A sodium hyaluronate composition with freckle removal effect, preparation method thereof and application thereof

Abstract

The present invention discloses a sodium hyaluronate composition with freckle removal effect, a preparation method thereof and an application thereof, wherein the composition contains 1-10 mg / ml sodium hyaluronate, 0.8-8 mg / ml peptides, 0.05-1 mg / ml amino acids, 1-10 mg / ml freckle removal components, 0.001-0.03 mg / ml vitamins and a buffer, wherein the weight average molecular weight (Mw) of sodium hyaluronate is 1 million-1.6 million and its intrinsic viscosity is 1.5-3.0 L / g. The sodium hyaluronate composition of the present invention significantly reduces the problems of injection site irritation, swelling, hemolysis and pain that may be caused during injection, improves the stability of the composition and its moisturizing effect, and can quickly achieve a therapeutic effect, prevent melanin aggregation, and deeply inhibit melanin production.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a sodium hyaluronate composition with good stability, a preparation method thereof and an application thereof. Background Art

[0002] Skin aging can lead to changes in skin structure, function, tissue loss, wrinkles, dry skin, roughness and yellowing, pigmentation, and reduced elasticity. Injection filling technology has become an effective means to achieve skin rejuvenation.

[0003] Hyaluronic acid (HA) is a macromolecular acidic mucopolysaccharide composed of D-glucuronic acid and N-acetylglucosamine disaccharide units, which is widely distributed in human joint cartilage, lens, skin dermis and other tissues. Hyaluronic acid has the functions of improving skin nutrition metabolism, preventing skin aging, moisturizing, and being a good transdermal absorption promoter. It can significantly improve the softness, smoothness, wrinkle removal, and elasticity of the skin. Hyaluronic acid gel injected into the superficial dermis of human skin can maintain moisture in the skin, promote the supply of nutrients and the excretion of metabolites, promote the proliferation and differentiation of epidermal cells, remove oxygen free radicals, and prevent skin aging, beautify and nourish the skin.

[0004] The degradation of sodium hyaluronate in vivo is mainly achieved by specific hyaluronidase, whose specific recognition site is the carboxyl group. The carboxyl group in the sodium hyaluronate molecule forms an amide bond with the amino group in the amino acid, thereby delaying the degradation rate of sodium hyaluronate in vivo and prolonging its action time.

[0005] Chloasma (liver spots) is a yellow-brown pigmentation on the face, which is mostly symmetrically butterfly-shaped and distributed on the cheeks and cheeks. It can also affect the periorbital area, forehead, upper lip and nose. The edges are generally obvious, and there are no subjective symptoms or systemic discomfort. The depth of the spots is related to factors such as season, sun exposure, endocrine, tension, staying up late, and fatigue. The cause of chloasma is that the microcirculation between tissue cells is blocked, the cells dissolve and die, and the melanin increases, forming pigmentation. The face has the thinnest epidermis, the most abundant capillaries, and is most prone to pigmentation. The pigmentation site is mainly in the basal layer of the epidermis, and the melanin particles increase significantly. The high estrogen level in women's blood is the main cause of chloasma, and it is related to female pregnancy, long-term oral contraceptives, menstrual disorders, etc. Treatment methods include drug therapy (such as hydroquinone, retinoic acid preparations, etc.), laser, etc., but drug therapy has large side effects and the effect is not significant. Laser is ineffective for acquired pigmentary diseases such as melanosis and chloasma, and sometimes even aggravates the symptoms.

[0006] Tranexamic acid (tranexamic acid) is a plasminogen activator inhibitor, clinically used as an antifibrinolytic hemostatic agent. After entering the body, tranexamic acid can inhibit the plasminogen system, reduce the activity of melanocytes and tyrosinase, play an antioxidant and anti-inflammatory role, inhibit the production of melanin in the skin and treat chloasma. However, there are problems such as large oral dosage, long time, and slow effect.

[0007] Nicotinamide is a derivative of vitamin B3 (niacin), which is highly safe and stable, and is not easily destroyed by acid, alkali, or heat. Nicotinamide is used as a basic vitamin supplement in dermatology to treat pellagra caused by niacinamide or niacin deficiency, reduce facial pigmentation, sebum secretion, epidermal water loss, erythema, and irritation symptoms, prevent skin yellowing, significantly improve skin texture, and shrink pores to make the skin smoother.

