KR20180067197A - Filler for soft tissue having particles of bead type and, manufacturing methods for the same - Google Patents

Abstract

A filler for soft tissues having according to the present invention can be injected into the human body with low extrusion force even when the filler contains a small amount of linear hyaluronic acid since the cross-linked hyaluronic acid particles are spherical, and the duration in the human body is increased and side effects are reduced even when a small amount of a cross-linking agent is used in manufacturing processes.

Description

Technical Field [0001] The present invention relates to a filler for soft tissue having spherical particles and a method for manufacturing the same.

The present invention relates to a filler for a soft tissue, and more particularly, since a cross-linked hyaluronic acid particle has a spherical shape, it can be injected into a human body with a small extrusion force even if it contains a small amount of linear hyaluronic acid, Even with a small amount of cross-linking agent in the manufacturing process, the duration is increased in the human body and the side effect is small. In addition, the present invention also relates to a method for producing such a filler.

In general, tissue enhancement such as soft tissue augmentation has been used for medical and cosmetic purposes. Such enhancement may be accomplished surgically through plastic surgery or by non-surgical methods of injecting a biocompatible material (filler) to increase the volume of the soft tissue. For example, fillers have been used cosmetically to increase the volume of the balls, lips, chest, and hips, and to reduce the fine lines and deep wrinkles of the skin.

Hyaluronic acid is a biopolymer material in which a repeating unit composed of N-acetyl-D-glucosamine and D-glucuronic acid is linearly linked. It is present in many vitamins such as ocular globules, synovial fluid, It is widely used for medical and medical applications such as ophthalmic surgery supplements, joint function improving agents, drug delivery materials, eyedrops and wrinkle removers, and cosmetics.

However, since hyaluronic acid itself has a short half-life period of only a few hours in the human body, its application is limited, and studies have been conducted to increase the half-life (persistence of the body) through cross-linking. Examples of the synthesis of crosslinked hyaluron derivatives using compounds having two functional groups such as divinyl sulfone, bisepoxide, bishalide, and formaldehyde as a crosslinking agent have been reported in various publications. Various products are commercially available as dermal fillers for skin soft tissue. U.S. Patent No. 4,582,865 discloses a crosslinked hyaluron derivative using divinylsulfone (DVS) as a crosslinking agent. The hydrogel form thereof is commercially available under the trade name Hylaform ( ^R) . U.S. Patent No. 5,827,937 discloses a multifunctional epoxy compound Discloses a method for producing a hyaluronan derivative crosslinked product using a crosslinking agent as a crosslinking agent, and a hydrogel of a hyaluronic acid crosslinked product prepared by using 1,4-butanediol diglycidyl ether (BDDE) as a crosslinking agent as a multifunctional epoxy compound Restylane ^® , approved by the US Food and Drug Administration (FDA), is available worldwide as a tissue augmentation filler. All of these products are produced by combining a hydroxy group of hyaluronic acid with a crosslinking agent, and although the persistence of the hyaluronic acid is increased in comparison with that of uncrosslinked hyaluronic acid, there is still a problem of low bio-persistence such as decomposition within 6 months.

Increasing the crosslinker content in the preparation of hyaluronic acid to increase the duration in the human body may result in an inflammatory reaction since the crosslinking agent is recognized as a foreign substance in the human body. When the content of the crosslinking agent is decreased, the resulting material has a low viscoelasticity and is disintegrated in the human body in a short time. Therefore, a filler that contains a small amount of a cross-linking agent and is long-lasting in the human body is required.

On the other hand, when crosslinked hyaluronic acid (cHA) is injected into the human body using a syringe, a large extrusion force is required. Therefore, in actual use, the cross-linked hyaluronic acid is converted into linear hyaluronic acid Conjugated hyaluronic acid, linear HA). Linear hyaluronic acid serves as a lubricant when injecting hyaluronic acid using a syringe, and commercially available hyaluronic acid fillers have a ratio (wt%) of cross-linked hyaluronic acid (cHA) to linear hyaluronic acid of about 71: 25 to 60:40. However, the higher the content of linear hyaluronic acid, the easier the injection into the human body, but the linear hyaluronic acid is undesirably decomposed in the human body.

