Sodium hyaluronate composite solution for injection and preparation method thereof

Abstract

The invention provides a sodium hyaluronate composite solution for injection and a preparation method thereof, and belongs to the technical field of medical cosmetology. On the basis of the low-molecular-weight sodium hyaluronate, the injection requirement of a hydro-optical needle is met, and the sodium hyaluronate gel has better fluidity and can be uniformly distributed in skin tissues; hydroxylated fullerene is added and is subjected to non-covalent bond combination with sodium hyaluronate, so that the molecular state of sodium hyaluronate is changed, the degradation period of sodium hyaluronate is prolonged, the sodium hyaluronate fully plays a role, and a relatively good beautifying effect is achieved; in addition, hydroxylated fullerene has good biological safety, and potential safety hazards caused by amino acid are avoided.

Description

Technical Field

[0001] The present invention belongs to the field of medical cosmetology technology, and in particular relates to a sodium hyaluronate composite solution for injection and a preparation method thereof. Background Art

[0002] As we age, the skin on the face and other sun-exposed areas gradually shows obvious signs of aging, which is mainly manifested by changes in skin color, skin texture and elasticity, such as dull skin color, rough skin and enlarged pores. At present, there are many treatment methods for facial rejuvenation, such as photoelectric therapy and mesodermal injection. Photoelectric therapy for thermal damage requires a long recovery period, so mesodermal injection, which is less painful, has fewer adverse reactions, is safe, has a quick effect and a short downtime, is more widely used. Water light needle is a commonly used mesodermal injection therapy that can target the injection of sodium hyaluronate to improve facial problems. Sodium hyaluronate can regulate the water balance in the tissue through its hydration, promote the excretion of metabolic waste and pigments, and increase skin elasticity by promoting fibroblast secretion and synthesizing collagen and elastic fibers, thereby effectively improving facial problems such as enlarged pores.

[0003] The main ingredients of water light needle products on the market are mostly sodium hyaluronate, which is divided into cross-linked sodium hyaluronate and sodium hyaluronate composite solution. Due to the large gel strength and granular appearance of the cross-linked sodium hyaluronate itself, the pushing force of the product is increased, making it difficult to inject the product through the ultra-fine needle of the water light needle for superficial injection; and the cross-linked sodium hyaluronate gel product has poor fluidity and cannot be evenly distributed in the superficial layer. It is easy to form bulges and cannot be degraded and eliminated in a short period of time, and the cosmetic moisturizing performance is poor. The molecular weight of sodium hyaluronate in the sodium hyaluronate composite solution is small, and the degradation cycle of low molecular weight sodium hyaluronate is very short, and the cosmetic effect is limited, so it is often used in combination with a variety of amino acids; amino acids specifically bind to the N-terminus of hyaluronidase through their own characteristic molecular structure, or bind to large molecular sodium hyaluronate through hydrogen bonding, forming a spatial steric hindrance for the binding of hyaluronidase and sodium hyaluronate, which plays a role in inhibiting the activity of hyaluronidase; and long-term, excessive or rapid infusion of amino acids can cause potential metabolic acidosis and even affect liver and kidney function. Summary of the invention

[0004] The object of the present invention is to provide a sodium hyaluronate composite solution for injection and a preparation method thereof. The sodium hyaluronate composite solution for injection provided by the present invention can be evenly distributed in the superficial layer, has a good cosmetic and moisturizing effect, and has no safety hazards.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a sodium hyaluronate composite solution for injection, which comprises, by weight percentage, 0.5% to 1% of sodium hyaluronate, 0.1% to 0.3% of hydroxylated fullerene, and the remainder of water for injection; the molecular weight of the sodium hyaluronate is 20w to 80w.

[0007] Preferably, the sodium hyaluronate composite solution for injection comprises, by mass percentage, 0.6% to 0.8% sodium hyaluronate, 0.15% to 0.25% hydroxylated fullerene, and the balance water for injection.

[0008] Preferably, the molecular weight of the sodium hyaluronate is 30w to 50w.

[0009] Preferably, the sodium hyaluronate composite solution for injection further comprises 0.2% to 0.5% lidocaine hydrochloride, calculated by mass percentage.

[0010] Preferably, the sodium hyaluronate composite solution for injection further comprises 0.8% to 1% sodium chloride in terms of mass percentage.

