Tissue repair composition

Abstract

The present invention provides a tissue repair composition that uses a non-toxic biocompatible polymer. The tissue repair composition includes a copolymer obtained by polymerizing a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer, and the copolymer is dispersed in water to form a colloidal phase, and the colloidal phase is a phase in which the viscosity of the copolymer dispersed in water is increased by heating.

Description

[Technical field]

[0001] The present invention relates to a composition for tissue repair, and more particularly to a composition for tissue repair using a polymer.

[0002] This application claims priority to and the benefit of Korean Patent Application No. 10-2019-0151669, entitled “Composition for Tissue Repair,” filed on November 22, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] As the structure of society changes and the population grows, the number of patients with burns, bedsores, trauma, plastic surgery, intractable ulcers, and mysterious deaths from diabetic skin diseases is gradually increasing, and treatment methods for damaged skin are also being developed accordingly. Thirty years ago, if more than 60% of the body surface area was damaged by burns, it was common for the patient to die from sepsis, but the recent development of artificial skin has made it possible to prevent moisture loss and infection, significantly reducing the mortality rate. Artificial skin can be broadly divided into wound dressings and cultured skin.

[0004] Wound dressings can be applied to localized wounds or wounds that are not too deep, and serve to protect the wound until skin grafting can be performed, or to protect the wound for the 3-4 weeks required until autologous cultured skin is completed, and to facilitate the application of cultured skin.

[0005] Cultured skin is used in treatments to minimize scar tissue in cases of severe skin defects or extensive wounds. Skin cells are sufficiently multiplied using cell culture technology, and then transplanted for permanent survival. However, cultured skin requires extensive safety testing through bacteria, fungi, toxicity resistance, and mycoplasma tests, and it is cumbersome to manufacture it after confirming safety through various virus tests [HIV 1&2, HTLV II II, CMV IgM, Hepatitis B & C, adenovirus]. In addition, when transplanting cadaveric skin, there is a problem that it is not possible to know the origin and origin of the skin, and in processing, there is a disadvantage that the above-mentioned deadly viruses cannot be sterilized 100% because human body components cannot be heat-treated. In addition, it takes at least one week to culture and transplant cells, making it difficult to use in patients who require emergency treatment.

[0006] On the other hand, wound dressings have the advantages of being applicable to a wider area than cultured skin, being easy to handle, and being applicable to patients who require first aid. However, wound dressings are used for temporary coverage, making it difficult to ensure permanent survival. In addition, wound dressings made of natural polymers such as chitin, chitosan, and collagen have low mechanical strength, are expensive, and are difficult to mass-produce, while wound dressings made of synthetic polymers such as silicone and polyurethane have low affinity for cells and lack adhesion to the wound site.

[0007] Recently, many products using hyaluronic acid gel have been developed, but hyaluronic acid is very quickly reabsorbed in the body within 2 weeks to 2 months, which is problematic. Therefore, as in Patent Document 1, products that extend the reabsorption period by crosslinking hyaluronic acid and crosslinking material are sold. However, problems have been reported with such crosslinked products due to the toxicity of the crosslinking material.

[0008] Due to these problems, many tissue repair products using polymers that degrade in vivo have been developed recently, but the conventional filler formulations using biocompatible polymers have been developed and used in the form of micro-sized particles of water-insoluble polymers that are then dispersed through a viscous medium. Forms in which 20-50um polylactic acid (PLA) particles are dispersed in a carboxymethyl cellulose (CMC) aqueous solution, or 20-50um polycaprolactone (PCL) particles are dispersed in a CMC and glycerin aqueous solution are used, but these have problems in that the microparticles get stuck in the needle during injection, and that the particles are not uniformly dispersed, resulting in a lack of uniform tissue repair effects.

[0009] In addition, Klaus Laeschke, "Biocompatibility of Microparticles into Soft Tissue Fillers," Semin Cutan Med Surg 23, 2004, pp. 214-217, states that polymer-based tissue repair products should have a particle diameter of 40 um or more to avoid phagocytosis in the body and maintain long-term efficacy. However, when using a dosage form with a particle diameter of 20 um or more, there are problems such as the inconvenience of the microparticles clogging the needle and the inconsistent dispersion of the particles, which results in a lack of uniform tissue repair effects. There is an urgent need to develop a tissue repair product that can solve the above problems. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Korean Patent Publication No. 10-2004-0072008 Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, the present invention has been devised to solve the above problems, and aims to provide a composition for tissue repair that uses a non-toxic polymer. [Means for solving the problem]

[0012] In order to solve the above-mentioned technical problems, the present invention provides a composition for tissue repair, which comprises a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, and the copolymer is dispersed in water to form a colloidal phase, and the colloidal phase is a phase in which the viscosity of the copolymer dispersed in water is increased by heating the copolymer.

[0013] The colloidal phase has a viscosity upon heating of 20 to 200,000 cP.

[0014] The composition also provides a composition for tissue repair, characterized in that the K value, represented by the following mathematical formula 1, is in the range of 0.01 to 5. [Formula 1] K = (m 100 *M h 2 *10) / (M l *HLB 2 ) where m 100 is the number of moles of polymer in 100 g of aqueous solution, and M h is the molecular weight of the hydrophilic part, and M l is the molecular weight of the hydrophobic portion, and HLB is a value expressed by the following mathematical formula 2. [Formula 2] HLB = 20*M h / M

[0015] Here, M h is the molecular weight of the hydrophilic portion and M is the molecular weight of the entire molecule.

