KR102403554B1 - Hybrid hydrogel injection for dermal filler application based on hyaluronic acid containing biodegradable polymer microparticle and method for preparing the same - Google Patents

Abstract

The present invention relates to biodegradable polymer microparticles, a hybrid hydrogel filler injection containing the same, and a method for manufacturing the same.
The present invention has developed a method for producing biodegradable polymer microparticles simply in a shorter time than the existing process, and the injection for hybrid filler containing the biodegradable polymer microparticles of the present invention has a solid formulation. Even with the lapse of time, the initial pH is maintained, so that it has better safety and stability.

Description

Hybrid hydrogel injection for dermal filler application based on hyaluronic acid containing biodegradable polymer microparticle and method for preparing the same}

The present invention relates to biodegradable polymer microparticles, a hybrid hydrogel filler injection containing the same, and a method for preparing the same.

Biodegradable polymers or hydrogels are injected into the dermis of the facial tissue and used as an injection to physically fill the space, and have the effect of temporarily improving wrinkles through injection. Injections for this anti-wrinkle effect are generally called dermal fillers, and dermal fillers are largely divided into biodegradable polymer-based fillers and hyaluronic acid (HA)-based hydrogels based on their materials. do.

Although biodegradable polymer microparticles are hydrophobic and insoluble in water, they are hydrolyzed by water and are decomposed over a short period of months to years. Biodegradable polymer-based dermal fillers are mainly composed of biodegradable polymer microparticles of appropriate size for injection, and after injection into the body, it stimulates the production of autologous collagen around the injected particles according to a foreign body reaction. There are characteristics. On the other hand, hyaluronic acid-based dermal fillers mainly use hydrophilic hyaluronic acid, and have a hydrogel form through a cross-linking reaction to increase the retention period in the body. Hyaluronic acid-based fillers currently account for most of the market demand, and are in the spotlight for their soft volume and natural anti-wrinkle effects.

However, the biodegradable polymer microparticle filler has the disadvantage of reducing the initial volume, and in the case of the hyaluronic acid filler, although there is a satisfactory volume at the beginning, there is no mechanism to stimulate autogenous collagen production. Development of a technology for mixing these materials in a hybrid form This is actively going on. In this regard, Korean Patent No. 10-2094407 discloses a method for producing a hybrid hydrogel in which a biodegradable polymer and hyaluronic acid are mixed. It takes a lot of time, and the problem of low pH due to hydrolysis of biodegradable polymer microparticles in a water-based hydrogel was not considered. If the pH of the injection is lowered, it can cause necrosis and inflammation of the surrounding tissues, which can be a problem.

Under this background, the inventors of the present invention completed the present invention by developing a new formulation in consideration of the simple manufacturing process of biodegradable polymer microparticles and the pH of the filler injection as a result of earnest efforts to further improve the commercialization of hybrid fillers.

One object of the present invention is to (a) mixing a biodegradable polymer into an organic solution, wherein the organic solution contains 90 parts by volume of an organic solvent and 10 parts by volume of water; (b) preparing biodegradable polymer microparticles by spray-drying the solution in which the biodegradable polymer is mixed; (c) preparing a hyaluronic acid hydrogel by adding a crosslinking agent to a first composition containing hyaluronic acid; (d) preparing a mixed composition by adding the biodegradable polymer microparticles and the hyaluronic acid hydrogel to a second composition containing hyaluronic acid; and (e) freeze-drying the mixed composition; to provide a method for preparing an injection for a hybrid hydrogel filler, including.

Another object of the present invention is to provide an injection for a filler prepared by the above method.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by the specific descriptions described below.

One aspect of the present invention for achieving the above object is a step of (a) mixing a biodegradable polymer in an organic solution, wherein the organic solution comprises 90 parts by volume of an organic solvent and 10 parts by volume of water; (b) preparing biodegradable polymer microparticles by spray-drying the solution in which the biodegradable polymer is mixed; (c) preparing a hyaluronic acid hydrogel by adding a crosslinking agent to a first composition containing hyaluronic acid; (d) preparing a mixed composition by adding the biodegradable polymer microparticles and the hyaluronic acid hydrogel to a second composition containing hyaluronic acid; and (e) freeze-drying the mixed composition;

