Chromogenic filler compositions comprising vitamin-modified hyaluronic acid derivatives and methods of making the same

Abstract

The present disclosure relates to a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component and a method for manufacturing the same. More specifically, the aim is to provide a color-developing filler composition that is harmless to the human body by having excellent color retention and biocompatibility and not including a separate artificial color, by pre-modifying the hyaluronic acid gel with various vitamin components and providing a color-developing filler composition containing the same.

Description

Technology Field

[0001] The present disclosure relates to a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component and a method for manufacturing the same. More specifically, the aim is to provide a color-developing filler composition that is harmless to the human body by having excellent color retention and biocompatibility and not including a separate artificial color, by pre-modifying the hyaluronic acid gel with various vitamin components and providing a color-developing filler composition containing the same. Background Technology

[0002] With active research recently being conducted on anti-aging to prevent skin aging, cosmetic compositions containing hyaluronic acid as a main ingredient are attracting attention. In particular, hyaluronic acid is a component naturally produced by fibroblasts that make up the dermis of the skin; it is known that if the skin's natural production of hyaluronic acid decreases due to various environmental and physical factors, problems such as reduced skin elasticity, sagging, and wrinkle formation occur.

[0003] To improve skin conditions such as dryness and wrinkles caused by a deficiency of hyaluronic acid, cosmetic compositions containing hyaluronic acid and various biocompatible ingredients are being proposed as various dermal fillers. These dermal fillers are introduced into specific areas of the skin to expand soft tissues and are widely used to improve skin elasticity or reduce wrinkles.

[0004] However, conventional filler compositions containing hyaluronic acid have a problem in that they fail to sufficiently exhibit the required biocompatibility depending on various factors, such as the content of the constituent components and the manufacturing process, as well as factors such as the skin condition of the subject to application.

[0005] In addition, conventional filler compositions containing hyaluronic acid provide separate beneficial effects to the skin by including additional functional ingredients, but since these functional ingredients are included in the composition by mixing with the already manufactured hyaluronic acid gel, they are not uniformly distributed within the matrix structure of the hyaluronic acid gel, and as a result, there is a problem that the release of the functional ingredients is inconsistent or uneven.

[0006] Furthermore, in the case of color-producing filler compositions intended to express or improve color in specific skin areas, they additionally contain ingredients to produce color; however, current color-producing fillers contain artificial pigments, and consequently, when these filler compositions are introduced into the body, they appear unnatural and lack biocompatibility, leading to problems such as inflammation. The problem to be solved

[0007] The problem that the present disclosure aims to solve is to provide a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component, which has excellent color retention ability, excellent biocompatibility, and is harmless to the human body.

[0008] Another problem that the present disclosure aims to solve is to provide a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component, which has excellent ability to repair soft tissue, increase volume, and / or improve wrinkles, possesses excellent color-developing power, and is useful for improving skin appearance.

[0009] Another problem that the present disclosure aims to solve is to provide a method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component, wherein the color-developing filler composition has excellent color retention, excellent biocompatibility, and is harmless to the human body.

[0010] Another problem that the present disclosure aims to solve is to provide a method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component, wherein the color-developing filler composition has excellent ability to repair soft tissue, increase volume, and / or improve wrinkles, possesses excellent color-developing power, and is useful for improving skin appearance.

[0011] The objects of the present invention are not limited to those mentioned above, and other unmentioned objects and advantages of the present invention may be understood from the following description and will be more clearly understood by the embodiments of the present invention. Furthermore, it will be readily apparent that the objects and advantages of the present invention can be realized by the means and combinations thereof described in the specification. means of solving the problem

[0012] According to one embodiment of the present disclosure for achieving the aforementioned objectives, a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component may be provided.

[0013] For example, the hyaluronic acid derivative may comprise one or more of hyaluronic acid, a salt thereof, and a cross-linked hyaluronic acid gel thereof.

[0014] For example, the weight average molecular weight of the hyaluronic acid included in the hyaluronic acid derivative may be 1,000 to 5,000,000 Da.

[0015] For example, the content of hyaluronic acid included in the hyaluronic acid derivative may be 1 to 5 weight percent based on 100 weight percent of the total color-developing filler composition.

[0016] For example, the above vitamin component may include vitamin B12.

[0017] For example, the vitamin B12 may be one or more selected from the group consisting of cyanocobalamin, methylcobalamin, deoxyadenosylcobalamin, and hydroxycobalamin.

[0018] For example, the above vitamin B12 may be cyanocobalamin.

[0019] For example, the content of the vitamin B12 may be 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0020] For example, the above vitamin component may additionally include vitamin B5.

[0021] For example, the content of the vitamin B5 may be 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0022] For example, the cross-linked hyaluronic acid gel may be cross-linked using a cross-linking agent.

[0023] For example, the crosslinking may be performed under one or more alkaline aqueous solutions selected from the group consisting of NaOH, KOH, NaHCO3 and LiOH, and the concentration of the alkaline aqueous solution may be 0.1 to 0.5 N.

[0024] For example, the crosslinking agent may vary as a compound containing two or more epoxy functional groups. Crosslinking agents that may be used in the present disclosure include 1,4-butanediol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, and diglycerol polyglycidyl ether. It may be one or more selected from the group consisting of diglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, 1,2-bis(2,3-epoxypropoxy)ethylene, pentaerythritol polyglycidyl ether, and sorbitol polyglycidyl ether.

[0025] For example, the crosslinking agent may be one or more selected from 1,4-butanediol diglycidyl ether (BDDE) and neopentyl glycol diglycidyl ether.

[0026] For example, the above-mentioned color-developing filler composition may additionally include an anesthetic.

[0027] For example, the anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dicyclonine, Ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine (octacaine), orthocaine,It may be selected from the group consisting of oxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

[0028] For example, the anesthetic may be lidocaine or a salt thereof.

[0029] For example, the anesthetic may be lidocaine hydrochloride.

[0030] For example, the content of the anesthetic may be included in an amount of 0.1 to 1.0 weight% based on 100 weight% of the total color-developing filler composition.

[0031] For example, the color-developing filler composition may additionally include a buffer solution.

[0032] For example, the buffer component included in the above buffer solution may be one or more selected from the group consisting of sodium monohydrogen phosphate or its hydrate, sodium dihydrogen phosphate or its hydrate, and sodium chloride.

[0033] For example, the buffer component included in the above buffer solution may be included at a concentration of about 0.1 to about 10.0 g / L, for example, about 0.3 to about 2 g / L, based on the total buffer solution.

[0034] For example, the above-mentioned color-developing filler composition may additionally include one or more of polynucleotides and succinic acid as regenerative components.

[0035] For example, the content of the regenerating component may be 0.001 to 10.0 weight% based on 100 weight% of the total color-developing filler composition.

[0036] For example, the weight ratio of polynucleotide and succinic acid included in the above-mentioned regenerating component may be 10:1 to 1:10.

[0037] For example, the above-mentioned color-developing filler composition may additionally include one or more of tranexamic acid and niacinamide as whitening ingredients.

[0038] For example, the content of the whitening ingredient may be 0.001 to 10.1 weight% based on 100 weight% of the total color-developing filler composition.

[0039] For example, the weight ratio of polynucleotide and succinic acid included in the whitening ingredient may be 10:1 to 1:10.

[0040] For example, the color-developing filler composition may further include a dialkyl ester having 2 to 10 carbon atoms.

[0041] According to another embodiment of the present disclosure for achieving the aforementioned objectives, a method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component may be provided.

[0042] For example, the method for manufacturing the above-mentioned color-developing filler composition may be a method comprising the following.