[0016] In addition, the present invention provides a composition for tissue repair, wherein the HLB value in the formula 2 is in the range of 0.1 to 20.

[0017] The present invention also provides a composition for tissue repair, wherein the hydrophobic biocompatible polymer is one or more polymers selected from the group consisting of polyglycolic acid, polycaprolactone, polylactic acid, polydioxanone, polytrimethylene carbonate, polyhydroxybutyric acid, and copolymers containing the same.

[0018] The present invention also provides a composition for tissue repair, wherein the hydrophilic biocompatible polymer is one or more polymers selected from the group consisting of methoxypolyethylene glycol, dihydroxypolyethylene glycol, monoalkoxypolyethylene glycol, and polyethylene glycol.

[0019] The present invention also provides a composition for tissue repair, wherein the bond structure of the copolymer includes a structure represented by the following formula 1, 2, or 3: [Chemical formula 1] XY [Chemical formula 2] YXY [Chemical formula 3] XYX

[0020] Here, X is a hydrophilic biocompatible polymer and Y is a hydrophobic biocompatible polymer.

[0021] The present invention also provides a composition for tissue repair, wherein the hydrophilic biocompatible polymer has a molecular weight of 100 to 50,000 g / mol.

[0022] The present invention also provides a composition for tissue repair, wherein the hydrophobic biocompatible polymer has a molecular weight of 500 to 70,000 g / mol.

[0023] The present invention also provides a composition for tissue repair, characterized in that the copolymer has a molecular weight of 600 to 120,000 g / mol.

[0024] The present invention also provides a composition for tissue repair, characterized in that the concentration of the copolymer in the colloidal solution is 10 to 50% by weight. Effect of the Invention

[0025] According to the present invention, a colloidal tissue repair composition can be provided that contains a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, which is safe and non-toxic when injected into the body and can be used for emergency patients. [Brief description of the drawings]

[0026] [Figure 1] 1 is a photograph of the colloidal aqueous solution according to the present invention taken with a DSLR (D3000, Nikon, Japan). [Diagram 2] 1 shows photographs of the results of Experimental Example 3 of the present invention taken with a DSLR (D3000, Nikon, Japan). [Diagram 3] The photographs were taken with a DSLR (D3000, Nikon, Japan) to check the presence or absence of leakage of the samples after injecting PBS and colloidal aqueous solution. [Figure 4] Photographs taken through an optical microscope showing the change in skin thickness over time after injection of a colloidal aqueous solution. [Diagram 5] 3 is a photograph taken by an optical microscope of collagen over time after injecting a colloidal aqueous solution. [Figure 6] Photographs taken through an optical microscope showing the thickness of the skin over time after PBS injection. [Figure 7] This is a photograph taken by an optical microscope of collagen over time after PBS was injected. [Figure 8] 1 is a graph showing skin thickness over time after injection of PBS and an aqueous colloid solution. [Figure 9] The results of Experimental Example 2 are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Hereinafter, the present invention will be described in detail through preferred embodiments. Before that, the terms and words used in the present specification and claims should not be interpreted only in their ordinary or dictionary sense, but should be interpreted in the meaning and concept that corresponds to the technical idea of ​​the present invention based on the principle that the inventor can appropriately define the concept of the term to best describe his / her invention. Therefore, it should be understood that the configurations of the embodiments described in this specification are only the most preferred embodiments of the present invention and do not fully represent the technical idea of ​​the present invention, and therefore, at the time of filing the present invention, there may be various equivalents and modifications that can replace them. In addition, throughout the specification, when a certain part "includes" a certain element, this means that it further includes other elements, not excluding other elements, unless otherwise specified.

[0028] The inventors researched biocompatible polymers in order to produce a tissue repair composition that can be used on emergency patients, can be produced relatively inexpensively, and is non-toxic and safe. As a result, they discovered that a copolymer obtained by polymerizing a hydrophilic biocompatible polymer and a hydrophobic biocompatible polymer is non-toxic in the body, can repair tissue safely, and is applicable to emergency patients, thereby arriving at the present invention.

[0029] Therefore, the present invention discloses a composition for tissue repair comprising a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, the copolymer being in a colloidal phase dispersed in water.

[0030] FIG. 1 is a photograph of an aqueous colloidal solution according to the present invention. The colloid refers to a state in which fine particles larger than molecules or ions are dispersed in a gas or liquid, and the entire colloidal state is called a colloid.

[0031] In conventional filler products, the particle size could be distinguished with the naked eye, but in the present invention, the particle size of the colloidal phase cannot be distinguished with the naked eye and no insoluble foreign matter is present. The insoluble foreign matter refers to insoluble foreign matter that can be easily detected with the naked eye when the solution preparation is placed in a cleaned container and observed directly under a white light source at a brightness of about 2750 to 3000 lx, according to the insoluble particulate test method, which is a general test method of the United States Pharmacopeia (USP).

[0032] In the present invention, the size of the particles is such that they cannot be distinguished by the naked eye, and when the composition is injected into the body, a matrix structure is formed by bonds between polymers, and the composition exerts a long-term tissue repair effect within the skin without phagocytosis.