The biodegradable polymer of the present invention is polydioxanone (PDO), polylactic acid (Poly-Lactic acid, PLA), poly-L-lactic acid (Poly-L-Lactic acid, PLLA), poly-D-lactic acid ( Poly-D-Lactic acid, PDLA), poly-ε-caprolactone (PCL), polyglycolic acid (Polyglycolic acid, PGA), one selected from the group consisting of copolymers and mixtures thereof may be more than It may be at least one selected from these copolymers and mixtures thereof. These copolymers may be, for example, polylactic acid-glycolic acid copolymer, polydioxanone-caprolactone copolymer, polylactic acid-caprolactone copolymer, and the like. The biodegradable polymer of the present invention may specifically be polydioxanone (PDO), and the polydioxanone is a polymer in which ether-ester units are repeated and is mainly used as a biomedical material such as a suture. Polydioxanone may be included in the filler injection of the present invention to stimulate the skin's autologous collagen production.

The organic solvent of the present invention is HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol), acetone (Acetone), acetic acid (Acetic acid), dioxane (Dioxane), ethanol (Ethanol), methanol ( Methanol), isopropyl alcohol (Isopropyl alcohol, IPA), propanol (Propanol), tetrahydrofuran (Tetrahydrofuran, THF), and may be at least one selected from the group consisting of mixtures thereof. The organic solvent of the present invention may specifically be HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol), which is a fluorinated solvent and has very strong volatility due to its low boiling point and high vapor pressure. has HFIP may be included as a solvent of the biodegradable polymer solution for preparing the biodegradable polymer microparticles of the present invention.

"Organic solution" of the present invention means a solution containing the organic solvent and water, and is mixed with a biodegradable polymer to prepare the biodegradable polymer microparticles of the present invention. In the present invention, the concentration of the organic solution may be 85 to 95% (v/v), specifically 87 to 93% (v/v), and more specifically 90% (v/v). In the present invention, the concentration of the organic solution means the concentration of a solution in which the organic solvent is mixed with water, and the 90% (v/v) organic solution of the present invention includes 90 parts by volume of the organic solvent and 10 parts by volume of water. will be. In a specific embodiment of the present invention, biodegradability using a mixture of 90 ml of HFIP and 10 ml of purified water, that is, HFIP of 90% (v/v) concentration, and 100% (v/v) of HFIP not mixed with purified water As a result of preparing the polymer microparticles, it was confirmed that fine particles were preferably formed when 90% (v/v) HFIP was used, whereas fine particles were not formed when 100% (v/v) HFIP was used ( 1 and 3).

The "solution in which the biodegradable polymer is mixed" of the present invention means a solution in which the biodegradable polymer is mixed in an organic solution. The concentration of the biodegradable polymer mixed solution in the present invention may be 0.4 to 0.8% (w / v), specifically 0.5 to 0.7% (w / v), more specifically 0.6% (w / v) have. In a specific embodiment of the present invention, as a result of preparing polydioxanone microparticles using a 0.6% (w/v) polydioxanone solution and a 1% (w/v) polydioxanone solution, 0.6% When a (w/v) polydioxanone solution is used, fine particles are preferably formed, whereas when a 1% (w/v) polydioxanone solution is used, the shape of the particles is not spherical or some particles are formed It was confirmed that it did not (FIGS. 1 and 2). That is, the present invention is characterized in that the optimal conditions for the production of biodegradable polymer microparticles using the spray drying method were identified.

As a method for preparing fine particles, spray drying method, solvent evaporation method, solvent extraction method, membrane emulsification method, microfluidic method etc. Among them, "spray drying" of the present invention is a process of dispersing a liquid substance into a high-temperature dry medium to make it a dry powder state. Specifically, it is a principle of generating solid particles by strongly spraying a liquid sample such as a dispersion or suspension to form a droplet and evaporating the solvent instantaneously through a drying process. The spray drying method is cost-effective, has the advantage of being able to scale-up in ton units, and is being used in various fields because it can produce fine particles in a very simple and quick way. In the present invention, a PDO mixture solution in which polydioxanone (PDO) is mixed in a 90% (v/v) HFIP solution at a concentration of 0.6% (w/v) in a spray dryer at 85 to 95° C. is injected at a rate of 0.1 L/hr and nitrogen gas was injected at a pressure of 4.5 to 5.5 bar to obtain spray-dried polydioxanone fine particles (Example 1). As such, in the case of producing fine particles by the spray drying technique, compared to the case of manufacturing by the solvent evaporation technique, since the use of a separate surfactant is unnecessary and the time to wash them is omitted, the process time can be reduced by more than half ( 5).