[0043] A first step of mixing sodium hyaluronate and vitamin B12, and then adding a first alkaline aqueous solution to modify the sodium hyaluronate into vitamin B12;

[0044] A second step of crosslinking into a first hyaluronic acid gel by adding a second alkaline aqueous solution containing a crosslinking agent to an aqueous sodium hyaluronate solution modified with vitamin B12;

[0045] A third step of preparing a second hyaluronic acid gel by grinding the hyaluronic acid gel and adding a buffer solution to adjust the pH of the aqueous solution to a range of 6 to 8;

[0046] Step 4: preparing a third hyaluronic acid gel by grinding and homogenizing the second hyaluronic acid gel and then adjusting the content using a buffer solution;

[0047] Step 5: Preparing a color-developing filler composition using a hyaluronic acid derivative comprising a third hyaluronic acid gel.

[0048] For example, the first alkaline aqueous solution of the first step above may be one or more alkaline aqueous solutions selected from the group consisting of NaOH and KOH.

[0049] For example, the first alkaline aqueous solution of the first step may be an aqueous solution further comprising a dialkyl ester having 2 to 10 carbon atoms.

[0050] For example, the vitamin B12 of the first step above may be cyanocobalamin and may be included in an amount of 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0051] For example, the crosslinking agent of the second step may be one or more selected from 1,4-butanediol diglycidyl ether (BDDE) and neopentyl glycol diglycidyl ether.

[0052] For example, the second alkaline aqueous solution of the second step above may be an aqueous solution further containing aminosalicylic acid.

[0053] For example, the second alkaline aqueous solution of the second step may be one or more alkaline aqueous solutions selected from the group consisting of NaOH, KOH, NaHCO3, and LiOH.

[0054] For example, the buffer solution of the third step may additionally contain an anesthetic.

[0055] For example, the anesthetic may be lidocaine or a salt thereof.

[0056] For example, the anesthetic may be lidocaine hydrochloride.

[0057] For example, the content of the anesthetic may be included in an amount of 0.1 to 1.0 weight% based on 100 weight% of the total color-developing filler composition.

[0058] For example, the buffer component included in the above buffer solution may be one or more selected from the group consisting of sodium monohydrogen phosphate or its hydrate, sodium dihydrogen phosphate or its hydrate, and sodium chloride.

[0059] For example, the buffer component included in the above buffer solution may be included at a concentration of about 0.1 to about 10.0 g / L, for example, about 0.3 to about 2 g / L, based on the total buffer solution.

[0060] For example, in the fourth step above, the buffer solution may additionally contain vitamin B5.

[0061] For example, the content of the vitamin B5 may be 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0062] For example, in the fourth step above, the buffer solution may additionally include one or more of polynucleotides and succinic acid as regenerating components.

[0063] For example, the content of the regenerating component may be 0.001 to 10.0 weight% based on 100 weight% of the total color-developing filler composition.

[0064] For example, the weight ratio of polynucleotide and succinic acid included in the above-mentioned regenerating component may be 10:1 to 1:10.

[0065] For example, in the fourth step above, the buffer solution may additionally include one or more of tranexamic acid and niacinamide as whitening ingredients.

[0066] For example, the content of the whitening ingredient may be 0.001 to 10.1 weight% based on 100 weight% of the total color-developing filler composition.

[0067] For example, the weight ratio of tranexamic acid and niacinamide included in the whitening ingredient may be 10:1 to 1:10. Effects of the invention

[0068] According to the present disclosure, a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component can be provided, which has excellent color retention ability, excellent biocompatibility, and is harmless to the human body.

[0069] In addition, according to the present disclosure, a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component may be provided, which has excellent ability to repair soft tissue, increase volume, and / or improve wrinkles, possesses excellent color-developing power, and is useful for improving the appearance of the skin.

[0070] In addition, according to the present disclosure, a method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component can be provided, wherein the color-developing filler composition has excellent color retention ability, excellent biocompatibility, and is harmless to the human body.

[0071] In addition, according to the present disclosure, a method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component may be provided, which has excellent ability to repair soft tissue, increase volume, and / or improve wrinkles, possesses excellent color-developing power, and is useful for improving the appearance of the skin.

[0072] In addition to the effects described above, specific effects of the present invention are described together with the following explanation of specific details for implementing the invention. Furthermore, the effects of the present invention are not limited to those mentioned above and can be easily realized by means and combinations thereof described in the specification. Brief explanation of the drawing

[0073] FIG. 1 is a flowchart schematically illustrating a method for manufacturing a color-developing filler composition according to one embodiment of the present disclosure. Specific details for implementing the invention

[0074] The terms or words used in this specification and claims are not intended to be interpreted as being limited to their commonly accepted dictionary meanings, and a person of ordinary knowledge in the art to which this disclosure pertains will clearly understand that said terms or words are used in the sense of conveying what this disclosure means within the scope of expressing the concept that this specification and claims obviously intend to convey.

[0075] Furthermore, a person skilled in the art will clearly understand that the embodiments and configurations described in this specification are merely preferred embodiments presented as examples to enable a person skilled in the art to understand and reproduce the present disclosure, and are not intended to limit the present disclosure thereto.

[0076] Furthermore, the descriptions and specific embodiments regarding each configuration described in this specification may be obviously applicable to each other descriptions and embodiments. That is, a person skilled in the art will clearly understand that all combinations of the various configurations and specific embodiments disclosed in this specification fall within the scope disclosed herein.

[0077] As used herein, the term 'and / or' is a term comprising each of the mentioned items and all combinations of one or more thereof. Additionally, the singular form includes the plural form unless otherwise noted.

[0078] As used herein, the terms 'comprising' and / or 'comprising' do not exclude the existence or addition of items other than those mentioned.

[0079] In this specification, a numerical range indicated by the term 'to' represents a numerical range that includes the values ​​listed before and after the term as a lower limit and an upper limit, respectively. Where multiple numerical values ​​are disclosed as the upper and lower limits of an arbitrary numerical range, the numerical range disclosed in this specification may be understood as an arbitrary numerical range in which any one of the multiple lower limits and any one of the multiple upper limits are set as the lower limit and upper limit, respectively.

[0080] The terms ‘about’ or ‘approximately’ used in this specification, when used, mean a value or numerical range within 10% of the value or numerical range listed after the said term.

[0081] As used herein, the term "composition" includes a product comprising a specific component in a specific amount and any product directly or indirectly caused by a combination of a specific component in a specific amount.

[0082] Terms or words used in this specification and claims should not be interpreted as being limited to their ordinary dictionary meanings, but should be interpreted in a meaning and concept consistent with the technical spirit of this disclosure, based on the principle that the discloser may appropriately define the concept of the terms to best describe their disclosure. Accordingly, the configurations described in the embodiments described in this specification are merely one preferred embodiment of this disclosure and do not represent all of the technical spirit of this disclosure; therefore, it should be understood that various equivalents and modifications that can replace them may exist at the time of filing this application.

[0083] Meanwhile, each description and embodiment disclosed in this specification may also be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed in this specification fall within the scope of this disclosure, and descriptions omitted in one embodiment may be interpreted in the same manner as described in other embodiments. Furthermore, the scope of this disclosure should not be considered limited by the specific descriptions provided below.

[0084] According to one embodiment of the present disclosure, a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component may be provided.

[0085] The term "hyaluronic acid" as used in this disclosure is used to mean all of the following: hyaluronic acid itself, salts of hyaluronic acid, cross-linked hyaluronic acid gels of hyaluronic acid and / or salts thereof, and combinations thereof.

[0086] Hyaluronic acid is a non-sulfurized glycosaminoglycan widely distributed throughout the human body, including connective tissue, epithelial tissue, and nerve tissue. It is abundant in various layers of the skin and, based on its excellent hydration ability, maintains skin moisture levels and increases elasticity. It is a component with various functions, such as performing important functions in the composition and maintenance of various cell matrices and participating in tissue repair mechanisms.

[0087] Furthermore, hyaluronic acid is a biopolymer composed of linearly linked repeating units of N-acetyl-D-glucosamine and D-glucuronic acid. It plays a role in supplying moisture to the skin, binding to elastin and collagen fibers to increase skin elasticity and smoothness, and filling the spaces between cells; therefore, a deficiency in hyaluronic acid can lead to dry skin and the formation of wrinkles. Based on these characteristics, various dermal fillers are formulated to contain hyaluronic acid to increase the skin's moisture content when injected, thereby improving skin elasticity and reducing wrinkles.

