KR20220115130A - Solution used for production of composition of hyaluronic acid filler and composition of hyaluronic acid filler using the same - Google Patents

Abstract

The present invention relates to a solution used for manufacturing a hyaluronic acid filler composition and a hyaluronic acid filler composition using the same. The hyaluronic acid filler composition manufactured using the solution according to the present invention has an effect of preventing calcification and consequent formation of nodules, which are typical side effects caused by combining with calcium ions present in body fluids during in vivo injection, thereby being safely used not only as a facial filler injected in a small amount, but also as a filler injected in a large amount to increase the volume of tissues such as breasts and buttocks.

Description

A solution used for the preparation of a hyaluronic acid filler composition and a hyaluronic acid filler composition using the same

The present invention relates to a solution used for the preparation of a hyaluronic acid filler composition and a hyaluronic acid filler composition using the same, and more particularly, to a hyaluronic acid with a controlled total content of phosphate for inhibiting calcification in the body due to the hyaluronic acid filler composition. It relates to a gel washing solution and a hyaluronic acid filler composition using the same.

As people age, wrinkles occur under the influence of ultraviolet rays, facial expression changes, gravity, etc., and so-called aging, in which the volume of related tissues is reduced along with the loss of adipose tissue, proceeds. In addition, various factors may cause scars in which the skin is depressed.

Fillers have been developed to improve wrinkles, skin depressions, and reduction in tissue volume. Fillers are complementary materials or contents that are injected or inserted into body parts to increase volume, such as wrinkles or pitted scars.

When the filler is injected into the skin or under the skin, its durability should be maintained for a certain period of time, and with the functionality to induce a soft, smooth and natural appearance, side effects such as allergic reactions, swelling, nodules and granulomas should be minimized when injected into the human body. do.

Hyaluronic acid (HA) (also known as hyaluronan), which is used as the main component of the filler, is a type of glycosaminoglycans (GAGs), and is a major component of the extracellular matrix. and because of its widespread distribution in animal tissues, it offers the advantage that the risk of allergic reactions is significantly reduced. Hyaluronic acid is abundantly present in several different layers of the skin, and its main functions include, for example, the function of correcting hydration of the skin, the function of assisting the tissue of the extracellular matrix, the function of acting as a filling material, and the mechanism of tissue regeneration. It has complex functions such as being involved in

However, despite such excellent safety and efficacy, the hyaluronic acid filler composition binds with calcium ions in the body to cause precipitation and calcification reaction, which may cause side effects such as nodules at the injection site of the filler. This problem may be particularly noticeable when a large amount of filler is injected for the purpose of breast or butt surgery, which increases the probability of binding to calcium ions present in body fluid as the injection amount increases, and the occurrence of nodules due to calcification also increases.

The present inventors are searching for a way to reduce side effects such as calcification and nodules caused by such filler injection, while the total content of phosphate in Phosphate Buffered Saline (PBS) used in manufacturing the filler is adjusted. In the case of the composition, the present invention was completed by confirming that calcification was significantly reduced in reaction with a biological solution.

It is an object of the present invention to provide a cleaning solution of a hyaluronic acid gel in which the total content of phosphate is adjusted, and a hyaluronic acid filler composition using the same, for suppressing calcification in the body, which is a major side effect that occurs during hyaluronic acid filler injection.

The present invention provides a solution used for preparing a hyaluronic acid filler composition, characterized in that it contains a phosphate, the content of the phosphate is 0.1 mM or more to less than 10 mM, and is for suppressing calcification in the body due to the hyaluronic acid filler composition do.

The solution may further comprise sodium chloride.

The solution may be for washing the hyaluronic acid gel.

The phosphate content of the solution may be 1 mM to 7 mM.

The phosphate of the solution may include any one or more selected from the group consisting of monohydrogen phosphate and dihydrogen phosphate.

In one embodiment of the present invention, there is provided a hyaluronic acid filler composition comprising the hyaluronic acid gel washed with the solution.

The hyaluronic acid filler composition may include cross-linked hyaluronic acid or a salt thereof.

The hyaluronic acid filler composition may be a monophasic hyaluronic acid gel having a MoD of 1% to 13%.

