Composition of water-soluble polymer filler comprising biodegradable polymer microparticles and manufacturing method thereof

Abstract

Disclosed in the present invention are a composition of water-soluble polymer filler comprising biodegradable polymer microparticles, which is in an independent formulation, reduces a reconstitution time, and improves an abnormal injection force, thus improving convenience in use.

Description

Composition of water-soluble polymer filler containing biodegradable polymer microparticles and method for producing the same

[0001] The present invention relates to a composition of a water-soluble polymer filler including biodegradable polymer microparticles and a method for producing the same, and more particularly, to the development of a formulation in which a sodium hyaluronate aqueous solution and biodegradable polymer microparticles exist independently and are mixed before use, for the purpose of improving the long hydration process and injection force of a freeze-dried formulation in which hyaluronic acid and a biodegradable polymer are mixed, thereby increasing the convenience of use.

[0002] The current plastic surgery trend is a growing preference for simpler, injectable methods over traditional surgical methods. Injectable methods offer advantages such as simple procedures and lower costs compared to surgery. Among these, injectable methods using polymer fillers are attracting particular attention.

[0003] Fillers are used to fill sagging or wrinkled areas of the skin, filling in the gaps and achieving a visual improvement. These fillers are categorized by their active ingredients. Hyaluronic acid currently accounts for 90% of the filler market. Hyaluronic acid is a safe substance found in the human body's synovial fluid and cartilage, and its inherent volume helps maintain skin volume.

[0004] Next, fillers that have recently gained much attention are those using biodegradable polymers. These ingredients function by inducing collagen production as the polymer biodegrades after injection, restoring and maintaining skin volume. Biodegradable polymers include polylactic acid (PLA), polyglycolic acid (PLGA), and poly-ε-caprolactone (PCL).

[0005] Polylactic acid (PLA), a type of biodegradable polymer, is divided into poly-L-lactic acid (PLLA) and poly-D,L-lactic acid (PDLLA), which forms a racemic structure. Poly-D,L-lactic acid (PDLLA) has the characteristic of having a shorter biodegradation time than poly-L-lactic acid (PLLA) because it does not form a crystal structure.

[0006] Representative products containing biodegradable polymer particles and water-soluble polymers include Juvelook ® , Vaim) is a freeze-dried product for the purpose of tissue repair biomaterial filled in a glass vial. In order to inject it into the human body using a syringe, it must go through a process of reconstitution by adding saline solution or distilled water. However, due to the nature of the freeze-dried formulation, it takes time to dissolve, and there is a risk of product contamination due to long-term exposure, and there is a problem of low usability, such as continuous mixing to prevent polymers from precipitating after reconstitution. In addition, since the freeze-dried formulation including the polymer is not completely dissolved, there is a phenomenon in which the injection needle becomes clogged or the injection force increases when injected into the human body. Therefore, the present invention has been completed by developing a technology that can solve this problem.

[0007] [Prior Art Literature]

[0008] [Patent Document]

[0009] (Patent Document 1) Korean Patent No. 10-2587872

[0010] (Patent Document 2) Korean Patent No. 10-1142234

[0011] The inventors of the present invention have developed biodegradable polymer microparticles and water-soluble polymers as independent formulations to improve the long reconstruction time and high injection force abnormality occurrence rate of products containing biodegradable polymer microparticles as their main component, and have attempted to solve this problem. In addition, the inventors of the present invention have developed a composition of a polymer filler capable of overcoming the shortcomings of existing products and producing a strong collagen regeneration effect and a water-gloss effect by using high concentrations of water-soluble polymer and biodegradable polymer microparticles, and have attempted to provide a method for producing the same.

[0012] In order to solve the above problem, the present invention discloses the following means.

[0013] In one aspect, the present invention provides a polymer filler comprising biodegradable polymer microparticles and a water-soluble polymer to solve the above problem, wherein the biodegradable polymer microparticles have an average particle diameter of less than D(50)dl 50 μm, and the biodegradable polymer microparticles in powder form and the water-soluble polymer in liquid form filled in a pre-filled syringe each have independent formulations.