[0008] CN104189952B discloses an injection for correcting skin wrinkles, including high molecular weight polysaccharides, amino acids, water-soluble vitamins and L-carnosine, but it has the following defects: first, the injection pain and stimulation are obvious, and the user's epidermis is red and swollen after use; second, the moisture retention, stability and durability need to be improved; third, the high viscosity of hyaluronic acid medical gel affects the filtration efficiency, and it is easy to clog, and the frequent replacement of the filter membrane leads to high costs and long production cycles. For this reason, it is necessary to develop a sodium hyaluronate composition with freckle removal effect and a preparation method thereof. Summary of the invention

[0009] The present invention provides a sodium hyaluronate composite solution composition with freckle removal effect, which contains, by mass volume percentage (m / v), 1-10 mg / ml of sodium hyaluronate, 0.8-8 mg / ml of peptides, 0.05-1 mg / ml of amino acids, 1-10 mg / ml of freckle removal components, 0.001-0.03 mg / ml of vitamins and a buffer, wherein the weight average molecular weight (Mw) of sodium hyaluronate is 1 million to 1.6 million and its intrinsic viscosity is 1.5-3.0 L / g, and the peptides are selected from L-carnosine, collagen polypeptide, acetyl polypeptide, oligopeptide, glutathione, base The present invention relates to any one or a combination of peptides and hexapeptides, the amino acid is selected from any one or a combination of lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and cysteine. In the preferred technical scheme of the present invention, the freckle removing component is selected from one or more of tranexamic acid, niacinamide, and lipoic acid, the vitamin is selected from any one or a combination of vitamin B2, vitamin H, vitamin C, and vitamin E, and the buffer is selected from any one or a combination of phosphate and citrate.

[0010] In a preferred technical solution of the present invention, the composition is sterilized by moist heat sterilization at 110-130° C. for 8-30 min, preferably at 115-125° C. for 10-25 min.

[0011] In the preferred technical scheme of the present invention, the composition is sterilized by wet heat at 118-125°C for 10-25 minutes, and the composition contains 3-9 mg / ml of sodium hyaluronate, 1-7 mg / ml of peptides, 0.1-0.8 mg / ml of amino acids, 2-6 mg / ml of anti-freckle components, 0.003-0.01 mg / ml of vitamins and phosphate buffer, measured by mass volume percentage (m / v), wherein the Mw of sodium hyaluronate is 800,000-1.1 million and its intrinsic viscosity is 1-2 L / g.

[0012] In the preferred technical scheme of the present invention, the composition is sterilized by wet heat at 120-125°C for 10-25 minutes, and the composition contains 4-7 mg / ml of sodium hyaluronate, 2-6 mg / ml of peptides, 0.2-0.6 mg / ml of amino acids, 3-5 mg / ml of anti-freckle components, 0.004-0.008 mg / ml of vitamins and phosphate buffer, measured by mass volume percentage (m / v), wherein the Mw of sodium hyaluronate is 850,000-1.05 million and its intrinsic viscosity is 1.2-1.7 L / g.

[0013] In the preferred technical solution of the present invention, the pH of the composition is 6-8, preferably pH 6.5-7.5, and more preferably pH 6.8-7.2.

[0014] In a preferred technical solution of the present invention, the osmotic pressure of the composition is 100mOsmol / kg-320mOsmol / kg, preferably 120mOsmol / kg-280mOsmol / kg, and more preferably 150mOsmol / kg-260mOsmol / kg.

[0015] Another object of the present invention is to provide a method for preparing a sodium hyaluronate composition, wherein the composition contains 1-10 mg / ml of sodium hyaluronate, 0.8-8 mg / ml of peptides, 0.05-1 mg / ml of amino acids, 1-10 mg / ml of anti-freckle components, 0.001-0.03 mg / ml of vitamins and a buffer, in terms of mass volume percentage (m / v), wherein the weight average molecular weight (Mw) of sodium hyaluronate is 1 million to 1.6 million and its intrinsic viscosity is 1.5-3.0 L / g, and the peptides are selected from L-carnosine, collagen polypeptide, acetyl polypeptide, oligopeptide, glutathione, basal peptide, hexapeptide any one or a combination thereof, the amino acid is selected from any one or a combination of lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and cysteine; in the preferred technical scheme of the present invention, the freckle removing component is selected from one or more of tranexamic acid, nicotinamide, and lipoic acid; the vitamin is selected from any one or a combination of vitamin B2, vitamin H, vitamin C, and vitamin E; the buffer is selected from any one or a combination of phosphate and citrate; and the method comprises the following steps:

[0016] 1) Weigh the required amount of components, add the required amount of buffer, sodium hyaluronate, anti-freckle component, peptide and amino acid to the injection water in sequence under stirring, stir until completely dissolved, then add the required amount of vitamins, stir until completely dissolved, and filter;

[0017] 2) Collect the filtrate, sterilize it by wet heat at 110-130°C for 8-30 minutes, and store it away from light.

