CN117357699B - A sodium hyaluronate composition with freckle removal effect, preparation method thereof and application thereof - Google Patents
A sodium hyaluronate composition with freckle removal effect, preparation method thereof and application thereof Download PDFInfo
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- CN117357699B CN117357699B CN202310826669.5A CN202310826669A CN117357699B CN 117357699 B CN117357699 B CN 117357699B CN 202310826669 A CN202310826669 A CN 202310826669A CN 117357699 B CN117357699 B CN 117357699B
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- sodium hyaluronate
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
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Abstract
本发明公开了一种祛斑功效的透明质酸钠组合物及其制备方法和应用，组合物中含有透明质酸钠1‑10mg/ml，肽类0.8‑8mg/ml，氨基酸0.05‑1mg/ml，祛斑组分1‑10mg/ml，维生素0.001‑0.03mg/ml和缓冲剂,其中，透明质酸钠的重均分子量(Mw)为100万‑160万和其特性黏数为1.5‑3.0L/g。本发明的透明质酸钠组合物显著减少注射时可能引起的注射部位刺激、肿胀、溶血和疼痛等问题，提高了组合物的稳定性及其保湿效果，而且可以迅速地实现治疗效果，防止黑色素聚集，深层抑制黑色素生成。
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
The invention belongs to the technical field of medicines, and particularly relates to a sodium hyaluronate composition with good stability, a preparation method and application thereof.
Background
Skin aging can result in changes in the skin that result in structural changes, altered function, tissue loss, formation of wrinkles, dry skin, rough yellowing, pigmentation, reduced elasticity, and the like. Injection filling technology is an effective means to address skin rejuvenation.
Hyaluronic acid (hyaluronic acid) is a macromolecular acidic mucopolysaccharide composed of D-glucuronic acid and N-acetylglucosamine disaccharide units, and is widely distributed in human body tissues such as articular cartilage, crystalline lens, skin dermis and the like. Hyaluronic acid has effects of improving skin nutrition metabolism, preventing skin aging, keeping moisture, and good transdermal absorption promoter, and can remarkably improve skin tenderness, smoothness, wrinkle removing, and elasticity increasing. The hyaluronic acid gel is injected into the superficial dermis of human skin, and has effects in maintaining skin moisture, promoting nutrient supply and metabolite excretion, promoting proliferation and differentiation of epidermal cells, scavenging oxygen free radicals, preventing skin aging, caring skin, etc.
In vivo degradation of sodium hyaluronate is mainly achieved by specific hyaluronidases, the specific recognition site of which is a carboxyl group. The carboxyl in the sodium hyaluronate molecule forms an amide bond with the amino in the amino acid to delay the in vivo degradation speed of the sodium hyaluronate and prolong the action time of the sodium hyaluronate.
Chloasma (liver spots) is yellow brown pigmentation of the face, and is distributed on cheeks of cheeks in a multiple symmetrical butterfly shape, and can also affect periorbital, forehead, upper lip and nose, and the edge is generally obvious without subjective symptoms and general discomfort. The depth of the color spots is related to the seasons, sun, endocrine, tension, stay up and tiredness. The formation of chloasma is caused by pigmentation formed by pigmentation due to the fact that the microcirculation among tissue cells is blocked, the cells are dissolved and dead, and melanin is increased. The facial epidermis layer is the thinnest, the most abundant capillaries, and the most prone to pigmentation. The pigmentation part is mainly at the basal layer of epidermis, the melanin particles are obviously increased, and the high estrogen level in the blood of women is the main cause of chloasma, and is related to female pregnancy, long-term oral contraceptive, menstrual disorder and the like. The treatment method comprises drug treatment (such as hydroquinone, retinoic acid preparation, etc.), laser, etc., but the drug treatment has the advantages of great side effect and insignificant effect, and the laser is ineffective for treating acquired pigment diseases such as melanosis and chloasma, and sometimes even aggravates symptoms.
Tranexamic acid (tranexamic acid) is a plasminogen activator inhibitor, and is clinically used as an antiplasmin hemostatic agent. After tranexamic acid enters the body, the tranexamic acid can inhibit a plasminogen system, promote the reduction of melanocyte activity and tyrosinase activity, play roles of resisting oxidization, diminishing inflammation and the like, inhibit the generation of melanin by skin and treat chloasma. But has the problems of large dosage, long time, slow effect and the like for oral administration.