[0088] Furthermore, based on its excellent biocompatibility, hyaluronic acid can be included in filler compositions that are injected into soft tissues to enhance their volume and fullness to the desired level. In particular, various hyaluronic acid derivatives can improve the inherent properties of hyaluronic acid or impart other characteristics by modifying its chemical structure; for example, hyaluronic acid derivatives possess more stable shape retention than hyaluronic acid, allowing the intended shape to last longer, controlling the rate of degradation and absorption into soft tissues, and enhancing the moisture retention capacity of specific skin areas.

[0089] For example, the hyaluronic acid derivative may comprise one or more of hyaluronic acid, a salt thereof, or a cross-linked hyaluronic acid gel thereof. The formulation of the hyaluronic acid derivative may be a liquid, a gel, etc., and may exhibit a natural skin radiance when applied to a skin filler by having high light transmittance.

[0090] For example, the salts of the hyaluronic acid mentioned above include all inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, and cobalt hyaluronate, and organic salts such as tetrabutylammonium hyaluronate, but are not limited to these. In the present disclosure, hyaluronic acid itself or each of its salts may be used individually, and two or more of these may be used in combination.

[0091] For example, the weight average molecular weight of the hyaluronic acid included in the hyaluronic acid derivative may be 1,000 to 5,000,000 Da, preferably about 1,000,000 to 5,000,000 Da, and more preferably about 1,800,000 to 2,600,000 Da.

[0092] If the weight average molecular weight of the hyaluronic acid is less than 1,000 Da, there is a problem that the shape retention ability is insufficient when applied to a skin filler because the degree of crosslinking of the hyaluronic acid is insufficient due to the use of ultra-low molecular weight hyaluronic acid, and if the weight average molecular weight of the hyaluronic acid is greater than 5,000,000 Da, there is a problem that the morphology of the hyaluronic acid increases more than necessary, resulting in a large difference from the morphology of the soft tissue when the skin filler is applied to the soft tissue. Therefore, it is desirable for the weight average molecular weight of the hyaluronic acid to satisfy the above numerical range.

[0093] For example, the content of hyaluronic acid included in the hyaluronic acid derivative may be 1 to 5 weight% based on 100 weight% of the total color-developing filler composition, preferably 1.5 to 4.0 weight%, more preferably 1.8 to 3.5 weight%, and even more preferably 1.9 to 2.8 weight%. If the hyaluronic acid is included in an amount of less than 1 weight% based on 100 weight% of the total color-developing filler composition, there is a problem that the shape-maintaining power of the color-developing filler composition is insufficient, and if the hyaluronic acid derivative is included in an amount of more than 5 weight% based on 100 weight% of the total color-developing filler composition, there is a problem that uneven color development occurs because the hyaluronic acid is not sufficiently modified with vitamin components; therefore, it is desirable for the content of the hyaluronic acid derivative to satisfy the above numerical range.

[0094] According to one embodiment of the present disclosure, the vitamin component may include vitamin B12.

[0095] As used in this disclosure, the term "vitamin B12" refers to an essential vitamin that plays a significant role in numerous physiological processes within the human body. It is a water-soluble vitamin of great importance, particularly in hematology and the nervous system. It is known that a deficiency of cobalamin can lead to skin symptoms such as hyperpigmentation, changes in hair and nails, and oral changes including glossitis. Vitamin B12 exists in various forms within the body and is a cofactor for homocysteine ​​methyltransferase and methylmalonyl-CoA mutase. However, vitamin B12 is not produced endogenously in fungi, plants, or animals, and can be synthesized virtually only by prokaryotes such as bacteria. Consequently, humans and other animals obtain vitamin B12 from food or supplements. Furthermore, due to the chemical complexity of vitamin B12, it is very difficult to synthesize it anew, so it is commercially produced by microbial fermentation.

[0096] In addition, the above vitamin B12 exists in various forms, including cyano-, methyl-, deoxyadenosyl-, and hydroxy-cobalamin forms, and among these, cyanocobalamin is a form of vitamin commonly used in dietary supplements such as multivitamins because it is a particularly stable form, although it does not occur naturally.

[0097] The four forms of vitamin B12 mentioned above are all deep red crystals due to the color of the cobalt-corine complex. Among these, cyanocobalamin is one of the vitamin forms of vitamin B12 because it can be metabolized in the body into an active coenzyme form. Cyanocobalamin is a synthetic form of vitamin B12; although it does not occur naturally, it is a stable form and is therefore the form of vitamin commonly used in dietary supplements such as multivitamins. In other words, because the cyanocobalamin form is easy to crystallize and is not sensitive to air oxidation, it can generally be used as a form of B12 in food additives and many common multivitamins. Commercially, it is produced by bacteria. Pure cyanocobalamin exhibits a deep pink color associated with most of the octahedral cobalt(II) complex, and its crystals form easily and grow to millimeter sizes.

[0098] For example, the vitamin B12 may be one or more selected from the group consisting of cyanocobalamin, methylcobalamin, deoxyadenosylcobalamin, and hydroxycobalamin, and for example, the vitamin B12 may be cyanocobalamin.

[0099] A color-developing filler composition according to one embodiment of the present disclosure can exhibit pink or red color-developing characteristics when containing cyanocobalamin as vitamin B12. In particular, it was confirmed that the color-developing filler composition exhibited stability over a period of up to 90 days and excellent color-developing power, even though it does not contain artificial colorants or artificial pigments. Furthermore, by pre-modifying sodium hyaluronate with vitamin B12, the color-developing filler composition can have an excellent effect with a smaller amount compared to when vitamin B12 is included during the cross-linking process of sodium hyaluronate, and color retention is also improved.

[0100] For example, the content of the vitamin B12 may be 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition, preferably 0.01 to 0.8 weight%, more preferably 0.02 to 0.7 weight%, and even more preferably 0.04 to 0.6 weight%.

[0101] According to one embodiment of the present disclosure, the vitamin component may additionally include vitamin B5, and the content of vitamin B5 may be 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0102] The above-mentioned color-developing filler composition may additionally have a moisturizing effect by additionally including vitamin B5, and the vitamin B5 may provide an additional moisturizing effect to the skin tissue to which the color-developing filler is applied by including it in an amount satisfying the above numerical range.

[0103] According to one embodiment of the present disclosure, the color-developing filler composition may include additional components, and the additional components may be one or more selected from the group consisting of glycosaminoglycans, proteoglycans, atelocollagen, and beta-glucan.

[0104] The above glycosaminoglycans, proteoglycans, atelocollagens, and beta-glucans are components found in skin tissue and are known to perform the function of ensuring skin elasticity and maintaining moisture content. When the filler composition according to the present disclosure includes the above additional components, the filler composition can maintain or enhance the natural characteristics of the skin by delivering the above additional components to surrounding soft tissue when applied.

[0105] For example, the additional component may be included in an amount of 2.0 to 4.0 weight% based on 100 weight% of the total color-developing filler composition. If the amount of the additional component is less than 2.0 weight% based on 100 weight% of the total filler composition, there is a problem that the antioxidant capacity and skin improvement effect provided by the additional component are insufficient, and if the amount of the additional component is more than 4.0 weight% based on 100 weight% of the total filler composition, there is a problem that the additional component included in the filler composition is not sufficiently emulsified. Therefore, it is desirable for the amount of the additional component included in the filler composition to satisfy the above numerical range, and more preferably, the amount of the additional component included in the filler composition may be 2.5 to 3.5 weight% based on 100 weight% of the total filler composition, and even more preferably, the amount of the additional component included in the filler composition may be 2.8 to 3.2 weight% based on 100 weight% of the total filler composition.

