阅读说明：本技术 填充剂及填充剂的制备方法 (Filler and preparation method of filler ) 是由 南中赫 崔斗烈 金敏秀 于 2021-07-08 设计创作，主要内容包括：公开了一种填充剂及填充剂的制备方法。填充剂的制备方法可包括混合搅拌可生物降解高分子溶液与油制造高分子胶束的胶束制造步骤；通过交联前述高分子胶束,制造内部填充了油的水凝胶微珠的微珠制造步骤；及去除前述水凝胶微珠中含有的油,制造空心形状微珠的空心微珠制造步骤。(Discloses a filler and a preparation method thereof. The preparation method of the filler can comprise a micelle manufacturing step of mixing and stirring the biodegradable polymer solution and the oil-made polymer micelle; a bead production step of producing hydrogel beads filled with oil by crosslinking the polymer micelles; and a hollow microsphere production step of removing the oil contained in the hydrogel microspheres to produce hollow microspheres.)

1. A preparation method of a filling agent is characterized by comprising the following steps: comprises the micelle preparation steps of mixing biodegradable polymer solution and oil to prepare polymer micelle: a step of preparing hydrogel microbeads filled with oil by crosslinking the polymer micelles; and a hollow microsphere production step of removing the oil contained in the hydrogel microspheres to produce hollow microspheres.

2. The method for producing a filler according to claim 1, wherein: further comprising an additive filling step of filling an additive into the hollow-shaped microbeads; and a classification step of classifying the microbeads according to diameters.

3. The method for producing a filler according to claim 1, wherein: also comprises a mixing step of mixing the biodegradable polymer solution with the micro-beads.

4. The method for producing a filler according to claim 1, wherein: the crosslinking agent used in the bead production step is at least one selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N' -dicyclohexylcarbodiimide, butanediol diglycidyl ether, polyethylene glycol diglycidyl ether, N-hydroxysuccinimide, N-hydroxysulfonic acid succinimide, and combinations thereof.

5. The method for producing a filler according to claim 2, wherein: the additive is at least one selected from dexamethasone, anti-inflammatory agents, vitamins, antioxidants, local anesthetics, skin regeneration factors, collagen, gelatin, and combinations thereof.

6. The method for producing a filler according to claim 2, wherein: the additive is at least one selected from the group consisting of hyaluronic acid, modified starch, pullulan, dextran, a poly-gamma-glutamic acid derivative, a polyamino acid derivative, methylcellulose, collagen, gelatin, alginic acid, carboxymethyl cellulose, hydroxypropyl methylcellulose, polymethyl methacrylate, dietary fiber, poloxamer, a poloxamer derivative, and a combination thereof.

7. The method for producing a filler according to claim 1, wherein: the diameter of the beads classified in the classification step is 50 to 500 ㎛.

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

Technical Field

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

Background

Dermal fillers are often used for therapeutic or cosmetic purposes. For example, if the filler is injected into fine wrinkles of the skin, the skin wrinkles are reduced as the soft tissue volume expands, thereby achieving a cosmetic effect. In this regard, Korean registered patent publication No. 10-1967153 discloses a technique of a filler composition.

Hyaluronic acid, which is one of the constituent materials of fillers, is a biopolymer substance, which is present in the human body and has excellent biocompatibility, and thus is widely used in medical or cosmetic applications. However, since hyaluronic acid itself is decomposed in a human body within several hours, and thus its application is limited, studies to increase the durability of hyaluronic acid in the body by crosslinking have been conducted. If the content of the crosslinking agent is increased during the production in order to increase the duration of hyaluronic acid in the body, the human body may see that the crosslinking agent is a foreign substance and an inflammatory reaction occurs. If the content of the crosslinking agent is reduced, the resulting material has low viscoelasticity and is decomposed in a short time in the human body. Therefore, it is required to develop a filler which can be sustained in the human body for a long time while reducing the content of the crosslinking agent.

On the other hand, in the conventional filler production method in which, after the crosslinked hydrogel is produced, microbeads are produced through a mechanical processing step (for example, pulverization), it is difficult to adjust the diameter of the microbeads during pulverization, and it is difficult to produce microbeads having a round-like shape and a smooth surface, such as unevenness of the surfaces of the microbeads or deformation of the microbeads.

In addition, homogeneous crosslinked hydrogel microbeads crosslinked with a uniform degree of crosslinking inside and outside the microbeads are not easily filled with a useful substance because of a narrow internal space of the microbeads, and are difficult to apply to a sustained release technique for sustained release of a useful substance.