Simultaneously or sequentially with the step of preparing the biodegradable polymer microparticles, a hyaluronic acid hydrogel is provided by adding a crosslinking agent to the first composition containing hyaluronic acid. In the present invention, the first composition containing hyaluronic acid means a composition in which hyaluronic acid is dissolved in an aqueous alkali solution, and the aqueous alkali solution is, for example, sodium hydroxide (NaOH), potassium hydroxide (KOH), and aqueous ammonia (NH ₃ ) It may include one or more selected basic compounds, but is not limited thereto, and any basic compound capable of preparing an aqueous alkali solution may be used.

Hyaluronic acid of the present invention is a polysaccharide that exists in a state in which a high molecular compound composed of glucuronic acid and N-acetyl-glucosamine is connected. It supports fibers and has hydrophilic properties, so that a large amount of water is absorbed in the space between cells. It plays a decisive role in making the skin elastic by containing and maintaining it. In the present invention, hyaluronic acid includes all of hyaluronic acid, a salt of hyaluronic acid, or a mixture thereof. The salt of hyaluronic acid includes a metal salt or an organic salt of hyaluronic acid. The salt of hyaluronic acid is, for example, lithium hyaluronate, sodium hyaluronate, potassium hyaluronate, rubidium hyaluronate, cesium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, hyaluronic acid. It may be a cobalt ronic acid salt, a tetrabutylammonium hyaluronic acid salt, a combination thereof, and the like, but is not limited thereto.

In the present invention, the number average molecular weight (Mn) of hyaluronic acid is, for example, 50,000 Dalton to 5,000,000 Dalton, 100,000 Dalton to 5,000,000 Dalton, 100,000 to 3,000,000 Dalton, or 100,000 to 2,000,000 Dalton. If the number average molecular weight of hyaluronic acid is less than 50,000 Daltons, the decomposition rate of cross-linked hyaluronic acid may increase and thus may not be suitable as a biomaterial for fillers. If the number average molecular weight of hyaluronic acid exceeds 5,000,000 Daltons, it may be difficult to process due to high viscoelasticity, so it may be difficult to prepare a hydrogel having a uniform size and quality.

The crosslinking agent of the present invention is butanediol diglycidyl ether (1,4-butandiol diglycidyl ether, BDDE), ethylene glycol diglycidyl ether (EGDGE), hexanediol diglycidyl ether (1,6) -hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether , neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether polyglycidyl ether), trimethylpropane polyglycidyl ether, bisepoxypropoxyethylene (1,2-(bis(2,3-epoxypropoxy)ethylene), pentaerythritol polyglycidyl ether (pentaerythritol polyglycidyl ether) and sorbitol polyglycidyl ether (sorbitol polyglycidyl ether) may be at least one selected from the group consisting of. In the present invention, a crosslinking agent is added to the first composition and stirred, and then left to stand for a certain period of time to make the hyaluronic acid hydrogel Prepare. Crosslinking by crosslinking agent can proceed while stirring and / or while left to stand after stirring.After adding the crosslinking agent to the first composition, the stirring time is not particularly limited, and for example, 1 to 60 minutes, The time left to stand without stirring is also not particularly limited and is, for example, 0.1 to 24 hours.

As the hyaluronic acid dissolved in the first composition is cross-linked by the cross-linking agent, a hyaluronic acid matrix is formed, and a hyaluronic acid hydrogel containing water is formed. After the hyaluronic acid hydrogel is formed, it may further include washing with an aqueous solution. The aqueous solution used for washing the hyaluronic acid hydrogel may be a phosphate buffer solution (PBS), and impurities such as unreacted crosslinking agents may be removed by such washing.

Next, a mixed composition is prepared by adding the biodegradable polymer microparticles and the hyaluronic acid hydrogel to a second composition containing hyaluronic acid. In the present invention, the second composition containing hyaluronic acid means a composition in which hyaluronic acid is dissolved in purified water, and the content of hyaluronic acid included in the second composition is 0.01 to 10% (w/v), specifically 0.01 to 5% (w/v), more specifically 0.1 to 3% (w/v). The mixed composition of the present invention may be prepared by mixing the second composition, the biodegradable polymer microparticles, and the hyaluronic acid hydrogel, followed by mixing.