[0106] According to one embodiment of the present disclosure, the cross-linked hyaluronic acid gel of the hyaluronic acid and / or its salt may comprise a cross-linked hyaluronic acid gel, and the cross-linked hyaluronic acid gel may be prepared by cross-linking the hyaluronic acid and / or its salt. The cross-linked hyaluronic acid gel or hyaluronic acid complex prepared by cross-linking the hyaluronic acid and / or its salt may be cross-linked using a cross-linking agent, and may be made to form a cross-linked form by controlling the acid-base balance.

[0107] For example, the cross-linked hyaluronic acid gel may be cross-linked using a cross-linking agent.

[0108] When the above-mentioned cross-linked hyaluronic acid gel or hyaluronic acid complex is cross-linked using a cross-linking agent, a method of using the cross-linking agent under an alkaline aqueous solution may be used. For example, the cross-linking may be performed under one or more alkaline aqueous solutions selected from the group consisting of NaOH, KOH, NaHCO3, and LiOH, and the concentration of the alkaline aqueous solution may be 0.1 to 0.5 N. For example, an aqueous NaOH solution may be used as the alkaline aqueous solution, and may be used at a concentration of about 0.25 N.

[0109] For example, the crosslinking agent may vary as a compound containing two or more epoxy functional groups. Crosslinking agents that may be used in the present disclosure include 1,4-butanediol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, and diglycerol polyglycidyl ether. It may be one or more selected from the group consisting of (diglycerol polyglycidyl ether), glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, 1,2-bis(2,3-epoxypropoxy)ethylene, pentaerythritol polyglycidyl ether, and sorbitol polyglycidyl ether, but is not limited thereto.

[0110] For example, the crosslinking agent may be 0.001 to 5 weight% based on 100 weight% of the total color-developing filler composition, and preferably 0.005 to 4 weight%.

[0111] For example, the crosslinking agent may be one or more selected from 1,4-butanediol diglycidyl ether (BDDE) and neopentyl glycol diglycidyl ether.

[0112] For example, the crosslinking agent may be 1,4-butanediol diglycidyl ether (BDDE). When the crosslinking agent is 1,4-butanediol diglycidyl ether, the biocompatibility of the color-developing filler composition according to the present disclosure may be further improved, and it may exhibit relatively low toxicity.

[0113] For example, the crosslinking agent may be neopentyl glycol diglycidyl ether. When the crosslinking agent is neopentyl glycol diglycidyl ether, the color-developing filler composition according to the present disclosure may have excellent biocompatibility while the color characteristics due to vitamin B12 may be expressed more stably.

[0114] When the above-mentioned cross-linked hyaluronic acid gel or hyaluronic acid complex is formed into a cross-linked form by controlling acid-base equilibrium, the above-mentioned cross-linked hyaluronic acid gel or hyaluronic acid complex may be an auto-crosslinkable hyaluronic acid complex utilizing acid-base equilibrium. The above-mentioned auto-crosslinkable hyaluronic acid complex utilizing acid-base equilibrium may be prepared by crosslinking a high molecular weight hyaluronic acid component and a low molecular weight hyaluronic acid component through bicomponent mixing utilizing acid-base equilibrium and an oxidation-reduction process, for example, by the step of preparing a first mixture having a pH of 2.0 to 3.0 containing a first hyaluronic acid component; and the step of preparing a second mixture having a pH of 5.5 to 6.5 containing a second hyaluronic acid component; It can be manufactured according to a method for manufacturing a hyaluronic acid complex, comprising the step of mixing the first mixture and the second mixture and adjusting the pH to 6.5 to 7.5 to manufacture a cross-linked hyaluronic acid complex.

[0115] In the method for preparing the hyaluronic acid complex above, the step of preparing the first mixture may include: preparing an aqueous solution in which a first hyaluronic acid component having a number average molecular weight of 1,000 to 20,000 kDa is dissolved; and preparing the first mixture by mixing 2-ethoxyethanol and Na2CO3 with the aqueous solution.

[0116] In the method for preparing the hyaluronic acid complex above, the first hyaluronic acid component included in the first mixture may be 25 to 35 parts by weight based on 100 parts by weight of the first mixture.

[0117] In the method for preparing the hyaluronic acid complex above, the 2-ethoxyethanol included in the first mixture may be 1.5 to 3.0 parts by weight based on 100 parts by weight of the first mixture.

[0118] In the method for preparing the hyaluronic acid complex above, the Na2CO3 included in the first mixture may be 2.5 to 4.0 parts by weight based on 100 parts by weight of the first mixture.

[0119] In the method for preparing the hyaluronic acid complex above, the step of preparing the second mixture may include: preparing an aqueous solution in which a second hyaluronic acid component having a number average molecular weight of 100 to 500 kDa is dissolved; and preparing the second mixture by mixing 2-hydroxybenzaldehyde and NaHCO3 with the aqueous solution.

[0120] In the method for manufacturing the hyaluronic acid complex above, the second hyaluronic acid component included in the second mixture may be 20 to 45 parts by weight based on 100 parts by weight of the second mixture.

[0121] In the method for preparing the hyaluronic acid complex above, the 2-hydroxybenzaldehyde included in the second mixture may be 2.5 to 3.5 parts by weight based on 100 parts by weight of the second mixture.

[0122] In the method for preparing the hyaluronic acid complex above, the NaHCO3 included in the second mixture may be 2.5 to 4.0 parts by weight based on 100 parts by weight of the second mixture.

[0123] In the method for preparing the hyaluronic acid complex above, the step of mixing the first mixture and the second mixture and adjusting the pH to 6.5 to 7.5 may include the step of mixing the first mixture and the second mixture, then adding hydrogen peroxide and stirring; and the step of adding NaOH to the stirred mixture to adjust the pH to 6.5 to 7.5.

[0124] According to one embodiment of the present disclosure, the color-developing filler composition may further include an anesthetic, and the anesthetic may be an anesthetic known in the art, preferably a local anesthetic, and one type of anesthetic may be used, or two or more types of anesthetics may be used. The anesthetic, when included in the color-developing filler composition, may help to alleviate pain that occurs during the process of introducing the color-developing filler composition into soft tissue and during the process of stably placing the color-developing filler composition in soft tissue for a certain period of time from introduction.

[0125] For example, the above anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dicyclonine, Ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine (octacaine), orthocaine,It may be selected from the group consisting of oxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

[0126] For example, the anesthetic may be lidocaine or a salt thereof, and for example, the anesthetic may be lidocaine hydrochloride. The anesthetic may be included in a buffer solution, for example, described below, and the content of the anesthetic may be 0.1 to 1.0 weight% based on 100 weight% of the total color-developing filler composition.

[0127] According to one embodiment of the present disclosure, the color-developing filler composition may further include a buffer solution.

[0128] For example, the above buffer solution comprises citric acid, sodium monohydrogen phosphate or its hydrate, sodium dihydrogen phosphate or its hydrate, acetic acid, diethyl barbituric acid, sodium acetate, TAPS ((tris(hydroxymethyl)methylamino)propanesulfonic acid), Bicine ((2-bis(2-hydroxyethyl)amino)acetic acid), tris(tris(hydroxymethyl)ammonium methane), Tricine (N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), TES (2-[[1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl]amino]methanesulfonic acid) and PIPES It may be an aqueous solution of one or more buffer components selected from the group consisting of (piperazine-N,N'-bis(2-ethanesulfonic acid)).

[0129] For example, the buffer component included in the above buffer solution may be one or more selected from the group consisting of sodium monohydrogen phosphate or its hydrate, sodium dihydrogen phosphate or its hydrate, and sodium chloride.

[0130] For example, the buffer component included in the above buffer solution may be included at a concentration of about 0.1 to about 10.0 g / L, for example, about 0.3 to about 2 g / L, based on the total buffer solution.

[0131] According to one embodiment of the present disclosure, the color-developing filler composition may additionally include one or more of polynucleotides and succinic acid as regenerative components. When the polynucleotide is included in the color-developing filler composition according to the present disclosure, it can improve tissue damage of surrounding soft tissue, and succinic acid can also achieve skin regeneration functions by accelerating the tissue regeneration rate of surrounding soft tissue.