[0011] Preferably, the sodium hyaluronate composite solution for injection further comprises 0.003% to 0.006% sodium dihydrogen phosphate in terms of mass percentage.

[0012] Preferably, the sodium hyaluronate composite solution for injection further includes 0.018% to 0.025% disodium hydrogen phosphate in terms of mass percentage.

[0013] The present invention also provides a method for preparing the sodium hyaluronate composite solution for injection described in the above technical solution, comprising mixing the components to obtain the sodium hyaluronate composite solution for injection.

[0014] Preferably, the mixing comprises: adding sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate to water for injection to obtain a solution; and adding sodium hyaluronate, lidocaine hydrochloride and hydroxylated fullerene to the solution to obtain a sodium hyaluronate composite solution for injection.

[0015] Preferably, the mixing includes sterilization, the sterilization is moist heat sterilization, the sterilization temperature is 115° C. to 120° C., and the sterilization time is 20 min to 30 min.

[0016] The present invention provides a sodium hyaluronate composite solution for injection, which includes, by mass percentage, 0.5% to 1% sodium hyaluronate, 0.1% to 0.3% hydroxylated fullerene, and the remainder of water for injection; the molecular weight of the sodium hyaluronate is 20w to 80w. The present invention is based on low molecular weight sodium hyaluronate, meets the injection requirements of water light needle, has good fluidity, and can be evenly distributed in the skin tissue; by adding hydroxylated fullerene, it is non-covalently bonded with sodium hyaluronate to change the molecular state of sodium hyaluronate, thereby extending the degradation cycle of sodium hyaluronate, allowing sodium hyaluronate to fully exert its role and have a good cosmetic effect; moreover, hydroxylated fullerene has good biosafety and avoids the safety hazards caused by amino acids. The test results show that the sodium hyaluronate composite solution for injection provided by the present invention has no skin sensitization reaction, no clinical abnormalities in the subjects, and no statistical differences in liver and kidney function; the DPPH free radical scavenging rate reaches 82.96%. DETAILED DESCRIPTION

[0017] All raw materials of the present invention have no particular limitation on their sources and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0018] There is no particular limitation on the purity of all raw materials in the present invention. The present invention preferably uses analytically pure raw materials or raw materials with a purity commonly used in the medical cosmetology field.

[0019] The present invention provides a sodium hyaluronate composite solution for injection, which comprises, by weight percentage, 0.5% to 1% of sodium hyaluronate, 0.1% to 0.3% of hydroxylated fullerene, and the remainder of water for injection; the molecular weight of the sodium hyaluronate is 20w to 80w.

[0020] In terms of mass percentage, the sodium hyaluronate composite solution for injection provided by the present invention includes 0.5% to 1% of sodium hyaluronate, preferably 0.6% to 0.8%. As an embodiment of the present invention, the mass content of sodium hyaluronate can be 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%. When the mass content of sodium hyaluronate is within the above range, the cosmetic effect of sodium hyaluronate can be exerted, and adverse reactions such as irritation or swelling caused by excessive use can be avoided.

[0021] In the present invention, the molecular weight of the sodium hyaluronate is 20w-80w, preferably 30w-50w. As an embodiment of the present invention, the molecular weight of the sodium hyaluronate can be 28w, 32w, 37w, 42w, 55w, 65w or 75w. When the molecular weight of the sodium hyaluronate is within the above range, the sodium hyaluronate has good fluidity and permeability, can replenish the moisture of the dermis, and improve the problems of dry skin, dull skin color, etc.

[0022] In terms of mass percentage, the sodium hyaluronate composite solution for injection provided by the present invention includes 0.1% to 0.3% of hydroxylated fullerene, preferably 0.15% to 0.25%. As an embodiment of the present invention, the mass content of hydroxylated fullerene can be 0.1%, 0.14%, 0.18%, 0.2%, 0.24% or 0.28%. The mass content of hydroxylated fullerene within the above range can bind to sodium hyaluronate through non-covalent bonds, change the molecular state of sodium hyaluronate, thereby extending the degradation cycle of sodium hyaluronate, so that sodium hyaluronate can fully exert its cosmetic effect, and can avoid excessive use causing adverse reactions such as excessive skin moisturizing or inflammation; at the same time, hydroxylated fullerene has excellent antioxidant and whitening and moisturizing effects, which can further improve the cosmetic effect of the composite solution; moreover, hydroxylated fullerene has good biosafety, avoiding the potential safety hazards brought by amino acid composite solutions.