The pH of the hyaluronic acid filler composition may be 5.5 to 8.5.

The osmotic pressure of the hyaluronic acid filler composition may be 200mOsmol/kg to 400mOsmol/kg.

The hyaluronic acid filler composition may further include an anesthetic.

The hyaluronic acid filler composition may be for administration in a small dose of 0.1 mL to less than 10 mL.

The hyaluronic acid filler composition may be for large-capacity administration of 10mL to 200mL.

The hyaluronic acid filler composition may be for improving wrinkles and tissue volume reduction for soft tissues selected from the group consisting of face, neck, chest, buttocks, arms, armpits, hands, legs and feet, or for treating wounds, scars or stretch marks .

The hyaluronic acid filler composition prepared by using the solution according to the present invention has the effect of preventing calcification and nodules, which are typical side effects that can occur by combining with calcium ions present in body fluids during in vivo injection, and is injected in a small amount. It can be safely used not only as a facial filler, but also as a filler injected in a large volume to increase the tissue volume of the chest and buttocks.

1 is a result of confirming whether a biological solution having a composition similar to that of a body fluid is suitable for the detection of a calcification reaction.
2 shows a reaction of Phosphate Buffer adjusted to have different pH (weight ratio of monohydrogen phosphate and dihydrogen phosphate) and total phosphate content according to a preliminary embodiment of the present invention (Preparative Experimental Examples 1 to 5) with a biological solution. This is a preliminary result of observing the calcification reaction.
3 is a hyaluronic acid gel was washed using Phosphate Buffered Saline (PBS) having a total phosphate content of 1, 5, and 7 mM, respectively, according to an embodiment of the present invention (Experimental Examples 1 to 3), but an anesthetic was not added. This is the result of observing the calcification reaction for 14 days after reacting the non-hyaluronic acid filler composition with the biological solution.
4 is a hyaluronic acid filler composition that is not added to the hyaluronic acid gel using Phosphate Buffered Saline (PBS) having a total phosphate content of 10 mM according to an embodiment of the present invention (Comparative Experimental Example 1). This is the result of observing the calcification reaction for 14 days after reacting with the biological solution.
Figure 5 is a hyaluronic acid filler composition to wash the hyaluronic acid gel using Phosphate Buffered Saline (PBS) having a total phosphate content of 5 mM according to another embodiment (Experimental Example 4) of the present invention, but without anesthetic This is the result of observing the calcification reaction for 14 days after reacting with the biological solution.
6 is a hyaluronic acid gel wash using Phosphate Buffered Saline (PBS) having a total phosphate content of 5 mM according to another embodiment of the present invention (Experimental Example 4), but similar to a hyaluronic acid filler composition with anesthetic added After reacting with the biological solution, the calcification reaction was observed for 14 days.
7 is a result of observing the calcification reaction for 14 days after reacting a commercially available filler composition (Bv) with a biological solution (a) with the naked eye and (b) with a microscope.
8 is a result of observation of a calcification reaction for 14 days through (a) the naked eye and (b) a microscope after reacting a commercially available filler composition (Cs) with a biological solution.
9 is a result of observation of a calcification reaction for 14 days through (a) the naked eye and (b) a microscope after reacting a commercially available filler composition (Nv) with a biological solution.
10 is a result of visually observing the calcification reaction for 14 days after reacting a commercially available filler composition (CN°4) with a biological solution.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is those well known and commonly used in the art.

Conventional hyaluronic acid-based filler compositions have a problem of causing side effects such as nodules at the injection site of the filler. Accordingly, as a result of collecting literature information to solve the side effects, it was confirmed that calcification may occur when calcium is bound to the carboxyl group of amino acids and then phosphate is added. Based on the literature analysis results, the present inventors observed the calcification reaction after reacting the currently commercially available hyaluronic acid filler composition with a biological solution. was analyzed using SEM-EDS (scanning electron microscope, LEO SUPRA55, Carl zeiss, Germany), and as a result, it was confirmed that the crystal component was calcium phosphate. Accordingly, the present inventors confirmed that calcification caused by the reaction between the hyaluronic acid filler composition and the biological solution is suppressed by optimizing the total content of phosphate in Phosphate Buffered Saline (PBS) used in the preparation of the hyaluronic acid filler composition. was completed.