[0018] In the preferred technical solution of the present invention, step 1) and step 2) are carried out under nitrogen protection conditions.

[0019] In the preferred technical solution of the present invention, the stirring is magnetic stirring, and the stirring speed is 400-500 rpm.

[0020] In the preferred technical solution of the present invention, the moist heat sterilization condition is sterilization at 115-125°C for 10-25 minutes.

[0021] In the preferred technical scheme of the present invention, the composition is sterilized by wet heat at 118-125°C for 10-25 minutes, and the composition contains 3-9 mg / ml of sodium hyaluronate, 1-7 mg / ml of peptides, 0.1-0.8 mg / ml of amino acids, 2-6 mg / ml of anti-freckle components, 0.003-0.01 mg / ml of vitamins and phosphate buffer, measured by mass volume percentage (m / v), wherein the Mw of sodium hyaluronate is 800,000-1.1 million and its intrinsic viscosity is 1-2 L / g.

[0022] In the preferred technical scheme of the present invention, the composition is sterilized by wet heat at 120-125°C for 10-25 minutes, and the composition contains 4-7 mg / ml of sodium hyaluronate, 2-6 mg / ml of peptides, 0.2-0.6 mg / ml of amino acids, 3-5 mg / ml of anti-freckle components, 0.004-0.008 mg / ml of vitamins and phosphate buffer, measured by mass volume percentage (m / v), wherein the Mw of sodium hyaluronate is 850,000-1.05 million and its intrinsic viscosity is 1.2-1.7 L / g.

[0023] In the preferred technical solution of the present invention, the pH of the composition is 6-8, preferably pH 6.5-7.5, and more preferably pH 6.8-7.2.

[0024] In a preferred technical solution of the present invention, the osmotic pressure of the composition is 100mOsmol / kg-320mOsmol / kg, preferably 120mOsmol / kg-280mOsmol / kg, and more preferably 150mOsmol / kg-260mOsmol / kg.

[0025] Another object of the present invention is to provide a combined use method of a sodium hyaluronate composition having a freckle removal effect, wherein the sodium hyaluronate composition is used in combination with any one or a combination of other injectable fillers, anesthetics, anti-inflammatory agents, and antiallergic agents; the sodium hyaluronate composition contains 1-10 mg / ml of sodium hyaluronate, 0.8-8 mg / ml of peptides, 0.05-1 mg / ml of amino acids, 1-10 mg / ml of freckle removal components, 0.001-0.03 mg / ml of vitamins, and a buffer, wherein the weight average molecular weight (Mw) of sodium hyaluronate is 1 million to 1.6 million and its intrinsic viscosity is 1.5-3.0 L / g, and the peptide is selected from any one of L-carnosine, collagen polypeptide, acetyl polypeptide, oligopeptide, glutathione, base peptide, and hexapeptide The invention relates to a pharmaceutical composition comprising the following: a pharmaceutical composition comprising ...

[0026] In the preferred technical solution of the present invention, the other injectable fillers are selected from any one of collagen, polymethyl methacrylate, polyacrylamide, silicone, autologous fat or a combination thereof.

[0027] In the preferred technical solution of the present invention, the anesthetic is selected from any one of lidocaine, procaine, tetracaine, bupivacaine, ropivacaine, diclofenac, morphine, hydrocodone, oxycodone, codeine, fentanyl, sodium pentobarbital, sodium phenobarbital, sodium thiopental, chloralose, ethyl carbamate, and chloral hydrate, or a combination thereof.

[0028] In the preferred technical scheme of the present invention, the anti-inflammatory agent is selected from any one of fluocinolone, hydrocortisone, betamethasone, aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, disalsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac, fenprofen, ketoprofen, ketorolac, tetraclofenamic acid, sulindac, and tolmetin, or a combination thereof.

[0029] In the preferred technical scheme of the present invention, the antiallergic agent is selected from any one of diphenhydramine, promethazine, chlorpheniramine, sodium cromoglycate, ketotifen, betahistine, montelukast, zafirlukast, salbutamol, calcium gluconate, and adrenal glucocorticoids, or a combination thereof.