Therefore, a filler having a small linear hyaluronic acid and a small syringe pressure output is required.

The present invention has been made to solve the above problems. It is an object of the present invention to provide a filler having an increased duration in a human body and a small side effect even if a small amount of a cross-linking agent is used in the manufacturing process.

It is another object of the present invention to provide a filler which can be injected into the human body with a small extrusion force even if the linear hyaluronic acid is small.

It is still another object of the present invention to provide a method for manufacturing such a filler.

In order to solve the above problems, a soft tissue filler according to a preferred embodiment of the present invention comprises 2.0 to 3.3 parts by weight of hyaluronic acid based on 100 parts by weight of water contained in the filler; And 0.2 to 0.5 parts by weight of an anesthetic agent.

The hyaluronic acid has a hyaluronic acid content of 85 wt% to 97 wt% and a non-crosslinked linear hyaluronic acid content of 3 wt% to 15 wt% after cross-linking with a crosslinking agent. The crosslinked hyaluronic acid has an entangled molecular structure and the particles are spherical and have a diameter of 90 to 1400 m.

The filler may further comprise 5 to 15 parts by weight of PBS. The anesthetic agent is preferably lidocaine, and the cross-linking agent is preferably BDDE.

Another aspect of the present invention is a method for manufacturing a soft tissue filler comprising the steps of: (a) preparing a cross-linked hyaluronic acid (cHA) composition by adding a polymer hyaluronic acid into an alkali aqueous solution and stirring the mixture; (b) cutting the hyaluronic acid composition to a small size and then neutralizing the acidic aqueous solution; (c) placing the neutralized composition on a plate having a circular through-hole of a predetermined diameter, and applying pressure to the composition so that the composition moves down through the circular through-hole to form spherical particles having a constant diameter step; (d) stirring the spherical particles of the hyaluronic acid composition at 30 DEG C to 70 DEG C to remove a part of the liquid component so that the content of hyaluronic acid in the composition is 1.8 wt% or more and 3 wt% or less, Causing the lonic acid molecule to become an entangled structure; And (e) mixing unmodified and non-crosslinked linear hyaluronic acid with the composition through step (d) so that hyaluronic acid is contained in the composition in an amount of 1.8 wt% to 3 wt%.

The mixing ratio of step (e) is 85 wt% to 97 wt% of the composition after step (d), and 3 wt% to 15 wt% of unmodified unmodified linear hyaluronic acid. In the final product, the diameter of the particles is 90 占 퐉 to 1400 占 퐉.

Of the above steps, step (c) may be performed before step (d), but step (c) may be performed after step (d).

The step (d) may be performed after the step (d) is performed after the step (c) or after the step (d) after the neutralized hyaluronic acid composition ) In a vessel of a stirrer and stirring at 100-200 RPM for 48-72 hours under gauge pressure of -0.85 bar to -0.9 bar.

In the step (a), 3 to 6 wt% of polymer hyaluronic acid is mixed with the crosslinked hyaluronic acid (cHA) composition, and 3 to 6 wt% of the crosslinking agent is mixed as BDDE.

Prior to step (e), the untreated and non-crosslinked hyaluronic acid powder and P.B.S. And lidocaine to form a linear hyaluronic acid mixture, and in step (e), the linear hyaluronic acid composition is mixed into the composition obtained in step (d).

In the step (b), it is preferable to cut the gel-state hyaluronic acid composition into cubes of ³ mm ³ to 10 mm ³ .

The diameter of the circular through-hole is preferably 60% to 80% of the particle diameter of the final product.

Between steps (a) and (b), a crosslinked hyaluronic acid composition solution is put in a dish, covered with a lap, and gelled in an oven at 20 to 50 ° C for 24 to 72 hours .