Hereinafter, the present invention will be described in detail.

Solutions used in the preparation of hyaluronic acid filler compositions

The present invention comprises a phosphate, the content of the phosphate is 0.1 mM or more to less than 10 mM, and a solution used for the preparation of a hyaluronic acid filler composition, characterized in that it is for suppressing calcification in the body due to the hyaluronic acid filler composition to provide.

The solution according to the invention may further comprise sodium chloride.

The solution according to the present invention is used for the preparation of a hyaluronic acid filler composition, in particular, it can be used for washing the hyaluronic acid gel.

First, the solution according to the present invention contains phosphate, the content of which needs to be adjusted in order to prevent calcification in the body. The content of the phosphate in the composition is characterized in that 0.1 mM or more and less than 10 mM, more preferably 1 mM to 7 mM, but is not limited thereto. At this time, when the content of phosphate in the composition is less than 0.1 mM, there is a problem that NaOH used to prepare the cross-linked hyaluronic acid gel is not completely washed, and when the content of phosphate in the composition is 10 mM or more, calcification is not sufficiently prevented. There is a problem that it does not.

On the other hand, the phosphate salt may be one or more hydrogen phosphate salts, and preferably include any one or more selected from the group consisting of monohydrogen phosphate and dihydrogen phosphate. The one or more hydrogen phosphate salts may each independently exist in the form of x hydrate (where x is any integer or fraction, and when x = 0, it is anhydrous (hydrated)), and monohydrogen phosphate or phosphoric acid In the case of a hydrogen salt, it may be represented as (Na,K) ₂ HPO ₄ ·xH ₂ O or (Na,K)H ₂ PO ₄ ·xH ₂ O, respectively. As an aspect of the present invention, in order to adjust the pH of the final hyaluronic acid filler composition, when the monohydrogen phosphate salt is in an anhydrous form and the dihydrogen phosphate salt is in a dihydrate form, the weight ratio of the monohydrogen phosphate salt and the dihydrogen phosphate salt is It is preferably 1:5 to 28:1, but is not limited thereto. At this time, when the ratio of the monohydrogen phosphate increases, there is a problem that the pH increases, and when the ratio of the dihydrogen phosphate increases, there is a problem that the pH decreases, which is different from the pH of the human body in the final hyaluronic acid filler composition Accordingly, there is a problem that may cause pain when administered in the body.

Next, the solution according to the present invention contains sodium chloride, the sodium chloride serves to control the osmotic pressure of the final hyaluronic acid filler composition. The concentration of sodium chloride in the composition is preferably 0.33 to 1.46 (w/v)%, more preferably 0.47 to 1.16 (w/v)%, but is not limited thereto.

Hyaluronic acid filler composition

The present invention provides a hyaluronic acid filler composition comprising the hyaluronic acid gel washed with the solution.

The hyaluronic acid filler composition comprises hyaluronic acid or a salt thereof, preferably cross-linked hyaluronic acid or a salt thereof. The concentration of hyaluronic acid or a salt thereof in the hyaluronic acid filler composition is preferably 1.0 (w/v)% to 3.0 (w/v)%, and 1.5 (w/v)% to 2.5 (w/v)% More preferably, but not limited thereto.

The hyaluronic acid filler composition is preferably a monophasic hyaluronic acid gel having 1% to 13% MoD (MoD (%) = moles of crosslinking agent / moles of hyaluronic acid disaccharide or its salt repeating unit) Х100), but is not limited thereto. does not

On the other hand, when the average particle size of the cross-linked hyaluronic acid or a salt thereof is small, the reaction with the biological solution becomes active as a result due to the high surface area, so that the calcification reaction can be accelerated. Accordingly, it is preferable that a large particle size such as a biphasic filler with an average particle size (D50) of 250 to 900 μm can effectively inhibit calcification in the body, but the filler composition may move after injection due to low cohesive force there is Therefore, in the present invention, it is preferable that the average particle size (D50) is monophasic with an average particle size of 50 μm to 500 μm, but is not limited thereto.

