KR20200004503A - Manufacturing method of composition for filler - Google Patents

Abstract

The present invention relates to a manufacturing method of a composition for a filler, which comprises a vibration compression step of applying vibration to a cross-linked hyaluronic acid gel composition in order to increase viscoelasticity and can extend the duration of an effect at the low cost.

Description

Manufacturing method of filler composition {MANUFACTURING METHOD OF COMPOSITION FOR FILLER}

The present invention relates to a method for producing a composition for filler, and more particularly, to a method for producing a composition for filler including hyaluronic acid (HA).

Filler (Filler) is a substance similar to skin tissue and is used in wrinkle improvement or contour correction by inserting in a specific area and expanding soft tissue, and is also called dermal filler.

These fillers can be classified into two types according to the mechanism of action as follows.

First, it is a filler that directly increases the volume and expands the effect. The main ingredient of the dermal filler is composed of a substance such as collagen or hyaluronic acid.

Secondly, there is a filler that exerts an enlargement effect by inducing a foreign body reaction for a certain period of time or inducing autogenous collagen formation for a certain period of time, as well as a part of directly increasing the volume, such as a crosslinked text box.

As a filler currently used, many products mainly contain collagen and hyaluronic acid, respectively. First of all, collagen-derived skin fillers include EVOLENCE 30 (ColBar LifeScience), pig collagen (Zolder LifeScience), bovine collagen (Zyderm, Zyplast (Inamed)), and human collagen. CosmoDerm and CosmoPlast (Inamed) etc. which are main components are known.

The main ingredients of hyaluronic acid include Rofilan (Rofil / Philoderm), Perlane, Restylane (above Medicis / Q-MedAB), Teosyal (Teoxane SA), Surgiderm (Corneal Laboratoire).

However, the skin fillers based on collagen or hyaluronic acid are expensive, but the duration of the effect is too short, and side effects due to harmful ingredients have been reported.

Therefore, there is a need for a technique for producing a composition for a filler that can extend the duration of the effect at a lower cost.

It is an object of the present invention to provide a method for preparing a composition for a filler which can prolong the duration of the effect at a lower cost.

In addition, it is an object of the present invention to provide a method for producing a composition for filler, which can maintain the viscoelasticity of the filler composition and reduce the amount of crosslinking agent added.

In order to achieve the above object, according to an aspect of the present invention, the vibration compression step of applying a vibration to the cross-linked hyaluronic acid gel composition to increase the viscoelasticity; It provides a method for producing a composition for filler comprising a.

In addition, in the vibration compression step, the cross-linked hyaluronic acid gel composition includes that the vibration is applied for 18 to 22 minutes at 140 to 180 rpm.

In addition, in the vibration compression step, the cross-linked hyaluronic acid gel composition includes that vibration is applied for 20 minutes at 160 rpm.

In addition, the vibration compression step is performed by a vibration device for applying vibration to the crosslinked hyaluronic acid gel composition, the vibration device comprising: a container having a predetermined space to accommodate the crosslinked hyaluronic acid gel composition; A spring support for supporting the container and providing vibration; And a vibrator provided to supply vibration to the spring support for transmitting vibration to the container. It includes.

In addition, the viscoelasticity of the crosslinked hyaluronic acid gel composition after completion of the vibratory compression step includes an increase of 5% to 10% relative to the viscoelasticity of the crosslinked hyaluronic acid gel composition before the vibration compression step.

Also, before the vibration compression step, a bubble removing step; Further comprising a bubble removing step, the grinding step of pulverizing the crosslinked composition obtained in the previous step; And a defoaming step of removing bubbles of the pulverized crosslinked composition to obtain a crosslinked hyaluronic acid gel composition. It includes.

In addition, before the bubble removing step, the first mixing step of stirring and mixing the raw material; A second mixing step of adding a crosslinking agent to the mixed raw materials and stirring and mixing to obtain a raw material mixture; A crosslinking reaction step of crosslinking the raw material mixture to obtain a crosslinked composition; And a dialysis step of removing the unreacted crosslinking agent included in the crosslinked composition; It further includes.

