

[0082] Preparation Example 8

[0083] Methoxy polyethylene glycol-polycaprolactone copolymer 7775g / mol

[0084] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 220 g of polyethylene glycol monomethyl ether (5000 g / mol) and 72 g of caprolactone monomer.

[0085] Preparation Example 9

[0086] Methoxy polyethylene glycol-polycaprolactone copolymer 7882g / mol

[0087] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 290 g of polyethylene glycol monomethyl ether (5000 g / mol) and 72 g of caprolactone monomer.

[0088] Preparation Example 10

[0089] Methoxy polyethylene glycol-polycaprolactone copolymer 10342g / mol

[0090] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 230 g of polyethylene glycol monomethyl ether (8000 g / mol) and 114 g of caprolactone monomer.

[0091] Preparation Example 11

[0092] Methoxypolyethylene glycol-polycaprolactone copolymer 9776g / mol

[0093] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 220 g of polyethylene glycol monomethyl ether (8000 g / mol) and 72 g of caprolactone monomer.

[0094] Preparation Example 12

[0095] Methoxy polyethylene glycol-polycaprolactone copolymer 11711 g / mol

[0096] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 290 g of polyethylene glycol monomethyl ether (8000 g / mol) and 72 g of caprolactone monomer.

[0097] Preparation Example 13

[0098] Methoxypolyethylene glycol-polycaprolactone copolymer 847g / mol

[0099] A methoxy polyethylene glycol-polycaprolactone copolymer was prepared in the same manner as in Preparation Example 1 using 230 g of polyethylene glycol monomethyl ether (400 g / mol) and 114 g of caprolactone monomer.

[0100] Comparative Example 1

[0101] Cross-linked hyaluronic acid injection for tissue repair

[0102] It is a tissue repair injection (product name: The Chaeum Premium No. 1, manufacturer: Acros Co., Ltd.) in the form of a hydrogel containing 2.2% cross-linked hyaluronic acid (1.1 mL) and filled in a prefilled syringe.

[0103] Comparative Example 2

[0104] Cross-linked hyaluronic acid injection for tissue repair

[0105] It is a tissue repair injection (product name: The Chaeum Premium No. 2, manufacturer: Acros Co., Ltd.) in the form of a hydrogel containing 2.2% cross-linked hyaluronic acid (1.1 mL) and filled in a prefilled syringe.

[0106] Comparative Example 3

[0107] Polycaprolactone tissue repair injection

[0108] It is a tissue repair injection (product name: Elance, manufacturer: Sinclair) in the form of a hydrogel (1 mL) containing 25% polycaprolactone and 75% carboxymethyl cellulose and filled in a prefilled syringe.

[0109] Example 1

[0110] Tissue repair composition containing methoxypolyethylene glycol-polycaprolactone copolymer

[0111] Phytophosphate buffered saline was added so that the concentration of the methoxypolyethylene glycol-polycaprolactone copolymers of Preparation Examples 1 to 13 was 20%, respectively, and then mixed and stirred to prepare aqueous solutions.

[0112] Example 2

[0113] Tissue repair composition containing methoxypolyethylene glycol-polycaprolactone copolymer

[0114] Phytophosphate buffered saline was added so that the concentration of the methoxy polyethylene glycol-polycaprolactone copolymers of Preparation Examples 1 to 12 was 30%, respectively, and then mixed and stirred to prepare aqueous solutions.

[0115] Example 3

[0116] Tissue repair composition containing methoxypolyethylene glycol-polycaprolactone copolymer

[0117] Phytophosphate buffered saline was added so that the concentration of the methoxypolyethylene glycol-polycaprolactone copolymers of Preparation Examples 1 to 12 was 40%, respectively, and then mixed and stirred to prepare aqueous solutions.

[0118] Example 4

[0119] Tissue repair composition containing methoxypolyethylene glycol-polycaprolactone copolymer

[0120] Phytophosphate buffered saline was added so that the concentration of the methoxy polyethylene glycol-polycaprolactone copolymers of Preparation Examples 1, 4, 5 and 6 was 10%, respectively, and then mixed and stirred to prepare aqueous solutions.