[0030] Another object of the present invention is to provide a sodium hyaluronate composition with freckle removal effect as an injectable filler, wherein the sodium hyaluronate composition contains 1-10 mg / ml of sodium hyaluronate, 0.8-8 mg / ml of peptides, 0.05-1 mg / ml of amino acids, 1-10 mg / ml of freckle removal components, 0.001-0.03 mg / ml of vitamins and a buffer, wherein the weight average molecular weight (Mw) of sodium hyaluronate is 1 million to 1.6 million and its intrinsic viscosity is 1.5-3.0 L / g, the peptides are selected from any one of L-carnosine, collagen polypeptide, acetyl polypeptide, oligopeptide, glutathione, base peptide, hexapeptide or a combination thereof, and the amino acids are selected from lysine, Any one or a combination of histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and cysteine. In the preferred technical scheme of the present invention, the freckle removing component is selected from one or more of tranexamic acid, niacinamide, and lipoic acid, the vitamin is selected from any one or a combination of vitamin B2, vitamin H, vitamin C, and vitamin E, and the buffer is selected from any one or a combination of phosphate and citrate; the composition is sterilized by wet heat at 110-130°C for 8-30min, preferably by wet heat sterilization at 115-125°C for 10-25min.

[0031] In a preferred technical solution of the present invention, the injection filling site is selected from any one of the face, neck, abdomen, chest, buttocks, thigh, calf, upper arm, and lower arm, or a combination thereof.

[0032] In a preferred technical solution of the present invention, the injectable filler is used to improve any one or a combination of facial emaciation, fat atrophy, sunken cheeks, sunken eye sockets, and skin wrinkles in patients.

[0033] Unless otherwise specified, the present invention uses a Waters Arc high performance liquid chromatography (detection conditions: chromatographic column: Waters Ultrahydrogel 1000 7.8*300mm, detector: 2414 RI Detector, flow rate: 1ml / min, column temperature: 30°C, injection volume: 50μl) to detect the molecular weight of sodium hyaluronate. The present invention uses an Ubbelohde viscometer to measure the intrinsic viscosity of sodium hyaluronate. The present invention uses a rotational rheometer at a shear rate of 0.01s -1 ~100s -1The shear viscosity of the hyaluronic acid composition was detected under the conditions of.

[0034] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0035] Compared with the prior art, the present invention has the following beneficial technical effects:

[0036] 1. The sodium hyaluronate composition of the present invention dissolves sodium hyaluronate in phosphate buffer, significantly improves the solubility, fluidity and biocompatibility of hyaluronic acid, and is more conducive to injection filling. The osmotic pressure of the composition is 100mOsmol / kg to 320mOsmol / kg, pH 6-8, and significantly reduces the problems of injection site irritation, swelling, hemolysis and pain that may be caused during injection; scientific selection of wet heat sterilization conditions significantly improves the sterilization efficiency and significantly shortens the production cycle, and synergistically utilizes the low molecular weight hyaluronic acid with moisturizing, lubricating and stabilizing effects produced by wet heat sterilization, thereby improving the stability of the composition and its moisturizing effect, and has the advantages of better filling protection effect, good stability, high sterilization efficiency, high yield, better cost, safety and effectiveness, etc.

[0037] 2. The present invention scientifically screens the contents of sodium hyaluronate and freckle-removing components such as tranexamic acid and nicotinamide. Sodium hyaluronate injection can directly inject tranexamic acid into skin-related areas and layers, uses a smaller dosage, has fewer adverse reactions, and can quickly achieve therapeutic effects, prevent melanin aggregation, deeply inhibit melanin production, block melanin transmission paths, inhibit tyrosinase activity, and dilute pigmentation such as chloasma, sunburn, and dark spots. The present invention rationally screens the proportions of each component, so that the sodium hyaluronate composite solution for injection also has the effects of anti-aging, improving skin barrier, and shrinking pores. When used for anti-inflammatory, whitening, etc., it can be used in conjunction with other drugs to play a synergistic effect.

[0038] 3. The preparation method of the sodium hyaluronate composition of the present invention has the advantages of simple operation, higher production efficiency, better cost, and easy industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 Changes in pH value of the sodium hyaluronate composite solutions of Examples 1-6 and Comparative Example 1;

[0040] Figure 2 Viscosity changes of the sodium hyaluronate composite solutions of Examples 1-6 and Comparative Example 1. DETAILED DESCRIPTION

[0041] The present invention will be specifically described below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the essence of the present invention.

[0042] Example 1: Preparation of Sodium Hyaluronate Composition

[0043] Composition and ratio of the composition:

[0044]

[0045] The preparation of the sodium hyaluronate composition comprises the following steps:

[0046] 1) Weighing the required amount of sodium dihydrogen phosphate hydrate and disodium hydrogen phosphate hydrate, and dissolving them in the required amount of water for injection to prepare a phosphate buffer;

[0047] 2) At 400-500 rpm, add the required amount of sodium hyaluronate to phosphate buffer, stir for 1.5-2 hours, mix thoroughly, then add base peptide and amino acids, mix well, add the required amount of vitamin B2 before filtering, mix well, filter, and sterilize the filtrate at 120°C for 10 minutes.

