阅读说明：本技术 填充剂组合物及其制备方法 (Filler composition and method of making the same ) 是由 姜敏桂 朴善熙 南中赫 于 2021-07-02 设计创作，主要内容包括：公开了一种填充剂组合物及其制备方法。填充剂组合物的制备方法可以包括将粘度调节剂和胶原蛋白与磷酸盐缓冲生理盐水混合搅拌制成搅拌物的搅拌物制备步骤；在交联的葡聚糖和上述搅拌物中添加磷酸盐缓冲生理盐水制成混合物的混合步骤；以及诱导上述混合物中所含的胶原蛋白变性的诱导变性步骤。(A filler composition and a method for preparing the same are disclosed. The preparation method of the filler composition can comprise a stirring material preparation step of mixing and stirring the viscosity regulator, the collagen and the phosphate buffered saline to prepare a stirring material; a mixing step of adding phosphate buffered physiological saline to the cross-linked dextran and the stirred mixture to prepare a mixture; and a denaturation-inducing step of inducing denaturation of collagen contained in the mixture.)

1. A method of preparing a filler composition, characterized by: a stirring material preparation step of mixing and stirring the viscosity regulator, the collagen and the phosphate buffer normal saline to prepare a stirring material; a mixing step of adding phosphate buffered physiological saline to the cross-linked dextran and the stirred mixture to prepare a mixture; and a denaturation-inducing step for inducing denaturation of collagen contained in the mixture.

2. The process for preparing a filler composition according to claim 1, characterized in that: further comprising a swelling step of swelling the crosslinked glucan; a filtration step of filtering the crosslinked glucan swollen in the swelling step; and a stirring step of mixing and stirring the dextran filtered in the filtering step with phosphate buffered saline.

3. The process for preparing a filler composition according to claim 1, characterized in that: further comprising an adjusting step of adjusting the pH value of the mixture prepared in the mixing step to a certain range; and a defoaming step of removing bubbles remaining in the mixture produced in the mixing step.

4. The process for preparing a filler composition according to claim 1, characterized in that: in the above-mentioned stirred material preparation step, polymethyl methacrylate was further added to prepare a stirred material.

5. The process for preparing a filler composition according to claim 1, characterized in that: in the above-mentioned induced denaturation step, collagen contained in the mixture is thermally denatured into gelatin by heating.

6. The process for preparing a filler composition according to claim 3, characterized in that: also comprises removing the above-mentioned

A filling step of filling the mixture defoamed in the foaming step into a syringe; in the above filling step, a Prefilled syringe (Prefilled syringe) is used as the syringe.

7. A filler composition prepared according to the process of any one of claims 1 to 6.

Technical Field

The invention relates to a filler composition and a preparation method thereof.

Background

In general, when a soft tissue constituting the skin of a human body is damaged due to impact, aging, or the like, a dermal filler composition is injected into the corresponding site to expand the soft tissue, thereby restoring or correcting the shape thereof.

The dermal filler composition has the effects of improving skin wrinkles and improving the cubic effect and elasticity of the skin when injected into the dermis of the face, and thus is widely used for the relief of facial wrinkles, facial contour surgery, and the like. In this regard, Korean laid-open patent publication No. 10-2011-0137907 discloses a technique of a filler composition for skin filling.

The conventional filler composition is injected into the skin through a needle, and if the viscosity of the filler composition is too high, it may be difficult to inject with a thin needle, and further, when it is injected into the skin, it may cause pain to the patient, or the pressing force required for injection becomes large, and when the syringe is injected, the operator needs to exert excessive force and it is not easy to inject.

Disclosure of Invention

The technical idea of the present invention is to solve the above problems, and an object of the present invention is to provide a technique for producing a filler composition that is easily injected even with a syringe using a fine needle.

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

In addition, another object of the technical idea of the present invention is to provide a technique for preparing a filler composition that can be easily injected into the skin with little effort at the time of injection.

Another object of the technical idea of the present invention is to provide a technique for producing a filler composition, which simplifies the production process of the filler composition, improves the process efficiency, and has excellent physical properties.

Meanwhile, another object of the technical idea of the present invention is to provide a technique for producing a filler composition capable of stably maintaining its original form in vivo even at a low viscosity.