[0023] The present invention has no special requirements on the source of the hydroxylated fullerene, and commercial products or homemade products can be used. In the embodiment of the present invention, the hydroxylated fullerene is homemade.

[0024] The sodium hyaluronate composite solution for injection provided by the present invention also includes water for injection. The present invention uses water for injection as a solvent to dissolve and disperse sodium hyaluronate and hydroxylated fullerene.

[0025] In the present invention, the sodium hyaluronate composite solution for injection preferably further comprises 0.2% to 0.5%, more preferably 0.3% to 0.4%, of lidocaine hydrochloride by mass percentage. The present invention effectively reduces the pain during injection and the inflammatory response after injection by adding lidocaine hydrochloride, thereby improving the comfort level and patient acceptance in clinical application.

[0026] In the present invention, the sodium hyaluronate composite solution for injection preferably further comprises 0.8% to 1% sodium chloride, more preferably 0.9%, by mass percentage. By adding sodium chloride and limiting the amount within the above range, the present invention can make the composite solution closer to human body fluids, reduce discomfort, facilitate the flow and penetration of the composite solution in the human body, and thus better play a cosmetic role.

[0027] In the present invention, the sodium hyaluronate composite solution for injection preferably further comprises 0.003% to 0.006% of sodium dihydrogen phosphate, more preferably 0.004% to 0.005% by mass percentage. By adding sodium dihydrogen phosphate and limiting the amount to the above range, the stability of the pH value of the composite solution is maintained, which is conducive to improving the stability and safety of the composite solution during use.

[0028] In the present invention, the sodium hyaluronate composite solution for injection preferably further comprises 0.018% to 0.025% disodium hydrogen phosphate, more preferably 0.020% to 0.022% by mass percentage. By adding disodium hydrogen phosphate and limiting the amount to the above range, the pH value of the composite solution can be adjusted to be closer to the pH value of human skin, which is beneficial to improving the stability and safety of the composite solution during use.

[0029] The present invention is based on low molecular weight sodium hyaluronate, meets the injection requirements of water light needle, has good fluidity, and can be evenly distributed in the skin tissue; by adding hydroxylated fullerene, it non-covalently combines with sodium hyaluronate, changes the molecular state of sodium hyaluronate, thereby prolonging the degradation cycle of sodium hyaluronate, so that sodium hyaluronate can fully play its role and has a good cosmetic effect; moreover, hydroxylated fullerene has good biological safety and avoids the safety hazards caused by amino acids; at the same time, hydroxylated fullerene has excellent antioxidant and whitening and moisturizing effects, which can further improve the cosmetic effect of the composite solution.

[0030] The present invention also provides a method for preparing the sodium hyaluronate composite solution for injection described in the above technical solution, comprising: mixing the components to obtain the sodium hyaluronate composite solution for injection.

[0031] In the present invention, the mixing preferably includes: adding sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate to water for injection to obtain a solution; adding sodium hyaluronate, lidocaine hydrochloride and hydroxylated fullerene to the solution to obtain a sodium hyaluronate composite solution for injection. As an embodiment of the present invention, the mixing can be stirred; the stirring can be magnetic stirring; the stirring rate can be conventionally adjusted according to actual conditions; the stirring time can be conventionally adjusted according to the dissolution of the components; in an embodiment of the present invention, the stirring time is 3 hours.

[0032] In another embodiment of the present invention, sodium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate are first added to a beaker, and water for injection is added, followed by magnetic stirring for 3 minutes, and then sodium hyaluronate, lidocaine hydrochloride, and hydroxylated fullerene are added, and stirring is continued for 3 hours to completely dissolve them.

[0033] In the present invention, the mixing preferably includes sterilization. In the present invention, the sterilization method is preferably moist heat sterilization; the sterilization temperature is preferably 115°C to 120°C, more preferably 115°C; the sterilization time is preferably 20min to 30min, more preferably 30min. The present invention uses the above method and parameters for sterilization, which is conducive to reducing the degradation of sodium hyaluronate while ensuring the sterilization effect.

