KR20170123099A - Dermal Filler Composition Containing Polycaprolactone And Hyaluronic Acid - Google Patents

Abstract

The present invention relates to a skin filler composition containing polycaprolactone and hyaluronic acid. When the skin filler composition containing a) polycaprolactone microspheres as a filler main component and b) a hyaluronic acid gel as a carrier of the present invention is used, it is possible to obtain advantages of conventional hyaluronic acid fillers such as high biocompatibility, an immediate treatment effect, skin moisturizing properties, and advantages of a conventional polycaprolactone filler which induces the generation of collagen and lasts an effect for a long period of time, and to provide natural and smooth texture as particles are homogeneous, thereby being very useful as a skin filler.

Description

(Dermal Filler Composition Containing Polycaprolactone And Hyaluronic Acid) The present invention relates to a skin filler composition comprising a polycaprolactone and a hyaluronic acid,

The present invention relates to a skin filler composition comprising polycaprolactone and hyaluronic acid.

The structure of the human skin is maintained by an extracellular matrix containing collagen, elastin, etc. and glycosaminoglycan. When a soft tissue defect is caused by external shock, disease, aging, etc. And the shape of the tissue has been restored and corrected by expanding the soft tissues by inserting the biotissue or the synthetic polymer chemical into the site.

At this time, a substance similar to the skin tissue is inserted into a specific site to expand the soft tissue, and the material used for wrinkle correction or contour correction is called a soft tissue augmentation material and is generally called a dermal filler.

The skin filler is a injection-type medical device that replenishes the skin tissue by injecting safe materials into the face dermis layer to improve the wrinkles and to find the volume in the cosmetics. Botulinum toxin (Botox), autologous fat transplantation, Used in so-called anti-aging procedures, including needles, laser treatments, and depigmenting.

The first-generation skin filler developed for the first time is an animal-derived collagen filler, which is manufactured by extracting animal proteins such as cattle and swine, Zyderm, Zyplast, and Cosmoderm, which uses human collagen ) And Cosmoplast (Cosmoplast). However, the duration of the effect after the procedure is as short as 2 to 4 months, and it is not practiced recently because of the cumbersome task of performing a skin irritation test before the procedure.

The second-generation skin filler is a hyaluronic acid filler, which is a product of Hylaform, which uses hyaluronic acid derived from rooster, Restylane, which uses hyaluronic acid produced by bacteria ( Streptococcus equi ), and Juvederm Juvederm). Hyaluronic acid filler has longer duration of effect than collagen filler and is composed of polysaccharide which is similar to human constitutional component, so it does not require skin reaction test like collagen filler because side effects such as skin hypersensitivity are remarkably low, Of the total.

Particularly, hyaluronic acid is easy to perform and remove, has excellent viscoelasticity, and attracts 214 water molecules per molecule, thereby maintaining the moisture of the skin, maintaining the volume and elasticity of the skin, . However, since it is gradually absorbed into the human body and the holding time is relatively short as 6-12 months, it is troublesome to repeatedly perform it every 6-12 months. Recently, studies have been actively conducted to increase the particle size and molecular weight by inducing cross-linking of hyaluronic acid to prolong the duration.

The third-generation filler is a synthetic filler, which is made of polylactic acid (ScLptra), polymethylmethacrylate (PMMA), and trade name Artecoll, a product of polylactic acid (PLLA) Radiesse, a product of Calcium Hydroxyapatite, and Ellanse, a product of Polycaprolactone (PCL). Since the synthetic filler is not decomposed or slowly decomposed in the human body, it is evaluated and used as a semi-permanent filler as compared with collagen and hyaluronic acid filler which are absorbent fillers.

Polycaprolactone (PCL), which is used as a component of composite filler, is a synthetic polymer material, but it is a safe ingredient absorbed 100% in human body. It is slow in absorption after transplantation in the skin and promotes collagen production, It has the advantage of lasting for 2-3 years with a soft texture. However, after the procedure, the carboxymethylcellulose (CMC) gel carrier injected with the polycaprolactone was absorbed into the body, resulting in a temporary decrease in the volume for 3-4 days to 4 weeks, which was recovered after 6-8 weeks, It is disadvantageous that the satisfaction of the procedure is lower than that of the hyaluronic acid filler which shows the effect.

Accordingly, it is necessary to develop a new filler such as synthetic collagen and hyaluronic acid filler, which has a high biocompatibility and exhibits an immediate treatment effect, and maintains the effect of the treatment for a long time, such as a composite material filler.