Further, it is preferable that the step (b) and the step (c) further comprise a step of refining with an alcohol and water to remove the unreacted crosslinking agent contained in the neutralized composition.

The present invention has the following effects.

First, even if a small amount of cross-linking agent is used in the manufacturing process, the duration in the human body is increased, and the filler having a small side effect is provided.

Second, it provides a filler that can be injected into the human body with a small extrusion force even if it contains a small amount of linear hyaluronic acid.

Third, a method for manufacturing such a filler is provided.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flow chart showing a process of manufacturing a filler according to a preferred embodiment of the present invention. FIG.
Figure 2 shows the linear molecular structure of hyaluronic acid crosslinked by a cross-linking agent.
Figure 3 shows a cross-linked hyaluronic acid having a linear molecular structure into an entangled structure by a condensation process.

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately It should be interpreted in accordance with the meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined. Therefore, the embodiments described in the present specification and the configurations shown in the drawings are merely examples of the present invention and are not intended to represent all of the technical ideas of the present invention, so that various equivalents And variations are possible.

1 is a flow chart showing a process for manufacturing a filler according to a preferred embodiment of the present invention.

As shown in the figure, the method for producing a filler according to the present invention comprises the steps of (S1) preparing a crosslinked hyaluronic acid composition solution, (S2) gelling the cross-linked hyaluronic acid composition solution, (S5) of removing impurities such as unreacted cross-linking agent in the neutralized hyaluronic acid composition (step S5), and removing the impurities from the neutralized hyaluronic acid composition (S6) making the removed hyaluronic acid composition into spherical particles having a constant diameter, condensing the particle-controlled hyaluronic acid composition into an entangled structure (S7), linear hyaluronic acid (untreated Preparing a linear hyaluronic acid mixture (S8) by mixing a phosphate buffered saline (PBS) and an anesthetic agent in a non-crosslinked HA), mixing the crosslinked hyaluronic acid composition with a linear (S9) sterilizing the hyaluronic acid mixture, respectively, (S10) mixing the linear hyaluronic acid mixture with the crosslinked hyaluronic acid composition, and (S11) defoaming. Of the above steps, step S6 may be performed before step S7, but may be performed after step S7.

Each of the above steps will be described below in order.

(1) cross-linking (S1) and gelation (S2)

The polymer hyaluronic acid is added to an aqueous alkali solution, and the mixture is firstly stirred to disperse and linearize hyaluronic acid. Then, a cross-linking agent is added, and then the mixture is stirred for a second time to prepare a crosslinked hyaluronic acid solution. The crosslinked hyaluronic acid (cHA) solution preferably contains 3 to 6 wt% of hyaluronic acid and 3 to 6 wt% of the crosslinking agent as BDDE. More preferably, the polymer hyaluronic acid is 4 to 5 wt% and the crosslinking agent is 4 to 5 wt% as BDDE.

The temperature of the reaction (the temperature of the alkali aqueous solution) is preferably 30 ° C to 50 ° C.

In the present invention, the form of hyaluronic acid may be a physiologically acceptable salt of hyaluronic acid. For example, metal salts of hyaluronic acid such as sodium salts and potassium salts, or mixtures thereof may be used, but are not limited thereto. Preferably, a sodium salt (Sodium Hyaluronate) can be used.

The crosslinking rate of the composition may vary depending on the pH of the aqueous alkali solution and the physical properties may vary. Preferably, 0.1 to 0.2N NaOH is used. In addition, the average molecular weight of hyaluronic acid (HA) used is preferably about 1 million to 1.5 million daltons.

Specifically, 10 g of hyaluronic acid (HA) having an average molecular weight of 110,000 daltons was added to 171.5 ml (172 g) of 0.1 N NaOH, and the mixture was firstly stirred to obtain a linear structure of hyaluronic acid (HA). The primary agitation is carried out at 30 ° C to 50 ° C for 3 hours to 7 hours, preferably at 35 ° C for 5 hours.