[0014] In another aspect, the present invention provides a method for producing a polymer filler, comprising: (S1) producing biodegradable polymer microparticles in a powder form; (S2) producing a water-soluble polymer in a liquid form; and (S3) filling a liquid water-soluble polymer into a pre-filled syringe so that the biodegradable polymer microparticles and the liquid water-soluble polymer have independent formulations, and filling the powder-form biodegradable polymer microparticles into a vial.

[0015] In another aspect, the present invention provides a filler injection composition comprising biodegradable polymer microparticles and a water-soluble polymer, wherein the biodegradable polymer microparticles have an average particle diameter of D(50)dl less than 50 μm, and the filler injection composition comprises biodegradable polymer microparticles in a powder form and a water-soluble polymer in a liquid state.

[0016] In the last aspect, the present invention provides a method for preparing the filler injection composition, comprising: (S1) a step of preparing biodegradable polymer microparticles in a powder form; (S2) a step of preparing a water-soluble polymer in a liquid state; and (S3) a step of adding and mixing the biodegradable polymer microparticles in a powder form with a water-soluble polymer in a liquid state.

[0017] The polymer filler of the present invention has the advantage of improving the long reconstruction time of the freeze-dried formulation and the occurrence rate of high injection force abnormality, thereby improving contamination and usability.

[0018] Specifically, a manufacturing process can be provided that can shorten the reconstruction time and resolve the phenomenon of needle separation and clogging by setting the content of a water-soluble polymer in an independent formulation and the content and particle size of biodegradable polymer microparticles.

[0019] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0020] Figure 1 is a product image of a biodegradable polymer microparticle and a water-soluble polymer having a manufacturing process and an independent formulation.

[0021] Hereinafter, the present specification will be described in more detail.

[0022] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0023] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0024] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0025] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0026] Expressions such as “comprising” as used herein should be understood as open-ended terms that imply the possibility of including other embodiments.

[0027] The inventors of the present invention, while conducting research to improve the problems of long reconstitution time and high incidence of abnormal injection force due to non-uniform particle size of microparticles in freeze-dried products filled in vials made of glass, confirmed that it is possible to develop an independent formulation that can overcome the shortcomings of existing products by controlling the particle size of biodegradable polymer microparticles and the content of hyaluronic acid, thereby completing the present invention.

[0028] The present invention is described in detail below.

[0029] polymer filler

[0030] The present invention provides a polymer filler as follows.

[0031] Specifically, the present invention provides a polymer filler comprising biodegradable polymer microparticles and a water-soluble polymer, wherein the biodegradable polymer microparticles have an average particle diameter of less than D(50)dl 50 μm, and the biodegradable polymer microparticles in powder form and the water-soluble polymer in liquid form filled in a pre-filled syringe each have independent formulations.

[0032] In the present invention, the term “biodebgradable polymer” means a polymer that is physiologically harmless and is decomposed by enzymatic action within a living body.

[0033] In the present invention, the biodegradable polymer microparticles may be composed of poly-D,L-lactic acid (PDLLA) that forms a racemic structure among polylactic acid (PLA), but are not limited thereto.

[0034] In the present invention, the biodegradable polymer microparticles have an average particle diameter of D(50)dl less than 50 μm, specifically, D(50)dl may be less than 30 μm, specifically, may be 5 μm or more but less than 30 μm, and more specifically, may be 10 μm or more but less than 25 μm, but is not limited thereto.

[0035] In the present invention, the biodegradable polymer microparticles have the advantage of a fast reconstruction time and an improvement in the rate of occurrence of abnormal injection force when the average particle diameter is D(50)dl 10 μm or more and less than 25 μm.

[0036] In the present invention, the term “D(50)dl” means the median value in the diameter size distribution calculated by volume.

[0037] In the present invention, the weight of the biodegradable polymer microparticles may be less than 80 mg / vial, specifically, it may be 20 mg / vial or more but less than 80 mg / vial, and more specifically, it may be 30 mg / vial or more but less than 70 mg / vial, but is not limited thereto.

