KR102430642B1 - Dermal filler composition and method for manufacturing thr same - Google Patents

Abstract

A filler composition and a method for making the same are disclosed. The preparation method of the filler composition includes a stirring product preparation step of mixing a viscosity modifier and collagen with phosphate buffered saline and stirring to make a stirred product; A mixing step of creating a mixture by adding cross-linked dextran and phosphate buffered saline to the stirring; and a denaturation inducing step of inducing denaturation of the collagen contained in the mixture.

Description

Filler composition and its manufacturing method TECHNICAL FIELD

The present disclosure relates to a filler composition and a method for making the same.

Conventionally, when a defect occurs in the soft tissue constituting the human skin due to impact or aging, a procedure for restoring or correcting the shape by injecting a skin filler composition into the corresponding area and expanding the soft tissue has been performed.

When the skin filler composition is injected into the dermal layer of the face, it improves skin wrinkles and improves the volume and elasticity of the skin, so these compositions are widely used for facial wrinkles relief and facial contouring. In this regard, Korean Patent Application Laid-Open No. 10-2011-0137907 discloses a technology for a filler composition for filling the skin.

A conventional filler composition is injected into the skin through an injection needle. If the viscosity of the filler composition is too high, it may be difficult to inject with a thin injection needle, and it may cause discomfort to the patient when injected into the skin, or injection. There was a problem that the operator applied excessive force when pushing the syringe pusher as the required extrusion force increased, causing discomfort during injection.

The technical idea of the present disclosure is to solve the above problems, and an object of the present disclosure is to provide a technique for preparing a filler composition that is easy to inject even with a syringe having a fine needle thickness.

In addition, the technical idea of the present disclosure is another object to provide a technology for preparing a filler composition that can relieve the discomfort of the patient due to pain during injection.

And, another object of the technical idea of the present disclosure is to provide a technique for preparing a filler composition that is easily injected into the skin even with a small force during injection.

In addition, another object of the present disclosure is to provide a technique for manufacturing a filler composition having excellent physical properties while increasing the efficiency of the process by simplifying the manufacturing process of the filler composition.

In addition, another object of the present disclosure is to provide a technique for preparing a filler composition capable of stably maintaining its original shape in the body while having a low level of viscosity.

The problems to be solved by the present invention are not limited to the above problems, and other technical problems not mentioned will be clearly understood by those of ordinary skill in the art to which the present invention belongs from the following description.

In one embodiment of the present invention in order to achieve this object, a method for preparing a filler composition comprises a swelling step of swelling the cross-linked dextran; A filtering step of filtering the cross-linked dextran swollen in the swelling step; A stirring step of mixing and stirring phosphate buffered saline with the dextran filtered in the filtering step; Mixing a viscosity modifier and collagen with phosphate buffered saline and stirring to prepare a stirred product; A mixing step of mixing the cross-linked dextran, which has undergone the filtering step and the stirring step, with the stirring material and phosphate buffered saline to make a mixture; and a denaturation inducing step of inducing denaturation of collagen contained in the mixture, wherein the mixture made in the mixing step is composed of cross-linked dextran, carboxymethyl cellulose, collagen and phosphate buffered saline.

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And, the manufacturing method of the filler composition is a control step of adjusting the pH of the mixture made in the mixing step to a certain range; and a defoaming step of removing air bubbles remaining in the mixture made in the mixing step.

On the other hand, in the step of preparing the stirred material, polymethyl methacrylate may be further added to make the stirred material.

In addition, in the denaturation induction step, the collagen contained in the mixture may be heat-denatured into gelatin by heating.

And, the method of manufacturing the filler composition further includes a filling step of filling the syringe with the mixture defoamed in the defoaming step, wherein the syringe in the filling step may be provided as a prefilled syringe.

As another embodiment of the present invention in order to achieve this object, the filler composition may be prepared by the method for preparing the filler composition described above.