Korean Patent No. 1356320 discloses a skin filler composition comprising a hyaluronic acid gel containing pluracetate microparticles as an active ingredient.

Republic of Korea Patent Publication No. 2011-0137907 discloses a hydroxyapatite beads, Bio-glass beads, calcium carbonate beads, titanium dioxide beads, barium sulfate (BaSO ₄₎ beads, alumina (Al ₂ O ₃₎ beads, zirconia (ZiO ₂₎ bead and And an anionic polymer is adsorbed or covalently bonded to the surface of the same ceramic bead.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have tried to develop a new filler which has a high biocompatibility such as collagen or hyaluronic acid filler of the prior art and exhibits an immediate treatment effect and maintains the effect of the treatment for a long time like a synthetic material filler. As a result, it was found that when the polycaprolactone was used as a main component of the filler and hyaluronic acid was used as a carrier, the effect of the filler treatment was maintained for a long period of time while the biocompatibility was high and the volume did not decrease immediately after the procedure. .

Accordingly, an object of the present invention is to provide a filler composition for skin comprising (a) polycaprolactone microspheres as a filler main component and (b) a hyaluronic acid gel as a carrier.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a filler composition for skin comprising (a) polycaprolactone microspheres as a filler main component and (b) a hyaluronic acid gel as a carrier.

As used herein, the term "polycaprolactone" is a biodegradable polyester having a molecular weight of about 21 kDa, a density of 1.145 g / cm ³ , and a melting point of about 60 ° C. Polycaprolactone is a biodegradable substance that is degraded when the ester bond is hydrolyzed under physiological conditions such as in the human body. However, polycaprolactone is a biodegradable material that can be transplanted for a long time because of its very low decomposition rate, a drug delivery system (DDS) (Trade name: Monocryl), and biocompatible materials for tissue engineering.

As used herein, the term "microsphere" refers generally to spherical small particles having a diameter of 1-1000 mu m.

The microspheres of the present invention may be wholly spherical, spherical or incomplete spherical, and the surface may be entirely smooth or partially protruding.

As a result of studies on the size of polycaprolactone particles that can exert the best effects in clinical application, the present inventors have found that when the polycaprolactone particles are smaller than 25 탆, occlusion of blood vessels may occur, and when they are larger than 100 탆 It was confirmed that the main input (needle jam, etc.) could occur when injected with a syringe. Thus, the polycaprolactone microspheres contained as an active ingredient in the composition of the present invention may have a diameter of 25-100 mu m, specifically 25-95 mu m, more specifically 25-85 mu m, 25-75 mu m , But are not necessarily limited thereto.

The content of the polycaprolactone microspheres is 10-50 wt%, specifically 20-40 wt%, based on the total weight of the composition, but is not limited thereto.

As used herein, the term "carrier" refers to a filler composition that is prepared using a syringe. In general, when a main component of a filler (e.g., collagen, hyaluronic acid, polycaprolactone) , Which means that the filler is mixed with the main component of the filler to provide fluidity to the filler as a whole. Such a carrier has fluidity and must also be viscous so that the powder particles, which are the principal components of the filler, remain in the form and remain dispersed during injection into the skin.

As used herein, the term "hyaluronic acid" is a natural polymer material having disaccharide repeating units bonded to glucuronic acid and acetylglucosamine, which are present in many skin areas of animals and the like, and includes hydrophilic substances having a large number of hydroxyl groups it means. Hyaluronic acid acts as a moisturizing effect in the skin of animals such as humans, and is contained in cosmetics and the like, and regulates various physiological functions by reacting with CD44 protein expressed in various epithelial cells. Hyaluronic acid is classified as cross-linked hyaluronic acid and non-cross linked hyaluronic acid depending on whether it is cross-linked. The higher the cross-linking ratio of hyaluronic acid, the higher the molecular weight and biodegradability And the hydrogel is formed and becomes viscoelastic.

Hyaluronic acid has been used as a main component of a skin filler composition due to its excellent biocompatibility, biodegradability and viscoelasticity, but it has been disadvantageous in that it is absorbed into the body 6 months to 1 year after the procedure and the effect of wrinkle improvement and the like disappear.

In addition, carboxymethylcellulose (CMC) is used as a carrier in the case of a conventional commercialized polycaprolactone filler (Elance), and after 6 to 8 weeks of treatment, the polycaprolactone component is converted into collagen The effect of the carboxymethylcellulose carrier is absorbed into the body for 3 to 4 weeks after the procedure and the volume is temporarily reduced.