[0038] In the present invention, the term “water-soluble polymer” means a resin or polymer that can be dissolved in water or dispersed as fine particles in water.

[0039] In the present invention, the water-soluble polymer may be hyaluronic acid or a hyaluronic acid salt, and specifically, may be uncrosslinked hyaluronic acid or a uncrosslinked hyaluronic acid salt (specifically, uncrosslinked sodium hyaluronate), but is not limited thereto.

[0040] In the present invention, the term “non-crosslinked” refers to hyaluronic acid or a hyaluronic acid salt that is not introduced into a crosslinking reaction and is optionally added to the polymer filler according to the present invention, and means an aqueous gel of hyaluronic acid that is not crosslinked or modified, i.e. hyaluronic acid in which the polymer chains are not connected to each other by strong or covalent bonds.

[0041] In the present invention, the term "hyaluronic acid" refers to hyaluronic acid or HA, a biosynthetic natural substance abundantly present in the skin of animals and the like, and known as a hydrophilic substance due to its high content of hydroxyl groups (-OH). Here, hyaluronic acid includes hyaluronic acid, its salts such as physiologically acceptable salts such as sodium salts, potassium salts, zinc salts, and silver salts, its derivatives, and mixtures thereof.

[0042] In the present invention, the weight of the water-soluble polymer in a liquid state may be less than 20 mg / mL, specifically, it may be 1 mg / mL or more but less than 20 mg / mL, and more specifically, it may be 2 mg / mL or more but less than 15 mg / mL, but is not limited thereto.

[0043] In the present invention, the water-soluble polymer may be included in the liquid phase in an amount of 7.5 to 30 mg, but is not limited thereto.

[0044] In the present invention, the weight average molecular weight (Mw) of the water-soluble polymer may be less than 3,000 kDa, specifically, may be 100 kDa or more but less than 3,000 kDa, and more specifically, may be 500 kDa or more but less than 2,000 kDa, but is not limited thereto.

[0045] Specifically, the molecular weight of hyaluronic acid represents the weight average molecular weight (Mw) in Daltons (Da), which is calculated from intrinsic viscosity measurements using the following Mark-Houwink relationship:

[0046] Intrinsic viscosity (m 3 / kg) = 9.78 x 10 -5 x Mw 0.690 .

[0047] In the present invention, the liquid-state water-soluble polymer may be a water-soluble polymer dissolved in saline solution, filled into a pre-filled syringe, and subjected to high-temperature and wet sterilization conditions, but is not limited thereto.

[0048] Filler injection composition comprising biodegradable polymer microparticles and water-soluble polymer

[0049] The present invention provides a filler injection composition comprising biodegradable polymer microparticles and a water-soluble polymer as described below.

[0050] Specifically, the present invention provides a filler injection composition comprising biodegradable polymer microparticles and a water-soluble polymer, wherein the biodegradable polymer microparticles have an average particle diameter of D(50)dl less than 50 μm, and the filler injection composition comprises biodegradable polymer microparticles in powder form and a water-soluble polymer in a liquid state.

[0051] The above-described polymer filler content may be applied to all filler injectable compositions comprising the biodegradable polymer microparticles and water-soluble polymers, unless they are contradictory.

[0052] Method for manufacturing polymer filler

[0053] The present invention provides a method for producing a polymer filler as follows.

[0054] Specifically, the present invention provides a method for manufacturing a polymer filler, comprising: (S1) a step of manufacturing a biodegradable polymer microparticle in a powder form; (S2) a step of manufacturing a water-soluble polymer in a liquid form; and (S3) a step of filling a liquid water-soluble polymer into a pre-filled syringe and filling a powder biodegradable polymer microparticle into a vial so that the biodegradable polymer microparticle and the liquid water-soluble polymer each have independent formulations.

[0055] In the present invention, the step (S1) may include, but is not limited to, the following steps.