Next, a cross-linking agent is added to the mixture of the hyaluronic acid and the aqueous alkali solution, and the cross-linking reaction proceeds to crosslink the linear hyaluronic acid. Concretely, 9.45 ml (10 g) of BDDE and 19.06 ml (15 g) of ethanol as a crosslinking agent are mixed in the NaOH aqueous solution and then the HA is cross-linked by the second stirring. The secondary agitation is carried out at 30 ° C to 50 ° C for 38 to 58 hours, preferably at 35 ° C for 45 to 50 hours.

The crosslinking agent is not limited as long as it can crosslink the polymer chain of hyaluronic acid by chemical bonding, and examples thereof include 1,3-butadiene diepoxide, 1,2,7,8-diepoxyoctane, 1,5-hexadienediamine Alkyldexoxy compounds such as dodecane; Diglycidyl ethers such as ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, and bisphenol A diglycidyl ether; Divinyl sulfone; Epichlorohydrin, etc. may be used. In the present invention, BDDE is used as a crosslinking agent.

Next, the cross-linked hyaluronic acid composition solution is put into a dish, covered with a wrap, and put into an oven for gelation. Specifically, the inside of the oven is gelled by holding at 20 캜 to 50 캜, preferably 30 캜, for 24 to 72 hours, preferably 45 hours.

(2) cutting (S3) and neutralization reaction (S4)

For miniaturization, the gelled hyaluronic acid composition is cut into a small size and neutralized by putting it in an acidic aqueous solution. Since the composition is cut to a small size, the neutralization reaction can be smoothly performed in an acidic aqueous solution.

Specifically, the gelled hyaluronic acid composition is cut into cubes (cubes) of ³ mm ³ to 10 mm ³ , preferably 5 mm ³ , using a cutter or the like. The cut composition is then neutralized by adding 171.5 ml (172 g) of 0.1 N HCl aqueous solution.

(3) Cleaning (S5)

After the neutralization step, impurities contained in the neutralized composition (unpurified cHA hydrogel), for example unreacted crosslinking agent (unreacted BDDE), and the like are removed.

Specifically, the neutralized composition is contained in a mesh tube (made of stainless steel), purified and purified with 50% ethanol, and then subjected to secondary purification and purification with DI water.

The purified and purified hyaluronic acid composition is a bulk hydrogel, and most of the unreacted crosslinking agent (BDDE) is removed.

(4) Grain size adjustment (S6)

The purified and purified hyaluronic acid composition is made into spherical particles having a certain diameter.

Specifically, after the composition is placed on a plate having a circular-shaped through-hole having a predetermined diameter, pressure is applied to the composition so that the composition moves down through the circular through-hole to become spherical particles of a certain diameter. A nitrogen seedling can be used for such a process.

The diameter of the circular through-hole may be determined in consideration of the final particle diameter (about 90 μm to 1400 μm) of the product (filler) to be manufactured. Specifically, the circular through-hole preferably has a diameter of 60% to 80% of the final particle diameter, and most preferably has a diameter of 70%. Since the purified / purified hyaluronic acid composition is expanded after passing through the circular through-hole, the circular through-hole is formed to be smaller than the particle diameter of the final product.

On the other hand, as described above, step S6 may be performed before step S7, but may be performed after step S7.

(5) Condensation (S7)

(CHA hydrogel, when the S6 step is performed before the S7 step) or a purified and purified hyaluronic acid composition (when the step S6 is followed by the purified HA hydrogel, step S7) wt to not more than 3.0 wt%, preferably not less than 2.0 wt% and not more than 2.8 wt%, so that the cross-linked hyaluronic acid molecules are mutually entangled.

The spherical particles of the particle-adjusted composition have a linear molecular structure as shown in Fig. 2, and this linear molecular structure becomes a structure entangled by the condensation process. As shown in FIG. 3, the twisted structure is a structure in which the linear molecular structure is twisted and intertwined and twisted, and the twisted structure has a strength of gel of the gel (filler) together with cross- And increases the resistance to deformation. Accordingly, the filler containing hyaluronic acid after the condensation process is advantageous because it can last longer in the human body. Thus, when using the same amount of cross-linking agent (BDDE), the filler containing the condensed cHA (crosslinked hyaluronic acid) retains its shape for longer in the human body than the filler containing the cHA not subjected to the condensation process . For reference, the yellow bars in FIGS. 2 and 3 show cross-linking by a cross-linking agent, and the red circle represents a portion with a twisted structure.