Means for solving the above-described problems are merely exemplary, and should not be construed as limiting the present invention. In addition to the exemplary embodiments described above, there may be additional embodiments described in the drawings and detailed description.

As described above, according to various embodiments of the present invention, the following effects are obtained.

First, since the viscosity of the filler composition is maintained at a low level, there is an advantage of convenient injection even with a thin needle.

Second, when injecting the filler composition, the injection force required for injection is small, so it is easy for the operator to move the syringe pusher, so the injection of the filler composition into the skin is easy and convenient to use.

Third, since the filler composition can be gently injected into the skin during injection, the injection can be performed without causing pain or discomfort to the patient receiving the injection.

Fourth, since the sterilization of each component included in the filler composition and the denaturation of collagen contained in the mixture are performed simultaneously, the manufacturing process is simplified compared to the process in which the sterilization process and the denaturation process are performed separately, thereby reducing the time required for the process and improving workability There is an effect of improving process efficiency. Moreover, according to various embodiments of the present invention, it is possible to prepare a filler composition having the characteristics of an elastic body with low viscosity but high elasticity through the denaturation induction step in which all components are sterilized and collagen is denatured at the same time. It is easy to maintain the shape stably, and the viscosity is low, so it has the advantage of convenient injection into the body.

Effects according to various embodiments of the present invention are not limited to the above-mentioned effects, and other effects not mentioned will be clearly understood by those skilled in the art from the description of the claims.

1 is a flowchart illustrating a method of manufacturing a filler composition according to an embodiment of the present invention.
FIG. 2 is a graph showing the time-dependent storage modulus of a filler composition according to Example 2 and a filler composition according to Comparative Example 3 calculated and schematically illustrated.
FIG. 3 is a graph showing the time-dependent tangent delta values of the filler composition according to Example 2 and the filler composition according to Comparative Example 3 of the present invention calculated and schematized.

A preferred embodiment of the present invention will be described in more detail with reference to the accompanying drawings, but already known technical parts will be omitted or compressed for the sake of brevity of description.

It should be noted that references herein to “one” or “an” embodiment of the invention are not necessarily to the same embodiment, and they mean at least one.

In the following embodiments, terms such as first, second, etc. are used for the purpose of distinguishing one component from another, not in a limiting sense.

In the following examples, the singular expression includes the plural expression unless the context clearly dictates otherwise.

In the following embodiments, terms such as include or have means that the features or components described in the specification are present, and the possibility that one or more other features or components may be added is not excluded in advance.

In the drawings, the size of the components may be exaggerated or reduced for convenience of description. For example, since the size and thickness of each component shown in the drawings are arbitrarily indicated for convenience of description, the present invention is not necessarily limited to the illustrated bar.

In cases where certain embodiments are otherwise practicable, a specific process sequence may be performed different from the described sequence. For example, two processes described in succession may be performed substantially simultaneously, or may be performed in an order opposite to the order described. That is, each step of the method described herein can be suitably performed in any order unless otherwise stated in the specification or clearly contradicted by context.

A method of manufacturing a filler composition according to an embodiment of the present invention will be described according to the flowchart shown in FIG. 1, and will be described with reference to the remaining drawings, but for convenience, the description will be given in order.

1. Swelling step <S101>

In this step, a process of swelling the cross-linked dextran may be performed. In the present specification, cross-linked dextran means that produced by cross-linking dextran. In one embodiment, the weight average molecular weight of the cross-linked dextran may be applied to 10000-20000 g/mol, but is not limited thereto, and cross-linked dextran can be prepared with molecular weights of various sizes. In addition, depending on implementation, cross-linked dextran may be prepared by directly cross-linking uncross-linked dextran, or it is also possible to use a commercially available cross-linked dextran product (eg, DEAE-Sephadex A-50). do.