[0056] A step of preparing a continuous phase by dissolving polyvinyl alcohol in distilled water;

[0057] A step of preparing a dispersion phase by dissolving a biodegradable polymer in dichloromethane;

[0058] A step of injecting the continuous phase and the dispersed phase into a microchannel-based system;

[0059] A step of producing dichloromethane-biodegradable polymer particles by introducing the dichloromethane-biodegradable polymer recovered from the above system into a polyvinyl alcohol solution having the same concentration as the continuous phase;

[0060] A step of removing dichloromethane from a solution containing the above dichloromethane-biodegradable polymer particles and then precipitating the biodegradable polymer microparticles on a polyvinyl alcohol solution;

[0061] A step of removing and washing the polyvinyl alcohol solution; and

[0062] A step of manufacturing biodegradable polymer microparticles in powder form by vaporizing moisture under vacuum conditions after the above cleaning.

[0063] In the present invention, the step (S2) may be a step of adding sodium chloride to purified water to dissolve it, and then adding a water-soluble polymer to produce a liquid water-soluble polymer, but is not limited thereto.

[0064] In the present invention, the polymer filler is a biodegradable polymer microparticle in powder form and a water-soluble polymer in liquid form filled in a pre-filled syringe, and must be reconstituted before use. In this case, the reconstitution time is within 10 minutes.

[0065] In the present invention, the term “reconstruction” means a process of adding a biodegradable polymer to biodegradable polymer microparticles and homogeneously dissolving and dispersing the same, and “reconstruction time” means the time from the time of adding a biodegradable polymer to biodegradable polymer microparticles until the same is converted into a homogeneous solution state.

[0066] The above-described polymer filler can be applied to all methods for manufacturing the polymer filler, as long as they are not contradictory to each other.

[0067] Method for producing a filler injection composition comprising biodegradable polymer microparticles and water-soluble polymers

[0068] The present invention provides a method for producing a filler injection composition comprising biodegradable polymer microparticles and a water-soluble polymer as described below.

[0069] Specifically, the present invention provides a method for producing a filler injection composition, comprising: (S1) a step of producing biodegradable polymer microparticles in a powder form; (S2) a step of producing a water-soluble polymer in a liquid form; and (S3) a step of adding and mixing the biodegradable polymer microparticles in a powder form with a water-soluble polymer in a liquid form.

[0070] The above-described polymer filler, filler injectable composition containing biodegradable polymer microparticles and water-soluble polymer, and method for producing the polymer filler can all be applied to the method for producing the filler injectable composition containing biodegradable polymer microparticles and water-soluble polymer, unless they are contradictory to each other.

[0071] Hereinafter, the present invention will be described in detail. However, the following examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0072] Example

[0073] Example 1. Preparation of biodegradable polymer microparticles (preparation of poly-D,L-lactic acid microparticles)

[0074] The raw material was prepared by dissolving polyvinyl alcohol (PVA) in distilled water to prepare a continuous phase, and dissolving poly-D,L-lactic acid (PDLLA), a biodegradable polymer, in dichloromethane (DCM) to prepare a dispersed phase. The raw material was injected into a microchannel-based system, and the resulting DCM-biodegradable polymer was collected in a PVA solution having the same concentration as the continuous phase to produce particles (wherein, particles refer to DCM-biodegradable polymers that have been granulated through microchannels). The produced solution was stirred and heated to remove DCM, and the biodegradable polymer collected in the PVA solution was left for a certain period of time to collect the particles precipitated at the bottom (here, the particles refer to poly-D,L-lactic acid particles). In the process of removing the remaining PVA, biodegradable polymer microparticles were precipitated, and the upper solution was removed and filled with distilled water until the PVA concentration became below the standard. In addition, the moisture in the liquid sample after PVA washing was completed was vaporized under vacuum conditions to produce biodegradable polymer microparticles.

[0075] Example 2. Preparation of water-soluble polymer in liquid state

[0076] After dissolving sodium chloride (NaCl) and purified water at a concentration of 0.9% (w / w), 7.5 mg of non-crosslinked sodium hyaluronate having a weight average molecular weight (Mw) of 1,000 kDa (1,000,000 g / mol) was dissolved in 3 mL of sodium chloride aqueous solution to prepare a sodium hyaluronate solution (the weight of the water-soluble polymer in a liquid state is 2.5 mg / mL).