On the other hand, the filler composition of the present invention can be produced by using a hyaluronic acid gel carrier containing (i) a crosslinked hyaluronic acid or (ii) a mixture of crosslinked hyaluronic acid and non-crosslinked hyaluronic acid, instead of the carboxymethyl cellulose carrier, There is a special feature that the beauty effect lasts for 2-3 years immediately after the procedure without decreasing the volume.

According to an embodiment of the present invention, the non-crosslinked hyaluronic acid is used in an amount of 0.1-10% by weight, specifically 0.5-8% by weight, more specifically 0.5-5% by weight, based on the total weight of the hyaluronic acid gel carrier. , 1-5 wt%, 1-4 wt%, 1-3 wt%, or 1-2 wt%, and the crosslinked hyaluronic acid is 0.1-10 wt%, specifically 0.5-8 wt% May be 0.5-5 wt%, 1-5 wt%, 1-4 wt%, 1-3 wt%, or 1-2 wt%, but is not limited thereto.

The total content of the non-crosslinked hyaluronic acid and the crosslinked hyaluronic acid in the composition of the present invention may vary depending on the content ratio of the non-crosslinked hyaluronic acid and the crosslinked hyaluronic acid, and is generally, based on the total weight or volume of the composition of the present invention 0.1 to 10%, specifically 0.1 to 8%, more specifically 0.1 to 5%, 0.1 to 3%, 0.1 to 8%, 0.5 to 3%, or 1 to 3% to be. The% concentration can be (weight / weight)%, (weight / volume)%, (volume / volume)%.

In the composition of the present invention, the hyaluronic acid gel carrier may additionally contain glycerin.

The content of glycerin may be 10-50 wt%, specifically 20-40 wt%, more specifically 20-30 wt%, based on the total weight of the hyaluronic acid gel, but is not limited thereto.

The polycaprolactone microspheres, which are the main components of the composition of the present invention, are prepared through a process comprising the steps of:

(i) the temperature on the sol Sensitivity  To the aqueous polymer solution Polycaprolactone  Particle Dissolving  step

First, to prepare an aqueous solution of the matrix, which is a thermosensitive polymer, the thermosensitive polymer is dissolved in distilled water at 20 to 25 ° C. After confirming that the thermosensitive polymer is completely dissolved in distilled water, the polymer matrix is formed and heated to a hydrogel form and stirred. When the polymer is in the form of a hydrogel, stirring is stopped and the polymer aqueous solution is transferred to an ice bath and allowed to stand for 2 minutes to make a sol state again.

The aqueous solution of the thermosensitive polymer matrix according to the present invention can be prepared by mixing 10 to 30 parts by weight of the thermosensitive polymer with respect to 100 parts by weight of the water-soluble solvent.

The thermosensible polymer which can be used in the present invention is a thermoplastic resin such as a polyethylene oxide-polypropylene oxide copolymer, a polyethylene oxide-polylactic acid copolymer, a polyethylene oxide-polylactic glycolic acid copolymer, a polyisopropylacrylamide And the like.

When a polyethylene oxide-polypropylene oxide copolymer is used as the thermosensitive polymer, a pluronic series (F87, F127, P65, P85, P105; manufacturer: BASF) or a Poloxamer series (manufacturer: ICI) , And most specifically, Pluronic F127. In the case of Pluronic F127, it has a phase transition temperature range of 26 DEG C or lower at sol and 26-65 DEG C gel phase.

(ii) the compound prepared in step (i) Polycaprolactone -Temperature Sensitivity  The aqueous polymer solution Gel  step

The pulverized polycaprolactone is put into an aqueous solution of a thermosensitive polymer matrix in a sol state prepared in the step (i) to prepare a polymer matrix-polycaprolactone mixture. Thereafter, the mixture is stirred while raising the temperature, so that the polycaprolactone polymer particles are uniformly dispersed in the polymer matrix aqueous solution on the sol, and a polymer matrix is formed in the mixture to form a hydrogel state.

The polycaprolactone, which may be used in the present invention, may be pulverized by any method conventionally used in filler compositions, including freezing and pulverizing.

The particle size of the pulverized polycaprolactone is 25-100 mu m in diameter, specifically 25-95 mu m, more specifically 25-85 mu m, or 25-75 mu m, but is not limited thereto.