In addition, a raw material contains a sodium hydroxide solution and sodium hyaluronate, and a crosslinking agent contains butanediol diglycidyl ether (1, 4-butandiol diglycidyl ether: BDDE).

In addition, in the crosslinking reaction step, the crosslinking reaction temperature is 22 to 28 degrees (° C.), and the crosslinking reaction time is 12 to 18 hours, including performing a crosslinking reaction.

According to the present invention, since the vibrating compression step can be prepared by adding a smaller amount of the crosslinking agent to prepare a composition for the filler having a higher viscoelasticity, there is an effect that can extend the duration of the effect.

In addition, as the cross-linking agent is reduced, there is an effect that can reduce the dialysis solution and dialysis process for removing the unreacted cross-linking agent.

In addition, as the cross-linking agent is reduced, there is an effect that can reduce the side effects.

1 is a process flowchart of a method for preparing a composition for a filler according to an embodiment of the present invention.
2 is a schematic diagram showing a vibration device according to an embodiment of the present invention.
3 shows measurement results of Example 1, Example 2 and Comparative Example 1 of the present invention.

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings. Prior to this, terms or words used in the present specification and claims should not be construed as being limited to the common or dictionary meanings, and the inventors should properly explain the concept of terms in order to best explain their own invention. Based on the principle that can be defined, it should be interpreted as meaning and concept corresponding to the technical idea of the present invention.

In addition, irrespective of the reference numerals, the same or corresponding components will be given the same or similar reference numerals, and redundant description thereof will be omitted. For convenience of description, the size and shape of each component member may be exaggerated or reduced. Can be.

Therefore, the embodiments described in the specification and the drawings shown in the drawings are only the most preferred embodiment of the present invention and do not represent all of the technical idea of the present invention, various modifications that can be replaced at the time of the present application It should be understood that there may be equivalents and variations.

1 is a process flow diagram of a method for producing a composition for a filler according to an embodiment of the present invention, Figure 2 is a schematic diagram showing a vibration device according to an embodiment of the present invention.

Hereinafter, with reference to FIG. 1 and FIG. 2, the manufacturing method of the composition for filler of this invention is demonstrated in detail.

Referring to Figure 1, the method for producing a composition for filler of the present invention includes the following process steps.

More specifically, in the method for preparing a composition for a filler of the present invention, a first mixing step (S10) of stirring and mixing raw materials, a second mixing step (S20) of adding a crosslinking agent to the mixed raw materials and stirring and mixing to obtain a raw material mixture ), A crosslinking reaction step (S30) of crosslinking the raw material mixture to obtain a crosslinked composition, a dialysis step of removing unreacted crosslinking agent included in the crosslinked composition (S40), a pulverizing step of pulverizing the crosslinked composition, and pulverizing Bubble removal step (S50) comprising a degassing step of removing the bubbles of the crosslinked crosslinked composition to obtain a crosslinked hyaluronic acid gel composition, a vibration compression step of applying a vibration to the crosslinked hyaluronic acid gel composition to increase the viscoelasticity (S60) And a product manufacturing completion step (S70) of completing the product manufacturing.

The first mixing step (S10) is a step of mixing the raw material sodium hydroxide (NaOH) and sodium hyaluronate (Sodium Hyaluronate), the first step of preparing a sodium hydroxide solution, a predetermined amount of the sodium hydroxide solution prepared And a second step of mixing and stirring sodium hyaluronate.

More specifically, the first step is to prepare a sodium hydroxide solution, the sodium hydroxide solution, 3 to 15 parts by weight of sodium hydroxide (NaOH) based on 100 parts by weight of sodium hyaluronate to be added to the second step It can be prepared by subdividing into a beaker of SUS) and dissolving a predetermined amount of water for injection using an impeller mounted on an agitator. The sodium hydroxide (NaOH) may be added in the range of 3 to 15 parts by weight, 4 to 13 parts by weight or 5 to 10 parts by weight with respect to 100 parts by weight of sodium hyaluronate, but is not limited thereto. In addition, the injection amount of the water for injection may be appropriately adjusted by a person skilled in the art according to the amount of sodium hydroxide to be added, for example, may be in the range of 300 to 1500mL or 500 to 1000mL.