[0034] The present invention preferably performs filling, stoppering and capping on the obtained mixed solution in sequence before sterilization. The present invention has no special requirements on the specific process of filling, stoppering and capping, and conventional methods in the art can be used. In the embodiment of the present invention, a borosilicate glass tube injection bottle is used to load the filling liquid, the specification is 5mL / bottle, a bromobutyl rubber stopper is used for stoppering, and an aluminum-plastic composite cover for antibiotic bottles is used for capping.

[0035] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Example 1

[0037] A sodium hyaluronate composite solution for injection, which is composed, by weight percentage, of 0.5% sodium hyaluronate with a molecular weight of 37w, 0.3% lidocaine hydrochloride, 0.2% hydroxylated fullerene, 0.9% sodium chloride, 0.005% sodium dihydrogen phosphate, 0.022% disodium hydrogen phosphate and 98.073% water for injection.

[0038] The preparation method of the hydroxylated fullerene is:

[0039] ① Dissolution

[0040] Weigh 3g of fullerene C60 and put it into a 2000mL brown conical flask, measure 625mL of toluene, place it in the conical flask, and stir magnetically for 30min until it is completely dissolved, and the color of the solution changes from colorless to purple-red; then add 50mL of 1g / mL NaOH solution, 10mL of 30% H2O2 by mass, and 25mL of 40% TBAH by mass in sequence, and the color of the solution changes from purple-red to black; after magnetic stirring (800r / min) for 40min, black powder precipitates at the bottom of the flask, and the liquid changes from black to colorless; at room temperature, stir magnetically (800r / min) for 5d.

[0041] ②Separation and purification

[0042] After the reaction is completed, pour out the toluene layer and add 1000 mL of deionized water to dissolve the black powder; let it stand for 12 hours to completely separate the water layer and the residual toluene layer; separate and collect the aqueous phase with a separatory funnel, and then filter the aqueous phase to remove insoluble impurities; adjust the pH value to neutral with hydrochloric acid solution to obtain an orange-red solution; dialyze with a dialysis membrane (molecular retention 500Da) for 72 hours to remove other small molecules in the solution.

[0043] ③ Freeze-drying

[0044] The dialyzed solution was vacuum freeze-dried to obtain a yellow-brown hydroxylated fullerene solid powder, which was stored under dry conditions for future use.

[0045] The preparation method of the sodium hyaluronate composite solution for injection is:

[0046] Add sodium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate into a beaker in proportion, add water for injection, and stir magnetically for 3 minutes; add the formulated amount of sodium hyaluronate, lidocaine hydrochloride, and hydroxylated fullerene, and continue stirring for 3 hours to completely dissolve them. The solution is a transparent viscous liquid;

[0047] The above-mentioned liquid was filled into medium borosilicate glass tube injection bottles with a specification of 5 mL / bottle, plugged with bromobutyl rubber stoppers, and rolled with aluminum-plastic composite caps for antibiotic bottles, and sterilized at 115°C for 30 minutes.

[0048] Example 2

[0049] A sodium hyaluronate composite solution for injection, which is composed, by weight percentage, of 0.8% sodium hyaluronate with a molecular weight of 37w, 0.3% lidocaine hydrochloride, 0.2% hydroxylated fullerene, 0.9% sodium chloride, 0.005% sodium dihydrogen phosphate, 0.022% disodium hydrogen phosphate and 97.773% water for injection.

[0050] The hydroxylated fullerene is the hydroxylated fullerene prepared in Example 1; the preparation method of the sodium hyaluronate composite solution for injection is the same as that in Example 1.

[0051] Example 3

[0052] A sodium hyaluronate composite solution for injection, which is composed, by weight percentage, of 1% sodium hyaluronate with a molecular weight of 37w, 0.3% lidocaine hydrochloride, 0.2% hydroxylated fullerene, 0.9% sodium chloride, 0.005% sodium dihydrogen phosphate, 0.022% disodium hydrogen phosphate and 97.573% water for injection.

[0053] The hydroxylated fullerene is the hydroxylated fullerene prepared in Example 1; the preparation method of the sodium hyaluronate composite solution for injection is the same as that in Example 1.

[0054] Comparative Example 1

[0055] A sodium hyaluronate composite solution for injection comprises, by weight percentage, 1.0% sodium hyaluronate with a molecular weight of 37w, 0.9% sodium chloride, 0.005% sodium dihydrogen phosphate, 0.022% disodium hydrogen phosphate and 98.073% water for injection.