Nicotinamide is a derivative of vitamin B3 (nicotinic acid), has high safety and stable property, and is not easily damaged by acid-base heat. The nicotinamide is used as a dermatological basic vitamin supplement for treating brown skin diseases caused by nicotinamide or niacin deficiency, reducing facial pigmentation spots, sebum secretion, epidermal water loss rate, erythema and irritation symptoms, preventing skin yellowing, significantly improving skin texture, shrinking pores and smoothing skin.
CN104189952B discloses an injection for correcting skin wrinkles, which comprises high molecular polysaccharide, amino acid, water-soluble vitamin and L-carnosine, but has the following defects that firstly, injection pain and stimulation are obvious, red and swelling appear on the epidermis of a user after use, secondly, the moisture retention, stability, durability and the like are required to be improved, thirdly, the high viscosity of the medical gel of hyaluronic acid affects the filtering efficiency, and the medical gel is easy to block, and the filtering membrane is frequently replaced to cause the defects of high cost, long production period and the like. For this reason, there is a need to develop a sodium hyaluronate composition having a spot-removing effect and a method for preparing the same.
Disclosure of Invention
The invention provides a sodium hyaluronate composite solution composition with freckle removing effect, which comprises 1-10mg/ml of sodium hyaluronate, 0.8-8mg/ml of peptides, 0.05-1mg/ml of amino acids, 1-10mg/ml of freckle removing components, 0.001-0.03mg/ml of vitamins and buffer agents, wherein the weight average molecular weight (Mw) of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the characteristic viscosity number thereof is 1.5-3.0L/g, the peptides are selected from any one or combination of L-carnosine, collagen polypeptides, acetyl polypeptides, oligopeptides, glutathione, base peptides and hexapeptide, the amino acids are selected from any one or combination of lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine and cysteine, the preferred technical scheme of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the weight average molecular weight (Mw) is 1.5-3.0L/g, the peptides are selected from any one or combination of the vitamins, the vitamin is selected from any one or combination of vitamin E, vitamin E and vitamin E, vitamin E or vitamin E.
In a preferred embodiment of the invention, the composition is subjected to heat-moisture sterilization at 110-130 ℃ for 8-30min, preferably at 115-125 ℃ for 10-25min.
In the preferred technical scheme of the invention, after the composition is subjected to wet heat sterilization for 10-25min at 118-125 ℃, the composition contains 3-9mg/ml of sodium hyaluronate, 1-7mg/ml of peptides, 0.1-0.8mg/ml of amino acid, 2-6mg/ml of freckle-removing components, 0.003-0.01mg/ml of vitamins and phosphate buffer according to mass volume percentage (m/v), wherein the Mw of the sodium hyaluronate is 80 ten thousand-110 ten thousand and the characteristic viscosity number of the sodium hyaluronate is 1-2L/g.
In the preferred technical scheme of the invention, after the composition is subjected to wet heat sterilization for 10-25min at 120-125 ℃, the composition contains 4-7mg/ml of sodium hyaluronate, 2-6mg/ml of peptides, 0.2-0.6mg/ml of amino acid, 3-5mg/ml of freckle-removing components, 0.004-0.008mg/ml of vitamins and phosphate buffer, wherein the Mw of the sodium hyaluronate is 85 ten thousand-105 ten thousand and the characteristic viscosity thereof is 1.2-1.7L/g.
In a preferred embodiment of the invention, the pH of the composition is from 6 to 8, preferably from 6.5 to 7.5, more preferably from 6.8 to 7.2.
In a preferred embodiment of the invention, the composition has an osmolality of from 100mOsmol/kg to 320mOsmol/kg, preferably from 120mOsmol/kg to 280mOsmol/kg, more preferably from 150mOsmol/kg to 260mOsmol/kg.