The pH of the hyaluronic acid filler composition according to the present invention is physiologically acceptable, and about pH 5.5 to 8.5 is preferably in a range capable of inhibiting calcification in the body, but is not limited thereto.

The osmotic pressure of the hyaluronic acid filler composition according to the present invention may be in the range of about 150 mOsmol/kg to 500 mOsmol/kg without limitation as a physiologically acceptable range, and more preferably about 200 mOsmol/kg to 400 mOsmol/kg, but limited thereto doesn't happen

The hyaluronic acid filler composition according to the present invention may further include an anesthetic, and the concentration of the anesthetic in the filler composition may be an amount effective to relieve pain felt when injected into the body. Moreover, since the pH is lowered when an anesthetic is included in the filler composition, it is necessary to optimize the pH by adjusting the weight ratio of the monohydrogen phosphate and dihydrogen phosphate. The concentration of the anesthetic (preferably, local anesthetic) in the filler composition may be 0.1 to 5.0 (w/v)%, preferably 0.2 to 1.0 (w/v)%, and 0.3 (w/v)% It is more preferable, but is not limited thereto. Specifically, the local anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine (biphenamine), bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloro Procaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diferrodone ( diperodon), dicyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprosine (euprocin), phenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate), levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine , naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine, phena phenacaine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, procaine Panocaine, propanocaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol ( salicyl alcohol), tetracaine, tolycaine, trimecaine, zolamine, and salts thereof may be selected from the group consisting of, but lidocaine is preferred, and lidocaine hydrochloride is More preferably, but not limited thereto.

The hyaluronic acid filler composition according to the present invention may optionally include a buffer, preservative, isotonic agent, antioxidant, emulsifier, wetting agent, etc., but is not limited thereto, and may include other pharmaceutically acceptable ingredients.

The hyaluronic acid filler composition according to the present invention may further include other substances or combinations of substances that provide a beneficial effect when administered to a subject. Such beneficial substances include, without limitation, antioxidants, anti-itch agents, anti-cellulite agents, anti-scarring agents, anti-inflammatory agents, anesthetics, irritation-reducing agents, vasoconstrictors, vasodilators, anti-bleeding agents such as hemostatic agents or anti- fibrinolytic agents, exfoliating agents, firming agents, anti-acne agents, coloring agents, anti-pigmentation agents, or moisturizing agents.

The hyaluronic acid filler composition according to the present invention may be in a sterile state, for example, by autoclaving, or may be sterilized by heat, pressure, gamma irradiation, or the like. In certain embodiments of any of the above aspects, the subcutaneously or intradermally placed composition may provide immediate 'lifting', in part due to its cohesive or viscoelastic properties. This will smooth the lines and folds on the skin to provide a rejuvenating appearance of the skin.

The hyaluronic acid filler composition according to the present invention may be used as a facial filler injected in a small amount of about 0.1 mL to less than 10 mL, or may be used as a filler injected in a large capacity of 10 mL to 200 mL, but is not limited thereto. In particular, since the hyaluronic acid filler composition according to the present invention can effectively inhibit calcification in the body through optimization of the total content of phosphate, it can be safely used as a filler injected in a large amount to increase tissue volume such as breasts and buttocks There is this.

The hyaluronic acid filler composition according to the present invention is for improving wrinkles and tissue volume reduction for soft tissues selected from the group consisting of face, neck, chest, buttocks, arms, armpits, hands, legs and feet, or for treating wounds, scars or stretch marks It is characterized in that Yongin, but is not limited thereto. In this case, the scar may be a post-operative scar, an old scar, or a newly generated scar, and the wound may be an acute or chronic wound including a burn.