[0048] According to the method of the present invention, the weight average molecular weight of the hyaluronic acid in the composition is 860,000, the intrinsic viscosity is 1.5 L / g, the pH is 7.2, and the osmotic pressure is 150 mOsmol / kg.

[0049] Example 2: Preparation of Sodium Hyaluronate Composition

[0050] Composition and ratio of the composition:

[0051]

[0052] The preparation of the sodium hyaluronate composition comprises the following steps:

[0053] 1) Weigh the required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them in the required amount of water for injection to prepare phosphate buffer;

[0054] 2) At 400-500 rpm, add the required amount of sodium hyaluronate to phosphate buffer, stir for 1.5-2 hours, mix thoroughly, then add tranexamic acid, oligopeptide and amino acids, mix well, add the required amount of vitamin B2 before filtering, mix well, filter, and sterilize the filtrate at 125°C for 11 minutes.

[0055] According to the method of the present invention, the hyaluronic acid in the composition has a weight average molecular weight of 1,000,000, an intrinsic viscosity of 1.7 L / g, a pH of 7.2, and an osmotic pressure of 140 mOsmol / kg.

[0056] Example 3: Preparation of Sodium Hyaluronate Composition

[0057] Composition and ratio of the composition:

[0058]

[0059]

[0060] The preparation of the sodium hyaluronate composition comprises the following steps:

[0061] 1) Weigh the required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them in the required amount of water for injection to prepare phosphate buffer;

[0062] 2) At 400-500 rpm, add the required amount of sodium hyaluronate to phosphate buffer, stir for 1.5-2 hours, mix thoroughly, then add tranexamic acid, L-carnosine and various amino acids, mix well, add the required amount of vitamin B2 before filtering, mix well, filter, and sterilize the filtrate at 120° C. for 12 minutes.

[0063] According to the method of the present invention, the weight average molecular weight of the hyaluronic acid in the composition is 850,000, the intrinsic viscosity is 1.5 L / g, the pH is 7.2, and the osmotic pressure is 150 mOsmol / kg.

[0064] Example 4: Preparation of Sodium Hyaluronate Composition

[0065] Composition and ratio of the composition:

[0066]

[0067]

[0068] The preparation of the sodium hyaluronate composition comprises the following steps:

[0069] 1) Weigh the required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them in the required amount of water for injection to prepare phosphate buffer;

[0070] 2) At 400-500 rpm, add the required amount of sodium hyaluronate to phosphate buffer, stir for 1.5-2 hours, mix thoroughly, then add tranexamic acid, glutathione and amino acids, mix well, add the required amount of vitamin B2 before filtering, mix well, filter, and sterilize the filtrate at 120°C for 12 minutes.

[0071] According to the method of the present invention, the weight average molecular weight of the hyaluronic acid in the composition is 910,000, the intrinsic viscosity is 1.6 L / g, the pH is 7.2, and the osmotic pressure is 160 mOsmol / kg.

[0072] Example 5: Preparation of Sodium Hyaluronate Composition

[0073] Composition and ratio of the composition:

[0074]

[0075]

[0076] The preparation of the sodium hyaluronate composition comprises the following steps:

[0077] 1) Weigh the required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them in the required amount of water for injection to prepare phosphate buffer;

[0078] 2) At 400-500 rpm, add the required amount of sodium hyaluronate to phosphate buffer, stir for 1.5-2 hours, mix thoroughly, then add niacinamide, L-carnosine, glutathione and amino acids, mix well, add the required amount of vitamin B2 before filtering, mix well, filter, and sterilize the filtrate at 120°C for 12 minutes.

[0079] According to the method of the present invention, the weight average molecular weight of the hyaluronic acid in the composition is 900,000, the intrinsic viscosity is 1.6 L / g, the pH is 7.3, and the osmotic pressure is 160 mOsmol / kg.

[0080] Example 6: Preparation of Sodium Hyaluronate Composition

[0081] Composition and ratio of the composition:

[0082]

[0083]

[0084] The preparation of the sodium hyaluronate composition comprises the following steps:

[0085] 1) Under stirring at 400-500 rpm, weigh the required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them in the required amount of water for injection to prepare a phosphate buffer;

[0086] 2) Add the required amount of sodium hyaluronate to phosphate buffer, stir at 400-500 rpm for 1.5-2 hours, mix thoroughly, then add niacinamide, hexapeptide and amino acids, mix well, add the required amount of vitamin B2 before filtering, mix well, filter, and sterilize the filtrate at 120°C for 12 minutes.