[0033] In the present invention, the colloid phase is heated to increase its viscosity. More specifically, a colloid having an increased viscosity is formed by heating to a temperature between the melting point of the copolymer and the boiling point of water. Generally, a colloid phase in which a copolymer is dispersed in water has a very low viscosity because the copolymer is simply dispersed in water and no composition is prepared. However, the colloid phase according to the present invention is prepared into a composition by dispersing the copolymer in water and then reacting the copolymer by various methods, such as adding a small amount of organic solvent, and preferably by applying heat to cause the reaction.

[0034] In addition, the copolymers react with each other due to heat, so that the particle size becomes indistinguishable by the naked eye, insoluble foreign matter disappears, and the viscosity of the colloidal phase increases compared to before the reaction, and the increased viscosity does not decrease even when the temperature is lowered.

[0035] In the present invention, the viscosity of the colloidal phase, which is increased by the reaction between the copolymers according to the above-mentioned preparation method, is 20 to 200,000 cP (centipoise), preferably 25 to 190,000 cP.

[0036] In the present invention, the K value of the composition represented by the following formula 1 is in the range of 0.01 to 5, preferably 0.3 to 1.8, and more preferably 0.4 to 1.5. If the K value is less than 0.01 or exceeds 5, the efficacy of the dosage form may be reduced. [Formula 1] K = (m 100 *M h 2 *10) / (M l *HLB 2 ) In Formula 1, m 100 is the number of moles of polymer in 100 g of aqueous solution, and M h is the molecular weight of the hydrophilic part, and M l is the molecular weight of the hydrophobic portion, and HLB is a value expressed by the following mathematical formula 2. [Formula 2] HLB = 20*M h / M In formula 2, M h is the molecular weight of the hydrophilic portion and M is the molecular weight of the entire molecule.

[0037] In the colloidal aqueous solution in which the copolymer obtained by polymerizing a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer is dissolved in water, the number of moles of the copolymer dissolved in 100g of the aqueous solution does not have a constant value depending on the molecular weight of the hydrophobic biocompatible polymer, the molecular weight of the hydrophilic biocompatible polymer, and the mixing ratio, so that it is not possible to set the range of tissue repair efficacy of the composition for tissue repair of the present invention. Therefore, in order to derive the range of tissue repair efficacy of the composition for tissue repair, the present invention has studied the correlation between the number of moles of the copolymer dissolved in 100g of the aqueous solution in which the copolymer obtained by polymerizing a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer is dissolved in water, the hydrophilic biocompatible polymer, the hydrophobic biocompatible polymer, and HLB, and confirmed a constant value, which is defined as the K value.

[0038] In other words, in the present invention, the K value is a value that indicates the relationship between the number of moles of polymer dissolved in 100 g of an aqueous solution, the molecular weight of the hydrophobic biocompatible polymer, the molecular weight of the hydrophilic biocompatible polymer, and the HLB value, measured in a colloidal phase in which a copolymer obtained by polymerizing a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer is dispersed.

[0039] In the colloidal phase, the K value is a constant value depending on the number of moles of the polymer dissolved in 100 g of the aqueous solution, the molecular weight of the hydrophobic biocompatible polymer, the molecular weight of the hydrophilic biocompatible polymer, and the HLB.

[0040] The efficacy of the above dosage form means that before being introduced into the body, the hydrophilic polymer of the copolymer plays a major role, and due to the interaction between the solvent and the polymer, there is no insoluble foreign matter that can be identified by the naked eye, and a colloidal phase is formed in which the polymer is uniformly and stably dispersed in the aqueous solution. However, after being introduced into the body, the hydrophobic polymer plays a major role due to the influence of the internal environment, and the structure in which the polymer was stably dispersed in the aqueous solution collapses, and the matrix structure formed by the bonds between the polymers induces collagen to repair tissue. The tissue repair refers to a mechanism that attempts to restore tissue to its original state when tissue is mysteriously killed or damaged due to trauma, inflammation, etc., in skin tissue, etc.

[0041] In the present invention, the molecular weight of a polymer refers to a number average molecular weight (Mn). The number average molecular weight refers to an average molecular weight obtained by averaging the molecular weights of component molecules of a polymer compound having a molecular weight distribution by number fraction or molar fraction.

[0042] The HLB value according to the above formula 2 is in the range of 0.1 to 20, preferably in the range of 1 to 14, more preferably in the range of 2 to 12, and even more preferably in the range of 2.5 to 10. If the HLB value is less than 0.1, the polymerized polymer is not soluble in water, and if it exceeds 20, it may be absorbed into the body when injected into the body, and may not function as a dosage form.

[0043] In the present invention, the HLB value (Hydrophile-Lipophile Balance) is a value indicating the degree of affinity of an amphiphilic polymer for water and oil. A high HLB value indicates a high ratio of hydrophilic polymers, and a low HLB value indicates a low ratio of hydrophilic polymers.

[0044] The hydrophobic biocompatible polymer may be at least one polymer selected from the group consisting of polyglycolic acid, polycaprolactone, polylactic acid, polydioxanone, polytrimethylene carbonate, polyhydroxybutyric acid, and copolymers containing the same, so as to satisfy the K value according to Equation 1, and is preferably polycaprolactone.