In the present specification, the term "parts by weight" may mean a weight ratio between each component.

In addition, the second step is a step of mixing and stirring a predetermined amount of sodium hyaluronate in a sodium hydroxide solution, subdividing sodium hyaluronate into the reaction tank first, and then adding a sodium hydroxide solution, and added to the reactor And stirring to dissolve the sodium hyaluronate completely in the sodium hydroxide solution.

The second mixing step (S20) is a step of adding and stirring a crosslinking agent to the mixed raw materials. The crosslinking agent may include butanediol diglycidyl ether (1,4-Butanediol diglycidyl ether: BDDE). The crosslinking agent may be included in a ratio of 0.1 to 5 parts by weight, or 1 to 3 parts by weight with respect to 100 parts by weight of sodium hyaluronate.

More specifically, the second mixing step (S20) is a step of adding a crosslinking agent to a reaction tank filled with the mixed raw materials, and then stirring to obtain a raw material mixture.

Here, the raw material mixture may mean a raw material of the crosslinked hyaluronic acid gel composition to be described later.

The crosslinking reaction step (S30) is a step of crosslinking the raw material mixture.

More specifically, the crosslinking reaction step (S30), the third step of filling a predetermined amount of the raw material mixture in a tray having a predetermined standard, and the crosslinked composition by putting the tray filled with the raw material mixture in an incubator and crosslinking reaction It includes a fourth step of obtaining a.

Therefore, in the present invention, by sequentially proceeding the crosslinking reaction and dialysis process using the standardized tray, when increasing the production unit of the raw material, only the number of trays to be used in the process is increased, so the manufacturing unit can be easily expanded and the operation is convenient. Can be provided.

Here, the crosslinking reaction temperature is 22 to 28 degrees (° C), the crosslinking reaction time is 12 to 18 hours, it is preferable to perform the crosslinking reaction, more preferably to perform the crosslinking reaction for 25 degrees (℃), 18 hours Do.

After the crosslinking reaction as described above, the final preparation amount is calculated by measuring the weight of the crosslinked composition.

 Here, the crosslinked composition may mean a crosslinked hyaluronic acid gel composition, and the crosslinked hyaluronic acid gel composition means a composition before dialysis and bubbles are removed.

The dialysis step (S40) is a step of removing the unreacted crosslinking agent included in the crosslinked composition, through a fifth process, a fifth process of primary dialysis of the crosslinked composition through a predetermined sodium chloride (NaCl) solution. And a sixth step of secondary dialysis of the cross-dialyzed cross-linked composition through a predetermined diaphragm-containing physiological saline (PBS) solution.

More specifically, in the fifth step, the first step of adding purified water and subdivided sodium chloride into the dialysis vessel and stirring to completely dissolve to produce a sodium chloride solution, and the second step of dialysis of the composition crosslinked in the sodium chloride solution And a third step of repeating the first step and the second step at least two times.

Here, in the first step, it is preferable to add a small amount of sodium chloride in a dialysis vessel together with purified water in a volume ratio of 1: 0.5 to 1: 1.5, and then dissolve it using a stirrer. In one example, the sodium chloride batch may be 25 to 35 L, and may be added to the dialysis vessel within a weight range of 1000 g to 2500 g.

The sixth step is a step of secondary dialysis of the first dialysis of the cross-linked composition through a fifth process, adding the purified water and one serving of PBS raw material to another dialysis vessel and stirring to completely dissolve to produce a PBS solution A first step, and a second step of performing the dialysis of the cross-linked composition first dialyzed in the PBS solution, and a third step of repeating the first step and the second step at least two or more times.

Here, the one-time PBS raw material is a dose prepared by mixing sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, and one-time PBS raw material together with purified water. It is dissolved to prepare a dialysis PBS solution. In the above, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate and sodium chloride may be mixed in a ratio of 20 to 50 parts by weight, 5 to 30 parts by weight and 150 to 250 parts by weight, respectively. have.