[0077] Example 3. Preparation of water-soluble polymer in liquid state

[0078] After dissolving sodium chloride (NaCl) and purified water at a concentration of 0.9% (w / w), 15 mg of non-crosslinked sodium hyaluronate having a weight average molecular weight (Mw) of 1,000 kDa (1,000,000 g / mol) was dissolved in 3 mL of sodium chloride aqueous solution to prepare a sodium hyaluronate solution (the weight of the water-soluble polymer in a liquid state is 5.0 mg / mL).

[0079] Example 4. Preparation of water-soluble polymer in liquid state

[0080] After dissolving sodium chloride (NaCl) and purified water at a concentration of 0.9% (w / w), 22.5 mg of non-crosslinked sodium hyaluronate having a weight average molecular weight (Mw) of 1,000 kDa (1,000,000 g / mol) was dissolved in 3 mL of sodium chloride aqueous solution to prepare a sodium hyaluronate solution (the weight of the water-soluble polymer in a liquid state is 7.5 mg / mL).

[0081] Example 5. Preparation of water-soluble polymer in liquid state

[0082] After dissolving sodium chloride (NaCl) and purified water at a concentration of 0.9% (w / w), 30 mg of non-crosslinked sodium hyaluronate having a weight average molecular weight (Mw) of 1,000 kDa (1,000,000 g / mol) was dissolved in 3 mL of sodium chloride aqueous solution to prepare a sodium hyaluronate solution (the weight of the water-soluble polymer in a liquid state is 10.0 mg / mL).

[0083] Examples 6-9. Preparation of a filler injection comprising a prefilled syringe filling and a filler injection composition.

[0084] The sodium hyaluronate solutions prepared in Examples 2 to 5 were each filled into a prefilled syringe and sterilized in a high-pressure steam sterilizer to prepare a prefilled injection containing sodium hyaluronate as a main ingredient. The biodegradable polymer microparticles in powder form prepared according to Example 1 were sterilized with EO gas, and 50 mg of the biodegradable polymer microparticles were weighed under aseptic conditions and then filled into each vial.

[0085] Afterwards, a prefilled injection containing a liquid sodium hyaluronate as a main ingredient and a vial containing a powder-type biodegradable polymer microparticle, each having an independent formulation, were mixed and stirred with a vortexer to prepare a filler injection containing a filler injection composition.

[0086] Example 6 Example 7 Example 8 Example 9 Water-soluble polymer Example 2 Water-soluble polymer 7.5 mg Example 3 Water-soluble polymer 15 mg Example 4 Water-soluble polymer 22.5 mg Example 5 Water-soluble polymer 30 mg Biodegradable polymer microparticles (Example 1) 50 mg 50 mg 50 mg 50 mg

[0087] Hereinafter, the present invention will be described in detail. However, the following experimental examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0088] Experimental example.

[0089] Experimental Example 1. Particle Size Evaluation

[0090] In order to confirm the average diameter D(50)dl of the poly-D,L-lactic acid microparticles manufactured according to Example 1 of the present invention, the particle size of the poly-D,L-lactic acid microparticles was evaluated.

[0091] <Confirmation of biodegradable polymer particle size>

[0092] 200 mg of poly-D,L-lactic acid microparticles were added to 10 mL of distilled water, mixed at 5,000 rpm in a vortex, dispersed for 5 minutes in an ultrasonic disperser, and cooled at room temperature for 5 minutes to obtain a test solution. The test solution was then introduced into a particle measuring device, and the particle size was measured under the following conditions to obtain an average value.

[0093] <Analysis Conditions>

[0094] Test equipment: particle counter (Mastersizer 2000)

[0095] Measurement temperature: 25℃

[0096] Stirring speed: 2,500 rpm

[0097] Ultrasonic intensity: 10%

[0098] <Evaluation Results>

[0099] The measurement results for the average diameter D(50)dl of poly-D,L-lactic acid microparticles are as shown in Table 2. Referring to Table 2, the average diameter D(50)dl of poly-D,L-lactic acid microparticles manufactured according to Example 1 of the present invention was confirmed to be within 25 μm.