[0132] For example, the content of the regenerative component may be 0.001 to 10.0% by weight based on 100% by weight of the total color-developing filler composition. By including the regenerative component in an amount satisfying the above numerical range, the color-developing filler composition according to the present disclosure can provide a regenerative effect on surrounding tissue when introduced into skin tissue.

[0133] For example, the weight ratio of polynucleotide and succinic acid included in the regenerative component may be 10:1 to 1:10. By including the polynucleotide and succinic acid in the above weight ratio, the effect of regenerating tissue damage in surrounding soft tissue can be maximized.

[0134] According to one embodiment of the present disclosure, the color-developing filler composition may additionally include one or more of tranexamic acid and niacinamide as a whitening ingredient. The whitening ingredient, when included in the color-developing filler composition according to the present disclosure, can improve the radiance of the skin and promote the decomposition of deposited melanin pigment.

[0135] For example, the content of the whitening ingredient may be 0.001 to 10.0% by weight based on 100% by weight of the total color-developing filler composition. By including the whitening ingredient in an amount satisfying the above numerical range, the color-developing composition according to the present disclosure can provide brightening and whitening effects by improving radiance in addition to exhibiting a specific color when introduced into skin tissue.

[0136] For example, the weight ratio of tranexamic acid and niacinamide included in the whitening ingredient may be 10:1 to 1:10. By including the tranexamic acid and niacinamide in the above weight ratio, the skin radiance improvement effect can be maximized.

[0137] According to one embodiment of the present disclosure, the color-developing filler composition comprising the hyaluronic acid derivative and vitamin B12 may further comprise an isotonic agent.

[0138] For example, the isotonic agent may be sodium chloride, and the isotonic agent may be included in the buffer solution. The isotonic agent included in the buffer solution may be included at a concentration of about 5.0 to about 9.0 g / L based on the total buffer solution.

[0139] According to one embodiment of the present disclosure, the color-developing filler composition comprising the hyaluronic acid derivative and vitamin B12 may additionally include acceptable components that may be included in the manufacture of the filler, in addition to the components listed above.

[0140] For example, the above acceptable component may be a component that enables the color-developing filler composition to be very useful for cosmetic or therapeutic purposes due to its characteristic elastic properties, extrusion force, and enzyme resistance. For example, the above acceptable component may be a component that enables the color-developing filler composition to be usefully used as a composition for filling or replacing biological tissue, a composition for filling wrinkles, remodeling of the face, or increasing lip volume, a composition for use in the treatment of skin rehydration by mesotherapy, a composition for replacing or temporarily supplementing synovial fluid in arthritis, a composition for increasing the volume of the sphincter or urethra in urology / gynecology, a composition for an adjuvant in cataract surgery or for the treatment of glaucoma in ophthalmology, a gel that releases an active substance in pharmaceuticals, a composition for bone reconstruction, increasing vocal cord volume in surgery, or for the preparation of surgical tissue.

[0141] According to another embodiment of the present disclosure for achieving the aforementioned objectives, a method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component may be provided.

[0142] For example, the method for manufacturing the above-mentioned color-developing filler composition may be a method comprising the following.

[0143] A first step of mixing sodium hyaluronate and vitamin B12, and then adding a first alkaline aqueous solution to modify the sodium hyaluronate into vitamin B12;

[0144] A second step of crosslinking into a first hyaluronic acid gel by adding a second alkaline aqueous solution containing a crosslinking agent to an aqueous sodium hyaluronate solution modified with vitamin B12;

[0145] A third step of preparing a second hyaluronic acid gel by grinding the hyaluronic acid gel and adding a buffer solution to adjust the pH of the aqueous solution to a range of 6 to 8;

[0146] Step 4: preparing a third hyaluronic acid gel by grinding and homogenizing the second hyaluronic acid gel and then adjusting the content using a buffer solution;

[0147] Step 5: Preparing a color-developing filler composition using a hyaluronic acid derivative comprising a third hyaluronic acid gel.

[0148] For example, the first alkaline aqueous solution of the first step above may be one or more alkaline aqueous solutions selected from the group consisting of NaOH and KOH.

[0149] For example, the first alkaline aqueous solution of the first step may be an aqueous solution further comprising an alkyl acetate having 2 to 10 carbon atoms. When the first alkaline aqueous solution further comprises an alkyl acetate, the pre-modification of sodium hyaluronate by vitamin B12 is performed excellently, thereby improving the biocompatibility and color retention of the final resulting color-developing filler composition.

[0150] For example, the alkyl group of the alkyl acetate may be one or more selected from alkyls having 1 to 9 carbon atoms. For example, the alkyl acetate may be methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, etc., and the alkyl acetate may be included in the first alkaline aqueous solution at a concentration of 0.1 to 0.5 g / L.

[0151] For example, the vitamin B12 of the first step above may be cyanocobalamin and may be included in an amount of 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0152] For example, the crosslinking agent of the second step may be one or more selected from 1,4-butanediol diglycidyl ether (BDDE) and neopentyl glycol diglycidyl ether.

[0153] For example, the second alkaline aqueous solution of the second step may be an aqueous solution further comprising aminosalicylic acid. When the second alkaline aqueous solution further comprises aminosalicylic acid, the pre-modification of sodium hyaluronate by vitamin 12 is performed excellently, thereby improving the biocompatibility and color retention of the final resulting color-developing filler composition, and further improving the biocompatibility of the filler composition by imparting an additional anti-inflammatory effect to the composition.

[0154] For example, the aminosalicylic acid may be included in the second alkaline aqueous solution at a concentration of 1.2 to 1.8 g / L.

[0155] For example, the second alkaline aqueous solution of the second step may be one or more alkaline aqueous solutions selected from the group consisting of NaOH, KOH, NaHCO3, and LiOH.

[0156] For example, the buffer solution of the third step may additionally contain an anesthetic.

[0157] For example, the anesthetic may be lidocaine or a salt thereof.

[0158] For example, the anesthetic may be lidocaine hydrochloride.

[0159] For example, the content of the anesthetic may be included in an amount of 0.1 to 1.0 weight% based on 100 weight% of the total color-developing filler composition.

[0160] For example, the buffer component included in the above buffer solution may be one or more selected from the group consisting of sodium monohydrogen phosphate or its hydrate, sodium dihydrogen phosphate or its hydrate, and sodium chloride.

[0161] For example, the buffer component included in the above buffer solution may be included at a concentration of about 0.1 to about 10.0 g / L, for example, about 0.3 to about 2 g / L, based on the total buffer solution.

[0162] For example, in the fourth step above, the buffer solution may additionally contain vitamin B5.

[0163] For example, the content of the vitamin B5 may be 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition.

[0164] For example, in the fourth step above, the buffer solution may additionally include one or more of polynucleotides and succinic acid as regenerating components.

[0165] For example, the content of the regenerating component may be 0.001 to 10.0 weight% based on 100 weight% of the total color-developing filler composition.

[0166] For example, the weight ratio of polynucleotide and succinic acid included in the above-mentioned regenerating component may be 10:1 to 1:10.

[0167] For example, in the fourth step above, the buffer solution may additionally include one or more of tranexamic acid and niacinamide as whitening ingredients.

[0168] For example, the content of the whitening ingredient may be 0.001 to 10.1 weight% based on 100 weight% of the total color-developing filler composition.

[0169] For example, the weight ratio of polynucleotide and succinic acid included in the whitening ingredient may be 10:1 to 1:10.

[0170] According to one embodiment of the present disclosure, the method for preparing the color-developing filler composition may further include the step of filling and sterilizing the color-developing filler composition containing the hyaluronic acid derivative into a container, such as a vial or a pre-filled syringe.

[0171] The ingredients used in each of the above steps may follow the description above unless specifically mentioned below.

[0172] The present disclosure is described in more detail below using the following examples. Process conditions and preparation steps not specified in the following examples may be obvious in the art to which the present disclosure belongs, and a person skilled in the art will be able to select them without difficulty based on the present disclosure and reproduce the problem-solving principles of the present disclosure.