The problems to be solved by the present invention are not limited to the above-mentioned problems, and other technical problems not mentioned can be clearly understood from the following by those having ordinary skill in the art to which the present invention pertains.

Technical scheme for solving problems

To achieve this object, as one embodiment of the present invention, a method for preparing a bulking agent composition may include a blender preparation step of mixing and stirring a viscosity modifier and collagen with a phosphate buffered saline to prepare a blender; a mixing step of adding phosphate buffered physiological saline to the cross-linked dextran and the stirred mixture to prepare a mixture; and a denaturation-inducing step of inducing denaturation of collagen contained in the mixture.

The method for producing the filler composition may further comprise a swelling step of swelling the crosslinked glucan; a filtration step of filtering the crosslinked dextran swollen in the swelling step; and a stirring step of mixing and stirring the dextran filtered in the filtering step with phosphate buffered saline.

In addition, the preparation method of the filler composition can also comprise a regulating step of regulating the pH value of the mixture prepared in the mixing step to a certain range; and a defoaming step of removing bubbles remaining in the mixture produced in the mixing step.

In addition, polymethyl methacrylate may be added to prepare a kneaded material in the step of preparing the kneaded material.

In the denaturation-inducing step, collagen contained in the mixture is thermally denatured into gelatin by heating.

The method for producing the filler composition further includes a filling step of filling the mixture defoamed in the defoaming step into a syringe; the syringe in the above filling step may be a pre-filled syringe.

In order to achieve this object, as another embodiment of the present invention, the filler composition may be produced according to the above-described method for producing a filler composition.

The solution to the above problem is only exemplary and should not be construed as limiting the invention. In addition to the exemplary embodiments described above, there may be other embodiments that are set forth in the accompanying drawings and the detailed description of the invention.

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

First, since the viscosity of the filler composition is kept at a low level, there is an advantage in that the injection can be conveniently performed even with a syringe having a thin needle.

Second, since the pressing force required for injection is reduced when injecting the filler composition, the practitioner can easily push the syringe plunger, thereby easily injecting the dermal filler into the skin and facilitating the use.

Third, since the filler composition can be gently injected into the skin at the time of injection, the operation can be performed without causing pain or discomfort to the patient.

Fourthly, since sterilization of various components contained in the filler composition and denaturation of collagen contained in the mixture are simultaneously performed, the manufacturing process is simplified, the time required for the process is reduced, and the processability and process efficiency are improved, compared to a process requiring separate sterilization and denaturation. In particular, according to various embodiments of the present invention, a filler composition having low viscosity but high elasticity elastomer characteristics can be manufactured through an induced denaturation step in which sterilization of all components and denaturation of collagen are simultaneously performed, and thus it is easy to stably maintain the form of the filler composition. In addition, the low viscosity has the advantage of being convenient for injection into the body.

Effects according to various embodiments of the present invention are not limited to the above-described effects, and other effects not mentioned may be clearly understood by a general skilled person from the description of the claims.

FIG. 1 is a flow diagram of a method of making a filler composition according to one embodiment of the present invention;

FIG. 2 is a graph that calculates and plots the storage modulus at different times for the filler composition of example 2 and the filler composition of comparative example 3 according to the present invention;

fig. 3 is a graph in which tan δ values for different times of the filler composition according to example 2 of the present invention and the filler composition of comparative example 3 were calculated and graphed.

Preferred embodiments of the present invention will be described in more detail with reference to the accompanying drawings, but technical parts, which are already well known, will be omitted or compressed for the sake of brevity.

It should be noted that references to "an" or "one" embodiment of the invention in this specification are not necessarily to the same embodiment, but at least to one.

In the following embodiments, the use of the terms 1, 2, etc. is not intended to limit the meaning thereof, but is used to distinguish one technical feature from another.

In the following embodiments, the singular expressions include the plural expressions unless the context clearly dictates otherwise.

In the following embodiments, the terms 'comprising' or 'having' mean that there are features or technical characteristics described in the specification, and do not exclude the additional possibility of one or more other features or technical characteristics being present in advance.

In the drawings, the size of constituent parts may be enlarged or reduced for convenience of description. For example, the dimensions and thicknesses of the various components shown in the figures are arbitrarily labeled for convenience of description, and the present invention is not necessarily limited to the dimensions shown in the figures.