[0100] Test solution 1 Test solution 2 Test solution 3 Test solution 4 Test solution 5 Average diameter D(50)dl17.58 μm17.57 μm17.58 μm17.58 μm17.59 μm

[0101] Experimental Example 2. Reconstruction Time and Characterization Evaluation

[0102] When poly-D,L-lactic acid microparticles, which are biodegradable polymer microparticles having an independent formulation manufactured according to Examples 6 to 9 of the present invention, and sodium hyaluronate solution, which is a water-soluble polymer solution, were mixed, the properties of the mixture and the reconstruction time and sedimentation time were evaluated to confirm whether they were well mixed.

[0103] <Confirmation of the reconstruction time and properties of the mixture>

[0104] The reconstruction time was confirmed by mixing the poly-D,L-lactic acid microparticles and sodium hyaluronate solution at 5,000 rpm in a Vortex until mixing was complete, and the final mixing properties were visually observed and scored.

[0105] Character Verification Criteria: 3-point scale

[0106] 1 point: Biodegradable polymer microparticles and water-soluble polymers are well mixed.

[0107] 2 points: Biodegradable polymer particles and water-soluble polymers are mixed, but some of the polymers clump together.

[0108] 3 points: Biodegradable polymer particles and water-soluble polymers are not mixed.

[0109] <Check the settling time>

[0110] After mixing poly-D,L-lactic acid microparticles and sodium hyaluronate solution, the mixture was left on a laboratory bench, and the time required for all poly-D,L-lactic acid microparticles to precipitate was measured.

[0111] The results of the confirmation of the properties and the reconstruction time and sedimentation time are as shown in Table 3. As can be seen in Table 3, the reconstruction time of the filler injections manufactured according to Examples 6 to 9 of the present invention is within 3 minutes, which is higher than the commercial product Juvelook. ® ) was confirmed to be mixed within a shorter time than 50 minutes, which is the reconstruction time of the filler, and the properties of the filler injections manufactured according to Examples 6 to 9 of the present invention and the commercially available product Juvelook ® ) had no difference in visual appearance, and the precipitation time of the mixture was 90 minutes or 150 minutes or more for the filler injections manufactured according to Examples 6 to 9 of the present invention, and the commercially available product Juvelook ® ) was confirmed to have a sedimentation time similar to or slower than 120 minutes, which is the sedimentation time of the product.

[0112] Through the results of mixing time and sedimentation time, the filler injections prepared according to Examples 6 to 9 of the present invention were compared with the commercially available product Juvelook. ® ) We were able to confirm the advantages of ease of use due to the short reconstruction time and long sedimentation time.

[0113] Example 6 Example 7 Example 8 Example 9 Juvelook ® Water-soluble polymer Example 27.5 mg Example 315 mg Example 422.5 mg Example 530 mg 7.5 mg Biodegradable polymer microparticles 50 mg 50 mg 50 mg 50 mg 42.5 mg Properties (score) 1 point 1 point 1 point 1 point 1 point Mixing time < 2 minutes < 3 minutes < 3 minutes < 50 minutes Sedimentation time 90 minutes 150 minutes 200 minutes > 200 minutes 120 minutes

[0114] Experimental Example 3. Evaluation of Average Injection Power and Injection Power Anomalies

[0115] Filler injections manufactured according to Examples 6 to 9 of the present invention and Juvelook ® ) to evaluate the injection force abnormality rate, a 33 gauge syringe was connected to the syringe, and the injection force and needle abnormality rate were evaluated.

[0116] <Main Input Evaluation>

[0117] Filler injections and Juvelook prepared according to Examples 6 to 9 of the present invention ® ) A 33 gauge syringe needle was attached to the product, and the injection force was checked until it moved 30 mm at a speed of 13 mm / min, and the average value was obtained.

[0118] <Main Input Anomaly Evaluation>

[0119] Filler injections manufactured according to Examples 6 to 9 of the present invention and commercially available products, such as Juvelook ® ) A 33 gauge syringe needle was attached to the product and 96 experiments were conducted for each concentration. If the injection force was 10 N or more or the syringe and needle were separated and the injection force could not be measured, it was determined that an abnormal injection force phenomenon had occurred.