[0121] Example 5

[0122] Composition for tissue repair containing methoxypolyethylene glycol-polycaprolactone copolymer

[0123] Phytophosphate buffered saline was added to make the concentrations of the methoxypolyethylene glycol-polycaprolactone copolymers of Preparation Examples 1, 4, 5 and 6 5%, 10%, 20%, 25%, 30% and 40% respectively, and then mixed and stirred to prepare aqueous solutions.

[0124] Experimental Example 1

[0125] Evaluation of the properties of the composition based on the polymerization ratio and molecular weight of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer

[0126] 3 mL of the tissue repair composition prepared according to Example 1 and Example 2 was placed in a glass bottle, sealed and stored in a thermostat at 25° C. for 7 days. The formation of precipitates was visually determined, and compositions with precipitates were judged to be suspensions.

[0127] By hydrogen nuclear magnetic resonance spectroscopy ( 1 H-NMR) to analyze the molecular structure of the polymerized copolymer, such as Figure 1 As shown, after confirming each signal and analyzing the molecular structure, the molecular weight of the hydrophilic polymer and the molecular weight polymerization ratio of the hydrophobic polymer are calculated using the peak integration value.

[0128] Table 1

[0129]

[0130] As shown in Table 1 and Figure 2 As shown, among the compositions prepared according to Examples 1 and 2, the compositions containing the methoxy polyethylene glycol-polycaprolactone copolymers of Preparation Examples 1, 4, 5 and 6 did not produce precipitates and also exhibited significantly small average particle sizes.

[0131] Therefore, it can be seen that the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer has a polymerization ratio of 1:1 to 15:1 and a molecular weight of 1000 g / mol to 10000 g / mol and has excellent physical and chemical properties and characteristics.

[0132] Experimental Example 2

[0133] Evaluation of properties of a composition based on the concentration of a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer

[0134] The properties of the tissue repair compositions containing the methoxy polyethylene glycol-polycaprolactone copolymers of Preparation Example 1, Preparation Example 4, Preparation Example 5 and Preparation Example 6 at different concentrations were compared. The results are shown in Tables 2 and Figure 3 shown.

[0135] Table 2

[0136]

[0137] As shown in Table 2 and Figure 3 As shown, it was confirmed that the compositions containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Examples 1, 4, 5 and 6 at a concentration of 5 to 40% all maintained a sol or gel form.

[0138] Therefore, it can be seen that the composition of the present invention has excellent in vivo injectability when containing the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer at a concentration of 5% to 40%.

[0139] Experimental Example 3

[0140] Evaluation of viscosity according to temperature change of a composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer

[0141] The tissue repair composition containing the methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 1, Preparation Example 4 and Preparation Example 5 prepared according to the above-mentioned Example 1 and Example 3 was filled into a glass container, and after being immersed in a constant temperature water bath set at 5°C, 20°C, 25°C, 30°C and 35°C for 20 minutes, the viscosity was measured using a viscometer (VISCO B, ATAGO). The results are shown in Table 3 below.

[0142] Table 3

[0143]

[0144] As shown in Table 3 above, it was confirmed that the viscosity of the composition containing the methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 1, Preparation Example 4 and Preparation Example 5 prepared according to Example 1 and Example 3 decreased as the temperature increased.

[0145] Therefore, it can be seen that the composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer of the present invention has excellent in vivo injectability.

[0146] Experimental Example 4

[0147] Evaluation of injection force of a composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer

[0148] After being stored in a thermostat at 25°C for more than 48 hours, the composition for tissue repair containing the methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 1, Preparation Example 4, Preparation Example 5 and Preparation Example 6 prepared according to the Examples 1 and 2 was filled into a prefilled syringe, and then a 26G injection needle and a 30G injection needle were respectively tied and the injection force was confirmed. The injection force was measured by pushing the pusher at a speed of 12 mm / min using a compression tester (MCT-1150, AND). In Comparative Examples 1 to 3, the injection force was confirmed by bundling a 26G injection needle and a 30G injection needle to existing products, respectively. The results are shown in Table 4 below.