When an embodiment may be implemented differently, the particular sequence of steps may be performed in a different order than that described. For example, two steps described in succession may, in fact, be executed substantially concurrently, or the steps may sometimes be executed in the reverse order, to the order described, i.e., the methods described in the present specification may be executed in any order, unless otherwise indicated herein or otherwise clearly contradicted by context.

The method of preparing a bulking agent composition according to one embodiment of the present invention is illustrated in the flow chart shown in figure 1 and described with reference to the remaining figures. For convenience, the description will be in the order of the foregoing.

1. And a swelling step < S101 >.

In this step, a process of swelling the crosslinked glucan may be performed. In the present specification, the cross-linked glucan refers to a cross-linked glucan produced by cross-linking glucan. In one embodiment, the cross-linked dextran may have a weight average molecular weight of 10000 to 20000g/mol, but is not limited thereto, and the cross-linked dextran may be prepared with various molecular weights of different sizes. In addition, according to embodiments, the crosslinked glucan may be prepared by directly crosslinking uncrosslinked glucan, or using a commercially available crosslinked glucan product (e.g., DEAE-Sephadex A-50).

According to one embodiment, in the present step, 3 to 6 parts by weight of the crosslinked dextran may be mixed with 350-450 parts by weight of water for injection, and stirred at 120RPM for 3 to 4 hours at a temperature of 25 ℃ to swell the crosslinked dextran. The content of water for injection, temperature conditions, stirring speed, and stirring time when the crosslinked dextran swells are not limited to the above examples, and may be appropriately changed depending on the case. Also, in one embodiment, the water for injection may use water from which the microbial toxins (residues) are removed from sterilized distilled water (or sterilized purified water). In another embodiment, the water for injection may be water distilled from drinking water or purified water. In yet another embodiment, the water for injection may be water in which purified water is ultrafiltered using a reverse osmosis membrane, an ultrafiltration membrane, or a manufacturing system in which these membranes are combined.

As a specific example of the present step, the content of the cross-linked dextran may be 3 parts by weight, 4 parts by weight, 5 parts by weight, or 6 parts by weight. Meanwhile, the content of the cross-linked dextran may be one or more of the above values or a range of one or more and less.

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

If the amount of the added crosslinked dextran is less than 3 parts by weight, the tissue repair ability of the filler composition may be reduced, and if the amount of the crosslinked dextran exceeds 6 parts by weight, the viscosity of the filler composition may be increased, and the pressing force at the time of injection may be increased. Therefore, the content of the crosslinked glucan is preferably within the above range.

2. Filtering step < S102 >.

In this step, the glucan swollen in step S101 may be filtered. For example, in this step, a rubber gasket was attached between the buchner funnel and the erlenmeyer flask to prevent air leakage, filter paper was placed on the buchner funnel, the inside of the erlenmeyer flask was evacuated by a vacuum pump, and then swollen dextran was poured into the buchner funnel. At this time, moisture not absorbed into the swollen glucan is moved to the lower side of the funnel by the pressure and removed.

3. And a stirring step < S103 >.

In this step, the dextran filtered in step S102 may be mixed with the first phosphate buffered saline and stirred. After completion of the stirring in this step, dextran (i.e., cross-linked dextran) can be recovered from the first phosphate buffered saline and stored separately. In addition, in one embodiment, the first phosphate buffered saline may be a buffer solution including sodium chloride, potassium dihydrogen phosphate, sodium monohydrogen phosphate, and water for injection. In one embodiment, the first phosphate buffered saline may be prepared by mixing 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 dihydrogen phosphate with water for injection, and the total weight of the first phosphate buffered saline is 1000 parts by weight by itself, or a commercially available phosphate buffered saline may be used.

According to one embodiment, in the present 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 120RPM for 1 to 2 hours at a temperature of 25 ℃. 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 examples, and may be appropriately changed according to the circumstances.

In addition, according to the embodiment, after the completion of this step, the filtration step and the stirring step may be repeated. In one embodiment, after the completion of this step, the filtration step, the stirring step, the filtration step, and the stirring step may be repeated in this order.