The mixed composition of the present invention may include 4 to 10 parts by weight of the second composition, 85 to 95 parts by weight of the biodegradable polymer microparticles, and 1 to 5 parts by weight of the hyaluronic acid hydrogel, specifically, 7 parts by weight of the second composition , 90 parts by weight of biodegradable polymer microparticles, and 3 parts by weight of hyaluronic acid hydrogel.

Next, the prepared mixture composition is freeze-dried to obtain a hybrid hydrogel.

As used herein, the term “hybrid hydrogel” refers to an injection for a hydrogel formulation containing biodegradable polymer microparticles and cross-linked hyaluronic acid. The biodegradable polymer microparticle filler has the disadvantage of reducing the initial volume, and the hyaluronic acid filler has a short maintenance period and thus requires repeated treatment. can be supplemented. Specifically, the hybrid hydrogel is injected into the body and, while the cross-linked hyaluronic acid is decomposed, the volume change of the filler due to the decomposition of hyaluronic acid by easily inducing the growth of biomaterials such as collagen from the biodegradable polymer microparticles can suppress.

The "freeze drying" of the present invention uses the principle of sublimation, which freezes a water-containing sample and then uses a vacuum pump to lower the water vapor pressure to a triple point or less to directly turn ice into steam. This freeze-drying method has characteristics such as preservation of physical structure, chemical stability, and preservation of biological activity compared to other drying methods. In the present invention, the freeze-drying may be performed by freezing the mixed composition at -30 to -10°C for 6 to 18 hours, and then drying it in a freeze dryer for 60 to 84 hours, but freeze-drying the mixed composition to obtain a solid dosage form. If a hybrid hydrogel can be obtained, it is not limited thereto.

The hybrid hydrogel of the present invention is characterized by maintaining a pH range of 7.2 to 7.6 for 1 to 15 days. The biodegradable polymer microparticles contained in the injection for fillers are hydrolyzed in the water-based hydrogel to lower the pH of the injection, and when the pH is lowered, necrosis and inflammation of surrounding tissues can be a problem. Therefore, in a specific embodiment of the present invention, the pH change according to the storage of the lyophilized solid hydride hydrogel and the liquid hybrid hydrogel that has not undergone the lyophilization process was confirmed. As a result, in the case of the liquid formulation that did not go through the freeze-drying process, it was confirmed that the pH was lowered over time and thus not suitable for use as a filler (Table 1). Therefore, it can be seen that it is essential to secure a solid-phase formulation through freeze-drying.

Another aspect of the present invention for achieving the above object provides an injection for a filler prepared by the above method.

The injection for filler of the present invention can be used in the form of administration to the skin area of the recipient by using an injection device having the form of a fine needle or cannula.

The filler injection includes the hybrid hydrogel of the present invention, and may further include a biocompatible carrier. The biocompatible carrier is alginic acid and its salts, hyaluronic acid and its salts, carboxymethyl cellulose and its salts, dextran and its salts, collagen, gelatin. (gelatin), and may include one or more selected from elastin (elastin).

The filler injection may further include a physiologically active material, a local anesthetic, water for injection, sterile water, or distilled water depending on the use.

The present invention has developed a method for manufacturing biodegradable polymer microparticles simply in a shorter time than the existing process, and the hybrid filler injection containing the biodegradable polymer microparticles of the present invention has a solid formulation. Even with the lapse of time, the initial pH is maintained and thus has better safety and stability.

1 is a view showing a scanning electron microscope (SEM) image of the biodegradable polymer microparticles prepared according to the method of Example 1.
2 is a view showing a scanning electron microscope (SEM) image of the biodegradable polymer microparticles prepared according to the method of Comparative Example 1.
3 is a view showing a scanning electron microscope (SEM) image of the biodegradable polymer microparticles prepared according to the method of Comparative Example 2.
4 is a view taken of the injection for Example 2 hybrid hydrogel filler that has undergone a freeze-drying process.
5 is a diagram comparing the time required for the preparation of biodegradable polymer microparticles according to the solvent evaporation process and the spray drying process.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Preparation Example 1. Preparation of biodegradable polymer microparticles

Example 1. Preparation of biodegradable polymer microparticles through spray drying

As a biodegradable polymer, 0.6 g of polydioxanone (PDO, I.V. 1.55 dl/dg) is mixed with 90 ml of Hexafluoro-2-isopropanol (HFIP) and 10 ml of purified water, that is, a 90% (v/v) HFIP organic solution dissolved in After pre-adjusting the chamber temperature of the spray dryer to 90°C, a 0.6% (w/v) PDO solution is injected into the spray dryer equipment at a rate of 0.1 L/hr, and nitrogen gas is injected at the same time at a pressure of 5 bar to spray drying. The PDO microparticles of Example 1 were obtained. The obtained PDO microparticles are shown in FIG. 1 , and as a result, it was confirmed that the microparticles were prepared in the form of spherical particles.