In one embodiment, the present application was prepared by mixing 40.32 g of the sodium dihydrogen phosphate dihydrate, 14.72 g of sodium dihydrogen phosphate dihydrate, and 208.0 g of sodium chloride to prepare a PBS raw material. It can be added in the range of 35L to prepare a dialysis PBS solution.

As such, the primary and secondary dialysis according to the present invention provides an advantage of completely eliminating harmful effects to the human body by completely removing the crosslinking agent (BDDE) remaining in the product.

The bubble removing step (S50) includes a grinding step and a defoaming step, wherein the grinding step is a step of pulverizing the crosslinked composition, the defoaming step is to remove the bubbles of the pulverized crosslinked composition crosslinked hyaluronic acid gel It is a process of obtaining a composition.

Here, the crosslinked hyaluronic acid gel composition may refer to a crosslinked composition that has completed dialysis and bubble removal, that is, a crosslinked hyaluronic acid gel composition that has completed dialysis and bubble removal.

More specifically, the bubble removing step (S50), after mixing a predetermined PBS solution to a dialysis cross-linked composition in a predetermined ratio, is a process for performing a fine grinding process through a grinder to remove the bubbles.

The grinding step includes a seventh step of mixing a predetermined PBS solution to a dialysis-completed crosslinked composition in a constant ratio, and an eighth step of pulverizing the mixture prepared through the seventh step through a mill.

In addition, the defoaming step is a step of obtaining a cross-linked hyaluronic acid gel composition by removing the bubbles in the ground mixture through a defoaming machine.

In addition, according to the present invention, in the seventh step of mixing a predetermined PBS solution in a predetermined ratio to the dialysis-crosslinked composition, further adding lidocaine to the predetermined PBS solution, the step of stirring to mix evenly with the PBS solution May be included. Here, the lidocaine may be dissolved in a PBS solution of a predetermined volume. The lidocaine may be added in the range of 2 to 10 parts by weight or 3 to 7 parts by weight based on 100 parts by weight of the PBS raw material.

This is a method for preparing a biomaterial for analgesic tissue repair, and when lidocaine is added as described above, it is possible to prepare a biomolecule for tissue analgesic without tissue pain.

The vibration compression step (S60) is a step of increasing the viscoelasticity by applying a vibration to the cross-linked hyaluronic acid gel composition, it is a step of compacting the cross-linked hyaluronic acid gel composition using a vibration device (10, see FIG. 2).

More specifically, the vibration compression step (S60) is a step performed by the vibration device 10 for applying vibration to the cross-linked hyaluronic acid gel composition, the vibration device 10 is a container 100, a spring support ( 200 and vibrator 300.

In particular, the crosslinked hyaluronic acid gel composition, the crosslinked hyaluronic acid gel composition, may be subjected to vibration for 18 to 22 minutes at 140 to 180 rpm, more preferably at 160 rpm, may be applied for 20 minutes.

As described above, the vibration compression step (S60) is a method for compacting the dispersed gel, by applying a cross-linked hyaluronic acid gel composition for 18 to 22 minutes at 140 to 180 rpm, more preferably at 160 rpm for 20 minutes, Due to the oscillation supplied with the pores formed therein, the pores may be reduced, the density may be improved, and the viscoelasticity may be improved.

More specifically, the viscoelasticity of the crosslinked hyaluronic acid gel composition after completion of the vibration compression step may increase by 5% to 10% relative to the viscoelasticity of the crosslinked hyaluronic acid gel composition before the vibration compression step when applying vibration in the aforementioned range. .

That is, since it is possible to prepare a cross-linked hyaluronic acid gel composition having a higher viscoelasticity through the vibration compression step, the gel having improved viscoelasticity has an effect of longer time to maintain the product form.

The container 100 of the vibration device 10 performing the vibration compression step S60 may have a predetermined space to accommodate the crosslinked hyaluronic acid gel composition.

In addition, the spring support 200 may support the container 100 and may be provided to transmit vibrations.

In addition, the vibrator 300 may be provided to supply the vibration to the spring support 200 in order to transmit the vibration to the container (100).