According to one embodiment, in this step, 3-6 parts by weight of cross-linked dextran is mixed with 350-450 parts by weight of water for injection, and the cross-linked dextran can be swollen by stirring at 120 RPM at a temperature of 25° C. for 3-4 hours. have. In addition, the content of water for injection, temperature conditions, stirring speed, and stirring time during swelling of the cross-linked dextran are not limited to the above-described examples and may be appropriately changed according to circumstances. And, in one embodiment, the water for injection may be applied to water in which toxins (remnants) of microorganisms are removed from sterile distilled water (or sterile purified water). In another embodiment, water for injection may be applied as distilled water or purified water, and in another embodiment, water for injection may be applied as ultrafiltration of purified water using a reverse osmosis membrane, ultrafiltration membrane, or a manufacturing system combining these membranes.

As a specific example of this step, the content of the cross-linked dextran may be provided in 3 parts by weight, 4 parts by weight, 5 parts by weight or 6 parts by weight. In addition, the content of the cross-linked dextran may be in the range of at least one of the above values and less than or equal to one of the above values.

For example, the content range of the crosslinked dextran may be provided in a range of 3 parts by weight to 5 parts by weight, 4 parts by weight to 6 parts by weight, 5 parts by weight to 6 parts by weight, or 3 parts by weight to 6 parts by weight. The cross-linked dextran according to an embodiment may maintain the physical properties of the filler composition at an excellent level within the above range.

If the cross-linked dextran is added in less than 3 parts by weight, the tissue repair ability of the filler composition may be reduced, and if the cross-linked dextran exceeds 6 parts by weight, the viscosity of the filler composition increases and the extrusion force during injection may increase. Therefore, the content of the cross-linked dextran is preferably carried out within the above-described range.

2. Filtering step <S102>

In this step, it is possible to filter the swollen dextran in step S101. For example, in this step, a rubber gasket is attached between the Buchner funnel and the Erlenmeyer flask to prevent air leakage, put filter paper on the Buchner funnel, and vacuum the inside of the Erlenmeyer flask using a vacuum pump. When the swollen dextran is put into the inside of the Buchner funnel after making, the moisture that is not absorbed inside the swollen dextran can be removed by moving to the lower side of the funnel by pressure.

3. Stirring step <S103>

In this step, the first phosphate buffered saline may be mixed with the dextran filtered in step S102 and stirred. When stirring in this step is completed, dextran (ie, cross-linked dextran) can be recovered from the first phosphate buffered saline and stored separately. And, in one embodiment, the first phosphate buffered saline may be applied as a buffer solution containing sodium chloride, potassium chloride, potassium dihydrogen phosphate, sodium monohydrogen phosphate and water for injection. In one embodiment, the first phosphate buffered saline is mixed with 8 to 80 parts by weight of sodium chloride, 0.2 to 2 parts by weight of potassium chloride, 0.2 to 2.5 parts by weight of potassium dihydrogen phosphate, and 1.4 to 15 parts by weight of sodium monohydrogen phosphate in water for injection, It can be prepared directly by adding water for injection so that the total weight is 1000 parts by weight, or it is possible to use commercially available phosphate buffered saline.

According to one embodiment, in this step, after recovering the filtered dextran, it may be mixed with 400 to 500 parts by weight of the first phosphate buffered saline and stirred at a temperature of 25° C. at 120 RPM for 1 to 2 hours. In addition, in this step, the content and temperature conditions of the phosphate buffered saline, the stirring speed and the stirring time are not limited to the above-described examples and may be appropriately changed according to circumstances.

And, depending on the implementation, when this step is finished, the filtering step and the stirring step may be repeatedly performed. In one embodiment, after this step is completed, the filtering step, the stirring step, the filtering step, and the stirring step may be repeated in the order.

4. Agitated material preparation step <S104>

In this step, the viscosity modifier and collagen can be mixed with the second phosphate buffered saline and stirred to make a stirred product. Since this step is performed separately from the swelling step, the filtering step or the stirring step, it may be carried out before the swelling step, before the filtering step, or before the stirring step, or it may be carried out simultaneously with the swelling step, the filtering step or the stirring step.