4. And a blend manufacturing step < S104 >.

In this step, the viscosity modifier and collagen may be mixed with a second phosphate buffered saline and stirred to form a stirred material. This step is carried out separately from the swelling step, the filtering step or the stirring step, and may be carried out before the swelling step or before the filtering step or before the stirring step, or may be carried out simultaneously with the swelling step, the filtering step or the stirring step.

In this step, a buffer solution having the same composition as that of the first phosphate buffered saline may be used as the second phosphate buffered saline, and 40 to 50 parts by weight of the second phosphate buffered saline may be added.

In one embodiment, the viscosity modifier may use carboxymethyl cellulose. As a specific example of this step, the content of the viscosity modifier may be 0.1 part by weight, 0.2 part by weight, or 0.3 part by weight. The content of the viscosity modifier may be in a range of one or more of the above values or less.

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

If the amount of the viscosity modifier to be added is less than 0.1 part by weight, the viscosity of the filler composition becomes too low, and the filler composition may not be able to maintain its original form and may be easily dispersed when injected into the body. If the viscosity modifier exceeds 0.3 parts by weight, the viscosity of the filler composition increases, and the extrusion force during injection may increase, causing pain. Therefore, the content of the viscosity modifier is preferably within the above range.

Additionally, in one embodiment, atelocollagen may be used for the collagen. In this step, the content of collagen may be prepared 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. The collagen according to one embodiment may maintain the physical properties of the filler composition at an excellent level within the above range.

If the amount of collagen put in is less than 0.2 parts by weight, it may be difficult to adjust the viscosity of the filler composition to a level at which injection is easy at the time of injection. If the collagen is added in an amount exceeding 2 parts by weight, the improvement in physical properties is partially insignificant compared to the amount added, but the manufacturing cost may be increased. Therefore, the content of collagen is preferably within the above range.

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

In another embodiment, the stirred material may be prepared by adding 0.5 to 2 parts by weight (for example, 0.5 part by weight, 1 part by weight, 1.5 parts by weight, or 2 parts by weight) of polymethyl methacrylate to the mixture in the present step.

5. Mixing step < S105 >.

In this step, a third phosphate buffered saline may be added to the cross-linked dextran subjected to step S103 and the stirred material subjected to step S104, and stirred to prepare a mixture. In this step, the mixture can be prepared by stirring at a temperature of 25 ℃ for 1 to 2 hours at 120 RPM. Of course, the temperature conditions, the stirring speed, and the stirring time are not limited to the above examples, and may be appropriately changed depending on the case.

Further, in this step, the third phosphate buffered saline may use a buffer solution having the same composition as the first phosphate buffered saline. The content of the third phosphate buffered saline may be appropriately adjusted to make the total amount of the mixture to 100 parts by weight. That is, the amount of the third phosphate buffered saline added is the remaining amount of 100 parts by weight minus the contents of the cross-linked dextran having undergone step S103 and the contents of the. For example, in this step, 40 to 55 parts by weight of a third phosphate buffered saline may be added.

6. Adjustment step < S106 >.

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

7. And a defoaming step < S107 >.

After step S106, a process of removing bubbles remaining in the mixture may be performed at this step. In one embodiment, the bubbles in the mixture may be removed by vacuum debubbling using a vacuum pump.

8. Filling step < S108 >.

After step S107, in this step, the syringe may be filled with the deaerated mixture. In one embodiment, the syringe may be used as a pre-filled syringe.

9. Step < S109> of inducing denaturation.

After step S108, in this step, a process of inducing denaturation of collagen contained in the mixture may be performed. Specifically, in this step, collagen contained in the mixture is thermally denatured into gelatin by heating. For example, in the present step, the syringe is heated at a temperature (e.g., 110 to 130 ℃) and a pressure range (1.2 to 3kgf/㎠) for 15 to 20 minutes to induce collagen denaturation, and sterilization of the mixed components filled into the syringe (i.e., the cross-linked dextran, the viscosity modifier, the collagen, and the phosphate buffered saline) may also be simultaneously accomplished together.

Hereinafter, the present invention will be described in more detail by way of specific examples. The following example is only one example to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

Preparation of the Filler composition.