[0045] The hydrophilic biocompatible polymer is at least one polymer selected from the group consisting of methoxypolyethylene glycol, dihydroxypolyethylene glycol, monoalkoxypolyethylene glycol, and polyethylene glycol, so as to satisfy the K value according to Equation 1, and is preferably methoxypolyethylene glycol.

[0046] The bond structure of the copolymer may be represented by the following Chemical Formula 1, Chemical Formula 2, or Chemical Formula 3, but is not limited thereto. [Chemical formula 1] XY [Chemical formula 2] YXY [Chemical formula 3] XYX In Chemical Formulae 1 to 3, X is a hydrophilic biocompatible polymer, and Y is a hydrophobic biocompatible polymer.

[0047] The molecular weight of the hydrophilic biocompatible polymer is 100 to 50,000 g / mol, which corresponds to the K value according to Equation 1, but is preferably 300 to 20,000 g / mol, more preferably 700 to 15,000 g / mol, and even more preferably 1,000 to 10,000 g / mol.

[0048] The molecular weight of the hydrophobic biocompatible polymer is 500 to 70,000 g / mol, which corresponds to the K value according to Equation 1, but is preferably 1,000 to 30,000 g / mol, more preferably 1,500 to 27,500 g / mol, and even more preferably 2,000 to 25,000 g / mol.

[0049] The molecular weight of the copolymer is 600 to 120,000 g / mol, which corresponds to the K value according to Equation 1, but is preferably 1,300 to 50,000 g / mol, more preferably 2,200 to 42,500 g / mol, and even more preferably 3,000 to 35,000 g / mol.

[0050] The concentration of the copolymer in the colloidal solution is 10 to 50% by weight, which corresponds to the K value in Equation 1. If it exceeds 50%, the viscosity of the colloidal aqueous solution becomes very high and it takes on a gel-like property, which may make it very difficult to inject using a syringe, and if it is less than 10%, it may not be effective as a dosage form.

[0051] The colloid phase exhibits no change or an increase in turbidity when water is added. Although the turbidity of a general colloid phase decreases when water is added, the turbidity of the colloid phase of the present invention does not decrease. In the present invention, the polymers dispersed in the colloid phase, both hydrophilic and hydrophobic biopolymers, form a structure that allows them to dissolve in water. However, when water is added, the solubilized structure formed by the hydrophilic and hydrophobic biopolymers is destroyed. Therefore, when water is added as described above, bonds are formed between the hydrophobic biopolymers, resulting in no change or an increase in turbidity.

[0052] In another aspect, the present invention provides a method for producing the composition for tissue repair. The method includes the steps of polymerizing a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer to prepare a copolymer, and adding water to the copolymer to obtain a colloidal solution.

[0053] In this case, in the case of a colloidal solution in which the copolymer is dispersed in water, a phase with increased viscosity is formed by heating to a temperature between the melting point of the copolymer and the boiling point of water, and further, a colloidal phase in which the particle size cannot be distinguished by the naked eye and no insoluble foreign matter is present is formed.

[0054] The tissue repair composition prepared by the above-mentioned method exhibits a tissue repair effect of forming collagen when injected into the skin.

[0055] The present invention will be described in detail below with reference to specific Preparation Examples and Examples. The abbreviations for chemical substances used in the description of Preparation Examples and Examples are as follows. -mPEG: methoxypolyethylene glycol -PCL: Polycaprolactone

[0056] Preparation Example 1: Preparation of mPEG2000-PCL2000 Polymeric Dosage Form A copolymer (mPEG2000-PCL2000) was prepared by polymerizing methoxypolyethylene glycol with a molecular weight of 2,000 g / mol as a hydrophilic biocompatible polymer and polycaprolactone monomer with a molecular weight of 2,000 g / mol as a hydrophobic biocompatible polymer under a catalyst.

[0057] Preparation Example 2: Preparation of mPEG2000-PCL4000 polymeric dosage form The same preparation method as in Preparation Example 1 was carried out, except that polycaprolactone having a molecular weight of 4,000 g / mol was polymerized instead of polycaprolactone having a molecular weight of 2,000 g / mol.

[0058] Preparation Example 3: Preparation of mPEG2000-PCL5000 polymeric dosage form The same preparation method as in Preparation Example 1 was used, except that polycaprolactone having a molecular weight of 5,000 g / mol was used in place of polycaprolactone having a molecular weight of 2,000 g / mol.

[0059] Preparation Example 4: Preparation of mPEG2000-PCL7500 polymeric dosage form The same preparation method as in Preparation Example 1 was carried out, except that polycaprolactone having a molecular weight of 7,500 g / mol was polymerized instead of polycaprolactone having a molecular weight of 2,000 g / mol in Preparation Example 1.

[0060] Preparation Example 5: Preparation of mPEG2000-PCL10000 polymeric dosage form The same preparation method as in Preparation Example 1 was carried out, except that polycaprolactone having a molecular weight of 10,000 g / mol was polymerized instead of polycaprolactone having a molecular weight of 2,000 g / mol.

[0061] Preparation Example 6: Preparation of mPEG2000-PCL12500 polymeric dosage form The same preparation method as in Preparation Example 1 was used, except that polycaprolactone having a molecular weight of 12,500 g / mol was used in place of polycaprolactone having a molecular weight of 2,000 g / mol.