Meanwhile, if the hydrogel beads are too small in size, the hydrogel beads have a poor tissue repair effect when injected into the body, are rapidly decomposed by the macrophage function, and are absorbed into the dermis or mobilized into the blood to cause side effects. If the size of the hydrogel micro beads is too large, pain is caused by pressure increase at the time of injection, injection is not easy, and it is difficult to form a fine natural shape after injection. Therefore, there is a need to develop a new technology that can obtain microbeads having a diameter in an appropriate range in high yield and can improve the existing problems.

Disclosure of Invention

Technical problem to be solved

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 obtaining hydrogel microbeads having a specific size in high yield.

In addition, another object of the technical idea of the present invention is to provide a technique capable of manufacturing hydrogel microbeads having a spherical shape.

Still another object of the technical idea of the present invention is to provide a technique for producing hydrogel microbeads that can contain a useful substance in the hydrogel microbeads and release the useful substance over time.

Meanwhile, another object of the technical idea of the present invention is to provide a technique capable of appropriately controlling the content of the crosslinking agent in manufacturing hydrogel microbeads.

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 an embodiment of the present invention, a method for preparing a filler may include a micelle-producing step of mixing and stirring a biodegradable polymer solution with an oil-produced polymer micelle; a bead production step of producing hydrogel beads filled with oil by crosslinking the polymer micelles; and a hollow microsphere production step of removing the oil contained in the hydrogel microspheres to produce hollow microspheres.

Moreover, the method for preparing the filler may further include an additive filling step of filling the additive into the hollow beads; and a classification step of classifying the aforementioned microbeads by diameter.

Furthermore, the method for preparing the filler may further include a mixing step of mixing the biodegradable polymer solution with the aforementioned microbeads.

The crosslinking agent used in the bead production step may be at least one selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N' -dicyclohexylcarbodiimide, butanediol diglycidyl ether, polyethylene glycol diglycidyl ether, N-hydroxysuccinimide, and combinations thereof.

The additive may be at least one selected from dexamethasone, anti-inflammatory agents, vitamins, antioxidants, local anesthetics, skin regeneration factors, collagen, gelatin, and combinations thereof.

The additive may be at least one selected from the group consisting of hyaluronic acid, modified starch, pullulan, dextran, poly-gamma-glutamic acid derivatives, polyamino acid derivatives, methylcellulose, collagen, gelatin, alginic acid, carboxymethyl cellulose, hydroxypropylmethyl cellulose, polymethyl methacrylate, dietary fiber, poloxamer derivatives, and combinations thereof.

In addition, the diameter of the microbeads classified in the classification step may be prepared to be 50 to 500 ㎛.

In order to achieve this object, as another embodiment of the present invention, the filler may be produced according to the aforementioned filler production method.

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.

ADVANTAGEOUS EFFECTS OF INVENTION

As described above, according to various embodiments of the present invention, since hydrogel microbeads having a diameter of 50 to 250 ㎛ are manufactured in high yield, a sorting process for sorting the size of hydrogel microbeads by diameter can be simplified, thereby improving production efficiency.

In addition, according to various embodiments of the present invention, hydrogel microbeads having a round and smooth surface like a sphere can be manufactured in large quantities.

Also, according to various embodiments of the present invention, by manufacturing hollow-shaped microbeads and filling functional additives into the microbeads, a sustained release function of additives from the microbeads continuously over time can be achieved.

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.

Drawings

FIG. 1 is a flow chart for manufacturing a filler according to an embodiment of the present invention;

FIG. 2 is a perspective view schematically showing the structure of an impeller used in the micelle manufacturing step according to an embodiment of the present invention;

FIG. 3 is a photograph of hydrogel microbeads (magnification X100) according to example 1 of the present invention taken by a scanning electron microscope;

FIG. 4 is a photograph of hydrogel microbeads according to comparative example 5 (magnification X40) taken by a scanning electron microscope;

FIG. 5 is a photograph of hydrogel microbeads according to comparative example 6 (magnification X40) taken by a scanning electron microscope;

FIG. 6 is a photograph showing the occurrence of discoloration during crosslinking when hydrogel microbeads were produced according to comparative example 7.

Detailed Description

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 examples, the terms 'comprising' or 'having' mean that there are features or techniques described in the specification

Features, not to foreclose additional possibilities of more than one other feature or technical features.