(iii) Gelling  The temperature formed in step Sensitivity  Within the polymer matrix Polycaprolactone  Melting the particles to form spherical microspheres

When it was confirmed that the polymer matrix-polycaprolactone mixture was stirred while raising the temperature to become a hydrogel state, the stirring was stopped, the temperature was raised to 60-65 ° C, and the temperature was maintained for 30 minutes to allow the polycaprolactone polymer particles to react with the polymer matrix structure So as to form a stable spherical microspheres.

(iv) Sensitivity  Step of removing the polymer matrix

To the polycaprolactone mixture, distilled water at a low temperature (for example, 4 ° C) is added and transferred to an ice bath, followed by stirring to allow the thermosensitive polymer matrix to be in a sol state. Next, the mixture is centrifuged at a low temperature to allow the thermosensitive polymer to precipitate and separate into the supernatant and the supernatant, and the supernatant is discarded to remove the thermosensible polymer. The remaining temperature sensitive polymer is washed and the precipitated polycaprolactone microspheres are filtered with 10 μm filter paper, then further washed with distilled water, washed with NaOH aqueous solution and finally washed with distilled water. The washed polycaprolactone microspheres are dried and sterilized to be used as the main component of the filler composition of the present invention.

The distilled water and the aqueous NaOH solution are used to remove impurities and endotoxins that may remain in the produced polycaprolactone microspheres. In addition to the above methods, Any method for drying and sterilizing the above-mentioned polycaprolactone microspheres can be used, and all the methods for drying and sterilizing particles in the field related to the present invention can be used, and the method is not limited thereto .

The hyaluronic acid gel as a carrier of the composition of the present invention is prepared through a process comprising the following steps.

(i) adding hyaluronic acid to the water-soluble solvent Dissolve  Step of preparing aqueous solution of hyaluronic acid

I) crosslinked hyaluronic acid, or ii) non-crosslinked hyaluronic acid and crosslinked hyaluronic acid are mixed in a water-soluble solvent such as a phosphate buffered saline to prepare a hyaluronic acid aqueous solution.

The hyaluronic acid that can be used in the present invention includes all crosslinked / unbonded hyaluronic acid commonly used in a filler composition, regardless of the form of powder, granule, aqueous solution or gel, and in the case of crosslinked hyaluronic acid, Is not limited. According to one embodiment of the present invention, the non-crosslinked hyaluronic acid is in the form of a powder, and the crosslinked hyaluronic acid is in the form of a gel, but is not limited thereto.

(ii) mixing glycerin into the hyaluronic acid aqueous solution prepared in the step (i)

The hyaluronic acid aqueous solution and the glycerin prepared as above were autoclaved separately at 121 ° C for 20 minutes, and then sterilized hyaluronic acid aqueous solution and glycerin were uniformly mixed to prepare the hyaluronic acid gel carrier of the present invention .

In step (i), the non-crosslinked hyaluronic acid may be used in an amount of 0.1-10% by weight, specifically 0.5-8% by weight, more specifically 0.5-5% by weight, more preferably 1-5-5% by weight based on the total weight of the hyaluronic acid gel carrier 1-4 wt%, 1-3 wt%, or 1-2 wt%, and the crosslinked hyaluronic acid is 0.1-10 wt%, specifically 0.5-8 wt%, more specifically 0.5-5 wt% 1-5 wt%, 1-4 wt%, 1-3 wt%, or 1-2 wt%, based on the total weight of the composition.

 In the step (ii), the content of the glycerin may be 10-50 wt%, specifically 20-40 wt%, more specifically 20-30 wt%, based on the total weight of the hyaluronic acid gel, no.

The inventors of the present invention have studied about the combination of hyaluronic acid and glycerin which can exert the optimum effect in clinical application. As a result, in step (ii), the hyaluronic acid aqueous solution and glycerin are separately sterilized by high- When sterilized, discoloration occurred in the hyaluronic acid gel, confirming that it was not suitable as a filler.

The skin filler composition of the present invention has excellent properties because the effect of the filler treatment is maintained for a long period with polycaprolactone, which induces the production of collagen upon injection into the skin, as a main component.

In addition, the skin filler composition of the present invention is suitable as a carrier since it has excellent viscoelasticity and high biocompatibility. Unlike the carboxymethyl cellulose carrier used in conventional polycaprolactone filler products, the skin filler composition has an advantage in that the volume does not decrease immediately after the procedure have.