[0056] The preparation method of the sodium hyaluronate composite solution for injection is the same as that in Example 1.

[0057] Comparative Example 2

[0058] A composite solution for injection, which is composed of 0.4% hydroxylated fullerene, 0.9% sodium chloride, 0.005% sodium dihydrogen phosphate, 0.022% disodium hydrogen phosphate and 98.673% water for injection, calculated by mass percentage.

[0059] The hydroxylated fullerene is the hydroxylated fullerene prepared in Example 1; the preparation method of the sodium hyaluronate composite solution for injection is the same as that in Example 1.

[0060] Test Example 1: Skin Allergy Test

[0061] 7-week-old BALB / c mice were randomly divided into groups, and the backs of mice in each group were depilated with a depilatory agent before the experiment. A certain amount of sodium hyaluronate collagen composite gel was diluted with vaseline and applied to the depilatory area on the left back of each group of mice and fixed for 6 hours. The same method was repeated once on the 7th and 14th days. 14 days after the last administration of sensitization, the same amount of the test substance as above was applied to the depilatory area on the right back of the mouse. The test substance was removed after 6 hours and observed immediately, and then the skin allergy condition was observed again at 24h, 48h, and 72h.

[0062] According to the skin irritation reaction scoring standard in Table 1, the observed skin irritation is scored, and the sensitization rate is determined according to the sensitization rate classification in Table 2. Calculation of sensitization rate: the number of animals with skin erythema and edema (regardless of severity) divided by the total number of animals tested.

[0063] Table 1 Skin irritation reaction scoring standard

[0064] Skin reactions grade No significant change 0 Scattered or semipunctate erythema 1 Moderate confluent erythema 2 Severe erythema and / or edema 3

[0065] Table 2 Sensitization rate classification table

[0066] Sensitization rate (%) Reaction intensity 0～10 Weak allergenicity 20～30 Mild allergenicity 40～60 Moderate sensitization 70～80 Highly allergenic 90～100 Extremely allergenic

[0067] Table 3 Statistics of sensitization rate of gels obtained by different preparation processes

[0068]

[0069] Results: Under the test conditions, none of the test samples caused skin sensitization.

[0070] Test Example 2: DPPH free radical scavenging rate test

[0071] ① Sample dilution

[0072] Solution a: Take 1.0 ml of sample solution of Example 1, Comparative Example 1 and Comparative Example 2 respectively;

[0073] Solution b: Take 0.5 ml of sample solution of Example 1, Comparative Example 1 and Comparative Example 2 and add 0.5 ml of distilled water, mix well, and obtain;

[0074] Solution c: Take 0.25 ml of sample solution of Example 1, Comparative Example 1 and Comparative Example 2 respectively and add 0.75 ml of distilled water, mix well, and obtain the solution.

[0075] Take 3 test tubes for each of the above solutions, number them 1, 2, and 3 respectively, and add reagents according to the combination in Table 4 to each test tube.

[0076] Table 4 Reagent addition record

[0077] Solution name No. 1 (As) No. 2 (Ac) No. 3 (Ab) DPPH solution (50.0 μg / mL) 3.0mL - 3.0mL Sample solution 1.0mL 1.0mL - Sample solvent solution - - 1.0mL Anhydrous ethanol solution - 3.0mL -

[0078] Add 3.0mL DPPH solution and 1.0mL sample solution to test tube No. 1 as the test group (As); add 1.0mL sample solution and 3.0mL anhydrous ethanol solution to test tube No. 2 as the control group (Ac); add 3.0mL DPPH solution and 1.0mL sample solvent solution to test tube No. 3 as the blank group (Ab). After fully mixing, react at room temperature in the dark for 30 minutes, and measure the absorbance value with a UV spectrophotometer at a wavelength of 517nm (sample solvent zero calibration).

[0079] Calculate according to formula (1)

[0080]

[0081] Where:

[0082] P: clearance rate;

[0083] As: absorbance of the mixture of the test solution and DPPH solution;

[0084] Ac: absorbance of the mixture of the test solution and anhydrous ethanol solution;

[0085] Ab: absorbance of the mixture of DPPH solution and sample solvent solution.