Referring to FIG. 2, the vibrator 10 includes a main body 101 in which the vibrator 300 is accommodated.

On the upper portion of the main body 100, a spring support 200 may be provided to support the container 100.

More specifically, the spring support part 200 supports the first support member 210 and the first support member 210 for supporting the container 100 provided to be spaced apart from the main body 101 by a predetermined distance, and the vibrator ( It includes a spring 230 to increase the amount of vibration transmitted from 300.

Here, the container 100 may be disposed to be spaced apart by a predetermined interval in the vertical direction from the central portion of the main body 101.

The spring 220 may be mounted to the second support member 220 extending from the upper portion of the main body 101 to connect the first support member 210 and the main body 101.

In addition, the vibrator 300 may include a vibrating member 310 provided to transmit vibration to the first support member 210.

The vibration member 310 may be connected to the bottom surface of the first support member 210 to transmit vibration to the container 100 from the vibrator 300 generating vibration.

That is, the first support member 210 and the vibrator 300 may be connected by the vibration member 310.

Here, the vibrator 300 may supply vibration in a vertical direction, and may be electrically connected to a power supply device (not shown) that supplies power to the vibrator 300.

Here, the vibrator 300 may be, for example, a motor, and may apply vibration to the crosslinked hyaluronic acid gel composition by adjusting the rpm of the motor.

The operating principle of the vibration device 10 formed as described above is as follows.

First, the bubble removing step (S50) is completed and the prepared crosslinked hyaluronic acid gel composition is filled in the container 100.

Thereafter, when the vibrator 300 is operated to transmit vibration from the vibrator 300 to the vibration member 310, the vibration is supplied to the first support member 210 connected to the vibration member 310.

The vibration supplied to the first support member 210 is transmitted to the container 100, and at this time, by the spring 230 supporting the first support member 210, the supplied vibration is increased to the container 100. Vibration is supplied to the crosslinked hyaluronic acid gel composition filled therein.

As described above, the crosslinked hyaluronic acid gel composition supplied with vibration has a more improved viscoelasticity as the voids formed therein by vibration are reduced and the density is improved.

As described above, the vibration compression step S60 of the present invention may produce a composition having higher viscoelasticity.

In other words, since higher viscoelasticity can be obtained, there is an effect of reducing the amount of crosslinking agent introduced in the second mixing step (S20) to control the viscoelasticity of the hyaluronic acid gel composition.

As described above, as the amount of crosslinking agent is reduced, there is an advantage that can reduce the process of the dialysis step (S40) for removing the unreacted crosslinking agent.

For example, in order to prepare a product 1 having a 250 Pa viscoelasticity, generally, if 2 g of a crosslinking agent is added, the viscoelasticity of 250 Pa is obtained even if 1.8 g of a crosslinking agent is added through the vibration compression step (S60) of the present invention. It is possible to manufacture product 1 having the same.

In addition, in order to manufacture a product 1 having a viscoelasticity of 250 Pa, generally after the addition of 2g of the cross-linking agent, the vibration compression step (S60) of the present invention, the product 1 has a viscoelasticity of 280 Pa, It will be possible to manufacture products that take longer to maintain their shape.

In addition, the product manufacturing step (S70), the cross-linked hyaluronic acid gel composition obtained by completing the vibration compression step (S60) is filled in a prefilled syringe (Prefilled Syringe), the high pressure filled prefilled syringe It is a process to sterilize and sterilize through steam sterilizer to increase the stability of the product by completely killing the germs that may occur during the manufacture of the product in the final process.

Hereinafter, the present invention will be described in more detail with reference to examples according to the present invention and comparative examples not according to the present invention, but the scope of the present invention is not limited to the following examples.

Production Example  1: Complete the bubble removing step (S50) Crosslinked  Preparation of Hyaluronic Acid Gel Composition

Inject 800 mL of water for injection into a sterilized measuring cylinder, subdivide 8 g of sodium hydroxide into a beaker of sus material, add 800 mL of water for injection, and install an impeller into the stirrer to add sodium hydroxide to the water for injection. Sodium hydroxide solution was prepared by complete dissolution.