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 be executed substantially concurrently, or may be executed in the reverse order to the order described. That is, the methods described in this specification can be suitably practiced in any order, unless otherwise indicated herein or otherwise clearly contradicted by context.

The method of making the bulking agent 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. Biodegradable polymer solution preparation step < S101 >.

In this step, the biodegradable polymer may be mixed with an alkaline solution to prepare a biodegradable polymer solution. In one embodiment, the biodegradable polymer may be at least any one of hyaluronic acid and a salt thereof. For example, the hyaluronate may include inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and organic salts such as tetrabutylammonium hyaluronate. Depending on the method of implementation, the hyaluronic acid salt may be a combination of two or more of the foregoing. In one embodiment, the biodegradable polymer may have a weight average molecular weight of 100000 to 15000000g/mol, but is not limited thereto.

In one embodiment, the alkali solution may use a sodium hydroxide solution or a potassium hydroxide solution, but other kinds of alkali solutions capable of dissolving hyaluronic acid may also be used.

In a specific embodiment, sodium hyaluronate and 0.5-1N sodium hydroxide solution can be mixed to prepare sodium hyaluronate with a concentration of 10w/v%, and then the mixture is stirred for 3-4 hours to prepare biodegradable polymer solution. At this time, if the stirring temperature is kept at a high temperature (for example, 60 ℃), the stirring time can be shortened.

2. Micelle manufacturing step < S102 >.

In this step, the biodegradable polymer solution can be mixed with oil and stirred at high speed to produce the polymer micelle. That is, in this step, the biodegradable polymer surrounds the oil particles in the form of spheres, and is adsorbed on the oil particles to form polymer micelles. In one embodiment, the oil may be mineral oil, but is not limited thereto, and other types of oil may be used.

In one embodiment, the biodegradable polymer solution and the mineral oil may be mixed in a ratio of 1: 5 by volume. When the amount of the biodegradable polymer solution is larger than that of the mineral oil (for example, the volume ratio is 1: 6) during mixing, it is difficult to obtain microbeads of 50 to 500 μm in a high yield in a microbead production step described later. If the amount of the biodegradable polymer solution is smaller than that of the mineral oil (for example, the volume ratio is 1: 4), the biodegradable polymer aggregates during stirring, and the diameter of the beads exceeds 500. mu.m, making it difficult to produce beads of a desired appropriate size.

In addition, in the step, the impeller can rotate at 1000-2000 rpm for 30 minutes-15 hours to stir the mixed solution of the biodegradable polymer solution and the mineral oil at high speed. The particle size of the polymer micelle can be made fine by stirring with the impeller. Fig. 2 is a perspective view schematically showing the structure of an impeller used in the micelle manufacturing step according to an embodiment of the present invention. As shown in fig. 2, the impeller (100) may include a rotation shaft (110) rotating in a single direction; and a plurality of wires rotating together with the rotating shaft (110).

In one embodiment, two or three wires may be fixed to the rotating shaft (110) in a state of crossing each other at a certain angle. The center of the 1 st wire (121) is bent to form a shape facing the opposite wire. One end and the other end of the 1 st wire (121) may be fixed to the rotation shaft (110). The 1 st wire (121) has a structure that is wider from one end to the lower side, and thus the lower layer portion of the solution is easily stirred. The structure of the 2 nd steel wire (122) or the 3 rd steel wire (123) may be the same as that of the 1 st steel wire (121).

When the number of steel wires constituting the impeller (100) is less than 2, dispersibility during stirring is lowered, and it is difficult to form a fine-sized polymer micelle. When the number of the steel wires is more than 4, the steel wires are coagulated to form lumps during stirring, and the lumps adhere to gaps between adjacent steel wires, so that it is difficult to form fine polymer micelles. Therefore, it is preferable to control the number of wires within the above range.

3. Bead production step < S103 >.

In this step, hydrogel beads filled with oil can be produced by crosslinking the polymer micelles produced in step S102. That is, in this step, the cross-linking agent may be added to the stirred material stirred in step S102, and the mixture may be stirred at a constant speed (for example, 1000 to 2000rpm) to cross-link the polymer micelle. In addition, the step can be carried out at normal temperature for 24-72 hours.