[0087] According to the method of the present invention, the weight average molecular weight of the hyaluronic acid in the composition is 850,000, the intrinsic viscosity is 1.5 L / g, the pH is 7.3, and the osmotic pressure is 145 mOsmol / kg.

[0088] Comparative Example 1 Preparation of Sodium Hyaluronate Composition

[0089] Composition and ratio of the composition:

[0090]

[0091] The preparation of the sodium hyaluronate composition comprises the following steps:

[0092] At 400-500 rpm, add the required amount of sodium hyaluronate, L-carnosine and amino acids to water for injection, mix evenly, then add the required amount of sodium chloride and vitamin B2, mix evenly, filter and sterilize to obtain the composition. According to the method of the present invention, the pH value of the composition is 7.2 and the osmotic pressure is 70mOsmol / kg.

[0093] Test Example 1

[0094] The sodium hyaluronate composite solutions of Examples 1-6 were stored at a low temperature of 5°C, and their appearance, viscosity, and pH value were tested at 0 days, 3 months, 6 months, and 12 months. The appearance of the examples and the comparative examples were all colorless and transparent solutions. The pH value results are shown in Table 1. Figure 1 , viscosity results are shown in Figure 2 .

[0095] Test Example 2 Clinical trial of sodium hyaluronate composition for injection

[0096] People who were 18 years old or above and had a need to improve their facial skin were selected. A total of 64 subjects participated in this trial, with the youngest being 27.00 years old, the oldest being 67.00 years old, and an average age of 43.77 years old.

[0097] Inclusion criteria:

[0098] (1) Aged 18 or above;

[0099] (2) Subjects who have a strong desire to improve the current status of facial skin

[0100] (3) Subjects who agreed not to use other cosmetic treatments related to the study during the study;

[0101] (4) Subjects who understand and comply with the trial requirements and can complete the entire follow-up process;

[0102] (5) Voluntarily participate in this clinical study and sign the informed consent.

[0103] Exclusion criteria:

[0104] (1) Within 1 month before the screening period, the patient had received skin improvement treatment on the face, such as radiofrequency treatment, focused ultrasound treatment, grinding, chemical peeling, etc.;

[0105] (2) Subjects are known to be allergic to sodium hyaluronate, tranexamic acid, L-carnosine, glycine, proline, vitamin B2, phosphate, lidocaine or other local anesthetics; Subjects with a history of clinically significant skin allergies or systemic allergies;

[0106] (3) Subjects with facial scars, ulcers, skin infections, or a history of other active skin diseases or malignant skin diseases, which may affect the judgment of treatment efficacy;

[0107] (4) Subjects have a history of serious diseases of important organs or autoimmune diseases;

[0108] (5) Women who are pregnant or breastfeeding; female subjects of childbearing age who do not agree to take medically approved contraceptive measures (such as oral contraceptives, condoms, etc.) during the trial;

[0109] (6) The researchers judge that the abnormal laboratory test results are clinically significant and affect the subjects of the clinical trial;

[0110] (7) Subjects who have participated in other clinical trials within 30 days before the screening period;

[0111] (8) Subjects deemed by the researcher to be unsuitable for participation in this trial study.

[0112] 64 subjects were randomly divided into two groups, 23 in each group, one group was the test group and the other group was the control group. After washing the face before injection, the subjects applied the numbing cream for 30 minutes and then washed off the numbing cream. The test group was subcutaneously injected with the sodium hyaluronate composition of Example 3, and the control group was subcutaneously injected with the sodium hyaluronate composition of Comparative Example 1. After the injection, the subjects applied a refrigerated medical mask for 20 minutes.

[0113] 28 days is one cycle, and the initial administration of each cycle is once. After three consecutive administrations, the difference in the improvement rate of facial skin fine lines and the improvement rate of texture and spots of each subject and the control group are calculated. Compared with the control group, the difference in the improvement rate of facial skin texture in the test group reached 14.47%; the difference in the improvement rate of facial fine lines reached 18.83%; the difference in the improvement rate of facial spots reached 2.39%, and no adverse events that may be related to the test device were observed.

[0114] Test Example 3 Clinical trial of sodium hyaluronate composition for injection

[0115] People who were 18 years of age or older and had a need to improve their facial skin were selected. A total of 64 subjects participated in this trial, with the youngest being 25.00 years old, the oldest being 70.00 years old, and an average age of 42.12 years old.