Subsequently, 96 g of sodium hyaluronate was added to the reactor first, followed by adding 800 mL of sodium hydroxide solution, and using a stirrer, sodium hyaluronate was completely dissolved in the sodium hydroxide solution to complete the first mixing step (S10).

Then, the BDDE was added to the reactor to complete the second mixing step (S20) of obtaining a raw material mixture by operating a stirrer for 15 minutes so that the added BDDE was evenly mixed.

Then, the obtained raw material mixture was filled in a tray made of sus (SUS) material and crosslinked for 18 hours at 25 ° C. in an incubator to complete the crosslinking reaction step (S30) to obtain a crosslinked composition.

Then, the dialysis membrane was immersed in purified water of 90 ° C. or higher to activate for 20 minutes. At this time, the PBS solution into which the dialysis membrane is added was prepared by completely dissolving 10.08 g of sodium dihydrogen phosphate, 3.68 g of sodium hydrogen phosphate, and 52.0 g of sodium chloride in 3 L of water for injection using a beaker made of sus material. Was adjusted to 7.0.

Then, 3L of PBS solution was poured into the prepared bed, 5L of water for injection was added, and the activated dialysis membrane was soaked in PBS solution.

Then, the crosslinked composition obtained in the previous step was introduced to prevent bubbles from forming in the dialysis membrane, and both ends of the dialysis membrane were sealed.

Then, 32L of sodium chloride was added to 32L of purified water in a dialysis vessel, and then dissolved completely using a stirrer to prepare a sodium chloride solution. Then, the crosslinked composition put in the dialysis membrane was added to the sodium chloride solution.

Then, after installing the stirrer to fix the impeller, the first dialysis is performed by adjusting the rpm so that the crosslinked composition put into the dialysis membrane is stirred by the impeller, and the dialysis process is repeated to complete the fifth dialysis process. It was.

Thereafter, 40.32 g of sodium monohydrogen phosphate, 14.72 g of sodium dihydrogen phosphate, and 208.0 g of sodium chloride were dissolved together with 32 L of purified water to prepare a dialysis PBS solution, and then the first dialysis-crosslinked composition was prepared using dialysis PBS. Into the solution, and the secondary dialysis is performed by adjusting the rpm so as to be stirred by the impeller, the dialysis process is repeated to complete the sixth process of the second dialysis to remove the unreacted crosslinking agent contained in the crosslinked composition. Dialysis step (S40) was completed.

Through the dialysis step (S40) described above, the dialysis-crosslinked composition was taken out of the dialysis membrane and placed in a filling tank.

At this time, the PBS solution containing the pre-prepared lidocaine was added to the filling tank and stirred for 5 minutes while slowly increasing the rpm of the grinder to 500 to complete the seventh step, and then using a grinder to perform a fine grinding for 25 minutes The eighth process was completed.

In the eighth process, the timer was set to 25 minutes, and the rpm of the grinder was raised to 500, followed by 1 minute, slowly raised to 800 rpm, followed by 1 minute, and then raised to 1100 rpm to grind for the remaining time.

Then, by completing the degassing step of removing bubbles by using a degassing machine, the bubble removing step (S50) was completed to prepare a cross-linked hyaluronic acid gel composition.

The defoaming step may be performed for 40 minutes at 180 rpm after setting the timer to 40 minutes.

Example  One:

(1) Preparation of the crosslinked hyaluronic acid gel composition having completed the vibration compression step (S60)

The crosslinked hyaluronic acid gel composition prepared in Preparation Example 1 was filled in a container (fill tank), and at 160 rpm, a vibration compression step (S60) was performed for 10 minutes.

(2) viscoelasticity measurement

The viscoelasticity of the crosslinked hyaluronic acid gel composition prepared in Example 1 was measured. Viscoelasticity (G ′) was measured under the analytical conditions of Table 1 below using a viscoelasticity measuring instrument (KINEXUS Pro +, Model: KNX2212).

Target temperature 25 ℃ Start frequency 0.01 Hz End frequency 10 Hz Shear strain 1.0% Samples per decade 10

The result is shown in FIG.