The invention also aims to provide a preparation method of the sodium hyaluronate composition, which comprises 1-10mg/ml of sodium hyaluronate, 0.8-8mg/ml of peptides, 0.05-1mg/ml of amino acids, 1-10mg/ml of freckle removing components, 0.001-0.03mg/ml of vitamins and buffer agents, wherein the weight average molecular weight (Mw) of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the characteristic viscosity number thereof is 1.5-3.0L/g, the peptides are selected from any one or combination of L-carnosine, collagen polypeptides, acetyl polypeptides, oligopeptides, glutathione, base peptides and hexapeptide, the amino acids are selected from any one or combination of lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, cysteine, and the preferred technical scheme of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the weight average molecular weight (Mw) is 1.5-3.0L/g, the peptides are selected from any one or combination of L-carnosine, the vitamin is selected from any one or combination of vitamin E, vitamin E and vitamin E, vitamin E is selected from any one or combination thereof, and vitamin E is selected from the following steps:
1) Weighing the components with required amount, sequentially adding the buffer, sodium hyaluronate, freckle removing component, peptide and amino acid with required amount into water for injection under stirring, stirring until the components are completely dissolved, adding the vitamin with required amount, stirring until the components are completely dissolved, and filtering;
2) Collecting filtrate, sterilizing at 110-130deg.C for 8-30min, and storing in dark place.
In a preferred embodiment of the present invention, step 1) and step 2) are performed under nitrogen protection.
In the preferable technical scheme of the invention, the stirring is magnetic stirring, and the stirring rotating speed is 400-500 rpm.
In the preferred technical scheme of the invention, the wet heat sterilization condition is that the sterilization is carried out for 10-25min under the condition of 115-125 ℃.
In the preferred technical scheme of the invention, after the composition is subjected to wet heat sterilization for 10-25min at 118-125 ℃, the composition contains 3-9mg/ml of sodium hyaluronate, 1-7mg/ml of peptides, 0.1-0.8mg/ml of amino acid, 2-6mg/ml of freckle-removing components, 0.003-0.01mg/ml of vitamins and phosphate buffer according to mass volume percentage (m/v), wherein the Mw of the sodium hyaluronate is 80 ten thousand-110 ten thousand and the characteristic viscosity number of the sodium hyaluronate is 1-2L/g.
In the preferred technical scheme of the invention, after the composition is subjected to wet heat sterilization for 10-25min at 120-125 ℃, the composition contains 4-7mg/ml of sodium hyaluronate, 2-6mg/ml of peptides, 0.2-0.6mg/ml of amino acid, 3-5mg/ml of freckle-removing components, 0.004-0.008mg/ml of vitamins and phosphate buffer, wherein the Mw of the sodium hyaluronate is 85 ten thousand-105 ten thousand and the characteristic viscosity thereof is 1.2-1.7L/g.
In a preferred embodiment of the invention, the pH of the composition is from 6 to 8, preferably from 6.5 to 7.5, more preferably from 6.8 to 7.2.
In a preferred embodiment of the invention, the composition has an osmolality of from 100mOsmol/kg to 320mOsmol/kg, preferably from 120mOsmol/kg to 280mOsmol/kg, more preferably from 150mOsmol/kg to 260mOsmol/kg.
Another object of the present invention is to provide a combination of a sodium hyaluronate composition having a spot-removing effect, which is used in combination with any one of other injection fillers, anesthetics, anti-inflammatory agents, antiallergic agents, or a combination thereof; the sodium hyaluronate composition contains 1-10mg/ml of sodium hyaluronate, 0.8-8mg/ml of peptides, 0.05-1mg/ml of amino acids, 1-10mg/ml of freckle removing components, 0.001-0.03mg/ml of vitamins and buffer agents, wherein the weight average molecular weight (Mw) of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the characteristic viscosity thereof is 1.5-3.0L/g, the peptides are selected from any one or combination of L-carnosine, collagen polypeptides, acetyl polypeptides, oligopeptides, glutathione, base peptides and hexapeptide, the amino acids are selected from any one or 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 components are selected from one or more of tranexamic acid, nicotinamide and sulfur, the vitamins are selected from any one or combination of vitamins, vitamin E and vitamin E is selected from any one or combination of vitamin E and vitamin E is sterilized under the conditions of heat conditions of 25-25 ℃ and 10 ℃ of wet conditions are preferably selected from any combination of the vitamin and 10 ℃ and wet buffer conditions.
In a preferred embodiment of the present invention, the other injection filler is selected from any one of collagen, polymethyl methacrylate, polyacrylamide, silica gel, and autologous fat, or a combination thereof.
In a preferred embodiment 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 sulfatoxel, chloraldose, urethane, chloral hydrate, or a combination thereof.
In a preferred embodiment of the present invention, the anti-inflammatory agent is selected from any one or a combination of fluocinolone acetonide, hydrocortisone, betamethasone, aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, bissalicylate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac, fenprofen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, tolmetin.