The hyaluronic acid filler composition according to the present invention provides a method for treating soft tissue pathology by administering to a subject. In the present invention, "treating" refers to reducing or eliminating cosmetic or clinical symptoms of a soft tissue pathology characterized by a soft tissue imperfection, defect, disease, and/or disorder in a subject; or to delay or prevent the onset of the cosmetic or clinical symptoms of a condition characterized by a soft tissue imperfection, defect, disease, and/or disorder in a subject. Accordingly, the effectiveness of the filler composition can be measured by observing one or more cosmetic, clinical symptoms, and/or physiological indicators associated with the condition. Improvement of soft tissue defects, diseases, and/or disorders may also be indicated by a reduced need for concomitant therapy. Those skilled in the art will know the appropriate symptoms or indicators associated with a particular soft tissue defect, disease, and/or disorder and will know how to determine whether an individual is a candidate for treatment with a hyaluronic acid filler composition according to the present invention.

As used herein, the term “hyaluronic acid” is a microorganism-derived glycosaminoglycans (GAGs) used to formulate a filler mainly used for reducing facial wrinkles and enhancing volume. This is because the polymer chain is easily degraded by enzymes and free radicals found in humans, so the residence time of non-denatured hyaluronic acid is several days. Therefore, in order to improve the residence time in the human body, the linear chain of hyaluronic acid is generally cross-linked with a cross-linking agent such as BDDE.

As used herein, the term “calcification” refers to calcium salts, for example, calcium phosphate (Ca ₃ (PO ₄ ) _{2 ,} CaHPO ₄ ), amorphous amino acids/calcium phosphate, etc., abnormally deposited in living tissues. It is a phenomenon of hardening in living tissue, and it can be seen as a kind of side effect that may occur when a filler containing an excess of phosphate is administered into the body.

As used herein, the term “administering” refers to any mode of delivery that provides a subject with the composition that potentially produces a clinically, therapeutically, or experimentally beneficial result. The actual mode of delivery used to administer the composition to a subject will be determined by, but not limited to, the type of skin condition, location of the skin condition, cause of the skin condition, the severity of the skin condition, the degree of relief desired, as desired by those skilled in the art by those skilled in the art. duration of remission, the particular composition used, the rate of secretion of the particular composition used, the pharmacodynamics of the particular composition used, the nature of the other compounds included in the particular composition used, the particular route of administration, the particular characteristics, the individual's medical history and risk factors such as, for example, age, weight, general health, etc., or any combination thereof.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.

Verification of pseudo-biological solutions

The composition of the simulated biological solution (Simulated Body Fluid, Biosesang, Korea) used in the present invention is as follows: Na ⁺ 142.0 mM, K ⁺ 5.0 mM, Ca ²⁺ 2.5 mM, Mg ²⁺ 1.5 mM, Cl ^- 125.0 mM, HCO ^3- 27.0 mM, HPO ₄ ^2- 1.0 mM, SO ₄ ^2- 0.5 mM, Ca/P 2.5 mM in Tris Buffer (pH 7.4).

In order to check whether the biological solution prepared equivalent to the electrolyte concentration of the body fluid was prepared appropriately, H ₂ O (negative control), CaCl ₂ (positive control), NaH ₂ PO ₄ .2H ₂ O (test group 1) ), Na ₂ HPO ₄ (test group 2) was taken, 1.0 g each, mixed with 9.0 g of a biological solution, and then treated with ultrasound (Elamsonic P, ELMA) for 10 minutes to accelerate the reaction rate (Sonication condition: Pulse mode, Temp.: 35℃ power: 100, frequency: 80, kHz: 35).

As a result, as shown in FIG. 1 , a calcification reaction was confirmed in CaCl ₂ , which is a positive control, and it is confirmed that a similar biological solution was suitably prepared. In particular, a calcification reaction was confirmed in the test group, Na ₂ HPO ₄ , that is, monohydrogen phosphate, and it was confirmed that phosphate is an influencing factor that can induce calcification in the body.