Comparative Example 1. Preparation of fine particles according to the change in the concentration of the biodegradable polymer

Except that the concentration of PDO, a biodegradable polymer, was adjusted to 1% (w/v), PDO microparticles of Comparative Example 1 were obtained in the same manner as in Example 1 and the rest of the manufacturing process. The obtained PDO microparticles are shown in FIG. 2 . As a result, as shown in FIG. 2 , the shape of the particles was not completely spherical, but rather distorted, and it was confirmed that some particles were dispersed without forming particles. Through this, it was found that the concentration of the biodegradable polymer has an important effect on the preparation of microparticles.

Comparative Example 2. Preparation of fine particles according to change in concentration of organic solution

Except that HFIP was not mixed with purified water and 100% concentration of HFIP was used as an organic solvent, the rest of the manufacturing process was performed in the same manner as in Example 1 to obtain PDO microparticles of Comparative Example 2. The obtained PDO microparticles are shown in FIG. 3 . As a result, as shown in FIG. 3, it was confirmed that the biodegradable polymer did not form particles at all, and it was found that the concentration of the organic solution had an important effect on the preparation of fine particles.

Comparative Example 3. Through solvent evaporation Preparation of biodegradable polymer microparticles

A PDO solution was obtained by completely dissolving 6.6 g of PDO (I.V. 1.55 dl/dg), a biodegradable polymer, in 100 ml of HFIP, and 9 g of polyvinyl alcohol (PVA, average molecular weight 22,000 Da), a surfactant, was completely dissolved in 200 ml of purified water to obtain an aqueous PVA solution. got it The two solutions prepared above were mixed and the organic solvent was removed while stirring at 400 rpm for 2 days to obtain a composition including polymer microparticles. After the agitation was finished, it was left for 24 hours to precipitate the polymer microparticles, and then the supernatant was removed and the microparticles were separated. The separated polymer microparticles were washed by adding purified water and stirring again. This washing step was performed a total of 3 times to prepare biodegradable polymer microparticles.

Comparative Example 3 according to the solvent evaporation method and the method of Example 1 according to the spray drying method are shown in FIG. 5 to compare the process time required to prepare 30 g scale PDO microparticles. When manufacturing fine particles by spray-drying, since the use of a separate surfactant is unnecessary and the time to wash them is omitted, the process time is reduced by more than half.

Preparation Example 2. Preparation of injections for hyaluronic acid-based hybrid hydrogel fillers containing biodegradable polymer microparticles

Example 2. Preparation of an injection for a hybrid hydrogel filler of a solid dosage form

After dissolving 0.1 g of NaOH in 10 ml of purified water to prepare an aqueous alkali solution, 1 g of hyaluronic acid (HA, number average molecular weight 1,000,000 Da) was dissolved to prepare a first composition. After adding 0.05 ml of 1,4-butanediol diglycidyl ether (BDDE) to the composition, stirring was performed at 200 RPM for about 30 minutes, the stirring was stopped, and the crosslinking reaction was carried out at room temperature for 24 hours to prepare an HA hydrogel. The HA hydrogel was placed in 10 L of 0.9% saline and stored for 24 hours to remove unreacted substances. After performing the same process three more times with the saline, the saline was changed to a 1% PBS aqueous solution and additionally 4 times.

After dissolving 0.4 g of hyaluronic acid in 40 ml of purified water to prepare a second composition, the purified HA hydrogel and 9 g of the PDO microparticles obtained by the method of Example 1 were placed in a mixer (1500 W, 24,000 rpm). Thereafter, by mixing for a total of 10 times for 10 seconds, a mixed composition containing 0.3 g of HA hydrogel, 0.7 g of a second composition, and 9 g of fine particles was prepared.