In a preferred embodiment of the present invention, the antiallergic agent is selected from diphenhydramine, promethazine, chlorpheniramine, cromolyn sodium, ketotifen, betahistine, montelukast, zalutast, salbutamol, calcium gluconate, adrenoglucocorticoid, or any combination thereof.
The invention further aims to provide an application of the sodium hyaluronate composition with the freckle removing effect as an injection filling agent, wherein the sodium hyaluronate composition contains 1-10mg/ml of sodium hyaluronate, 0.8-8mg/ml of peptides, 0.05-1mg/ml of amino acids, 1-10mg/ml of freckle removing components, 0.001-0.03mg/ml of vitamins and buffer agents, wherein the weight average molecular weight (Mw) of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the characteristic viscosity number thereof is 1.5-3.0L/g, the peptides are selected from any one or combination of L-carnosine, collagen polypeptides, acetyl polypeptides, oligopeptides, glutathione, base peptides and hexapeptide, the amino acids are selected from any one or combination of lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine and cysteine, and the preferred technical scheme of the sodium hyaluronate is 100 ten thousand-160 ten thousand and the weight average molecular weight (Mw) is 1.5-160 ten thousand and the characteristic viscosity number thereof is 1.5-3.0L/g, the peptides are selected from any one or combination of amino acids, the amino acids are selected from any one or combination of heat sterilization conditions of vitamin E, vitamin E and vitamin E is selected from any one or combination of vitamin E is selected from the group of 25-10 ℃ and 10-25-10-150 wet conditions, and the preferred vitamin is selected from the combination thereof.
In a preferred embodiment of the present invention, the injection site is selected from any one of the face, neck, abdomen, chest, buttocks, thigh, calf, upper arm, lower arm, or a combination thereof.
In a preferred embodiment of the present invention, the injectable filler is used for improving any one or a combination of facial wasting, lipoatrophy, cheek subsidence, orbital subsidence, skin wrinkles in a patient.
The molecular weight of sodium hyaluronate was measured by high performance liquid chromatography (measurement conditions: chromatographic column: waters Ultrahydrogel, 7.8 x 300mm, detector: 2414, RI Detector, flow rate: 1ml/min, column temperature: 30 ℃, sample injection amount: 50 μl) of model WATERS ARC unless otherwise specified. The invention adopts a Wright viscosity tester to measure the characteristic viscosity number of sodium hyaluronate. The invention adopts a rotary rheometer to detect the shearing viscosity of the hyaluronic acid composition under the condition of shearing rate of 0.01s -1～100s-1.
Unless otherwise indicated, the invention relates to percentages between liquids which are volume/volume percentages, between liquids which are volume/weight percentages, between solids which are weight/volume percentages, between solids and liquids which are weight/volume percentages, and the balance being weight/weight percentages.
Compared with the prior art, the invention has the following beneficial technical effects:
1. The sodium hyaluronate composition disclosed by the invention has the advantages that sodium hyaluronate is dissolved in phosphate buffer, the solubility, fluidity and biocompatibility of hyaluronic acid are obviously improved, injection filling is facilitated, the osmotic pressure of the composition is 100 mOsmol/kg-320 mOsmol/kg, the pH is 6-8, the problems of irritation, swelling, hemolysis, pain and the like of injection parts possibly caused during injection are obviously reduced, the moist heat sterilization condition is scientifically screened, the sterilization efficiency is obviously improved, the production period is obviously shortened, the low molecular weight hyaluronic acid with the effects of moisturizing, lubrication, stability and the like generated by moist heat sterilization is cooperatively utilized, the stability and the moisturizing effect of the composition are improved, the filling protection effect is better, the stability is good, the sterilization efficiency is high, the yield is high, the cost is better, the safety and the effectiveness are better, and the like.
2. The content of sodium hyaluronate and spot-removing components such as tranexamic acid and nicotinamide are scientifically screened, the tranexamic acid can be directly injected into relevant areas and layers of skin by the sodium hyaluronate injection, the dosage is smaller, adverse reactions are less, the treatment effect can be rapidly realized, melanin aggregation is prevented, melanin generation is deeply inhibited, a melanin transmission path is blocked, tyrosinase activity is inhibited, and pigment precipitates such as chloasma, sunburn, black spot and the like are desalted. The invention reasonably screens the proportion of each component, so that the sodium hyaluronate composite solution for injection also has the effects of resisting aging, improving skin barrier, shrinking pores and the like. Can be used in combination with other medicines to achieve synergistic effect when used for anti-inflammatory and whitening.