In this step, the second phosphate buffered saline may be applied as a buffer solution of the same component as the first phosphate buffered saline, and 40-50 parts by weight of the second phosphate buffered saline may be added.

In one embodiment, the viscosity modifier may be applied as carboxymethyl cellulose. As a specific example of this step, the content of the viscosity modifier may be provided in 0.1 parts by weight, 0.2 parts by weight, or 0.3 parts by weight. In addition, the content of the viscosity modifier may be in the range of at least one of the above values and less than or equal to one of the above values.

For example, the content range of the viscosity modifier may be provided in a range of 0.1 parts by weight to 0.2 parts by weight, 0.2 parts by weight to 0.3 parts by weight, or 0.1 parts by weight to 0.3 parts by weight. The viscosity modifier according to an embodiment may maintain the physical properties of the filler composition at an excellent level within the above range.

If the viscosity modifier is added in less than 0.1 parts by weight, the viscosity of the filler composition is too low, so it may not maintain its original shape and spread easily when injected into the body. If the viscosity modifier exceeds 0.3 parts by weight, the viscosity of the filler composition The content of the viscosity modifier is preferably carried out within the above-described range because there is a risk of increasing the extrusion force during injection and causing pain.

Also, in one embodiment, the collagen may be applied as atelocollagen. In this step, the content of collagen may be provided in the range of 0.2 parts by weight, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight or 2 parts by weight. Collagen according to an embodiment may maintain the physical properties of the filler composition at an excellent level within the above range.

If the amount of collagen is less than 0.2 parts by weight, it may be difficult to adjust the viscosity of the filler composition to a level that is easy to inject at the time of injection. , since there is a risk of increasing the manufacturing cost, the content of collagen is preferably carried out within the above-mentioned range.

According to one embodiment, in this step, the viscosity modifier and collagen may be mixed with the second phosphate buffered saline and stirred at a temperature of 70 to 80° C. at 120 RPM for 2 to 3 hours. In addition, the temperature conditions, the stirring speed, and the stirring time in this step are not limited to the above-described examples and may be appropriately changed according to circumstances.

Meanwhile, according to another embodiment, in this step, 0.5 to 2 parts by weight of polymethyl methacrylate (for example, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight or 2 parts by weight) is additionally added to make a stirred material. can

5. Mixing step <S105>

In this step, triphosphate buffered saline may be added to the cross-linked dextran that has been passed through step S103 and the stirred water that has been passed through step S104, and stirred to make a mixture. In this step, a mixture can be prepared by stirring at a temperature of 25° C. at 120 RPM for 1 to 2 hours. Of course, the above-described temperature conditions, stirring speed, and stirring time are not limited to the above-described examples and may be appropriately changed according to circumstances.

In addition, in this step, the third phosphate buffered saline may be applied as a buffer solution of the same component as the first phosphate buffered saline, and the content of the third phosphate buffered saline may be appropriately adjusted so that the total amount of the mixture is 100 parts by weight. can That is, the third phosphate buffered saline may be added by the remaining amount after subtracting the content of the cross-linked dextran that has been passed through step S103 and the stirred product that has gone through step S104 from 100 parts by weight. For example, in this step, the third phosphate buffered saline may be added in an amount of 40 to 55 parts by weight.

6. Adjustment step <S106>

In this step, the pH of the mixture made in step S105 may be adjusted to a certain range. For example, in this step, the pH of the mixture may be adjusted by adding a 1-4M sodium hydroxide solution to the mixture so that the final pH of the mixture is 6-8.

7. Defoaming step <S107>

After step S106, a process of removing air bubbles remaining in the mixture may be performed in this step. In one embodiment, it is possible to remove the bubbles in the mixture by a reduced pressure defoaming method using a vacuum pump.

8. Filling step <S108>

After step S107, in this step, the defoamed mixture may be filled in a syringe. In one embodiment, the syringe may be applied as a prefilled syringe.