[0062] Preparation Example 7: Preparation of mPEG2000-PCL15000 polymeric dosage form The same preparation method as in Preparation Example 1 was used, except that polycaprolactone having a molecular weight of 15,000 g / mol was used in place of polycaprolactone having a molecular weight of 2,000 g / mol.

[0063] Preparation Example 8: Preparation of mPEG5000-PCL5000 polymeric dosage form A copolymer (mPEG5000-PCL5000) was prepared by polymerizing methoxypolyethylene glycol with a molecular weight of 5,000 g / mol as a hydrophilic biocompatible polymer and polycaprolactone monomer with a molecular weight of 5,000 g / mol as a hydrophobic biocompatible polymer under a catalyst.

[0064] Preparation Example 9: Preparation of mPEG5000-PCL7500 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 7,500 g / mol was polymerized instead of polycaprolactone having a molecular weight of 5,000 g / mol in Preparation Example 8.

[0065] Preparation Example 10: Preparation of mPEG5000-PCL10000 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 10,000 g / mol was used in place of polycaprolactone having a molecular weight of 5,000 g / mol.

[0066] Preparation Example 11: Preparation of mPEG5000-PCL12500 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 12,500 g / mol was used in place of polycaprolactone having a molecular weight of 5,000 g / mol.

[0067] Preparation Example 12: Preparation of mPEG5000-PCL15000 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 15,000 g / mol was used in place of polycaprolactone having a molecular weight of 5,000 g / mol.

[0068] Preparation Example 13: Preparation of mPEG5000-PCL17500 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 17,500 g / mol was used in place of polycaprolactone having a molecular weight of 5,000 g / mol.

[0069] Preparation Example 14: Preparation of mPEG5000-PCL20000 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 20,000 g / mol was used in place of polycaprolactone having a molecular weight of 5,000 g / mol.

[0070] Preparation Example 15: Preparation of mPEG5000-PCL25000 polymeric dosage form The same preparation method as in Preparation Example 8 was carried out, except that polycaprolactone having a molecular weight of 25,000 g / mol was used in place of polycaprolactone having a molecular weight of 5,000 g / mol.

[0071] Preparation Example 16: Preparation of mPEG10000-PCL10000 polymeric dosage form A copolymer (mPEG10000-PCL10000) was prepared by polymerizing methoxypolyethylene glycol with a molecular weight of 10,000 g / mol as a hydrophilic biocompatible polymer and polycaprolactone monomer with a molecular weight of 10,000 g / mol as a hydrophobic biocompatible polymer under a catalyst.

[0072] Preparation Example 17: Preparation of mPEG10000-PCL12500 polymeric dosage form The same preparation method as in Preparation Example 16 was carried out, except that polycaprolactone having a molecular weight of 12,500 g / mol was used in place of polycaprolactone having a molecular weight of 10,000 g / mol in Preparation Example 16.

[0073] Preparation Example 18: Preparation of mPEG10000-PCL15000 polymeric dosage form The same preparation method as in Preparation Example 16 was carried out, except that polycaprolactone having a molecular weight of 15,000 g / mol was used in place of polycaprolactone having a molecular weight of 10,000 g / mol in Preparation Example 16.

[0074] Preparation Example 19: Preparation of mPEG10000-PCL17500 polymeric dosage form The same preparation method as in Preparation Example 16 was carried out, except that polycaprolactone having a molecular weight of 17,500 g / mol was used in place of polycaprolactone having a molecular weight of 10,000 g / mol in Preparation Example 16.

[0075] Preparation Example 20: Preparation of mPEG10000-PCL20000 polymeric dosage form The same preparation method as in Preparation Example 16 was carried out, except that polycaprolactone having a molecular weight of 20,000 g / mol was used in place of polycaprolactone having a molecular weight of 10,000 g / mol.

[0076] Preparation Example 21: Preparation of mPEG10000-PCL25000 polymeric dosage form The same preparation method as in Preparation Example 16 was carried out, except that polycaprolactone having a molecular weight of 25,000 g / mol was used in place of polycaprolactone having a molecular weight of 10,000 g / mol.

[0077] Preparation Example 22: Preparation of mPEG10000-PCL30000 polymer dosage form The same preparation method as in Preparation Example 16 was carried out, except that polycaprolactone having a molecular weight of 30,000 g / mol was used in place of polycaprolactone having a molecular weight of 10,000 g / mol.

[0078] Example 1 Water was added to the polymers prepared in Preparation Examples 1 to 22, heated to 80° C., and mixed to prepare 5 wt % colloidal aqueous solutions of the polymers.

[0079] Example 2 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 10% by weight of the polymer.

[0080] Example 3 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 15 wt % of the polymer.

[0081] Example 4 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 20% by weight of the polymer.

[0082] Example 5 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 25% by weight of the polymer.

[0083] Example 6 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 30% by weight of the polymer.

[0084] Example 7 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 35% by weight of the polymer.

[0085] Example 8 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 40% by weight of the polymer.

[0086] Example 9 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 45% by weight of the polymer.

[0087] Example 10 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 50% by weight of the polymer.

[0088] Example 11 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 55% by weight of the polymer.

[0089] Example 12 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 60% by weight of the polymer.

[0090] Example 13 A colloidal aqueous solution was prepared in the same manner as in Example 1, except that the colloidal aqueous solution contained 65% by weight of the polymer.