According to an experimental example of the present invention, the polycaprolactone microspheres as a main component of the composition of the present invention were observed by scanning electron microscopy (SEM), and it was found that spherical homogeneous One particle. Therefore, the filler composition of the present invention provides a natural and smooth texture on the skin without the occlusion of blood vessels or the lowering of injector main input upon injection into the skin.

Therefore, the composition of the present invention has advantages of conventional hyaluronic acid filler such as high biocompatibility, immediate treatment effect, skin moisturizing ability, and collagen production, and has advantages of long-lasting effect of the polycaprolactone filler, Is homogeneous and provides a natural and smooth texture, so it can be very useful as a skin filler.

The features and advantages of the present invention are summarized as follows:

The present invention provides a skin filler composition comprising (a) polycaprolactone microspheres as a filler main component and (b) a hyaluronic acid gel as a carrier.

When the skin filler composition comprising a) the polycaprolactone microspheres as the filler main component and the hyaluronic acid gel as the carrier (b) of the present invention is used, the advantages of conventional hyaluronic acid fillers such as high biocompatibility, And the conventional polycaprolactone filler, which induces the production of collagen for a prolonged period of time. However, since the particles are homogeneous and provide a natural and smooth texture, they can be very useful as a skin filler.

1 shows the results of observation of the polycaprolactone microspheres of the present invention with a scanning electron microscope (SEM).

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Throughout this specification, "%" used to denote the concentration of a particular substance is intended to include solids / solids (wt / wt), solid / liquid (wt / The liquid / liquid is (vol / vol)%.

Example 1: Preparation of Polycaprolactone Microsphere of the Present Invention

1. Selection of polycaprolactone particles (25-75 μm)

Polycaprolactone (PCL), a polymer particle, was prepared by first preparing polycaprolactone (manufactured by VORNIA BIOMATERIALS) using a freezing mill (model name: Freezer / Mill 6870D; manufacturer SPEX) cycle (1 cycle / min). The freeze-pulverized polycaprolactone was selected from only 25-75 μm polycaprolactone particles using a vibratory sieve shaker (model name: analysette 3; manufactured by FRITSCH).

2. Preparation of Pluronic F127 Polymer Matrix

20 g of Pluronic F127 (manufacturer: Sigma Aldrich) was added to 100 ml of distilled water at 20 to 25 ° C to prepare a thermotropic polymeric polymer matrix, and the mixture was stirred at 180 rpm until dissolved . Confirming that the pluronic F127 was completely dissolved in the distilled water, the temperature was raised to 30 DEG C and stirring was continued at 180 rpm. When the aqueous solution of Pluronic F127 forms a polymer matrix and becomes a hydrogel form, the stirring is stopped and transferred to an ice bath and allowed to stand for 2 minutes. When the pluronic F127 gel in the ice bath was again in the sol state, the temperature was lowered to 7 ° C while stirring at 150 rpm.

3. Preparation and separation of polycaprolactone microspheres

1 g of 25-75 쨉 m polycaprolactone, which was freeze-pulverized in 1, was added to an aqueous solution of pluronic F127 in a sol form prepared in 2 above to prepare a pluronic F127-polycaprolactone mixture. Then, 180 and the temperature was raised to 26 캜 with stirring at rpm so that the polycaprolactone polymer particles were uniformly dispersed in the polymer matrix aqueous solution on the sol. When Pluronic F127 forms a polymer matrix at 26 DEG C in the above-mentioned pluronic F127-polycaprolactone mixture to become a hydrogel state, stirring is stopped, the temperature is raised to 60-65 DEG C, and the temperature is maintained for 30 minutes, The lactone polymer particles were melted in the Pluronic F127 polymer matrix structure to form stable spherical microspheres.

50 ml of distilled water at 4 캜 was added to the polycaprolactone mixture, and the mixture was transferred to an ice bath and stirred at 250 rpm for 30 minutes so that the pluronic F127 was in a sol state. Next, the mixture was centrifuged at 4 ° C for 2 minutes at 1000 rpm, so that the pluronic F127 was precipitated in the supernatant liquid in a sol state, and the produced polycaprolactone microspheres were precipitated and separated. The supernatant was discarded and the remaining pluronic F127 was washed with 4 째 C distilled water and centrifuged at 4 째 C and 1000 rpm for 2 minutes. The supernatant was discarded and the precipitated polycaprolactone microspheres were filtered through a 10 μm filter paper, washed with distilled water three times, and then washed twice with 0.1 N NaOH and three times with distilled water to remove endotoxin. The washed polycaprolactone microspheres were vacuum dried at 35 DEG C for 4 hours, and the polycaprolactone microspheres of the present invention were prepared by sterilizing the polycaprolactone microspheres by gamma irradiation.