In one embodiment, the content of the cross-linking agent may be 2% by volume of the total amount of the mixture of the biodegradable polymer solution and the mineral oil. If the content of the crosslinking agent is less than 2% by volume, the hydrogel beads are difficult to be spherical in shape, and the impact resistance is lowered, so that the beads are easily broken even by a little impact. If the content of the crosslinking agent exceeds 2% by volume, the hydrogel microbeads may be yellowed in color or the fluidity of the microbeads may be reduced, the microbeads are restricted in volume expansion during hydration, and side effects may be generated in the human body due to the crosslinking agent remaining in the microbeads. Therefore, the content of the crosslinking agent is preferably applied to the aforementioned content.

In one embodiment, the crosslinking agent may be at least one selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N' -dicyclohexylcarbodiimide, butanediol diglycidyl ether, polyethylene glycol diglycidyl ether, N-hydroxysuccinimide sulfonate, and combinations thereof, but is not limited thereto, and other known crosslinking agents may be used.

4. Hollow bead production step < S104 >.

In this step, the oil contained in the hydrogel microbeads crosslinked in step S103 may be removed to prepare cenospheres. In this case, the cenospheres refer to cenospheres in a hollow state after removing oil contained in the cenospheres.

In one embodiment, the hydrogel beads are washed with refined water more than 3 times to remove oil contained in the beads, and then the hydrogel beads washed with refined water are put into ethanol to react for 30 minutes. The oil contained in the hydrogel microbeads and the residual cross-linking agent, alkaline salts, unreacted cross-linking by-products and impurities in the hydrogel microbeads can be removed together by repeatedly washing with refined water and ethanol for 3 times.

5. Additive filling step < S105 >.

In this step, the additives in the microbeads in the hollow state prepared in step S104 may be filled. In one embodiment, the additive may be at least any one selected from the group consisting of dexamethasone, anti-inflammatory agents, vitamins (e.g., B1, B2, B12), antioxidants (e.g., calcium, zinc, etc.), local anesthetics (e.g., lidocaine), skin regeneration factors (e.g., RGD peptide consisting of arginine (R) -glycine (G) -aspartic acid (D) that enhances skin regeneration), collagen, gelatin, and combinations thereof.

Further, the additive may be selected from hyaluronic acid, modified starch, pullulan, dextran, a poly-gamma-glutamic acid derivative (for example, a poly-gamma-glutamic acid derivative in which a terminal position of poly-gamma-glutamic acid is substituted by 1 to 2 of C1-C6 alkyl group, aryl group, acetyl group substituted by C1-C6 alkyl group or aryl group, or sulfonyl group substituted by C1-C6 alkyl group or aryl group), a polyamino acid derivative (for example, poly (2-hydroxyethylasparagine), polysuccinimide, or the like), methylcellulose, collagen, gelatin, alginic acid, carboxymethylcellulose, hydroxypropylmethylcellulose, polymethylmethacrylate, dietary fiber (for example, glucomannan, guar gum, indigestible maltodextrin, soybean dietary fiber, wheat dietary fiber, barley dietary fiber, and the like, Oat, gum arabic, inulin, polydextrose, etc.), poloxamer derivatives, and at least one selected from the group consisting of these.

According to one embodiment, the hollow beads may be hydrated by immersing them in a buffer solution (e.g., phosphate buffered saline, borate buffer, physiological saline, etc.) mixed with an additive for 2 to 3 hours. During hydration, the additive penetrates into the hydrogel beads, thereby achieving filling of the additive.

6. The classification step < S106 >.

In this step, hydrogel microbeads filled with additives may be classified by diameter using a sieve or perforated mesh having a certain size of aperture. In one embodiment, after the hydrogel microbeads are recovered from the buffer solution, the hydrogel microbeads having a diameter of 50 to 500 μm can be sorted by screening.

7. Mixing step < S107 >.

In this step, the non-crosslinked biodegradable polymer solution may be mixed with the microbeads classified in step S106. The biodegradable polymer may be the same as the above-mentioned one. In one embodiment, the non-crosslinked biodegradable polymer solution can be prepared by mixing sodium hyaluronate with a solvent (e.g., purified water, phosphate buffered saline, etc.) to make sodium hyaluronate in a concentration of 1-15w/v% and stirring at 60 ℃. Here, the uncrosslinked biodegradable polymer solution means a solution in which a crosslinking reaction of a crosslinking agent does not occur because the crosslinking agent is not added to the solution.