[0091] Comparative Example Water was added to the polymer prepared in Preparation Example 5 and mixed to prepare a mixture containing 15 wt % of the polymer.

[0092] Experimental Example 1 For the tissue repair compositions prepared in Examples 1 to 13, the number of moles of polymer in 100 g of aqueous solution was measured, and the K value was measured according to the following Equation 1. Based on the result, the efficacy of the formulation was evaluated (parts where the formulation was effective are highlighted), and the results are shown in Tables 1 and 2 below. [Formula 1] K = (m 100 *M h 2 *10) / (M l *HLB 2 ) In Formula 1, m 100 is the number of moles of polymer in 100 g of aqueous solution, and M h is the molecular weight of the hydrophilic part, and M l is the molecular weight of the hydrophobic portion, and HLB is a value expressed by the following mathematical formula 2. [Formula 2] HLB = 20*M h / M In formula 2, M h is the molecular weight of the hydrophilic portion and M is the molecular weight of the entire molecule.

[0093] [Table 1] [Table 2] Referring to Table 1, the number of moles of polymer dissolved in 100 g of aqueous solution is shown, and it can be seen that the number of moles decreases as the HLB value decreases at a constant concentration.

[0094] If the concentration exceeds 45% by weight, the viscosity of the colloidal solution becomes too high, making it difficult to inject, and if the concentration is less than 15% by weight, the solution is absorbed into the body when injected, making the dosage form ineffective.

[0095] In addition, if the HLB value is less than 2.5, the proportion of hydrophobic biocompatible polymers is high and the polymers do not dissolve when water is added, and if it exceeds 10, they are absorbed into the body when injected, making the dosage form ineffective.

[0096] However, in Table 1, when judging based on the molecular weight of the polymerized polymer, not the ratio of hydrophilic biopolymer and hydrophobic biopolymer, comparing mPEG 2,000g / mol with mPEG 5,000g / mol, the number of moles of polymer in 100g of aqueous solution is higher in mPEG 2,000g / mol than in mPEG 5,000g / mol. Therefore, since the number of moles of polymer in 100g of aqueous solution cannot be said to be constant, it was converted to a constant value, and the K value was derived to measure the formation range of the composition for tissue repair according to the present invention.

[0097] Table 2 shows the relationship between the molecular weight of hydrophilic and hydrophobic biopolymers and the HLB value, unlike Table 1. If the molecular weight of the hydrophilic biopolymer is the same, the K value decreases as the molecular weight of the hydrophobic biopolymer increases. This is also true when determining the ratio of hydrophilic and hydrophobic biopolymers. In addition, even if the molecular weight of the hydrophilic biopolymer is different, if the ratio of the hydrophilic and hydrophobic biopolymers is the same, the K value is very similar.

[0098] The K value has a certain value within a certain concentration range described below, and the efficacy of the dosage form can be confirmed within that range. The K value is calculated to be about 0.12 to 3.26, but the effective range of the dosage form is 0.4 to 1.5. It has also been found that the aqueous colloidal solution is effective as a dosage form when the concentration is 15 to 45% by weight, the HLB is 2.5 to 10, and the K value is 0.4 to 1.5.

[0099] Experimental Example 2 The colloidal phase prepared according to Preparation Example 3 was used to measure the turbidity of the composition for tissue repair according to the present invention by the following method, and the results are shown in Figure 9. A formazan turbidity standard of 4000 NTU was used as the turbidity standard solution.

[0100] <Measurement method> (1) The standard solution and the colloidal phase prepared according to Preparation Example 3 were diluted 2-fold, 5-fold, 10-fold, and 20-fold to prepare solutions, which were then placed in vials to prepare comparative samples. The turbidity of the diluted standard solutions was 4000, 2000, 800, 400, and 200 NTU, respectively. (2) The outside of the vial containing the turbidity comparison sample was wiped, and under a white LED light source at a brightness of approximately 1000 lx, the change in turbidity due to dilution and the difference in turbidity at the same dilution ratio were observed with the naked eye.

[0101] Inspection of FIG. 9 shows that for the standards, going from left to right, the turbidity decreases as the solution becomes more diluted. On the other hand, in the case of the present invention, it can be seen with the naked eye from left to right that the turbidity does not decrease even when diluted, and in fact becomes thicker than the original solution.

[0102] Experimental Example 3 The viscosity of the colloidal aqueous solutions prepared in Examples 1 to 13, which were shown to have the efficacy of a dosage form, and the mixture prepared in the Comparative Example was measured at room temperature using a viscometer (Viscolead One, Fungilab), and the results are shown in Table 4 and Figure 2 below. In the case of Examples 1 to 13, the viscosity was measured for the colloidal aqueous solutions using the copolymers prepared in Preparation Examples 1 to 8, 10 to 11, and 13 to 14. In Figure 2, (b) shows the result for the colloidal aqueous solution of Example 3, which used the copolymer prepared in Preparation Example 5. The viscosity of the mixture prepared in the Comparative Example was shown to be 1.14 cP.

[0103] [Table 3]

[0104] Referring to FIG. 2, it can be seen that the heated colloidal aqueous solution (Example 1) did not produce precipitation or foreign matter and had an increased viscosity compared to the non-heated mixture (Comparative Example).