9. Degeneration induction step <S109>

After step S108, in this step, a process for inducing denaturation of collagen included in the mixture may be performed. Specifically, in this step, the collagen contained in the mixture may be heat-denatured into gelatin by heating. For example, in this step, the collagen is denatured by heating the syringe at a constant temperature (for example, 110 to 130° C.) and a pressure range (1.2 to 3 kgf/cm 2 ) for 15 to 20 minutes, and the mixture component filled in the syringe (ie, cross-linked dextran, viscosity modifier, collagen, and phosphate buffered saline) can be sterilized together.

Hereinafter, the present invention will be described in more detail through specific examples. Since the following examples are merely examples to help the understanding of the present invention, the scope of the present invention is not limited or limited thereto.

Preparation of filler composition

The cross-linked dextran (1) was weighed at the content (unit: g) shown in Table 1, mixed with 400 ml of water for injection, and stirred at a temperature of 25 ° C. at 120 RPM for 3 to 4 hours to swell the cross-linked dextran. After that, a rubber gasket is combined between the Buchner funnel and the Erlenmeyer flask to prevent air leakage, put filter paper on the Buchner funnel, and vacuum the inside of the Erlenmeyer flask using a vacuum pump. Filtering was performed to remove moisture from the dextran by putting the dextran into the inside of the Buchner funnel. The filtered dextran was recovered, mixed with 400 ml of phosphate buffered saline, and stirred at a temperature of 25° C. at 120 RPM for 1 to 2 hours. After the stirring was completed, the filtering and stirring processes were repeated twice again.

Meanwhile, prepare the viscosity modifier (2) and collagen (3) at the contents (unit: g) shown in Table 1, mix the viscosity modifier and collagen with 40 g of second phosphate buffered saline and 120 RPM at a temperature of 70 to 80 ° C. was stirred for 2 to 3 hours to make a stirred product. Thereafter, the cross-linked dextran, which had undergone the filtering and stirring process, was mixed with agitated material and triphosphate buffered saline, and stirred at a temperature of 25° C. at 120 RPM at 120 RPM for 1 to 2 hours to make a mixture. At this time, the content of the third phosphate ringworm physiological saline was added so that the total amount of the entire mixture was 100 parts by weight. Then, 4M sodium hydroxide solution was added to the mixture so that the pH of the mixture was 6-8. Thereafter, air bubbles in the mixture were removed using a vacuum pump, and the defoamed mixture was filled in a syringe. A syringe filled with the mixture was heat-treated for 15 minutes under a temperature of 121° C. and a pressure of 1.2 kgf/cm 2 , and denaturation of collagen contained in the mixture was induced to complete the preparation of the filler composition.

division Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 1) cross-linked dextran 3 4.67 6 3 2 7 2) Viscosity modifier 0.3 0.21 0.1 0.2 0 0.4 3) Collagen 2 0.2 0.5 One 0 3

Preparation of Comparative Example 3

Except for replacing collagen with gelatin, the filler composition was prepared in the same manner as in Example 2.

Determination of collagen content of filler composition

The collagen content of Examples 1 to 4 and Comparative Examples 1 to 3 prepared in the following order was measured, and the measured results are shown in Table 2 below.

① Take a 1g sample, add 1mL 35v/v% HCl, mix, and completely hydrolyze at 100℃.

② Neutralize with NaOH.

③ Measure the content of hydroxyproline using an amino acid analyzer.