[0149] Table 4

[0150]

[0151]

[0152] As shown in Table 4 above, the compositions containing the methoxypolyethylene glycol-polycaprolactone copolymers of Preparation Example 1, Preparation Example 4, Preparation Example 5 and Preparation Example 6 prepared according to Example 1 and Example 2 all exhibited an injection force of less than 15N in both the 26G injection needle and the 30G injection needle, thereby confirming that this is significantly lower than the injection force of the compositions of Comparative Examples 1 to 3.

[0153] Therefore, it can be seen that the composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer of the present invention has excellent in vivo injectability.

[0154] Experimental Example 5

[0155] Particle size analysis of compositions comprising copolymers of hydrophilic biocompatible polymers and hydrophobic biocompatible polymers

[0156] In order to measure the particle size of the composition prepared according to the above-mentioned Example 1 and Example 2, the composition was divided into a group of preparation examples that produced precipitates and a group of sol or gel that did not produce precipitates. The particle size of the composition containing the methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 7, Preparation Example 10, Preparation Example 11 and Preparation Example 12 prepared according to Example 1 that produced precipitates was measured by laser diffraction and scattering method using Mastersizer 2000 (manufacturer: MALVERN). The particle size of the composition containing the methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 1, Preparation Example 4, Preparation Example 5 and Preparation Example 6 prepared according to Example 1 and Example 2 in the form of sol and gel that did not produce precipitates was measured by dynamic light scattering method using ELSZ-1000 (manufacturer: OTSUKA ELECTRONICS). The results are shown in Table 5 below.

[0157] Table 5

[0158]

[0159]

[0160] As shown in Table 5 above, it was confirmed that the particle size of the composition of methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 1, Preparation Example 4, Preparation Example 5 and Preparation Example 6 prepared according to the sol and gel form of Example 1 and Example 2 without generating precipitate was small, and it was confirmed that the particle size was significantly smaller than the particle size of Comparative Example 3.

[0161] Therefore, it can be seen that the composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer of the present invention has excellent in vivo injectability.

[0162] Experimental Example 6

[0163] Evaluation of tissue repair ability of a composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer

[0164] In order to evaluate the biocompatibility and confirm the regeneration of collagen by intradermal transplantation of the composition for tissue repair of the present invention, the following experiment was conducted.

[0165] As an experimental group, a 30G injection needle (refer to Figure 4 ), and as a control group, 0.2 mL of saline was filled into a 1 cc syringe with a 30 G injection needle.

[0166] 0.2mL of the composition containing the methoxy polyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Example 1 and Example 2 was injected into the skin of the cervix of experimental rats (SD rat). After injection, the experimental rats were killed every 0 weeks, 1 week, 2 weeks, 4 weeks, 6 weeks, and 12 weeks, and then the skin of the injection site was cut and the skin tissue was taken out. Histopathological evaluation, skin thickness, collagen regeneration, etc. were confirmed by staining the skin tissue with hematoxyl-eosin staining and trichrome staining (Masson'sTrichrome). As shown in Table 6 below, the grade of histopathological evaluation of the injection site was calculated based on the histologic score, and the stained skin tissue was photographed using an optical microscope (BX51, Olympus) and a digital camera (DP74, Olympus) and cellsens software (Olympus) was used to measure the skin thickness, including only the epidermis (epidermis) and dermis (dermis) for measurement.

[0167] Table 6

[0168]

[0169] The results of histopathological evaluation of H&E-stained slides of the experimental and control groups were judged as grade 0 or 1 throughout the test period, confirming the absence of foreign body reaction.

[0170] And, if Figures 5 to 8 As shown, compared with normal tissue, the skin thickness and dermal density of the skin part injected with the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2 were confirmed to be increased, and based on this, collagen regeneration was also confirmed.

[0171] Experimental Example 7

[0172] Evaluation of biodegradability of compositions comprising copolymers of hydrophilic biocompatible polymers and hydrophobic biocompatible polymers

[0173] In order to confirm the biodegradation time of the composition for tissue repair of the present invention after intradermal implantation, the following experiment was conducted.

[0174] As in Experimental Example 6, a 30G injection needle was used as the experimental group, in which a 1cc syringe was filled with a composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2, and a 27G injection needle was used as the control group in Comparative Example 3 (product name: Elance).