Crosslinked dextran (1) was weighed to the content (unit: g) shown in Table 1, mixed with 400ml of water for injection, and stirred at 25 ℃ at 120RPM for 3 to 4 hours to swell the crosslinked dextran. Then, connect the rubber gasket between erlenmeyer flask and buchner funnel in order to prevent gas leakage, put filter paper on buchner funnel, with the vacuum pump with the inside vacuum state that becomes of erlenmeyer flask after, throw into inside the buchner funnel with bentonite dextran, carry out the filtration process of getting rid of dextran moisture. The filtered dextran was recovered and mixed with 400ml of the first phosphate buffered saline and stirred at 120RPM for 1-2 hours at 25 ℃. After stirring was completed, the filtration and stirring process was repeated 2 more times.

On the other hand, a viscosity modifier (2) and collagen (3) were prepared in the amounts (unit: g) shown in Table 1, and the viscosity modifier and collagen were mixed with 40g of a second phosphate buffered saline, and stirred at 70 to 80 ℃ and 120RPM for 2 to 3 hours to prepare a stirred material. Then, the cross-linked dextran subjected to the filtration and stirring process is mixed with a stirrer and a third phosphate buffered saline, and stirred at a temperature of 25 ℃ for 1 to 2 hours at 120RPM to prepare a mixture. At this time, the content of the third phosphate buffered saline was added until the total amount of the entire mixture reached 100 parts by weight. Then, a 4M sodium hydroxide solution is added to the mixture to adjust the pH of the mixture to 6 to 8. After that, bubbles in the mixture were removed using a vacuum pump, and the deaerated mixture was filled into a syringe. Most, the syringe filled with the mixture was heat-treated at a temperature of 121 ℃ and a pressure of 1.2kgf/㎠ for 15 minutes to induce denaturation of collagen contained in the mixture, thereby completing preparation of the filler composition.

[ TABLE 1 ]

。

Production of comparative example 3.

The setting of the other matters in the preparation of the filler composition was the same as in example 2 except that gelatin was used instead of collagen.

The collagen content of the filler composition was determined.

The collagen content of examples 1 to 4 and comparative examples 1 to 3 prepared in the following order was measured, and the measurement results are described in table 2 below.

1g of sample was taken and after addition of 1mL of 35v/v% HCl, hydrolysis was complete at 100 ℃.

② neutralizing by NaOH.

③ the hydroxyproline content was measured using an Amino acid analyzer (Amino acid analyzer).

And fourthly, calculating to obtain the collagen content by multiplying the measured hydroxyproline value by 100/13.5. When the derived collagen content is 5 or less, the evaluation is made that there is no collagen content in consideration of the interference value.

[ TABLE 2 ]

。

As shown in table 2, it was confirmed that in examples 1 to 4 and comparative example 2, since collagen contained in the mixture was denatured into gelatin by the denaturation-inducing step, the content of hydroxyproline contained in collagen was not detected.

And (4) viscosity evaluation.

The viscosity was measured at 25 ℃ (spindle 64, 20 rpm) using a Brookfield viscometer, and the results are reported in table 3 below. In Table 3, viscosity values are in cP (Centipoise).

[ TABLE 3 ]

。

As shown in Table 3, examples 1 to 4 had a viscosity ranging from 11400 cP to 14800cP, while comparative example 1 had a relatively low viscosity as compared with the examples, and the filler composition was in a form close to a liquid, and was easily dispersed or flowed from the site of administration when injected into the body, and thus was not suitable as a filler composition. In contrast, in comparative example 2, since the viscosity becomes too high, the operator is required to apply gravity when injecting into the body, and there is a problem that the injection is difficult and inconvenient, and thus the physical properties as an injection are lower than those of examples.

The extrusion force was measured.

The extrusion force of the filler composition was measured using a Universal Testing Machine (UTM). After filling the filler compositions of the examples and comparative examples into a syringe, a 27G 1/2 inch needle was attached to the syringe, and the plunger of the syringe was pushed at a speed of 50mm/min, and the value at the time of pushing was measured. The results are shown in Table 4 below.

[ TABLE 4 ]

。

As shown in Table 4, the extrusion force ranges of examples 1 to 4 are 0.033 to 0.049MPa, while the extrusion force value of comparative example 2 is too high, and when injected into the body, not only the injection is not easy for the operator, but also pain may be caused to the patient, and therefore, it is not suitable for use as a filler composition.