Pre-validation of pH (weight ratio of monohydrogen phosphate and dihydrogen phosphate) and total phosphate content in Phosphate Buffer that can inhibit calcification in the body

As shown in Table 1, by varying the weight ratio of Na ₂ HPO ₄ and NaH ₂ PO ₄ .2H ₂ O to prepare a Phosphate Buffer Stock solution so that the total content of phosphate for each pH is 100mM, diluted with tertiary water to give phosphate After adjusting the total content of Phosphate Buffer to 10 mM to 100 mM, 1.0 g of each Phosphate Buffer was mixed with 9.0 g of a biological solution. After that, it was left at room temperature for 20 minutes or treated with ultrasound (Elamsonic P, ELMA) for 10 minutes to accelerate the reaction rate (Sonication conditions: Pulse mode, Temp.: 35℃ power: 100, frequency: 80, kHz: 35).

manufacturing company
(CAS-No) Preliminary Comparative Experimental Example 1 Spare
Experimental Example 1 Spare
Experimental Example 2 Spare
Experimental Example 3 Spare
Experimental Example 4 Spare
Experimental Example 5 Preliminary Comparative Experimental Example 2 Phosphate Buffer Sodium monohydrogen phosphate
(anhydride) Merck
(7558-79-4) 0
g/g 2.32
g/g 5.42
g/g 9.39
g/g 12.22
g/g 13.51
g/g 14.20
g/g sodium dihydrogen phosphate
(dihydrate) Sigma Aldrich
(13472-35-0) 15.60
g/g 13.06
g/g 9.65
g/g 5.29
g/g 2.18
g/g 0.76
g/g 0
g/g 3rd degree 984.40 g 984.63 g 984.93 g 985.33 g 985.61 g 985.73 g 985.80 g pH 4.33 6.13 6.49 7.00 7.52 8.05 9.21

As a result, as shown in FIG. 2 , as the pH of the Phosphate Buffer and the total content of phosphate increased, it was confirmed that the calcification reaction was intensified. Therefore, it is necessary to minimize the total content of phosphate, and it is also necessary to maintain the pH similar to that of the human body.

Verification of hyaluronic acid filler composition by total phosphate content in Phosphate Buffered Saline (PBS) capable of inhibiting calcification

As shown in Table 2, a hyaluronic acid filler composition was prepared by washing the hyaluronic acid gel using Phosphate Buffered Saline (PBS) with different total phosphate content. After mixing 1.0 g of the finally prepared hyaluronic acid filler composition with 9.0 g of a biological solution, the calcification reaction was observed at 37°C for 14 days.

manufacturing company
(CAS-No) Experimental Example 1
(Phosphate 1 mM) Experimental Example 2
(Phosphate 5 mM) Experimental Example 3
(Phosphate 7 mM) Comparative Experiment Example 1
(Phosphate 10 mM) Phosphate Buffered
Saline
(PBS) Sodium monohydrogen phosphate
(anhydride) Merck
(7558-79-4) 0.1073 mg/mL 0.5364 mg/mL 0.7510 mg/mL 1.0728 mg/mL sodium dihydrogen phosphate
(dihydrate) Sigma Aldrich
(13472-35-0) 0.0381 mg/mL 0.1907 mg/mL 0.2670 mg/mL 0.3814 mg/mL sodium chloride Sigma Aldrich (7647-14-5) 8.6482 mg/mL 8.1806 mg/mL 7.9469 mg/mL 7.5962 mg/mL 3rd degree 991.2064 mg/mL 991.0923 mg/mL 991.0351 mg/mL 990.9496 mg/mL Hyaluronic acid filler composition cross-linked
Sodium Hyaluronate 24 mg/mL 24 mg/mL 24 mg/mL 24 mg/mL pH 6.88 7.28 7.22 7.19 osmotic pressure 215 230 231 274

As a result, as shown in FIG. 3, in the filler composition finally prepared in Phosphate Buffered Saline (PBS) having a total phosphate content of 1 mM, 5 mM and 7 mM, respectively, no calcification reaction was observed for 14 days. On the other hand, as shown in FIG. 4, in the case of the filler composition finally prepared with a total phosphate content of 10 mM in Phosphate Buffered Saline (PBS), a calcification reaction was significantly observed on day 14. Therefore, it was confirmed that the solution of the present invention preferably contains less than 10 mM of the total phosphate content, and more preferably less than 7 mM.