In this step, the crosslinked hydrogel microbeads and the non-crosslinked biodegradable polymer solution may be mixed in a weight ratio of 8: 2. When the filler is injected into the body using a syringe, the uncrosslinked biodegradable polymer solution can function as a lubricant to reduce the extrusion force.

The hydrogel microbead according to an embodiment, since it is a spherical particle, can be injected with the same or lower extrusion force as that of the existing filler when injected into the body, even if the content of the uncrosslinked biodegradable polymer solution is less than that of the filler in a polyhedral (e.g., cubic) shape. Therefore, when the filler is injected, the operation is convenient, and the possibility of causing pain is reduced.

In this step, a local anesthetic (e.g., lidocaine hydrochloride) and a functional drug may be added to a mixed solution of the crosslinked hydrogel beads and the uncrosslinked biodegradable polymer solution and mixed. On the other hand, according to an embodiment, this step may be performed earlier than step S106.

8. Mixture filling step < S108 >.

In this step, a mixture in which the crosslinked hydrogel microbeads and the non-crosslinked biodegradable polymer solution are mixed may be filled into a syringe. In one embodiment, the syringe may be a Prefilled syringe (Prefilled system).

9. Sterilization step < S109 >.

In this step, the contents filled in the syringe can be sterilized. For example, the syringe may be placed in an autoclave and sterilized at 110 to 130 ℃ for 20 to 40 minutes.

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.

Example of production of the Filler.

Mixing sodium hyaluronate with the weight-average molecular weight of 110 ten thousand daltons with 1N sodium hydroxide solution to prepare sodium hyaluronate with the concentration of 10w/v%, and then stirring for 3-4 hours to prepare biodegradable high polymer solution. Mixing 1ml of the prepared biodegradable polymer solution with 5ml of mineral oil, rotating the mixture for 30 minutes to 15 hours at 1000 to 2000rpm by using an impeller, and stirring the mixed solution of the biodegradable polymer solution and the mineral oil at a high speed. The impeller used for stirring was the same as that shown in FIG. 2, and three steel wires were used to cross each other at a predetermined angle and fixed to a rotating shaft. Then, a crosslinking agent (butanediol diglycidyl ether) was added to the stirred mixture, and after stirring at 1000rpm,

crosslinking the high molecular micelle for 24 hours at normal temperature. In this case, the content of the cross-linking agent is biodegradable polymer solution and mineral oil

2% by volume of the total mixture. After the crosslinking reaction was completed, the produced hydrogel microbeads were washed with refined water 3 times, and then

The hydrogel microbeads washed with refined water are soaked in ethanol for reaction for 30 minutes and washed repeatedly with refined water and ethanol for 3 times.

Then, the hydrogel beads were immersed in phosphate buffered saline mixed with an additive (dexamethasone) for 3 hours and filled

And adding an additive. After the hydrogel beads filled with the additives are recovered, hydrogel particles with a diameter of 50-500 ㎛ are screened and classified by using a screen

A microbead.

The classified hydrogel microbeads were mixed with an uncrosslinked biodegradable polymer solution (i.e., a solution in which sodium hyaluronate having a weight average molecular weight of 110 ten thousand daltons was dissolved in purified water at a concentration of 1.5 w/v%) in a weight ratio of 8: 2. Thereafter, lidocaine hydrochloride was added to the mixture until the concentration was 0.3 w/v%, and then the mixture was filled into a syringe. The filled syringe was sterilized in an autoclave at 120 ℃ for 40 minutes, thereby completing the preparation of the filler.

And (4) manufacturing hydrogel microspheres.

< example 1, comparative examples 1 to 4 >.

Mixing sodium hyaluronate with a 1N sodium hydroxide solution to enable the concentration of the sodium hyaluronate to reach 10w/v%, and stirring for 3-4 hours to prepare the biodegradable polymer solution. Mixing the prepared biodegradable polymer solution with mineral oil, rotating the mixture for 30 minutes to 15 hours at 1000 to 2000rpm by using an impeller, and stirring the mixed solution of the biodegradable polymer solution and the mineral oil at a high speed. When the biodegradable polymer solution was mixed with mineral oil, the contents were set to the values described in table 1 below. The impeller used for stirring was the same as that shown in FIG. 2, and three steel wires were used to cross each other at a predetermined angle and fixed to a rotating shaft.