Specifically, the composition (cHA) having a controlled particle size or the purified and purified hyaluronic acid composition is placed in a container of a stirrer at a temperature of 30 to 70 DEG C, preferably 50 to 100 to 200 RPM for 48 to 72 hours Is stirred under a gauge pressure of -0.85 bar to -0.9 bar such that some of the liquid components (e.g. water, ethanol, etc.) are removed from the composition. For example, 1600 g of the liquid component is removed in 2000 g of the granulated composition (cHA hydrogel) or the purified and purified hyaluronic acid composition (purified HA hydrogel) to make it 400 g so that it becomes a twisted molecular structure and increases the HA concentration.

P.B.S. may be added to the condensed cHA.

As described above, in the present invention, the cHA is made using a crosslinking agent, and then the cHA is made into an entangled structure, so that the duration is made longer in the human body.

(6) Preparation of linear hyaluronic acid (non-crosslinked unmodified hyaluronic acid) mixture (S8)

A linear hyaluronic acid mixture to be mixed with the condensed cHA is prepared. Specifically, hyaluronic acid powder (HA powder) and P.B.S. And an anesthetic agent (preferably lidocaine) are mixed in a warmed container to prepare a mixture containing 2 wt% of linear hyaluronic acid. The hyaluronic acid powder (HA powder) may be the same as the hyaluronic acid used for producing cHA.

As described above, linear hyaluronic acid is a non-crosslinked unmodified hyaluronic acid and serves as a lubricant when a filler is injected into a human body using a syringe.

(7) Sterilization (S9), mixing (S10) of a linear hyaluronic acid mixture and cross-linked hyaluronic acid composition, and defoaming (S11)

The linear hyaluronic acid (hyaluronic acid) mixture prepared in the step S8 and the crosslinked hyaluronic acid (cHA) composition prepared in the step S7 are sterilized. Specifically, the hyaluronic acid composition crosslinked with the linear hyaluronic acid mixture is placed in a high pressure autoclave and sterilized at 110 to 130 ° C for about 20 to 40 minutes.

Then, a 2 wt% mixture of sterilized linear hyaluronic acid (linear HA) and a cross-linked hyaluronic acid (cHA) composition was mixed, and 1.8 wt% to 3 wt% of hyaluronic acid (HA) % To 2.8 wt%.

At this time, the blending ratio is 85 wt% to 97 wt% of the cross-linked hyaluronic acid (cHA) composition (after S6 or S7 sterilization treatment), and linear hyaluronic acid (composition made by S8 process and sterilized) Is from 3 wt% to 15 wt%, preferably 90 wt% to 95 wt% of the crosslinked hyaluronic acid (cHA) composition and 5 wt% to 10 wt% of linear hyaluronic acid.

Subsequently, after the mixing, the bubbles contained in the mixture are removed and filled in a syringe (S11).

On the other hand, other fillers such as Restylane ^® have a linear hyaluronic acid ratio of 25 to 40 wt%, which is much higher than that of the filler of the present invention.

As described above, the filler according to the present invention is advantageous in that the content of linear hyaluronic acid is smaller and the content of cross-linked hyaluronic acid is higher than that of other fillers, so that the duration is longer in the human body. In addition, since the cross-linked HA is a structure twisted by the condensation process, there is an advantage that the duration in the human body is longer even when the content of the cross-linking agent is low.

In addition, since the crosslinked hyaluronic acid according to the present invention is a spherical particle, as compared with other products made of cubic particles, it is possible to obtain a hyaluronic acid having an equal or lower extrusion force even when the content of linear hyaluronic acid is small It can be injected into human body.