On the other hand, as shown in Table 3, after washing the hyaluronic acid gel using PBS in which the total content of phosphate in Phosphate Buffered Saline (PBS) was fixed at 5 mM, a hyaluronic acid filler composition with or without lidocaine was prepared. After mixing 1.0 g of the finally prepared hyaluronic acid filler composition with or without lidocaine with 9.0 g of a biological solution, calcification reaction was observed at 37°C for 14 days.

manufacturing company
(CAS-No) Experimental Example 4
(Phosphate 5 mM) Experimental Example 5
(Phosphate 5 mM) Phosphate
Buffered
Saline
(PBS) Sodium monohydrogen phosphate
(anhydride) Merck
(7558-79-4) 0.5364 mg/mL 0.5364 mg/mL sodium dihydrogen phosphate
(dihydrate) Sigma Aldrich
(13472-35-0) 0.1907 mg/mL 0.1907 mg/mL sodium chloride Sigma Aldrich
(7647-14-5) 8.1796 mg/mL 8.1796 mg/mL 3rd degree 991.0933 mg/mL 991.0933 mg/mL hyaluronic acid
filler
composition Cross-linked sodium hyaluronate 24 mg/mL 24 mg/mL lidocaine hydrochloride
(monohydrate) Delta Synthetic
Co., LTD
(73-78-9) N.A. 3.2 mg/mL pH 7.01 6.83 osmotic pressure 285 323

[Comparative example]

Take 1.0 g each of Bv (Company D, Korea), Cs (Company B, Korea), Nv (Company M, Korea) and CN°4 (Company H, Korea), which are currently commercially available in Korea, and 9.0 g of a biological solution After mixing, the calcification reaction was observed visually or through a microscope at 37°C for 14 days.

As a result, as in FIGS. 7 to 10 , calcification reactions were confirmed for all four commercially available products. Based on this, it is expected that all four commercially available products were washed with Phosphate Buffered Saline (PBS) with a total phosphate content exceeding 7 mM.

As described above, the present invention has been described through the above embodiments, but the present invention is not necessarily limited thereto, and various modifications can be made without departing from the scope and spirit of the present invention. Accordingly, the protection scope of the present invention should be construed to include all embodiments falling within the scope of the claims appended hereto.

Claims (14)

containing phosphate;
The phosphate content is 0.1 mM or more and less than 10 mM,
A solution used in the preparation of a hyaluronic acid filler composition, characterized in that for inhibiting calcification in the body due to the hyaluronic acid filler composition.
The solution of claim 1 , wherein the solution further comprises sodium chloride.
According to claim 1,
The solution is characterized in that for washing the hyaluronic acid gel, solution.
According to claim 1,
The solution, characterized in that the phosphate content is 1mM to 7mM.
According to claim 1,
The phosphate salt is a solution, characterized in that it comprises at least one selected from the group consisting of monohydrogen phosphate and dihydrogen phosphate.
A hyaluronic acid filler composition comprising the hyaluronic acid gel washed with the solution according to claim 1.
7. The method of claim 6,
The hyaluronic acid filler composition is characterized in that it comprises cross-linked hyaluronic acid or a salt thereof, hyaluronic acid filler composition.
7. The method of claim 6,
The hyaluronic acid filler composition is characterized in that the monophasic hyaluronic acid gel having a MoD of 1% to 13%, a hyaluronic acid filler composition.
7. The method of claim 6,
The pH of the hyaluronic acid filler composition is characterized in that 5.5 to 8.5, hyaluronic acid filler composition.
7. The method of claim 6,
The osmotic pressure of the hyaluronic acid filler composition is 200mOsmol/kg to 400mOsmol/kg, characterized in that the hyaluronic acid filler composition.
7. The method of claim 6,
The hyaluronic acid filler composition, characterized in that it further comprises an anesthetic, hyaluronic acid filler composition.
7. The method of claim 6,
The hyaluronic acid filler composition is characterized in that for small dose administration of 0.1mL to less than 10mL, hyaluronic acid filler composition
7. The method of claim 6,
The hyaluronic acid filler composition is characterized in that for large-capacity administration of 10mL to 200mL, hyaluronic acid filler composition.
7. The method of claim 6,
The hyaluronic acid filler composition is for improving wrinkles and tissue volume reduction targeting soft tissues selected from the group consisting of face, neck, chest, buttocks, arms, armpits, hands, legs and feet, or for treating wounds, scars or stretch marks to, a hyaluronic acid filler composition.

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