[0116] Inclusion criteria:

[0117] (1) Aged 18 or above;

[0118] (2) Subjects who have a strong desire to improve the current status of facial skin

[0119] (3) Subjects who agreed not to use other cosmetic treatments related to the study during the study;

[0120] (4) Subjects who understand and comply with the trial requirements and can complete the entire follow-up process;

[0121] (5) Voluntarily participate in this clinical study and sign the informed consent.

[0122] Exclusion criteria:

[0123] (1) Within 1 month before the screening period, the patient had received skin improvement treatment on the face, such as radiofrequency treatment, focused ultrasound treatment, grinding, chemical peeling, etc.;

[0124] (2) Subjects are known to be allergic to sodium hyaluronate, niacinamide, hexapeptide, glycine, alanine, vitamin B2, phosphate, lidocaine or other local anesthetics; Subjects with a history of clinically significant skin allergies or systemic allergies;

[0125] (3) Subjects with facial scars, ulcers, skin infections, or a history of other active skin diseases or malignant skin diseases, which may affect the judgment of treatment efficacy;

[0126] (4) Subjects have a history of serious diseases of important organs or autoimmune diseases;

[0127] (5) Women who are pregnant or breastfeeding; female subjects of childbearing age who do not agree to take medically approved contraceptive measures (such as oral contraceptives, condoms, etc.) during the trial;

[0128] (6) The researchers judge that the abnormal laboratory test results are clinically significant and affect the subjects of the clinical trial;

[0129] (7) Subjects who have participated in other clinical trials within 30 days before the screening period;

[0130] (8) Subjects deemed by the researcher to be unsuitable for participation in this trial study.

[0131] 64 subjects were randomly divided into two groups, each with 23 people, one group was the test group and the other group was the control group. After washing the face before injection, the subjects applied numbing cream for 30 minutes and then washed off the numbing cream. The test group was subcutaneously injected with the sodium hyaluronate composition of Example 6, and the control group was subcutaneously injected with the sodium hyaluronate composition of Comparative Example 1. After the injection, the subjects applied a refrigerated medical mask for 20 minutes.

[0132] 28 days is one cycle, and the initial administration of each cycle is once. After three consecutive administrations, the difference in the improvement rate of facial skin fine lines and the improvement rate of texture and spots of each subject and the control are calculated. Compared with the control, the difference in the improvement rate of facial skin texture in the test group reached 12.11%; the difference in the improvement rate of facial fine lines reached 19.93%; the difference in the improvement rate of facial spots reached 2.97%, and no adverse events that may be related to the test device were observed.

[0133] The above description is only an example of the implementation mode of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A sodium hyaluronate composition having freckle removal effect, characterized in that: The composition is composed of the following components, measured by mass volume percentage (m / v), sodium hyaluronate 1-10 mg / ml, peptides 0.8-8 mg / ml, amino acids 0.05-1 mg / ml, freckle removal components 1-10 mg / ml, vitamins 0.001-0.03 mg / ml and phosphate buffer, Wherein, the weight average molecular weight (Mw) of sodium hyaluronate is 1 million to 1.6 million and its intrinsic viscosity is 1.5 to 3.0 L / g, the peptides are selected from any one or a combination of L-carnosine, collagen polypeptide, acetyl polypeptide, oligopeptide, glutathione, base peptide, hexapeptide, and the amino acids are selected from any one or a combination of lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and cysteine; The freckle removing component is selected from one or more of tranexamic acid, niacinamide, and lipoic acid, and the vitamin is selected from any one of vitamin B2, vitamin H, vitamin C, and vitamin E or a combination thereof.

2. A sodium hyaluronate composition according to claim 1, characterized in that: The composition is sterilized by wet heat sterilization at 110-130° C. for 8-30 minutes.

3. A sodium hyaluronate composition according to claim 2, characterized in that: The composition is sterilized by wet heat sterilization at 115-125° C. for 10-25 min.

4. A sodium hyaluronate composition according to claim 1, characterized in that: The composition is sterilized by wet heat at 118-125° C. for 10-25 min, and contains, by mass volume percentage (m / v), 3-9 mg / ml of sodium hyaluronate, 1-7 mg / ml of peptides, 0.1-0.8 mg / ml of amino acids, 2-6 mg / ml of anti-freckle components, 0.003-0.01 mg / ml of vitamins and a phosphate buffer, wherein the Mw of sodium hyaluronate is 800,000-1.1 million and its intrinsic viscosity is 1-2 L / g.

5. A sodium hyaluronate composition according to claim 1, characterized in that: The composition is sterilized by wet heat at 120-125° C. for 10-25 min, and contains, by mass volume percentage (m / v), 4-7 mg / ml of sodium hyaluronate, 2-6 mg / ml of peptides, 0.2-0.6 mg / ml of amino acids, 3-5 mg / ml of anti-freckle components, 0.004-0.008 mg / ml of vitamins and a phosphate buffer, wherein the Mw of the sodium hyaluronate is 850,000-1.05 million and its intrinsic viscosity is 1.2-1.7 L / g.