The composition ratio of the filler made by such a process is 2 to 3.3 parts by weight of hyaluronic acid (the sum of cross-linked HA and linear HA), 100 parts by weight of lidocaine 0.2 to 0.5 parts by weight of an anesthetic such as hydrochloride, 5 to 15 parts by weight. (Composition prepared by sterilization after linear hyaluronic acid (HA) and S8 process) of 85% by weight to 97% by weight of hyaluronic acid cross-linked with hyaluronic acid (composition subjected to sterilization after cHA, S6 or S7 process) Is from 3 wt% to 15 wt%. And, BDDE less than 1ppm in comparison to filler weight is less than 1ppm,

If the content of the linear HA is less than 3 wt%, there is a problem that an excessively large pressure output is required when the filler is injected into the syringe. When the content of the linear HA exceeds 15 wt%, the pressure output becomes too low, so that the filler continues to be pushed out from the syringe even after a single pressure load, and the elastic modulus after sterilization becomes too low.

On the other hand, in the filler, the cross-linked hyaluronic acid particles are spherical in shape and have a diameter of 90 to 1400 m. When the particle diameter of the cross-linked hyaluronic acid is smaller than 90 탆, there is a problem that it is difficult to form a shape when injected into a human body. If the particle diameter is larger than 1400 mu m, it is difficult to form an elaborate and natural shape.

The appropriate skin area is different according to each particle diameter. The summary is as shown in [Table 1].

[Table 1]

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples in order to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

[Example 1]

10 g of hyaluronic acid (HA) having an average molecular weight of 110,000 daltons is added to 171.5 ml (172 g) of 0.1 N NaOH aqueous solution, and the mixture is firstly stirred to obtain an aqueous solution of linear structure hyaluronic acid (HA). Then, 9.45 ml (10 g) of BDDE and 19.06 ml (15 g) of ethanol were mixed with the aqueous solution of hyaluronic acid and NaOH, followed by secondary stirring to cross-link the hyaluronic acid (HA). The above procedures were carried out at 35 DEG C, the primary agitation was carried out for 5 hours and the secondary agitation was carried out for 48 hours.

Then, after the cross-linked HA gel composition solution and place in the oven for 45 hours at 30 ℃ cut into a cube (a cube) of 5mm ^3. Next, the cut gel was neutralized by adding 171.5 ml (172 g) of 0.1 N HCl. The neutralized gel was subjected to first purification and purification with 50% ethanol, followed by secondary purification and purification with DI water Most of the unreacted BDDE is removed.

The purified and purified gel is placed on a plate having a circular through-hole having a diameter of 140 탆, and pressure is applied to allow the gel to pass through the circular through-hole. The gel that has passed through the circular through hole is spherical particles having a constant diameter.

Subsequently, a gel composed of spherical particles of a predetermined diameter was put into a container, and then a portion of the liquid component contained in the gel was removed by stirring at 50 DEG C and 150R.PM under a pressure of -0.85 bar to -0.9 bar for 48 to 72 hours Condensate. Specifically, 1,600 g of the liquid component in 2,000 g of the particle-adjusted gel is removed and condensed. By this condensation process, HA becomes an entangled structure in the linear structure.

On the other hand, linear HA powders (untreated and unbonded HA) and P.B.S. And lidocaine to prepare a mixture containing 2 wt% of linear HA and sterilization of the linear HA mixture and the condensed mixture, respectively, followed by mixing at a weight ratio of 95 (condensed mixture): 5 (linear HA mixture). The bubbles contained in the mixture are then removed and filled in a syringe.

The composition ratio of the filler made by such a process was 2.4 parts by weight of hyaluronic acid (sum of cross-linked HA and linear HA), 0.3 part by weight of lidocaine, and 0.1 part by weight of lidocaine based on 100 parts by weight of water for injection (WFI) PBS 11 parts by weight. The weight ratio of the condensed mixture to the linear HA mixture is 95: 5, and the diameter of the spherical particles is 200 m.