[0105] Also, referring to Table 4, it can be seen that the viscosity of the heated colloidal aqueous solution ranges from 26.4 to 188,404.6 cP, and the viscosity tends to increase as the polymer concentration in the aqueous solution increases. It can be seen that the viscosity increases by at least about 25 times and at most about 190,000 times compared to the non-heated mixture (comparative example).

[0106] Experimental Example 4 In order to verify the efficacy of the tissue repair composition according to the present invention as a dosage form, animal experiments were carried out. Six-week-old SD rats (purchased from Orient Bio) were used as test animals. The experiment was carried out in 8 locations per 6-week-old SD rat, with one side assigned to phosphate buffered saline (PBS) and the other side to the test substance group, with a total of 10 rats divided into 3 groups. During the experiment, the rearing environment was set at 24±2°C, relative humidity 50±10%, and lighting time 12 hours, and food was available ad libitum.

[0107] PBS was injected as a negative control into the left subcutaneous layer of each rat in each group, centered on the midline, and 250 μl of a colloidal aqueous solution (concentration 25%, HLB 5.7, K value 0.8864) prepared by dissolving the polymer prepared in Preparation Example 3 in water was injected into the right subcutaneous layer. The presence or absence of leakage of the sample immediately after injection was observed, and the results are shown in Figure 3.

[0108] Immediately after (0 hr), 1 week, 2 weeks, 4 weeks, and 6 weeks after administration of the colloidal aqueous solution and PBS, the experimental animals were sacrificed, and the skin tissues at the sample-injected site and the uninjected skin tissues were excised and fixed in 10% neutral buffered formalin solution. They were then embedded in paraffin and hardened, and 5 μm sections were prepared. After staining with hematoxylin and eosin (H&E), inflammation / foreign body reaction was evaluated according to Table 3 below, and the increase in thickness of the entire skin (dermis layer, subcutaneous layer) due to the injection of the sample was observed by optical microscopy, and the results are shown in Figures 4, 6, and 8, respectively.

[0109] To evaluate the biosynthetic potential of new collagen in colloidal aqueous solution and PBS, collagen formation in the tissue was observed after staining with Masson's Trichrome (MT). The biocompatibility of the injected samples was evaluated by checking inflammation and foreign body reaction according to Table 4 below, which is the main criterion. The tissue slides were observed at 40x, 100x, 200x, and 400x magnifications using an optical microscope, and the main histological characteristics of each slide were read, and the results are shown in Figures 5 and 7.

[0110] In addition, the degree of inflammation and foreign body reaction due to the injected colloidal solution is divided into four stages, with the inflammation and foreign body reaction observed in the PBS administration group being set to no inflammation, and the more severe the inflammation and foreign body reaction, the more they are evaluated as almost clear (score 1), mild (score 2), moderate (score 3), or severe (score 4) according to Table 5 below (Duranti et al. Dermatol Surg 1998:24:1317-25).

[0111] [Table 4]

[0112] Fig. 3 is a photograph taken by a DSLR (D3000, Nikon, Japan) to check the presence or absence of leakage of the sample after injection of PBS and colloidal aqueous solution, Fig. 4 is a photograph taken by an optical microscope showing the thickness of the skin over time after injection of the colloidal aqueous solution, Fig. 5 is a photograph taken by an optical microscope showing the collagen over time after injection of the colloidal aqueous solution, Fig. 6 is a photograph taken by an optical microscope showing the thickness of the skin over time after injection of PBS, Fig. 7 is a photograph taken by an optical microscope showing the collagen over time after injection of PBS, and Fig. 8 is a graph showing the thickness of the skin over time after injection of PBS and colloidal aqueous solution.

[0113] Referring to FIG. 3, it can be seen that no sample leaked when observed immediately after administration of PBS and the colloidal aqueous solution.

[0114] Referring to Figures 4, 6, and 8, as a result of histopathological evaluation using H&E staining, it was found that the thickness of the subcutaneous layer of the tissue injected with the colloidal aqueous solution also increased over time up to 6 weeks, and that the degree of increase was significantly improved compared to Figure 6, in which PBS was injected.

[0115] Referring to Figures 5 and 7, as a result of histopathological evaluation using MT staining, it was confirmed that collagen was formed in the subcutaneous layer of the tissue into which the colloidal solution was injected. It was also found that the thickness of the subcutaneous layer increased over time up to 6 weeks due to the formation of collagen, and that the degree of increase was significantly improved compared to Figure 7, in which PBS was injected.

[0116] Furthermore, referring to Figures 4 to 7, when evaluating the foreign body reaction according to Table 5, no significant foreign body reaction was observed due to the injection of the colloidal aqueous solution, and the score was 1, with almost no inflammatory cells, lymphocytes, or giant cells in the fibrous tissue, which is no different from before the administration of the colloidal aqueous solution.

[0117] Thus, the present invention can provide a composition for tissue repair using a non-toxic biocompatible polymer when the concentration, HLB and K value are satisfied, and a method for producing the same.