[0086] Table 5 DPPH clearance statistics for each case

[0087]

[0088]

[0089] The results of scavenging rates of DPPH free radicals of each sample solution at different dilution multiples are shown in Table 5. It can be seen from Table 5 that the antioxidant activity of the composite solution provided by Example 1 is better than that of Comparative Example 1 using sodium hyaluronate alone and Comparative Example 2 using hydroxylated fullerene alone. Due to the non-covalent bond between sodium hyaluronate and hydroxylated fullerene, the action intensity of the original two substances is changed, achieving a synergistic effect.

[0090] Test case 3: Clinical trial

[0091] Test product: Sodium hyaluronate solution for injection prepared in Example 3 (model specification: 5 mL / bottle)

[0092] Subjects: 440 volunteers aged 18 to 60 years old were selected, with no gender restrictions and skin Fitzpatrick type II-IV. Among them, exclusion criteria: local facial skin infection (including viral, bacterial, and fungal); granuloma at the injection site; scar constitution; systemic disease (diseases involving multiple systems of the body, such as systemic lupus erythematosus, rheumatoid arthritis, etc.); active or progressive or isomorphic skin diseases such as acute eczema, flat warts, lichen planus, psoriasis vulgaris, etc.; abnormal liver, kidney or coagulation function (alanine aminotransferase or aspartate aminotransferase exceeds 2.5 times the upper limit of normal value; creatinine exceeds 1.5 times the upper limit of normal value; prothrombin time is prolonged by >3 seconds). Patients with malignant tumors or skin tumors of unknown nature; patients undergoing chemotherapy / radiotherapy; patients with mental illness or emotional instability; those who are pregnant, menstruating or breastfeeding; those who plan to become pregnant within six months; those who have participated in similar treatments within 6 months, including radiofrequency, photon, botulinum toxin injections, etc.; other situations that the researchers believe are not suitable for inclusion.

[0093] The trial adopted a no-treatment control and enrolled 440 cases. The trial group and the control group were assigned 1:1. The trial group was injected once every 4 weeks, for a total of 3 injections. The control group did not receive injections. Follow-up was carried out according to the protocol. The treatment efficacy was the primary effectiveness evaluation indicator, and the skin dryness test, global cosmetic effect (GAIS), dull skin color improvement effect score, skin dryness and dull skin color improvement comprehensive score, and patient satisfaction score were used as secondary effectiveness evaluation indicators. The occurrence of adverse events was the primary safety evaluation indicator, and vital signs and laboratory tests were used as secondary safety evaluation indicators. The effectiveness and safety of injectable sodium hyaluronate solution in improving dry skin and dull skin color were evaluated.

[0094] result:

[0095] ① In the effectiveness evaluation, the trial adopted a no-treatment control, and the subjects in the control group did not self-evaluate GAIS, skin dullness improvement effect score, skin dryness and skin dullness improvement comprehensive score. The self-evaluated GAIS, skin dullness improvement effect score, skin dryness and skin dullness improvement comprehensive score of the subjects in the experimental group showed similar increasing and decreasing trends at each visit time point as the results of the third-party and researcher evaluations. The subjects in the experimental group scored their satisfaction with the treatment effect of this clinical trial. In the FAS data set, the satisfaction score of the 1 / 4 patients 4 weeks after the first injection was 3.60±0.54, and the satisfaction rate was 97.67%; the satisfaction score of the patients 4 weeks after the second injection was 3.76±0.46, and the satisfaction rate was 98.58%; the satisfaction score of the patients 4 weeks after the third injection was 3.79±0.42, and the satisfaction rate was 99.53%. In the PPS data set, the patient satisfaction score was 3.61±0.53 4 weeks after the first injection, and the satisfaction rate was 98.11%; the patient satisfaction score was 3.76±0.46 4 weeks after the second injection, and the satisfaction rate was 98.58%; the patient satisfaction score was 3.79±0.42 4 weeks after the third injection, and the satisfaction rate was 99.53%.