3. The preparation method of the sodium hyaluronate composition has the advantages of simplicity and convenience in operation, higher production efficiency, better cost, easiness in industrial production and the like.
Drawings
FIG. 1 changes in pH of sodium hyaluronate complex solutions of examples 1-6 and comparative example 1;
Fig. 2 changes in viscosity of the sodium hyaluronate complex solutions of examples 1-6 and comparative example 1.
Detailed Description
The present invention will be specifically described below with reference to examples. The embodiments of the present invention are only for illustrating the technical solution of the present invention, and are not intended to limit the essence of the present invention.
EXAMPLE 1 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
The preparation of the sodium hyaluronate composition comprises the following steps:
1) Weighing required amount of sodium dihydrogen phosphate hydrate and disodium hydrogen phosphate hydrate, and dissolving the sodium dihydrogen phosphate hydrate and disodium hydrogen phosphate hydrate in required amount of water for injection to prepare phosphate buffer solution;
2) Adding sodium hyaluronate with required amount into phosphate buffer solution under 400-500 rpm, stirring for 1.5-2 hr, mixing, adding base peptide and amino acids, mixing, adding vitamin B2 with required amount before filtering, mixing, filtering, and sterilizing the filtrate at 120deg.C under moist heat for 10 min.
The hyaluronic acid in the composition, as measured by the method of the invention, has a weight average molecular weight of 86 ten thousand, an intrinsic viscosity of 1.5L/g, pH7.2 and an osmotic pressure of 150mOsmol/kg.
EXAMPLE 2 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
The preparation of the sodium hyaluronate composition comprises the following steps:
1) Weighing required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolving the sodium dihydrogen phosphate and disodium hydrogen phosphate in required amount of water for injection to prepare phosphate buffer solution;
2) Adding sodium hyaluronate with required amount into phosphate buffer solution under 400-500 rpm, stirring for 1.5-2 hr, mixing, adding tranexamic acid, oligopeptide and amino acids, mixing, adding vitamin B2 with required amount before filtering, mixing, filtering, and sterilizing the filtrate at 125deg.C under damp heat for 11 min.
The hyaluronic acid in the composition has a weight average molecular weight of 100 ten thousand, an intrinsic viscosity of 1.7L/g, pH7.2 and an osmotic pressure of 140mOsmol/kg, measured according to the method of the present invention.
EXAMPLE 3 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
The preparation of the sodium hyaluronate composition comprises the following steps:
1) Weighing required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolving the sodium dihydrogen phosphate and disodium hydrogen phosphate in required amount of water for injection to prepare phosphate buffer solution;
2) Adding sodium hyaluronate with required amount into phosphate buffer solution under 400-500 rpm, stirring for 1.5-2 hr, mixing, adding tranexamic acid, L-carnosine and amino acids, mixing, adding vitamin B2 with required amount before filtering, mixing, filtering, and sterilizing the filtrate at 120deg.C under damp-heat for 12 min.
The hyaluronic acid in the composition, as measured by the method of the invention, had a weight average molecular weight of 85 ten thousand, an intrinsic viscosity of 1.5L/g, pH7.2 and an osmotic pressure of 150mOsmol/kg.
EXAMPLE 4 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
the preparation of the sodium hyaluronate composition comprises the following steps:
1) Weighing required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolving the sodium dihydrogen phosphate and disodium hydrogen phosphate in required amount of water for injection to prepare phosphate buffer solution;
2) Adding sodium hyaluronate with required amount into phosphate buffer solution under 400-500 rpm, stirring for 1.5-2 hr, mixing, adding tranexamic acid, glutathione and amino acids, mixing, adding vitamin B2 with required amount before filtering, mixing, filtering, and sterilizing filtrate at 120deg.C under damp heat for 12 min.
The hyaluronic acid in the composition, as measured by the method of the invention, had a weight average molecular weight of 91 ten thousand, an intrinsic viscosity of 1.6L/g, pH7.2 and an osmotic pressure of 160mOsmol/kg.
EXAMPLE 5 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
the preparation of the sodium hyaluronate composition comprises the following steps:
1) Weighing required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolving the sodium dihydrogen phosphate and disodium hydrogen phosphate in required amount of water for injection to prepare phosphate buffer solution;
2) Adding sodium hyaluronate with required amount into phosphate buffer solution under 400-500 rpm, stirring for 1.5-2 hr, mixing, adding nicotinamide, L-carnosine, glutathione and amino acids, mixing, adding vitamin B2 with required amount before filtering, mixing, filtering, and sterilizing the filtrate at 120deg.C under damp heat for 12 min.