6. A sodium hyaluronate composition according to claim 1, characterized in that: The pH of the composition is 6-8.

7. A sodium hyaluronate composition according to claim 6, characterized in that: The pH of the composition is 6.5-7.

5.

8. A sodium hyaluronate composition according to claim 7, characterized in that: The pH of the composition is 6.8-7.

2.

9. The sodium hyaluronate composition according to claim 1, characterized in that: The osmotic pressure of the composition is 100 mOsmol / kg-320 mOsmol / kg.

10. A sodium hyaluronate composition according to claim 9, characterized in that: The osmotic pressure of the composition is 120mOsmol / kg-280mOsmol / kg.

11. A sodium hyaluronate composition according to claim 10, characterized in that: The osmotic pressure of the composition is 150mOsmol / kg-260mOsmol / kg.

12. A method for preparing a sodium hyaluronate composition according to any one of claims 1 to 11, characterized in that: The steps include: 1) Weigh the required amount of components, add the required amount of phosphate buffer, sodium hyaluronate, anti-freckle component, peptide and amino acid to the injection water in sequence under stirring, stir until completely dissolved, then add the required amount of vitamins, stir until completely dissolved, and filter; 2) Collect the filtrate, sterilize it by wet heat at 110-130°C for 8-30 minutes, and store it away from light.

13. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: Step 1) and step 2) are carried out under nitrogen protection conditions.

14. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: The stirring is magnetic stirring, and the stirring speed is 400-500 rpm.

15. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: The wet heat sterilization condition is sterilization at 115-125° C. for 10-25 minutes.

16. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: The composition is sterilized by wet heat at 118-125° C. for 10-25 min, and contains, by mass volume percentage (m / v), 3-9 mg / ml of sodium hyaluronate, 1-7 mg / ml of peptides, 0.1-0.8 mg / ml of amino acids, 2-6 mg / ml of anti-freckle components, 0.003-0.01 mg / ml of vitamins and a phosphate buffer, wherein the Mw of sodium hyaluronate is 800,000-1.1 million and its intrinsic viscosity is 1-2 L / g.

17. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: The composition is sterilized by wet heat at 120-125° C. for 10-25 min, and contains, by mass volume percentage (m / v), 4-7 mg / ml of sodium hyaluronate, 2-6 mg / ml of peptides, 0.2-0.6 mg / ml of amino acids, 3-5 mg / ml of anti-freckle components, 0.004-0.008 mg / ml of vitamins and a phosphate buffer, wherein the Mw of the sodium hyaluronate is 850,000-1.05 million and its intrinsic viscosity is 1.2-1.7 L / g.

18. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: The pH of the composition is 6-8.

19. The method for preparing a sodium hyaluronate composition according to claim 18, characterized in that: The pH of the composition is 6.5-7.

5.

20. The method for preparing a sodium hyaluronate composition according to claim 19, characterized in that: The pH of the composition is 6.8-7.

2.

21. The method for preparing a sodium hyaluronate composition according to claim 12, characterized in that: The osmotic pressure of the composition is 100 mOsmol / kg-320 mOsmol / kg.

22. The method for preparing a sodium hyaluronate composition according to claim 21, characterized in that: The osmotic pressure of the composition is 120mOsmol / kg-280mOsmol / kg.

23. The method for preparing a sodium hyaluronate composition according to claim 22, characterized in that: The osmotic pressure of the composition is 150mOsmol / kg-260mOsmol / kg.

24. Use of a sodium hyaluronate composition as claimed in any one of claims 1 to 11 as an injectable filler, characterized in that: The injection filling site is selected from any one of the face, neck, abdomen, chest, buttocks, thighs, calves, upper arms, lower arms, or a combination thereof.

25. Use of a sodium hyaluronate composition as claimed in claim 24 as an injectable filler, characterized in that: The injection filling site is the face.

26. Use of a sodium hyaluronate composition as an injectable filler according to claim 24, characterized in that: The injectable filler is used to improve any one or a combination of facial emaciation, fat atrophy, sunken cheeks, sunken eye sockets, and skin wrinkles.

27. Use of a sodium hyaluronate composition as claimed in any one of claims 1 to 11 as an injectable filler, characterized in that: The sodium hyaluronate composition is used in combination with any one or a combination of other injectable fillers, anesthetics, anti-inflammatory agents, and anti-allergic agents.

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