④ The collagen content is obtained by multiplying the measured hydroxyproline value by 100/13.5. When the derived collagen content is 5 or less, it was evaluated that there is no collagen content in consideration of the noise value.

division Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Collagen content doesn't exist doesn't exist doesn't exist doesn't exist doesn't exist doesn't exist doesn't exist

As shown in Table 2, in Examples 1 to 4 and Comparative Example 2, it was confirmed that the content of hydroxyproline contained only in collagen was not detected because the collagen contained in the mixture was denatured into gelatin through the denaturation induction step. can

viscosity evaluation

Viscosity at 25° C. (spindle 64, 20 rpm) was measured using a Brookfield viscometer, and the results are described in Table 3 below. In Table 3, the unit of the viscosity value is cP (Centi poise).

division Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 viscosity 14800 11400 12600 14300 10700 15500 14300

As shown in Table 3, Examples 1 to 4 have a viscosity in the range of 11400 to 14800 cP, whereas Comparative Example 1 has a relatively low viscosity compared to Examples, and the formulation of the filler composition is close to a liquid, so that when injected into the body It is unsuitable for use as a filler composition because there is a risk of it spreading or flowing easily from the site, and Comparative Example 2 requires excessive force from the operator when injecting into the body due to too high viscosity, which makes injection difficult and inconvenient. It can be seen that it is lowered compared to the examples.

extrusion force measurement

The extrusion force of the filler composition was measured using a universal testing machine (UTM). Filler compositions for each Example and Comparative Example are filled in a syringe, and a 27G 1/2-inch needle is mounted on the syringe, and then the value is measured when the syringe pusher is pushed at a speed of 50 mm/min, and the results are shown in Table 4 below. described.

division Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Extrusion force (Mpa) 0.049 0.033 0.035 0.041 0.030 0.075 0.052

As shown in Table 4, Examples 1 to 4 exhibit an extrusion force in the range of 0.033 to 0.049 Mpa, whereas Comparative Example 2 has an excessively high extrusion force value, which makes injection inconvenient for the operator and patient It can be seen that there is a risk of causing pain, so it is not suitable for use as a filler composition.

Viscoelasticity measurement

The rheological properties of each sample were measured using a rotary rheometer (Anton Paar MCR 702). The analysis conditions of the rheometer are as follows.

- Fixture (geometry): 25mm parallel plate

- Test condition: oscillation

(1) time sweep: strain 0.2%, frequency 1Hz, 250s

(2) frequency sweep: strain 0.2%, frequency 0.01~100Hz

- Sub check run condition

(1) strain(amplitude) sweep: strain 0.1~1.0%, frequency 1.58Hz(10rad/s)

In addition, storage modulus (elastic modulus, G'), loss modulus (G''), and tangent delta (tan δ) values of each sample were measured, and the results are shown in FIGS. 2 and 3 . Here, tangent delta is defined as loss modulus/storage modulus, and at a frequency of 1 Hz, the closer the tangent delta value to 1, the lower the elasticity, and the closer to 0, the higher the elasticity.

Figure 2 is a graph schematically showing the time-dependent storage modulus of elasticity of the filler composition according to Example 2 and Comparative Example 3 of the filler composition according to Example 2 of the present invention, and Figure 3 is the filler composition according to Example 2 of the present invention and Comparative Example It is a graph plotted by calculating the tangent delta value for each hour of the filler composition according to 3 . Referring to FIG. 2 , it can be seen that the hourly G' value of Example 2 at 1 Hz is lower than that of Comparative Example 3, so that Example 2 has relatively fluidity than the filler composition of Comparative Example 3. Referring to FIG. 3 , since the tangent delta value of Example 2 is close to 0 at 1 Hz, Example 2 can be interpreted as an elastomer with high elasticity.

Therefore, it can be seen that Example 2 in which collagen is heat-denatured has excellent formulation stability because it has elasticity despite lower viscosity and extrusion force compared to Comparative Example 3 containing gelatin. In general, the lower the viscosity, the better the formulation. There is a concern that the filler composition may easily spread or move to other parts when injected into the skin as it gets closer to this liquid, but in Example 2, it does not flow around or spread easily, so it is less likely to move, but the original shape can be continuously maintained, so formulation stability is improved. It is possible to prepare an excellent filler.

As described above, according to various embodiments of the present invention, since the viscosity of the filler composition is maintained at a low level, there is an advantage of convenient injection even with a thin needle.