Then, a crosslinking agent (butanediol diglycidyl ether) was added to the stirred mixture, and after stirring at 1000rpm, the polymer micelle was crosslinked at room temperature for 24 hours. At this time, the content of the cross-linking agent was 2% by volume of the total amount of the mixture of the biodegradable polymer solution and the mineral oil. After the crosslinking reaction is finished, the prepared hydrogel microbeads are washed by refined water for 3 times, then the hydrogel microbeads washed by the refined water are soaked in ethanol for reaction for 30 minutes, and then the hydrogel microbeads are repeatedly washed by the refined water and the ethanol for 3 times. Then, the hydrogel beads were immersed in phosphate buffered saline mixed with an additive (dexamethasone) for 3 hours, and the additive was filled. And (3) after the hydrogel microbeads filled with the additives are recovered, screening and classifying the hydrogel microbeads with the diameters of 50-500 ㎛ by using a screen.

[ TABLE 1 ]

。

< example 2, comparative examples 5 to 8 >.

The setup of the hydrogel microbeads was the same as in example 1 except that the content of the crosslinking agent was set as described in the following Table 2, and the hydrogel microbeads classified by the diameter of 50 to 500 μm were placed in a vacuum oven and vacuum-dried at 60 ℃ for 1 hour under 20 mmHg.

[ TABLE 2 ]

。

< examples 3 to 4, comparative examples 9 to 11 >.

The procedure of example 1 was repeated except that the number of wires of the impeller was changed to the values shown in Table 3, and the hydrogel beads were prepared.

[ TABLE 3 ]

。

Evaluation of productivity of hydrogel beads.

To confirm the productivity of the different volume ratios of the biodegradable polymer solution to the mineral oil, the following experiment was performed. In the production processes of the respective examples and comparative examples, after the hydrogel beads filled with the additives were recovered, the hydrogel beads were classified by size using a sieve. When the proportion of the microspheres having a diameter of 50 to 500 ㎛ in all the hydrogel microspheres prepared exceeds 80%, the productivity is evaluated to be excellent, and when the proportion is less than 80%, the productivity is evaluated to be poor. The results are shown in Table 4 below.

[ TABLE 4 ]

。

As shown in Table 4, in example 1, the ratio of beads having a diameter of 50 to 500 μm was 80% or more, and it was confirmed that the productivity of beads having a specific size was excellent. In addition, as a result of confirming that the hydrogel beads of example 1 were photographed by a scanning electron microscope (magnification × 100), it was found that spherical hydrogel beads having a round and smooth shape like a sphere were formed as shown in fig. 3.

Then, in comparative examples 1 and 2, when the amount of the mineral oil was smaller than that of the biodegradable polymer solution, aggregation and agglomeration of the biodegradable polymer occurred during the stirring, and the diameter of the produced microbeads exceeded 500 ㎛, confirming that productivity of microbeads having a specific size was low. In comparative examples 3 and 4, when the amount of the mineral oil was larger than that of the biodegradable polymer solution, a plurality of microbeads having a particle size of less than 50 ㎛ were formed, and it was confirmed that productivity of microbeads having a specific size was low.

Evaluation of physical properties of hydrogel microbeads.

In order to confirm the physical properties of the hydrogel beads according to the content of the crosslinking agent, the following experiment was performed. The hydrogel microbeads of each example and comparative example were observed with a scanning electron microscope (x 40), and the shape of the microbeads was confirmed, and if the shape of the microbeads was spherical, the shape was evaluated as good, and if the appearance of the microbeads was deformed or uneven, the shape was evaluated as poor. In addition, a crosslinking agent was added to the stirred material to confirm whether or not discoloration occurred during the stirring, and if discoloration did not occur, the evaluation was good, and if discoloration occurred, the evaluation was bad. Then, the hydrogel microbeads of each example and comparative example were soaked in phosphate buffered saline left in a constant temperature water bath at 37 ℃ for 2 hours for 24 hours, hydrated, and then the area of the hydrogel microbeads was measured by a microscopic infrared spectrometer. Comparing the micro-area of the hydrogel beads before hydration with the area of the hydrogel beads after hydration (㎛ 2), if the area is increased by 20 times or more, the expandability of the beads is evaluated as good, and if the area is increased by less than 20 times, the expandability is evaluated as bad. The results of each test are shown in table 5 below.