[0173] In addition, regarding the manufacturing method according to the present disclosure, unless otherwise specified, each step constituting the manufacturing method is carried out at room temperature (25°C), and each step is to be understood as being performed by means and tools that a person skilled in the art can derive without particular difficulty.

[0174] Preparation Example: Preparation of each component included in the filler composition according to the present disclosure

[0175] Sodium hyaluronate having a molecular weight of 1.8 to 2.6 MDa, an alkaline aqueous solution of 0.25 N NaOH, cyanocobalamin, 1,4-butanediol diglycidyl ether, and neopentyl glycol diglycidyl ether were prepared.

[0176] A buffer solution was prepared by dissolving sodium monohydrogen phosphate hydrate at a concentration of 1.25 g / L, sodium dihydrogen phosphate hydrate at 0.45 g / L, sodium chloride at 7.2 g / L, and lidocaine hydrochloride at 3 g / L in a tank containing PBS.

[0177] Example 1: Preparation of a filler composition according to the present disclosure

[0178] Sodium hyaluronate and cyanocobalamin were mixed, and then an alkaline aqueous solution of 0.25N NaOH was added as the first alkaline aqueous solution to modify the sodium hyaluronate with vitamin B12.

[0179] Subsequently, an alkaline aqueous solution of 0.25 N NaOH was added as a second alkaline aqueous solution containing 1,4-butanediol diglycidyl ether to the above vitamin B12-modified sodium hyaluronate aqueous solution to crosslink it into a first hyaluronic acid gel.

[0180] Subsequently, the first hyaluronic acid gel was crushed and homogenized, and then a portion of the buffer solution was used as the first buffer solution and transferred to a washing tank through a 0.22 μm filter. The manufactured and crushed hyaluronic acid gel was then transferred to a washing tank containing the first buffer solution and stirred to adjust the pH of the aqueous solution to a range of 6 to 8, and washed to produce the second hyaluronic acid gel.

[0181] Subsequently, the second hyaluronic acid gel was crushed and homogenized, and then a portion of the buffer solution was used as the first buffer solution and transferred to a washing tank through a 0.22 μm filter. The manufactured and crushed hyaluronic acid gel was then transferred to a washing tank containing the first buffer solution and stirred to adjust the pH of the aqueous solution to a range of 6 to 8, and washed to produce a third hyaluronic acid gel, thereby performing a first content correction.

[0182] Subsequently, the above third hyaluronic acid gel was transferred to a sterile tank and homogenized, its content was measured, and a buffer solution was added to perform a second content correction. The hyaluronic acid gel with the corrected content was heat-treated at a temperature of 121°C or higher for at least 8 minutes, and the composition of Example 1 was prepared by stirring and degassing the hyaluronic acid gel before filling. Subsequently, the composition of Example 1 was vacuum-filled into a syringe in a predetermined amount and simultaneously sealed by pushing it into a rubber stopper. The filled syringe was steam-sterilized in a final sterilizer at a temperature of 121°C or higher for at least 20 minutes.

[0183] Example 2: Preparation of a filler composition according to the present disclosure

[0184] The composition of Example 2 was prepared in the same manner as in Example 1, except that neopentyl glycol diglycidyl ether was used instead of 1,4-butanediol diglycidyl ether, and a filled syringe was prepared.

[0185] Examples 3 to 6: Preparation of filler compositions with different cyanocobalamin contents

[0186] Compositions of Examples 3 and 4 were prepared in the same manner as Example 1 and compositions of Examples 5 and 6 were prepared in the same manner as Example 2, except that cyanocobalamin was used in the amount listed in Table 1 below, and filled syringes were prepared.

[0187] Example 7: Preparation of a filler composition without a crosslinking agent

[0188] As the first hyaluronic acid component, 30g of sodium hyaluronate (number average molecular weight: 1,400,000 Da) was added to 65g of distilled water to prepare an aqueous solution of sodium hyaluronate. 2.0g of 2-ethoxyethanol and 3.0g of Na2CO3 were added to the aqueous solution of sodium hyaluronate, and a first mixture was prepared by mixing using a magnetic stirrer at a rotational speed of 300 RPM for 20 minutes.

[0189] As a second hyaluronic acid component, 30g of sodium hyaluronate (number average molecular weight: 3,000,000 kDa) was added to 64g of distilled water to prepare an aqueous solution of sodium hyaluronate. 3.0g of 2-hydroxybenzaldehyde and 3.0g of NaHCO3 were added to the aqueous solution of sodium hyaluronate, and a second mixture was prepared by mixing using a magnetic stirrer at a rotational speed of 300 RPM for 20 minutes.

[0190] The first and second mixtures were mixed using a magnetic stirrer at a rotational speed of 200 RPM for 10 minutes, then 7.5 g of a 40% aqueous hydrogen peroxide solution was added and stirred for 20 minutes. Afterward, the mixture was neutralized using a 1.0 M aqueous NaOH solution until its pH was approximately 7.0. Subsequently, water was removed to ensure that the first hyaluronic acid component and the second hyaluronic acid component each had a concentration of 16 g / l, thereby preparing a hyaluronic acid complex.

[0191] The composition of Example 7 was prepared in the same manner as Example 1, except that the hyaluronic acid complex prepared above was used instead of the hyaluronic acid prepared above, and no crosslinking agent was used, and a filled syringe was prepared.

[0192] Example 8: Preparation of a filler composition additionally containing a modifier during the pre-modification process

[0193] The composition of Example 8 was prepared in the same manner as Example 1, except that N-propyl acetate was included in the first alkaline aqueous solution at a concentration of 0.2 g / L, and a filled syringe was prepared.

[0194] Examples 9 and 10: Preparation of filler compositions additionally containing a modifier during the pre-modification process

[0195] Except for including 5-aminosalicylic acid at a concentration of 1.5 g / L in the second alkaline aqueous solution, the composition of Example 9 was prepared in the same manner as Example 1, and the composition of Example 10 was prepared in the same manner as Example 8, and a filled syringe was prepared.

[0196] Examples 11 and 12: Preparation of filler compositions further comprising vitamin B5

[0197] Except for the fact that vitamin B5 was additionally included in the buffer solution used in the process of preparing the third hyaluronic acid gel, the composition of Example 11 was prepared in the same manner as Example 1, and the composition of Example 12 was prepared in the same manner as Example 10, and a filled syringe was prepared.

[0198] Examples 13 to 21: Preparation of filler compositions further comprising regenerative components

[0199] Except for the fact that polynucleotide and / or succinic acid were additionally included in different amounts in the buffer solution used in the process of preparing the third hyaluronic acid gel, compositions of Examples 13 to 19 were prepared in the same manner as Example 1, composition of Example 20 was prepared in the same manner as Example 10, and composition of Example 21 was prepared in the same manner as Example 12, and a filled syringe was prepared.

[0200] Examples 22 to 31: Preparation of a filler composition further comprising a whitening ingredient

[0201] Except for the fact that tranexamic acid and / or niacinamide were additionally included in different amounts in the buffer solution used in the process of preparing the third hyaluronic acid gel, compositions of Examples 22 to 28 were prepared in the same manner as Example 1, composition of Example 29 was prepared in the same manner as Example 10, composition of Example 30 was prepared in the same manner as Example 12, and composition of Example 31 was prepared in the same manner as Example 21, and a filled syringe was prepared.

[0202] Each component included in the compositions of Examples 1 to 31 above is shown in Tables 1 to 4 below, and for simplification, "Examples" are indicated as "Sil."