Example 2: Preparation of hyaluronic acid gel carrier of the present invention

Linked hyaluronic acid gel (cross-linked hyaluronic acid gel; manufactured by: Takara Shuzo Co., Ltd.) at a concentration of 20 mg / ml was added to 40.2 g of 1X phosphate buffer solution (Phosphate Buffered Saline, PBS) containing 1.8 g of hyaluronic acid powder Freda) were added and stirred to prepare a hyaluronic acid aqueous solution.

Hyaluronic acid aqueous solution and 18 g of glycerin (manufacturer: Sigma Aldrich) manufactured by the above composition were separately autoclaved at 121 ° C for 20 minutes under high pressure steam, and sterilized hyaluronic acid aqueous solution and glycerin were mixed uniformly, Of hyaluronic acid gel carrier was prepared.

Example 3: Preparation of the polycaprolactone filler composition of the present invention

The polycaprolactone microspheres prepared in Example 1 and the hyaluronic acid gel carriers prepared in Example 2 were uniformly mixed at a weight ratio of 3: 7 to prepare the polycaprolactone filler composition of the present invention.

Experimental Example . The Polycaprolactone Microsphere  Scanning electron microscope observation

The polycaprolactone microspheres prepared in Example 1 were observed under a condition of 1.50 kV X600 by Scanning Electron Microscopy (SEM).

The results are shown in Fig.

As shown in Fig. 1, the polycaprolactone microspheres of the present invention were found to be spherical uniform particles having a diameter in the range of 25-75 mu m.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

(a) polycaprolactone microspheres as a filler main component and (b) a hyaluronic acid gel as a carrier.
The skin filler composition according to claim 1, wherein the polycaprolactone microspheres have a diameter of 25-100 mu m.
The skin filler composition according to claim 1, wherein the content of the polycaprolactone microspheres is 10-50 wt% based on the total weight of the composition, and the content of the hyaluronic acid gel is 50-90 wt% .
The skin filler composition of claim 1, wherein the hyaluronic acid gel comprises (i) crosslinked hyaluronic acid, or (ii) a mixture of crosslinked hyaluronic acid and non-crosslinked hyaluronic acid.
The skin filler composition according to claim 4, wherein the hyaluronic acid gel further comprises glycerin.
The skin filler composition according to claim 4, wherein the non-crosslinked hyaluronic acid is 0.1-10 wt% based on the total weight of the hyaluronic acid gel, and the crosslinked hyaluronic acid is 0.1-10 wt%.
The skin filler composition according to claim 5, wherein the glycerin is 10-50 wt% based on the total weight of the hyaluronic acid gel.
The method of claim 1, wherein the polycaprolactone microspheres
(i) dissolving polycaprolactone particles in an aqueous solution of a thermosensitive polymer on a sol;
(ii) gelatinizing the aqueous solution of the polycaprolactone-thermosensitive polymer prepared in the step (i);
(iii) melting the polycaprolactone particles in the thermosensitive polymer matrix formed in the gelling step (ii) to form spherical microspheres; And
(iv) removing the thermosensitive polymer matrix. The skin filler composition of claim 1,
The method of claim 8, wherein the thermosensitive polymer is selected from the group consisting of polyethylene oxide-polypropylene oxide copolymer, polyethylene oxide-polylactic acid copolymer, polyethylene oxide-polylactic glycolic acid copolymer, polyisopropylacrylamide, By weight or more, based on the total weight of the composition.
The skin filler composition according to claim 8, wherein the aqueous solution of the thermosensitive polymer matrix is prepared by mixing 10 to 30 parts by weight of the thermosensitive polymer with respect to 100 parts by weight of the water-soluble solvent.
The skin filler composition according to claim 8, wherein the thermosensitive polymer matrix in step (iv) is solubilized by removing the gelled polymer matrix.
The method of claim 1, wherein the hyaluronic acid gel
(i) dissolving hyaluronic acid in a water-soluble solvent to prepare a hyaluronic acid aqueous solution; And
(ii) mixing glycerin into the hyaluronic acid aqueous solution prepared in the step (i).
13. The skin filler composition according to claim 12, wherein the water-soluble solvent is a phosphate buffered saline.

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