As shown in FIG. 3, the viscoelasticity (G ′) of the crosslinked hyaluronic acid gel composition was found to be 193.5 Pa, and the viscoelasticity of Comparative Example 1 was increased by 1.89%.

Example  2:

(1) Preparation of the crosslinked hyaluronic acid gel composition having completed the vibration compression step (S60)

The crosslinked hyaluronic acid gel composition prepared in Preparation Example 1 was filled in a container (filling tank), and a vibration compression step was performed by applying vibration for 20 minutes at 160 rpm using a vibrator.

(2) viscoelasticity measurement

The viscoelasticity of the crosslinked hyaluronic acid gel composition prepared in Example 2 was measured.

Viscoelasticity measurement was measured under the same conditions as in Example 1.

The result is shown in FIG.

As shown in FIG. 3, the viscoelasticity (G ′) of the crosslinked hyaluronic acid gel composition that completed the vibration compression step (S60) was 207.0 Pa, and the viscoelasticity was increased by 9% compared to Comparative Example 1, Example 1 It was confirmed that it has a higher viscoelasticity.

Comparative example  One:

The viscoelasticity of the crosslinked hyaluronic acid gel composition prepared in Preparation Example 1 was measured. Viscoelasticity measurement was measured under the same conditions as in Example 1.

The result is shown in FIG.

As shown in FIG. 3, the viscoelasticity (G ′) of the crosslinked hyaluronic acid gel composition which was not subjected to the vibration compression step was found to be 189.9 Pa.

10: vibration device
100: container
200: spring support
300: vibrator

Claims (9)

A vibration compression step of applying vibration to the crosslinked hyaluronic acid gel composition to increase viscoelasticity; Method for producing a composition for filler comprising a. The method of claim 1,
In the vibration compression step,
The cross-linked hyaluronic acid gel composition, the vibration is applied for 18 to 22 minutes at 140 to 180 rpm, the method for producing a composition for filler. The method of claim 2,
In the vibration compression step,
The crosslinked hyaluronic acid gel composition is a vibration method is applied for 20 minutes at 160rpm, the method for producing a composition for filler. The method of claim 2,
Vibration compression stage,
Performed by a vibrating device for applying vibration to the crosslinked hyaluronic acid gel composition,
Vibration device,
A container having a predetermined space to receive the crosslinked hyaluronic acid gel composition; A spring support for supporting the container and providing vibration; And a vibrator provided to supply vibration to the spring support for transmitting vibration to the container. A method for producing a composition for filler comprising a. The method of claim 2,
The viscoelasticity of the crosslinked hyaluronic acid gel composition after completion of the vibration compression step is 5% to 10% increase compared to the viscoelasticity of the crosslinked hyaluronic acid gel composition before the vibration compression step. The method of claim 1,
Prior to the vibration compression step, a bubble removing step; Additionally contains
Bubble removal step,
Pulverizing the finely divided crosslinked composition obtained in the previous step; And
Defoaming step of removing bubbles of the ground crosslinked composition to obtain a crosslinked hyaluronic acid gel composition; A method for producing a composition for filler comprising a. The method of claim 6,
Prior to the bubble removal step,
A first mixing step of stirring and mixing the raw materials;
A second mixing step of adding a crosslinking agent to the mixed raw materials and stirring and mixing to obtain a raw material mixture;
A crosslinking reaction step of crosslinking the raw material mixture to obtain a crosslinked composition; And
A dialysis step of removing the unreacted crosslinking agent included in the crosslinked composition; Further comprising, Method for producing a composition for filler. The method of claim 7, wherein
The raw material contains a sodium hydroxide solution and sodium hyaluronate,
The crosslinking agent contains butanediol diglycidyl ether (1, 4-butandiol diglycidyl ether: BDDE), The manufacturing method of the composition for fillers. The method of claim 7, wherein
In the crosslinking reaction step,
The crosslinking reaction temperature is 22 to 28 degrees (° C.), the crosslinking reaction time is 12 to 18 hours, to perform the crosslinking reaction, a method for producing a composition for a filler.

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