[Example 2]

Is the same as Embodiment 1 except that the condensation step (S7) is not performed.

[Comparative Example 1]

The filler of Comparative Example 1 is Restylane ^®, which is commercially available. Of the total HA content of Restylane ^®, the cHA and linear HA contents are 75% and 25%, respectively, and are composed of cube particles.

[Comparative Example 2]

The cross-linked hyaluronic acid (cHA) gel prepared in the condensation process was placed on a plate having a "square" through-hole, and then pressure was passed through the through-hole to form a cube having a length of 161 μm on one side. Except for this point, Comparative Example 2 is the same as Example 1.

On the other hand, the volume of cubic particles having a length of 161 m on one side is the same as the volume of spherical particles (diameter 200 m) of Example 1.

[Comparative Example 3]

The same as Example 1 except that the weight ratio of the condensed mixture to the linear HA mixture was 98: 2.

[Comparative Example 4]

The same as Example 1 except that the weight ratio of the condensed mixture to the linear HA mixture was 84:16.

[Experimental Example 1]

The fillers of Examples 1 and 2 and Comparative Example 1 were injected into the eye wrinkles of the patient to evaluate the degree of wrinkle improvement and the results are summarized in Table 2 below.

For evaluation of eye wrinkles, a whole-body imaging system (Robo Skin Analyzer CS50, Inforward, INC., Japan) was applied.

[Table 2]

As shown in the table, it can be seen that the wrinkle improvement ratio of Example 1 is better than that of Example 2 and Comparative Example 1. This is because the filler of Example 1 has a structure in which the molecular structure of the cross-linked HA (cHA) is twisted by the condensation process, and such a twisted structure contributes to shape stability together with cross-linking.

In Example 2, the rate of wrinkle improvement is similar to that in Comparative Example 1. (95wt%) in the filler even when the cross-linking agent is used in a small amount, it can be seen that the wrinkle improvement lasts for almost the same level as the existing product (Comparative Example 1).

[Experimental Example 2]

The extrusion pressure (extrusion pressure) was measured for the fillers of Example 1 and Comparative Examples 1 to 4, and the results are summarized in Table 3. The pressure output was measured up to 6 mm at a constant speed of 1 mm / min using a 27 gauge needle mounted on a syringe and using an EZ-S SHIMADZU instrument.

[Table 3]

As shown in the above table, since the linear HA content of Example 1 (linear HA 5 wt%, spherical particles) is much smaller than that of Comparative Example 1 (linear HA 25 wt%, square particles) Which is similar to that of Therefore, the filler according to the present invention can obtain a desired pressure output even with a much smaller dose of linear HA, thereby increasing the proportion of crosslinked HA that does not decompose well in the human body, .

On the other hand, in Comparative Example 2, the content of linear HA (5 wt%) is the same as in Example 1, but it is not preferable because the particle size is a cubic body and the pressure output is excessively large.

In Comparative Example 3 (linear HA 2 wt%, spherical particles), the content of linear HA serving as a lubricating oil was low, and thus the pressure output was excessively large. In Comparative Example 4 (linear HA 16 wt%, spherical particles ) Has a problem in that the content of the linear HA is excessively large and the pressure output becomes too low, so that the filler continues to flow out even after removing the pressure to the syringe.

Claims (9)