[ TABLE 5 ]

。

As shown in table 5, example 2 confirmed that the bead shape was good, no discoloration occurred, and the bead expandability was good, whereas comparative example 5 formed a deformed appearance as shown in fig. 4. In comparative example 6, as shown in fig. 5, the surface of the bead was uneven or deformed, and the round shape like a sphere could not be formed. Comparative example 7 As shown in FIG. 6, the color turned yellow during the stirring process when the cross-linking agent was added to the stirred material. Comparative example 8 also confirmed that the color became pale yellow. In comparative examples 7 and 8, it was confirmed that the degree of crosslinking of the beads increased and the swelling property decreased as the amount of the crosslinking agent added increased.

Evaluation of physical properties of hydrogel microbeads according to the impeller structure.

To confirm the effect of the impeller structure on the physical properties of the hydrogel beads, the following experiments were performed. In the manufacturing processes of the examples and comparative examples, hydrogel microbeads filled with additives were collected and then sorted by size using a sieve, and when 80% or more of all the microbeads having a diameter of 50 to 500 ㎛ were accounted for, the productivity was evaluated as excellent, and when less than 80%, the productivity was evaluated as poor. The results are shown in Table 6 below.

[ TABLE 6 ]

。

As shown in Table 6, in examples 3 and 4, the ratio of beads having a diameter of 50 to 500 μm was 80% or more, and it was confirmed that the productivity of beads having a specific size was excellent. In comparative example 9, the particles were not smoothly refined in the stirring process using the impeller, and it was confirmed that the productivity of hydrogel beads was low. In comparative examples 10 and 11, the pellets formed by coagulation during stirring and adhered to the gaps between the adjacent steel wires, and it was confirmed that the productivity of microbeads having diameters of 50 to 500 ㎛ was low.

As described above, according to various embodiments of the present invention, since a large number of polymer micelles having a diameter of 50 to 250 ㎛ are prepared by stirring with an impeller (100) in a micelle manufacturing step, it is possible to simplify the process of classifying hydrogel microbeads by diameter, shorten the process time, and improve the work efficiency and productivity. Furthermore, hydrogel microbeads having a diameter of 50 to 250 μm can be produced in a certain yield even if the amounts of the biodegradable polymer solution and the oil are set to a large amount in the micelle production step. Therefore, microbeads having a specific size can be mass-produced.

If the hydrogel microbeads have a diameter of less than 50 ㎛, the tissue repair effect is reduced when injected into the body, and the macrophage-hydrogel-macrophage-hydrogel-macrophage-hydrogel-microbead can have a side effect. When the microbeads having a diameter of more than 250 μm are injected into the body, the pressing force is increased, pain is given to the patient, it is difficult for the operator to inject, and it is difficult for the operator to form a fine natural shape after injection. In various embodiments of the present invention, hydrogel microbeads having a diameter of 50 to 250 ㎛ can be easily produced with high yield.

Also, according to various embodiments of the present invention, spherical hydrogel microbeads having a sphere-like shape and a smooth surface can be mass-produced. Meanwhile, the surfaces of the hydrogel microspheres are crosslinked, so that the hydrogel microspheres have certain strength, are not easy to deform in vivo and can keep the shapes of the hydrogel microspheres for a long time.

Conventional microbeads having a microbead shape formed by mechanical processing after preparation of hydrogel have a structure in which it is difficult to incorporate a useful substance or to realize a sustained release function because they contain a crosslinked hydrogel having the same surface composition as the hydrogel. However, according to various embodiments of the present invention, by manufacturing hollow-shaped microbeads and filling various functional additives inside the microbeads, a sustained release function in which the additives are continuously released from the microbeads over time can be achieved.

Also, according to various embodiments of the present invention, side effects caused by the crosslinking agent can be prevented by adjusting the content of the crosslinking agent. In addition, the hydrogel beads according to various embodiments of the present invention have a high degree of crosslinking at the surface layer due to the concentrated crosslinking reaction at the surface portion of the beads, and thus can maintain the shape thereof in the human body for a longer time than the conventional beads in which the crosslinking reaction occurs inside and outside the beads, even though the same amount of the crosslinking agent is used, compared to the conventional beads in which the shape of the beads is formed by mechanical processing after the hydrogel is manufactured.

Also, the filler according to various embodiments of the present invention contains a small amount of uncrosslinked hyaluronic acid, as compared to the existing filler products, and relatively contains a high amount of crosslinked hyaluronic acid, thereby having an advantage of having a longer duration in the human body.

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.

Description of the symbols

100, an impeller;

110 is a rotating shaft;

121: 1 st steel wire;

122, No. 2 steel wire;

123: 3 rd steel wire.