The viscoelasticity was measured.

The rheology of each sample was determined using a rotational 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%, frequency1.58Hz(10rad/s)。

Also, the storage modulus (elastic modulus, G'), loss modulus (G ″), and tan δ values of each sample were also measured, and the results are shown in fig. 2 and 3. Tan δ is defined herein as loss modulus/storage modulus, and at a frequency of 1Hz, the closer the tan δ value is to 1, the lower the elasticity, and the closer to 0, the higher the elasticity.

FIG. 2 is a graph that calculates and plots the storage modulus at different times for the filler composition of example 2 according to the invention and the filler composition of comparative example 3. Fig. 3 is a chart in which tan δ values at different times are calculated and plotted for the filler composition according to example 2 of the present invention and the filler composition of comparative example 3. As can be seen from FIG. 2, the G' value at each time of example 2 was lower than that of comparative example 3 at 1Hz, and it was confirmed that the filler composition of example 2 had relatively more flowability than that of comparative example 3. As can be seen from fig. 3, in 1Hz, the tan δ value of example 2 is close to 0, and thus example 2 can be interpreted as an elastomer having high elasticity.

Therefore, it can be seen that example 2, in which collagen was heat-denatured, was more elastic and had excellent dosage form stability, despite low viscosity and extrusion force, compared to comparative example 3, which contained gelatin. Generally, the lower the viscosity, the closer the dosage form is to a liquid, and there is a problem that the filler composition is easily dispersed or may flow to other parts when injected into the skin. However, in example 2, the liquid does not flow around or easily disperses, and the liquid is not only less likely to move but also can be retained in the original form. Therefore, a filler having excellent formulation stability can be produced.

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 in that injection is facilitated even with a thin needle.

In addition, since the pressing force required for injecting the filler composition is reduced, it is easy for the operator to push the syringe plunger, and the operator can easily inject the filler composition into the skin, which is very convenient for use.

Also, since the filler composition can be injected gently into the skin, it does not cause pain and discomfort to the patient when administered.

In addition, since sterilization of various components contained in the filler composition and denaturation of collagen contained in the mixture are simultaneously performed, the manufacturing process is simplified, the time required for the process is reduced, and the processability and process efficiency are improved, compared to a process requiring separate sterilization and denaturation. In particular, according to various embodiments of the present invention, it is possible to manufacture a collagen having low viscosity but high elasticity due to the induced denaturation step simultaneously performed by sterilization of all components and denaturation of collagen

The filler composition having elastomer properties is easy to stably maintain the form of the filler composition, and has an advantage of being easily injected into the body due to its low viscosity.

Also, according to various embodiments of the present invention, since a prefilled syringe capable of prefilling a syringe with a filler composition is used, contamination of the contents or inflow of foreign substances from the outside can be prevented, as compared with a visual system in which an injection raw solution is filled in a ampoule and then extracted with a syringe.

The present invention is characterized in that, in the present invention, it was first confirmed that collagen denaturation is induced in a state of being mixed with other components, so that not only can the viscosity and extrusion force of the filler composition be reduced and injection be facilitated, but also a filler composition having excellent formulation stability can be produced. That is, the present inventors have found that the viscosity of the filler composition can be reduced by inducing collagen denaturation during the production process, and that the filler composition can be injected with a low extrusion force during injection while ensuring a certain degree of elasticity, and that the filler composition does not flow or scatter, and exhibits excellent formulation stability. The present inventors have completed the technique for producing a filler composition by utilizing this finding. In particular, the present inventors have found that such characteristics are attributable to the characteristic of inducing thermal denaturation of collagen in a state of being mixed with other components, and that the filling composition is more convenient to inject and has excellent dosage form stability because the extrusion force is reduced as compared with a filling composition prepared by simply adding gelatin.

As described above, the present invention is described in detail by way of examples with reference to the accompanying drawings. However, the above embodiments are merely descriptions of preferred embodiments of the present invention, and it should not be understood that the present invention is limited to the above embodiments. The scope of the claims of the present invention should be understood as being defined by the claims to be described later and their equivalents.