The hyaluronic acid in the composition, as measured by the method of the invention, had a weight average molecular weight of 90 ten thousand, an intrinsic viscosity of 1.6L/g, pH7.3 and an osmotic pressure of 160mOsmol/kg.
EXAMPLE 6 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
the preparation of the sodium hyaluronate composition comprises the following steps:
1) Weighing required amount of sodium dihydrogen phosphate and disodium hydrogen phosphate under the stirring condition of 400-500 r/min, and dissolving the sodium dihydrogen phosphate and disodium hydrogen phosphate in required amount of water for injection to prepare phosphate buffer solution;
2) Adding sodium hyaluronate into phosphate buffer, stirring for 1.5-2 hr under 400-500 rpm stirring, mixing, adding nicotinamide, hexapeptide and amino acids, mixing, adding vitamin B2, mixing, filtering, and sterilizing at 120deg.C under moist heat for 12 min.
The hyaluronic acid in the composition, as measured by the method of the invention, had a weight average molecular weight of 85 ten thousand, an intrinsic viscosity of 1.5L/g, pH7.3 and an osmotic pressure of 145mOsmol/kg.
Comparative example 1 preparation of sodium hyaluronate composition
Composition and proportion of the composition:
the preparation of the sodium hyaluronate composition comprises the following steps:
Adding required amount of sodium hyaluronate, L-carnosine and amino acids into water for injection under 400-500 rpm, mixing, adding required amount of sodium chloride and vitamin B2, mixing, filtering, and sterilizing. The pH of the composition, as measured by the method of the present invention, was 7.2 and the osmotic pressure was 70mOsmol/kg.
Test example 1
The sodium hyaluronate composite solutions of examples 1-6 were stored at a low temperature of 5 ℃ and were tested for changes in appearance, viscosity and pH at 0 day, 3 month, 6 month and 12 month, respectively, and the appearance of examples and comparative examples were colorless transparent solutions, the pH results are shown in fig. 1, and the viscosity results are shown in fig. 2.
Test example 2 clinical trials of sodium hyaluronate composition for injection
The population who was 18 years old and had a need for improvement of facial skin was selected, and the subjects who participated in the trial were 64 in total, at a minimum of 27.00 years old, at a maximum of 67.00 years old, and at an average age of 43.77 years old.
Inclusion criteria:
(1) Years old than 18 years old;
(2) Subjects with a strong need to improve facial skin status
(3) Subjects who did not use other cosmetic treatments related to the study during the study period were consented;
(4) Subjects who understand and follow the experimental requirements, can complete the entire follow-up procedure;
(5) Voluntarily participate in this clinical study and sign informed consent.
Exclusion criteria:
(1) The face is subjected to skin improvement treatment such as radio frequency treatment, focused ultrasound treatment, grinding, chemical stripping, etc. within 1 month before the screening period;
(2) Subjects are known to be allergic to sodium hyaluronate, tranexamic acid, L-carnosine, glycine, proline, vitamin B2, phosphate, lidocaine, or other local anesthetics;
(3) Subjects with facial scars, crumbles, skin infections, or other active skin diseases, history of skin malignancy, possibly affecting the judgment of the therapeutic effect;
(4) The subject has a history of severe or autoimmune diseases of the vital organs;
(5) Women in gestation or lactation, women in gestational age, subjects in women in childbearing age do not agree to take medically approved contraceptive measures (e.g., oral contraceptives, condoms, etc.) during the test period;
(6) A subject who judges that the laboratory test result is abnormal and has clinical significance and influences the clinical test through a researcher;
(7) Subjects who have had additional clinical trials added within 30 days prior to the screening period;
(8) Researchers consider the subjects not suitable for participation in this trial study.
64 Subjects were randomized into two groups of 23 persons each, one group being the test group and one group being the control group. After the face of the subject is cleaned before injection, the hemp paste is applied for 30min, and then the hemp paste is washed off. The test group was injected subcutaneously with the sodium hyaluronate composition of example 3 and the control group was injected subcutaneously with the sodium hyaluronate composition of comparative example 1. And after the injection of the subject is finished, applying a refrigerated mechanical word size mask for 20min.