[0118] The preferred embodiments of the present invention have been described in detail with reference to the drawings. The description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical concept or essential features of the present invention. Therefore, the scope of the present invention is defined by the claims set forth below rather than the above detailed description, and all modifications and variations derived from the meaning, scope and equivalent concepts of the claims should be interpreted as being included within the scope of the present invention. [1] A composition for tissue repair comprising a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, the copolymer being in a colloidal phase dispersed in water, The colloidal phase is a phase in which the viscosity of the copolymer dispersed in water is increased by heating. [2] The tissue repair composition described in [1], wherein the colloidal phase has a viscosity upon heating of 20 to 200,000 cP. [3] The composition for tissue repair according to [1] is characterized in that the K value represented by the following mathematical formula 1 is in the range of 0.01 to 5: [Formula 1] K = (m 100 *M h 2 *10) / (M l *HLB 2 ) where m 100 is the number of moles of polymer in 100 g of aqueous solution, and M h is the molecular weight of the hydrophilic part, and M l is the molecular weight of the hydrophobic portion, and HLB is a value expressed by the following mathematical formula 2. [Formula 2] HLB = 20*M h / M Here, M h is the molecular weight of the hydrophilic portion and M is the molecular weight of the entire molecule. [4] The composition for tissue repair described in [1], characterized in that the HLB value according to the above formula 2 is in the range of 0.1 to 20. [5] The composition for tissue repair described in [1] is characterized in that the hydrophobic biocompatible polymer is one or more polymers selected from the group consisting of polyglycolic acid, polycaprolactone, polylactic acid, polydioxanone, polytrimethylene carbonate, polyhydroxybutyric acid, and copolymers containing them. [6] The composition for tissue repair described in [1] is characterized in that the hydrophilic biocompatible polymer is one or more polymers selected from the group consisting of methoxypolyethylene glycol, dihydroxypolyethylene glycol, monoalkoxypolyethylene glycol, and polyethylene glycol. [7] The composition for tissue repair according to [1], characterized in that the bond structure of the copolymer includes a structure of the following chemical formula 1, chemical formula 2, or chemical formula 3: [Chemical formula 1]XY [Chemical formula 2]YXY [Chemical formula 3]XYX Here, X is a hydrophilic biocompatible polymer and Y is a hydrophobic biocompatible polymer. [8] The composition for tissue repair described in [1], wherein the hydrophilic biocompatible polymer has a molecular weight of 100 to 50,000 g / mol. [9] The composition for tissue repair described in [1], wherein the hydrophobic biocompatible polymer has a molecular weight of 500 to 70,000 g / mol.

[10] The composition for tissue repair described in [1], wherein the copolymer has a strength of 600 to 120,000 g / mol.

[11] The composition for tissue repair described in [1], characterized in that the concentration of the copolymer in the colloidal solution is 10 to 50% by weight.

[12] The composition for tissue repair described in [1], wherein the colloidal phase is characterized in that there is no change or an increase in turbidity when water is added.

Claims

1. A composition for tissue repair comprising a copolymer in which a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer are polymerized, the copolymer being dispersed in water in a colloidal phase, The colloidal phase is a phase in which the viscosity of the copolymer dispersed in water is increased by heating, The colloidal phase has a viscosity upon heating of 26.4 to 188404.6 cP; The composition has a K value represented by the following formula 1 in the range of 0.4 to 1.5, [Formula 1] K = (m １００ *M ｈ ２ *10) / (M ｌ *HLB ２ ) Here, m １００ is the number of moles of polymer in 100 g of aqueous solution, and M ｈ is the molecular weight of the hydrophilic portion, and M ｌ is the molecular weight of the hydrophobic portion, and HLB is a value represented by the following formula 2: [Formula 2] HLB = 20 * M ｈ / M Here, M ｈ is the molecular weight of the hydrophilic portion, M is the molecular weight of the entire molecule, The HLB value according to the above formula 2 is in the range of 2.5 to 10, A composition for tissue repair, wherein the concentration of the copolymer in the colloidal solution is 15 to 45% by weight.

2. The composition for tissue repair according to claim 1, characterized in that the hydrophobic biocompatible polymer is one or more polymers selected from the group consisting of polyglycolic acid, polycaprolactone, polylactic acid, polydioxanone, polytrimethylene carbonate, polyhydroxybutyric acid, and copolymers containing the same.

3. The composition for tissue repair described in claim 1, characterized in that the hydrophilic biocompatible polymer is one or more polymers selected from the group consisting of methoxypolyethylene glycol, dihydroxypolyethylene glycol, monoalkoxypolyethylene glycol, and polyethylene glycol.

4. 2. The composition for tissue repair according to claim 1, wherein the bond structure of the copolymer comprises the following structure of Formula 1, Formula 2, or Formula 3: [Chemical formula 1] XY [Chemical Formula 2] Y-X-Y [Chemical formula 3] X-Y-X Here, X is a hydrophilic biocompatible polymer and Y is a hydrophobic biocompatible polymer.

5. The composition for tissue repair according to claim 1, wherein the hydrophilic biocompatible polymer has a molecular weight of 100 to 50,000 g / mol.

6. The composition for tissue repair according to claim 1, wherein the hydrophobic biocompatible polymer has a molecular weight of 500 to 70,000 g / mol.

7. The tissue repair composition of claim 1, wherein the copolymer has a molecular weight of 600 to 120,000 g / mol.

8. The tissue repair composition according to claim 1, characterized in that the colloidal solution in which the copolymer is dispersed in water shows no change or increases in turbidity even when water is added at a dilution of 2 to 20 times.

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