[0175] 0.2 mL of the experimental group and the control group were injected into the skin of the cervix of experimental rats (SD rats), and the experimental rats were killed every 2 weeks, 4 weeks, 6 weeks, and 8 weeks after the injection time point, and then the skin of the injection site was cut and the skin tissue was taken out. The skin tissue was stained with hematoxyloxylin-eosin staining (Hemato & Eosin), and the stained skin tissue was photographed using an optical microscope (BX51, Olympus) and a digital camera (DP74, Olympus). Whether it has biodegradability was confirmed by whether there were particles of the tissue repair composition remaining at the injection site and foreign body reactions.

[0176] Results, such as Fig. 9 and Fig.10 As shown, in the skin area injected with the composition containing the methoxypolyethylene glycol-polycaprolactone copolymer of Preparation Example 5 prepared according to Examples 1 and 2, the foreign body reaction of the tissue repair composition observed in the first and second weeks after the injection of the composition could not be confirmed after 8 weeks, and the particles of the tissue repair composition could not be confirmed either.

[0177] On the other hand, in the case of the polycaprolactone-based tissue repair composition of Comparative Example 3, the foreign body reaction observed in the first and second weeks was confirmed until 8 weeks later, and the particles of the tissue repair composition ( Fig.11 ).

[0178] Therefore, it can be seen that the composition of the present invention has excellent in vivo biodegradability.

Claims

1. A composition for tissue repair, which is a composition comprising a copolymer of a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer, characterized in that: The weight ratio of the hydrophilic biocompatible polymer to the hydrophobic biocompatible polymer in the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is 1:1 to 15:1, and the molecular weight of the copolymer is 1000 g / mol to 10000 g / mol.

2. The composition for tissue repair according to claim 1, characterized in that: The weight ratio of the hydrophilic biocompatible polymer to the hydrophobic biocompatible polymer in the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is 2:1 to 8:

1.

3. The composition for tissue repair according to claim 1, characterized in that: The molecular weight of the copolymer is 3000 g / mol to 9000 g / mol.

4. The composition for tissue repair according to claim 1, characterized in that: The weight ratio of the hydrophilic biocompatible polymer to the hydrophobic biocompatible polymer in the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is 2:1 to 4:

1.

5. The composition for tissue repair according to claim 1, characterized in that: The concentration of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer in the composition is 1 weight percent to 50 weight percent.

6. The composition for tissue repair according to claim 1, characterized in that: The concentration of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer in the composition is 5 weight percent to 40 weight percent.

7. The composition for tissue repair according to claim 1, characterized in that: The particle size of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is less than 10 μm.

8. The composition for tissue repair according to claim 1, characterized in that: The particle size of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is less than 5 μm.

9. The composition for tissue repair according to claim 1, characterized in that: The particle size of the copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is less than 1 μm.

10. The composition for tissue repair according to claim 1, characterized in that: The viscosity of the composition decreases as the temperature increases.

11. The composition for tissue repair according to claim 1, characterized in that: The hydrophilic biocompatible polymer is at least one selected from the group consisting of methoxy polyethylene glycol, dihydroxy polyethylene glycol, monoalkoxy polyethylene glycol, monoacyl polyethylene glycol and polyethylene glycol.

12. The composition for tissue repair according to claim 1, characterized in that: The hydrophobic biocompatible polymer is at least one selected from the group consisting of polycaprolactone, polyglycolic acid, and copolymers thereof.

13. The composition for tissue repair according to claim 1, characterized in that: The composition is in the form of an injection.

14. The composition for tissue repair according to claim 13, characterized in that: The injection force of the injection dosage form is 15N or less.

15. The composition for tissue repair according to claim 13, characterized in that: The composition biodegrades within 12 weeks after intradermal injection.

16. The composition for tissue repair according to claim 13, characterized in that: The composition biodegrades within 10 weeks after intradermal injection.

17. The composition for tissue repair according to claim 13, characterized in that: The composition biodegrades between 2 and 8 weeks after intradermal injection.

18. The composition for tissue repair according to claim 1, characterized in that: The copolymer of the hydrophilic biocompatible polymer and the hydrophobic biocompatible polymer is a methoxy polyethylene glycol-polycaprolactone copolymer.

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