[0096] ② In the safety evaluation, 3 injection site adverse events occurred in this trial, with an incidence of 1.39%. Adverse events at the injection site included allergies and perioral dermatitis. There were no significant differences in most vital signs between the experimental group and the control group at each visit time point (immediately after the first injection, 1 week after the first injection, 2 weeks after the first injection, 4 weeks after the first injection, immediately after the second injection, 1 week after the second injection, 2 weeks after the second injection, 4 weeks after the second injection, immediately after the third injection, 1 week after the third injection, 2 weeks after the third injection, 4 weeks after the third injection, and 3 months after the third injection), P>0.05. Overall, the subjects had good vital signs during the trial and no related adverse events occurred. No laboratory tests were performed in the control group of this trial. The visit time points of the test group subjects (1 week after the first injection, 4 weeks after the first injection, 1 week after the second injection, 4 weeks after the second injection, 1 week after the third injection, 4 weeks after the third injection, 3 months after the third injection) were compared with those before enrollment. The results showed that there were no statistical differences in the blood routine examination results of the test group subjects at each visit time point compared with those before enrollment, and there were no statistical differences in the urine routine examination results 1 week after the first injection and 4 weeks after the first injection compared with those before enrollment; there were no statistical differences in the liver function test results 1 week after the first injection, 1 week after the second injection, and 3 months after the third injection compared with those before enrollment; there were no statistical differences in the renal function test results of 2 / 4 4 weeks after the first injection, 1 week after the second injection, 4 weeks after the second injection, 1 week after the third injection, and 4 weeks after the third injection compared with those before enrollment, all P>0.05. The number of cases with "no abnormality" and "abnormality without clinical significance" in laboratory test results at each visit time point was summarized, and the laboratory test results were divided into "no abnormality + abnormality without clinical significance" and "abnormality with clinical significance". The statistical results showed that there was no statistical difference in the laboratory test results (blood routine, urine routine, liver function, and kidney function) at each visit time point compared with before enrollment. There was no statistical difference in the incidence of AEs, the frequency of AEs, and the incidence of SAEs between the experimental group and the control group. After comprehensive analysis, it can be considered that the test device is safe.

[0097] It can be seen from the above examples and comparative examples that the sodium hyaluronate composite solution for injection provided by the present invention has good biosafety and global cosmetic effect.

[0098] The above is only a preferred embodiment 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 principle 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 composite solution for injection, comprising, by mass percentage: Sodium hyaluronate 0.5%-1%, hydroxylated fullerene 0.1%-0.3%, and the balance water for injection; The molecular weight of the sodium hyaluronate is 20w to 80w.

2. The sodium hyaluronate composite solution for injection according to claim 1, characterized in that: Calculated by mass percentage, the sodium hyaluronate composite solution for injection includes: 0.6% to 0.8% sodium hyaluronate, 0.15% to 0.25% hydroxylated fullerene, and the balance water for injection.

3. The sodium hyaluronate composite solution for injection according to claim 1, characterized in that: The molecular weight of the sodium hyaluronate is 30w-50w.

4. The sodium hyaluronate composite solution for injection according to any one of claims 1 to 3, characterized in that: Calculated by mass percentage, the sodium hyaluronate composite solution for injection also includes 0.2% to 0.5% lidocaine hydrochloride.

5. The sodium hyaluronate composite solution for injection according to any one of claims 1 to 3, characterized in that: Calculated by mass percentage, the sodium hyaluronate composite solution for injection also includes 0.8% to 1% sodium chloride.

6. The sodium hyaluronate composite solution for injection according to any one of claims 1 to 3, characterized in that: Calculated by mass percentage, the sodium hyaluronate composite solution for injection also includes 0.003% to 0.006% of sodium dihydrogen phosphate.

7. The sodium hyaluronate composite solution for injection according to any one of claims 1 to 3, characterized in that: Calculated by mass percentage, the sodium hyaluronate composite solution for injection also includes 0.018% to 0.025% disodium hydrogen phosphate.

8. A method for preparing the sodium hyaluronate composite solution for injection according to any one of claims 1 to 7, comprising: The components are mixed to obtain a sodium hyaluronate composite solution for injection.

9. The preparation method according to claim 8, characterized in that: The mixing comprises: adding sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate into water for injection to obtain a solution; and adding sodium hyaluronate, lidocaine hydrochloride and hydroxylated fullerene into the solution to obtain a sodium hyaluronate composite solution for injection.

10. The preparation method according to claim 9, characterized in that: The mixing process includes sterilization, which is wet heat sterilization, the sterilization temperature is 115° C. to 120° C., and the sterilization time is 20 min to 30 min.

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