[0203] Unit: Weight % Room 1 Room 2 Room 3 Room 4 Room 5 Room 6 Room 7 Hyaluronic acid component 30 30 30 30 30 30 30 Sodium hydroxide solution 1 1 1 1 1 1 1 1,4-butanediol diglycidyl ether 2 - 2 2 - - 2 Neopentyl glycol diglycidyl ether - 2 - - 2 2 - Cyanocobalamin 0.25 0.25 0.1 0.01 0.4 0.6 0.25 Lidocaine hydrochloride 0.03 0.03 0.03 0.03 0.03 0.03 0.03 purified water Remaining Remaining Remaining Remaining Remaining Remaining Remaining

[0204] Unit: Weight % Room 8 Room 9 10 threads Room 11 Room 12 Hyaluronic acid component 30 30 30 30 30 Sodium hydroxide solution 1 1 1 1 1 1,4-butanediol diglycidyl ether 2 - 2 2 - Neopentyl glycol diglycidyl ether - 2 - - 2 Cyanocobalamin 0.25 0.25 0.25 0.25 0.25 Lidocaine hydrochloride 0.03 0.03 0.03 0.03 0.03 N-propyl acetate 0.2 - 0.2 - 0.2 5-aminosalicylic acid - 1.5 1.5 - 1.5 Vitamin B5 - - - 0.1 0.1 purified water Remaining Remaining Remaining Remaining Remaining

[0205] Unit: Weight % Room 13 Room 14 Thread 15 Room 16 Room 17 Room 18 Room 19 20 threads Room 21 Hyaluronic acid component 30 30 30 30 30 30 30 30 30 Sodium hydroxide solution 1 1 1 1 1 1 1 1 1 1,4-butanediol diglycidyl ether 2 2 2 2 2 2 2 2 2 Neopentyl glycol diglycidyl ether - - - - - - - - - Cyanocobalamin 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Lidocaine hydrochloride 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 N-propyl acetate - - - - - - - 0.2 0.2 5-aminosalicylic acid - - - - - - - 1.5 1.5 Vitamin B5 - - - - - - - - 0.1 polynucleotide 2.5 5 - 0.3 1 4 4.7 2.5 2.5 Succinic acid 2.5 - 5 4.7 4 1 0.3 2.5 2.5 purified water Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining

[0206] Unit: Weight % Room 22 Room 23 Room 24 Thread 25 Thread 26 Room 27 Thread 28 Thread 29 30 threads Room 31 Hyaluronic acid component 30 30 30 30 30 30 30 30 30 30 Sodium hydroxide solution 1 1 1 1 1 1 1 1 1 1 1,4-butanediol diglycidyl ether 2 2 2 2 2 2 2 2 2 2 Neopentyl glycol diglycidyl ether - - - - - - - - - - Cyanocobalamin 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Lidocaine hydrochloride 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 N-propyl acetate - - - - - - - 0.2 0.2 0.2 5-aminosalicylic acid - - - - - - - 1.5 1.5 1.5 Vitamin B5 - - - - - - - - 0.1 0.1 polynucleotide - - - - - - - - - 2.5 Succinic acid - - - - - - - - - 2.5 Tranexamic acid 2.5 5 - 0.3 1 4 4.7 2.5 2.5 2.5 Niacinamide 2.5 - 5 4.7 4 1 0.3 2.5 2.5 2.5 purified water Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining

[0207] Comparative Examples 1 and 2: Preparation of comparative compositions using artificial colorants

[0208] Comparative Examples 1 and 2 compositions were prepared in the same manner as Examples 1 and 2, except that FD&C Red 40 (Allura Red AC) was used in equal amounts instead of cyanocobalamin, and filled syringes were prepared.

[0209] Comparative Example 3: Preparation of a comparative composition with a simple mixture of cyanocobalamin

[0210] Comparative Example 3 composition was prepared in the same manner as Example 1, except that cyanocobalamin was added together with a crosslinking agent, and a filled syringe was prepared.

[0211] Experimental Example 1: Osmotic Permeability Evaluation

[0212] To evaluate the osmotic pressure of the compositions of Examples 1 to 31 and Comparative Examples 1 and 2, they were calibrated with standard solutions of osmotic pressures of 0 and 400, and then the osmotic pressure was measured using an osmometer (OSMOMAT 3000 BASIC). The results are shown in Table 5 below.

[0213] (mOsmol / kg) Example 1 Example 2 Example 3 Example 4 Example 5 osmotic pressure 311 302 313 312 303 Example 6 Example 7 Example 8 Example 9 Example 10 osmotic pressure 304 298 293 315 318 Example 11 Example 12 Example 13 Example 14 Example 15 osmotic pressure 321 323 288 307 311 Example 16 Example 17 Example 18 Example 19 Example 20 osmotic pressure 303 298 291 302 287 Example 21 Example 22 Example 23 Example 24 Example 25 osmotic pressure 285 313 321 310 303 Example 26 Example 27 Example 28 Example 29 Example 30 osmotic pressure 311 293 291 285 283 Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 osmotic pressure 283 381 389 406

[0214] Referring to Table 5 above, the compositions of Examples 1 to 29 were confirmed to have excellent biocompatibility by exhibiting superior osmotic pressure values ​​when compared to the compositions of Comparative Examples 1 to 3, and in particular, significantly superior osmotic pressure values ​​were observed when compared to the composition of Comparative Example 3, confirming that a composition with improved biocompatibility can be provided when sodium hyaluronate is pre-modified with vitamin B12 and subsequently cross-linked.

[0215] In particular, the compositions of Examples 2, 5, and 6 exhibited superior osmotic pressure values ​​compared to the compositions of Examples 1, 3, and 4, confirming that a composition with better biocompatibility can be provided when neopentyl glycol diglycidyl ether is used as a crosslinking agent.

[0216] In addition, Examples 8 to 12 showed significantly lower osmotic pressure values ​​than Examples 1 and 2, confirming that when a modifier is additionally used in the process of modifying sodium hyaluronate with vitamin B12, a composition with excellent biocompatibility can be provided.

[0217] Experimental Example 2: Evaluation of Antioxidant Capacity

[0218] As an antioxidant activity test, the free radical scavenging effect of the samples was measured using 1,1-diphenyl-2-picrylhydrazyl (DPPH, Aldrich, USA). 0.8 mL of 0.4 mM DPPH solution dissolved in methanol, 2 mL of 0.1 M phosphate buffer (pH 6.5), 2 mL of 99.9% ethanol, and the compositions of Examples 1 to 11 and Comparative Examples 1 to 3, respectively, were mixed to make up 50% by weight of the total mixture. After mixing for 10 seconds at room temperature and reacting for 10 minutes, the absorbance was measured at 517 nm using an ELISA reader, and the DPPH radical scavenging activity was expressed as a percentage. The results are shown in Table 6 below.

[0219] (%) Example 1 Example 2 Example 3 Example 4 Example 5 active 81 83 21 45 23 Example 6 Example 7 Example 8 Example 9 Example 10 active 49 91 97 82 88 Example 11 Example 12 Example 13 Example 14 Example 15 active 89 92 97 91 91 Example 16 Example 17 Example 18 Example 19 Example 20 active 92 95 95 93 97 Example 21 Example 22 Example 23 Example 24 Example 25 active 97 99 96 95 97 Example 26 Example 27 Example 28 Example 29 Example 30 active 98 98 96 99 99 Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 active 99 4 5 56

[0220] Referring to Table 6 above, it was confirmed that the DPPH radical scavenging activity of the compositions of Examples 1 to 31 according to the present disclosure is significantly superior to that of Comparative Examples 1 to 3, and it was confirmed that improved antioxidant capacity is exhibited when the content of vitamin B12 included in the color-developing filler composition according to the present disclosure is included in the content of the preferred numerical range according to the present disclosure.

[0221] In particular, the compositions of Comparative Examples 1 and 2 containing artificial colorants exhibited very low DPPH radical scavenging activity, confirming that the color-developing filler composition according to the present disclosure exhibits excellent antioxidant ability by including vitamin B12.

[0222] Experimental Example 3: Evaluation of Skin Regeneration Properties

[0223] Among women in their 30s to 50s with dry skin and cracking on their upper and lower lips, 36 women were randomly selected and divided into 18 groups of 2 women each. Then, 0.5 cc of compositions of Examples 1, 2, 8 to 13, 20 to 22, and 29 to 31, and compositions of Comparative Examples 1 to 3 were injected into the subjects of 17 of the groups, respectively, while the remaining 1 group served as a control group without injecting any separate compositions and was maintained for 4 weeks. Prior to the experiment, the lip cracking condition of the subjects was measured using Primos CR (Canfield Scientific) to establish baseline values.