28 Days is a period, the initial administration of each period is carried out once, and after 3 continuous administration periods, the improvement rate difference of facial skin fine lines, the improvement rate of textures and spots of each subject and a control person are respectively calculated. The test group had a facial skin texture improvement rate of 14.47%, a facial fine line improvement rate of 18.83%, and a facial speckle improvement rate of 2.39% compared to the control, and no adverse events were observed that could be related to the test instrument.
Test example 3 clinical trials of sodium hyaluronate composition for injection
The population who was 18 years old and had a need for improvement of facial skin was selected, and the subjects who participated in the test were 64 in total, 25.00 years old at the minimum, 70.00 years old at the maximum, and the average age was 42.12 years old.
Inclusion criteria:
(1) Years old than 18 years old;
(2) Subjects with a strong need to improve facial skin status
(3) Subjects who did not use other cosmetic treatments related to the study during the study period were consented;
(4) Subjects who understand and follow the experimental requirements, can complete the entire follow-up procedure;
(5) Voluntarily participate in this clinical study and sign informed consent.
Exclusion criteria:
(1) The face is subjected to skin improvement treatment such as radio frequency treatment, focused ultrasound treatment, grinding, chemical stripping, etc. within 1 month before the screening period;
(2) Subjects are known to be allergic to sodium hyaluronate, nicotinamide, hexapeptide, glycine, alanine, vitamin B2, phosphate, lidocaine or other local anesthetic;
(3) Subjects with facial scars, crumbles, skin infections, or other active skin diseases, history of skin malignancy, possibly affecting the judgment of the therapeutic effect;
(4) The subject has a history of severe or autoimmune diseases of the vital organs;
(5) Women in gestation or lactation, women in gestational age, subjects in women in childbearing age do not agree to take medically approved contraceptive measures (e.g., oral contraceptives, condoms, etc.) during the test period;
(6) A subject who judges that the laboratory test result is abnormal and has clinical significance and influences the clinical test through a researcher;
(7) Subjects who have had additional clinical trials added within 30 days prior to the screening period;
(8) Researchers consider the subjects not suitable for participation in this trial study.
64 Subjects were randomized into two groups of 23 persons each, one group being the test group and one group being the control group. After the face of the subject is cleaned before injection, the hemp paste is applied for 30min, and then the hemp paste is washed off. The test group was injected subcutaneously with the sodium hyaluronate composition of example 6 and the control group was injected subcutaneously with the sodium hyaluronate composition of comparative example 1. And after the injection of the subject is finished, applying a refrigerated mechanical word size mask for 20min.
28 Days is a period, the initial administration of each period is carried out once, and after 3 continuous administration periods, the improvement rate difference of facial skin fine lines, the improvement rate of textures and spots of each subject and a control person are respectively calculated. Compared with the control, the difference of the improvement rate of the facial skin texture of the test group is 12.11%, the difference of the improvement rate of the facial fine lines is 19.93%, the difference of the improvement rate of the facial spots is 2.97%, and adverse events possibly related to the test instrument are not seen.
The foregoing is merely illustrative of embodiments of this invention and it will be appreciated by those skilled in the art that changes and modifications may be made without departing from the principles of the invention, which is also intended to be within the scope of the invention.
Claims (27)
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| KR20220090670A (en) * | 2020-12-22 | 2022-06-30 | 주식회사 유영제약 | Composition for injection comprising hyaluronic acid and dna fraction stabilized by ph control of buffer solution |
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| CN111467568B (en) * | 2019-01-23 | 2022-04-15 | 爱美客技术发展股份有限公司 | Cross-linked sodium hyaluronate composite solution preparation and preparation method and application thereof |
| KR102324076B1 (en) * | 2021-05-25 | 2021-11-08 | 김현아 | Composition for improving skin wrinkles and elasticity through induction of elastin and collagen |
| CN113521258A (en) * | 2021-08-03 | 2021-10-22 | 北京美神煦氰美啦医疗美容诊所有限公司 | Tissue injection for improving aging |
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| CN112386520A (en) * | 2020-11-24 | 2021-02-23 | 西安润玉医疗科技有限公司 | Mesoderm injection composition for comprehensively improving skin color and preparation method thereof |
| KR20220090670A (en) * | 2020-12-22 | 2022-06-30 | 주식회사 유영제약 | Composition for injection comprising hyaluronic acid and dna fraction stabilized by ph control of buffer solution |
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