3 ml of the mixture composition was put into a 10 ml vial and frozen at -20 °C for 12 hours, and then dried in a freeze dryer for 72 hours to obtain a final freeze-dried formulation.

The formulation of the injection for filler obtained through the above process is shown in FIG.

Comparative Example 4. Preparation of injection for hybrid hydrogel filler in liquid formulation

Among the manufacturing methods of Example 2, a liquid injection formulation for filler was prepared according to the remaining manufacturing methods except for the freezing and freeze-drying processes.

Evaluation Example 1. Confirmation of pH change due to storage of solid or liquid formulations

When PDO microparticles come in contact with water, the polymer is decomposed through hydrolysis, resulting in a drop in pH. Therefore, the PDO filler requires a solid-phase formulation technology rather than a liquid phase, and in order to confirm the necessity, the pH change according to the formulation of the injection for the filler of Example 2 and Comparative Example 4 was confirmed through this evaluation example.

Example 2 Comparative Example 4 0 days 7.41 7.39 7 days 7.40 5.91 14 days 7.39 4.64

As a result of confirming the change in pH according to the formulation of the injection for filler, the liquid formulation was not suitable for use as a filler because the pH decreased over time, whereas the solid injection of Example 2 of the present invention showed the same effect even after 14 days had elapsed. There was little change in pH, confirming the need to secure the formulation through freeze-drying.

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the following claims and their equivalents.

Claims (9)

(a) a step of mixing polydioxanone (PDO) as a biodegradable polymer in an organic solution, wherein the organic solution is HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) 90 including 10 parts by volume and 10 parts by volume of water;
(b) preparing biodegradable polymer microparticles by spray-drying the solution in which the biodegradable polymer is mixed;
(c) preparing a hyaluronic acid hydrogel by adding a crosslinking agent to a first composition containing hyaluronic acid;
(d) preparing a mixed composition by adding the biodegradable polymer microparticles and the hyaluronic acid hydrogel to a second composition containing hyaluronic acid; and
(e) freeze-drying the mixed composition; comprising, a hybrid hydrogel filler manufacturing method.
The method of claim 1, wherein the injection for hybrid hydrogel filler is freeze-dried to form a solid formulation.
delete The method of claim 1, wherein the (b) biodegradable polymer-mixed solution has a concentration of 0.4 to 0.8% (w/v).
The hybrid hydrogel of claim 1, wherein the (b) spray drying is performed by injecting the mixed solution into a spray dryer at 85 to 95° C. at a rate of 0.1 L/hr, and injecting nitrogen gas at a pressure of 4.5 to 5.5 bar. A method for manufacturing an injection for filler.
According to claim 1, wherein (c) the crosslinking agent is butanediol diglycidyl ether (1,4-butandiol diglycidyl ether, BDDE), ethylene glycol diglycidyl ether (ethylene glycol diglycidyl ether, EGDGE), hexanediol diglyc Cydyl ether (1,6-hexanediol diglycidyl ether), propylene glycol diglycidyl ether (propylene glycol diglycidyl ether), polypropylene glycol diglycidyl ether (polypropylene glycol diglycidyl ether), polytetramethylene glycol diglycidyl Ether (polytetramethylene glycol diglycidyl ether), neopentyl glycol diglycidyl ether (neopentyl glycol diglycidyl ether), polyglycerol polyglycidyl ether (polyglycerol polyglycidyl ether), diglycerol polyglycidyl ether (diglycerol polyglycidyl ether), glycerol Polyglycidyl ether (glycerol polyglycidyl ether), trimethylpropane polyglycidyl ether (tri-methylpropane polyglycidyl ether), bisepoxypropoxyethylene (1,2-(bis(2,3-epoxypropoxy)ethylene), pentae A method for producing an injection for a hybrid hydrogel filler, at least one selected from the group consisting of rithritol polyglycidyl ether (pentaerythritol polyglycidyl ether) and sorbitol polyglycidyl ether (sorbitol polyglycidyl ether).
The hybrid hydrogel of claim 1, wherein the (d) mixed composition comprises 4 to 10 parts by weight of the second composition, 85 to 95 parts by weight of biodegradable polymer microparticles, and 1 to 5 parts by weight of hyaluronic acid hydrogel. A method for manufacturing an injection for gel filler.
The method of claim 1, wherein the hybrid hydrogel maintains a pH of 7.2 to 7.6 for 1 to 15 days.
An injection for a filler prepared by the method of claim 1.

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