Claims 1. A filler for soft tissue containing water,
Based on 100 parts by weight of water contained in the filler,
2.0 to 3.3 parts by weight of hyaluronic acid; And
0.2 to 0.5 parts by weight of an anesthetic agent,
Wherein the hyaluronic acid has a hyaluronic acid content of 85 wt% to 97 wt% and a non-crosslinked linear hyaluronic acid content of 3 wt% to 15 wt% after cross-
Wherein the crosslinked hyaluronic acid particles have a spherical shape and a diameter of 90 占 퐉 to 1400 占 퐉. The method according to claim 1,
Further comprising 5 to 15 parts by weight of PBS,
The crosslinked hyaluronic acid has an entangled molecular structure,
Wherein the anesthetic is lidocaine,
Wherein the crosslinking agent is BDDE. (a) preparing a cross-linked hyaluronic acid (cHA) composition by adding a polymeric hyaluronic acid into an aqueous alkali solution and adding thereto a cross-linking agent;
(b) cleaving the hyaluronic acid composition to make it finer and then neutralizing it by adding it in an acidic aqueous solution;
(c) placing the neutralized composition on a plate having a circular through-hole, and then applying pressure to the composition so that the composition moves down through the circular through-hole to form spherical particles with a constant diameter;
(d) stirring the spherical particles of the hyaluronic acid composition at 30 DEG C to 70 DEG C to remove a part of the liquid component so that the content of hyaluronic acid in the composition is 1.8 wt% or more and 3 wt% or less, Causing the lonic acid molecule to become an entangled structure; And
(e) mixing unmodified and unmodified linear hyaluronic acid with the composition obtained through step (d) so that hyaluronic acid is contained in an amount of 1.8 wt% to 3 wt% of the total composition,
The mixing ratio of step (e) is 85 wt% to 97 wt% of the composition after step (d), 3 wt% to 15 wt% of unmodified unmodified linear hyaluronic acid,
Wherein the diameter of the particles in the final product is 90 占 퐉 to 1400 占 퐉. (a) preparing a cross-linked hyaluronic acid (cHA) composition by adding a polymeric hyaluronic acid into an aqueous alkali solution and adding thereto a cross-linking agent;
(b) cleaving the hyaluronic acid composition to make it finer and then neutralizing it by adding it in an acidic aqueous solution;
(c) stirring the neutralized hyaluronic acid composition at 30 DEG C to 70 DEG C to remove a part of the liquid component so that the hyaluronic acid content in the composition is 1.8 wt% or more and 3.0 wt% or less, and the crosslinked hyaluronic acid molecule is twisted to be an entangled structure;
(d) placing the composition in a twisted structure on a plate having a circular through-hole, and then applying pressure to the composition so that the composition moves down through the circular through-hole to form spherical particles having a constant diameter ; And
(e) mixing unmodified and unmodified linear hyaluronic acid with a composition comprising said spherical particles so that hyaluronic acid is from 1.8 wt% to 3 wt% of the total composition,
The mixing ratio of step (e) is 85 wt% to 97 wt% of the composition after step (d), 3 wt% to 15 wt% of unmodified unmodified linear hyaluronic acid,
Wherein the diameter of the particles in the final product is 90 占 퐉 to 1400 占 퐉. The method according to claim 3 or 4,
Wherein the spherical particle hyaluronic acid composition or the neutralized hyaluronic acid composition is placed in a container of a stirrer and the mixture is stirred at 100-200 RPM for 48 ~ Lt; 0 > C for 72 hours under gauge pressure,
In the step (a), 3 to 6 wt% of polymer hyaluronic acid is mixed with the crosslinked hyaluronic acid (cHA) composition, and 3 to 6 wt% of the crosslinking agent is mixed as BDDE. . The method according to claim 3 or 4,
Prior to step (e)
Further comprising the step of mixing the unmodified, non-crosslinked hyaluronic acid powder with PBS and lidocaine to form a linear hyaluronic acid mixture,
Wherein the step (e) comprises mixing the linear hyaluronic acid mixture with the composition obtained through step (d). 6. The method of claim 5,
Wherein the micronization is performed by cutting the hyaluronic acid composition into cubes of ³ mm ³ to 10 mm ³ ,
Wherein the diameter of the circular through-hole is 60% to 80% of the particle diameter of the final product. 8. The method of claim 7,
Between the step (a) and the step (b)
Gelling the crosslinked hyaluronic acid composition in an oven at 20 DEG C to 50 DEG C for 24 hours to 72 hours. 9. The method of claim 8,
Between the step (b) and the step (c)
Further comprising refining with an alcohol and water to remove the unreacted crosslinking agent contained in the neutralized composition.

Images