[0120] <Evaluation Results>

[0121] The results of the average injection force and injection force abnormality are as shown in Table 4. Referring to Table 4, the average injection force and maximum injection force of the filler injections manufactured according to Examples 6 to 9 of the present invention are 2.5 N or less, and the commercially available product Juvelook ® ) of the average injection force and the maximum injection force are 2.0 N or less, and the filler injection agent manufactured according to Examples 6 to 9 of the present invention and the commercial product Juvelook ®) was lower than 10~15N, which is the difficulty that users experience when using the main agent. The rate of occurrence of abnormal phenomena was 2% or less for the filler injections manufactured according to Examples 6 to 9 of the present invention, which is lower than the commercially available product Juvelook ® ) was confirmed to be lower than the abnormal phenomenon occurrence rate of 30.20%.

[0122] Example 6 Example 7 Example 8 Example 9 Juvelook ® Water-soluble polymer Example 27.5 mg Example 315 mg Example 422.5 mg Example 530 mg 7.5 mg Biodegradable polymer microparticles 50 mg 50 mg 50 mg 50 mg 42.5 mg Average injection force 1.38 N 1.69 N 1.46 N 2.21 N 1.26 N Maximum injection force 1.52 N 1.70 N 2.12 N 2.30 N 1.55 N Abnormal phenomenon occurrence rate 1.92% 0% 0.96% 0.96% 30.20%

[0123] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. A polymer filler comprising biodegradable polymer microparticles and water-soluble polymers, The above biodegradable polymer microparticles have an average particle diameter of D(50)dl less than 50 μm, A polymer filler characterized in that the biodegradable polymer microparticles in powder form and the water-soluble polymers in liquid form filled in a prefilled syringe each have independent formulations.

2. In paragraph 1, The above biodegradable polymer microparticles are a polymer filler characterized in that they are composed of poly-D,L-lactic acid (PDLLA) that forms a racemic structure among polylactic acid (PLA).

3. In paragraph 1, The above biodegradable polymer microparticles are polymer fillers having an average particle diameter of D(50)dl less than 30 μm.

4. In paragraph 1, A polymer filler wherein the weight of the biodegradable polymer microparticles is less than 80 mg / vial.

5. In paragraph 1, A polymer filler wherein the water-soluble polymer is hyaluronic acid or a hyaluronic acid salt.

6. In paragraph 1, A polymer filler wherein the weight of the water-soluble polymer in the liquid state is less than 20 mg / mL.

7. In paragraph 1, A polymer filler having a weight average molecular weight (Mw) of the water-soluble polymer of less than 3,000 kDa.

8. In paragraph 1, The above liquid water-soluble polymer is a polymer filler that is prepared by dissolving the water-soluble polymer in saline solution, filling it into a pre-filled syringe, and then subjecting it to high-temperature and wet sterilization conditions.

9. In the manufacturing method of polymer filler, (S1) A step of manufacturing biodegradable polymer microparticles in powder form; (S2) a step of producing a water-soluble polymer in a liquid state; and (S3) A step of filling a liquid-state water-soluble polymer into a pre-filled syringe and filling a powder-type biodegradable polymer microparticle into a vial so that the biodegradable polymer microparticle and the liquid-state water-soluble polymer each have independent formulations; A method for producing a polymer filler according to claim 1, comprising:

10. A filler injection composition comprising biodegradable polymer microparticles and a water-soluble polymer, wherein the biodegradable polymer microparticles have an average particle diameter of D(50)dl less than 50 μm, and the filler injection composition comprises biodegradable polymer microparticles in a powder form and a water-soluble polymer in a liquid state. 11.(S1) Manufacturing step of biodegradable polymer microparticles in powder form; (S2) a step of producing a water-soluble polymer in a liquid state; and (S3) A step of adding biodegradable polymer microparticles in powder form to a water-soluble polymer in a liquid state and mixing them; A method for producing a filler injection composition according to claim 10, comprising:

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