[0224] At the 4-week mark from the start of the experiment, the lip cracking condition of each subject was evaluated based on the value obtained by multiplying the total depth and length of the cracks and wrinkles. The results were averaged by group and compared with the baseline value to convert the degree of improvement (cracking characteristics) into a percentage unit, which is shown in Table 7 below.

[0225] unit: % Example 1 Example 2 Example 8 Example 9 Example 10 Example 11 Week 4 79 81 88 91 93 83 unit: % Example 12 Example 13 Example 20 Example 21 Example 22 Example 29 Week 4 94 97 98 98 89 94 unit: % Example 30 Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 control group Week 4 95 99 64 61 49 3

[0226] Referring to Table 7 above, it was confirmed that when the color-developing filler composition according to the present disclosure is applied, skin cracking is significantly improved. In particular, it was confirmed that skin cracking is significantly improved when a modifier is additionally included and when a regenerative component is additionally included, and further increased improvement in skin cracking is confirmed when both types of modifiers and regenerative components are included.

[0227] Experimental Example 4: Evaluation of Skin Whitening Properties

[0228] Thirty-six Korean female workers in their 30s to 50s who go to work around 9:00 AM and leave around 6:00 PM were randomly selected and divided into 18 groups of two people each. Then, 0.5cc of compositions of Examples 1, 2, 8 to 13, 20 to 22, and 29 to 31, and comparative example compositions 1 to 3 were injected into each of the subjects in 17 of the groups, at a position 1cm from the connection point between the ring finger and the middle finger on the back of the left hand toward the wrist. The remaining one group served as a control group and was not injected with any separate composition. During the experiment, the subjects were instructed to carry on with their daily lives for seven days starting from June 1st and not to receive any separate skin treatments.

[0229] On the start date of the experiment, the injection site of the composition was photographed under specified conditions, and after 7 days, the injection site of the composition was photographed under the same conditions. Then, the degree of skin darkening was analyzed through image analysis, converted into a % unit, and shown in Table 8 below.

[0230] unit: % Example 1 Example 2 Example 8 Example 9 Example 10 Example 11 7 days later 11 10 8 7 6 10 unit: % Example 12 Example 13 Example 20 Example 21 Example 22 Example 29 7 days later 8 10 9 9 4 3 unit: % Example 30 Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 control group 7 days later 3 3 14 14 13 15

[0231] Referring to Table 8 above, it was confirmed that when the color-developing filler composition according to the present disclosure is applied, skin cracking is significantly improved. In particular, it was confirmed that skin cracking is significantly improved when a modifier is additionally included and when a whitening ingredient is additionally included, and further increased improvement in skin cracking is confirmed when both types of modifiers and whitening ingredients are included.

[0232] Experimental Example 5: Evaluation of Color Durability

[0233] Sterile syringes loaded with the compositions of Examples 1 to 31 and Comparative Examples 1 to 3, respectively, were kept sealed at room temperature and maintained until the time points of Day 1, Day 30, Day 60, and Day 90. Subsequently, the syringes maintained at each time point were observed over time under white light and a white background by a panel of 10 trained individuals to confirm the persistence of color development. Based on Day 1, the best color development was rated as 5 points and the worst as 0 points, and the results for Days 30, 60, and 90 were evaluated using a 5-point scale. The results are shown in Table 9 below.

[0234] Example 1 Example 2 Example 3 Example 4 Example 5 persistence 5.0 / 4.9 / 4.7 5.0 / 4.9 / 4.9 4.1 / 3.1 / 2.7 5.0 / 4.8 / 4.3 4.2 / 3.6 / 2.9 Example 6 Example 7 Example 8 Example 9 Example 10 persistence 5.0 / 4.9 / 4.6 5.0 / 4.8 / 4.7 5.0 / 4.9 / 4.8 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 Example 11 Example 12 Example 13 Example 20 Example 21 persistence 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 Example 22 Example 29 Example 30 Example 31 persistence 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.9 Comparative Example 1 Comparative Example 2 Comparative Example 3 persistence 5.0 / 4.9 / 4.9 5.0 / 4.9 / 4.8 4.9 / 4.7 / 4.4

[0235] Referring to Table 4 above, it was confirmed that the compositions of Examples 1 and 2 according to the present disclosure exhibited a level of color retention equivalent to that of Comparative Examples 1 and 2, in which artificial pigments were used. It was confirmed that the compositions could achieve color performance equivalent to that of the case where artificial pigments are used while having excellent biocompatibility, thus confirming the excellent effect of the color-developing filler composition according to the present disclosure.

[0236] Although preferred embodiments of the present disclosure have been described in detail above, the scope of the present disclosure is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concepts of the present disclosure as defined in the following claims are also included within the scope of the present disclosure.

Claims

Claim 1 A color-developing filler composition comprising a hyaluronic acid derivative modified with vitamin B12, wherein the hyaluronic acid derivative comprises one or more of hyaluronic acid, a salt thereof, and a cross-linked hyaluronic acid gel thereof, wherein the hyaluronic acid derivative modified with vitamin B12 is prepared by a method comprising: a first step of mixing sodium hyaluronate and vitamin B12, and then adding a first alkaline aqueous solution to modify the sodium hyaluronate with vitamin B12; and a second step of adding a second alkaline aqueous solution containing a cross-linking agent to the sodium hyaluronate aqueous solution modified with vitamin B12 to cross-link it into a first hyaluronic acid gel, wherein the first alkaline aqueous solution comprises N-propyl acetate and the second alkaline aqueous solution comprises 5-aminosalicylic acid. Claim 2 The color-developing filler composition according to claim 1, wherein the color-developing filler composition further comprises one or more of polynucleotides and succinic acid as regenerating components. Claim 3 The color-developing filler composition of claim 1, wherein the color-developing filler composition further comprises one or more of tranexamic acid and niacinamide as whitening ingredients. Claim 4 A color-developing filler composition according to claim 1, wherein the weight average molecular weight of the hyaluronic acid included in the hyaluronic acid derivative is 1,000 to 5,000,000 Da. Claim 5 A color-developing filler composition according to claim 4, wherein the content of hyaluronic acid included in the hyaluronic acid derivative is 1 to 5 weight% based on 100 weight% of the total color-developing filler composition. Claim 6 A color-developing filler composition according to claim 5, wherein the vitamin B12 is one or more selected from the group consisting of cyanocobalamin, methylcobalamin, deoxyadenosylcobalamin, and hydroxycobalamin. Claim 7 A color-developing filler composition according to claim 6, wherein the content of vitamin B12 is 0.001 to 0.9 weight% based on 100 weight% of the total color-developing filler composition. Claim 8 delete Claim 9 A method for preparing a color-developing filler composition comprising a hyaluronic acid derivative modified with a vitamin component, comprising: a first step of mixing sodium hyaluronate and vitamin B12, and then adding a first alkaline aqueous solution to modify the sodium hyaluronate with vitamin B12; a second step of adding a second alkaline aqueous solution containing a crosslinking agent to the sodium hyaluronate aqueous solution modified with vitamin B12 to crosslink into a first hyaluronic acid gel; a third step of preparing a second hyaluronic acid gel by grinding the first hyaluronic acid gel and adding a buffer solution to adjust the pH of the aqueous solution to a range of 6 to 8; a fourth step of preparing a third hyaluronic acid gel by grinding and homogenizing the second hyaluronic acid gel and then using a buffer solution to correct the content; and a fifth step of preparing a color-developing filler composition using a hyaluronic acid derivative comprising the third hyaluronic acid gel, wherein the first alkaline aqueous solution A method for preparing a color-developing filler composition comprising N-propyl acetate, wherein the second alkaline aqueous solution comprises 5-aminosalicylic acid. Claim 10 delete

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