In addition, when injecting the filler composition, the injection force required for injection is reduced, so it is easy for the operator to move the syringe pusher, so the injection of the filler composition into the skin is easy and convenient to use.

And, since the filler composition can be gently injected into the skin during injection, the injection can be performed without causing pain or discomfort to the patient receiving the injection.

In addition, since the sterilization of each component included in the filler composition and the denaturation of collagen contained in the mixture are performed simultaneously, the manufacturing process is simplified compared to the process in which the sterilization process and the denaturation process are performed separately, thereby reducing the time required for the process and improving the workability There is an effect of improving process efficiency. Moreover, according to various embodiments of the present invention, through the denaturation induction step in which all components are sterilized and collagen is denatured at the same time, a filler composition having the characteristics of an elastic body with low viscosity but high elasticity can be prepared. It is easy to maintain a stable shape and has a low viscosity, so it is convenient to inject into the body.

And, according to various embodiments of the present invention, since a pre-filled syringe capable of pre-filling the filler composition in the syringe is used, the contents are contaminated or external to the vial method in which the undiluted solution for injection is put in an ampoule and extracted with a syringe. It can prevent foreign substances from entering.

In the present invention, when collagen is denatured in a mixed state with other components, the viscosity and extrusion force of the filler composition are lowered to facilitate injection, and it is characterized for the first time that a filler composition with excellent formulation stability can be prepared. have. That is, the present inventors have found that when the denaturation of collagen is induced during the manufacturing process, the viscosity of the filler composition is lowered, so that a certain level of elasticity can be secured while the extrusion force is low at the time of injection, so that the filler composition does not flow or disperse, so that the formulation stability is excellent. It was found that it exhibits properties, and the technology for producing a filler composition was completed using this. In particular, this characteristic is due to the induction of heat denaturation of collagen in a mixed state with other ingredients, and the extrusion force is lower than that of a filler composition prepared by simply adding gelatin, so injection is convenient and formulation stability is excellent. It was found that

As described above, the detailed description of the present invention has been made by the embodiments with reference to the accompanying drawings, but since the above-described embodiments have only been described with preferred examples of the present invention, the present invention is limited only to the above embodiments It should not be understood as being, and the scope of the present invention should be understood as the following claims and their equivalents.

Claims (7)

a swelling step of swelling the cross-linked dextran;
A filtering step of filtering the cross-linked dextran swollen in the swelling step;
A stirring step of mixing and stirring phosphate buffered saline with the dextran filtered in the filtering step;
Mixing a viscosity modifier and collagen with phosphate buffered saline and stirring to prepare a stirred product;
A mixing step of mixing the cross-linked dextran, which has undergone the filtering step and the stirring step, with the stirring material and phosphate buffered saline to make a mixture; and
A denaturation inducing step of inducing denaturation of collagen contained in the mixture;
The mixture made in the mixing step is characterized in that it consists of cross-linked dextran, carboxymethyl cellulose, collagen and phosphate buffered saline.
A method for preparing a filler composition. delete According to claim 1,
The method for preparing the filler composition is
adjusting the pH of the mixture made in the mixing step to a certain range; and
Defoaming step of removing air bubbles remaining in the mixture made in the mixing step; characterized in that it further comprises
A method for preparing a filler composition. According to claim 1,
In the step of preparing the stirred material, polymethyl methacrylate is further added to make the stirred material.
A method for preparing a filler composition. According to claim 1,
In the denaturation induction step, the collagen contained in the mixture is heat-denatured into gelatin by heating.
A method for preparing a filler composition. 4. The method of claim 3,
The method for preparing the filler composition is
A filling step of filling a syringe with the mixture defoamed in the defoaming step; further comprising, wherein in the filling step, the syringe is provided as a prefilled syringe
A method for preparing a filler composition. A filler composition prepared by the method according to any one of claims 1, 3, 4, 5 and 6.

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