Application of oligopeptides in improving the stability of vitamins and / or amino acids

Abstract

The present application provides an application of an oligopeptide in improving the stability of vitamins and / or amino acids, an application of an oligopeptide in improving the pH stability of an injectable hyaluronic acid gel containing vitamins and / or amino acids, and an injectable hyaluronic acid gel. During storage, vitamins and amino acids are susceptible to degradation under the influence of factors such as active oxygen, light, and high temperature in water, resulting in unstable situations such as reduced content, so that the injectable hyaluronic acid gel containing vitamins and / or amino acids does not achieve effective results. Adding a certain amount of oligopeptides to the injectable hyaluronic acid gel of vitamins and / or amino acids can improve the stability of vitamins and / or amino acids, and improve the pH stability of injectable hyaluronic acid gel. Using cross-linked hyaluronic acid gel as a matrix and compounding other nutrients can play a role in moisturizing, stimulating fibroblast activity, and increasing fibroblast synthesis substrates, thereby improving the effect of skin quality.

Description

Technical Field

[0001] The present application relates to an oligopeptide, and in particular to the use of an oligopeptide in improving the stability of vitamins and / or amino acids. Background Art

[0002] With economic development and social progress, people pay more and more attention to their appearance. The skin is the outermost and largest organ of the human body. Like other organs of the human body, it will gradually age, weaken or lose its functions, which not only affects the appearance, but also increases the incidence of various skin diseases. In addition, due to its superficial exposure, the skin has a strong psychological effect, and delaying skin aging has gradually become one of the hot topics of people's attention. In particular, minimally invasive facial beauty rejuvenation is sought after by many beauty seekers and is also one of the research hotspots in the field of life sciences at home and abroad.

[0003] Hyaluronic acid (HA) is a commonly used hyaluronic acid injection material. Generally, appropriate vitamins and / or amino acids are added to the hyaluronic acid injection material. However, during the sterilization and storage process, vitamins and amino acids are prone to degradation, resulting in reduced content, changes in pH value, and unstable solution color changes, making the final hyaluronic acid injection fail to achieve effective results. Summary of the invention

[0004] In response to the problems existing in the prior art, the inventors discovered through a large number of experiments and creative work that oligopeptides have the effect of enhancing the stability of vitamins and / or amino acids. Adding a certain amount of oligopeptides to the injectable hyaluronic acid gel containing vitamins and / or amino acids can enhance the stability of the vitamins and / or amino acids in the injectable hyaluronic acid gel, and at the same time improve the pH stability of the injectable hyaluronic acid gel containing vitamins and / or amino acids.

[0005] The specific plan is as follows:

[0006] 1. Application of an oligopeptide in improving the stability of vitamins and / or amino acids.

[0007] 2. Application of an oligopeptide in improving the pH stability of an injectable hyaluronic acid gel containing vitamins and / or amino acids.

[0008] 3. According to the use described in item 1 or 2, the oligopeptide is anserine, oligopeptide 1, glutathione or carnosine, preferably anserine or oligopeptide 1.

[0009] 4. The use according to item 1 or 2,

[0010] The amino acid is contained in an amount of (0.001 to 5) parts by weight, preferably (0.05 to 2.5) parts by weight, relative to 1 part by weight of the oligopeptide.

[0011] 5. The use according to item 1 or 2,

[0012] The vitamin is present in an amount of (0.001 to 5) parts by weight, preferably (0.0015 to 2.5) parts by weight, relative to 1 part by weight of the oligopeptide.

[0013] 6. The use according to item 1 or 2,

[0014] The amino acids are selected from one or more of glycine, proline, hydroxyproline, lysine, lysine hydrochloride, isoleucine, leucine, serine, alanine, aspartic acid, tyrosine, glutamic acid, phenylalanine, arginine, valine, threonine, histidine, tryptophan, methionine, cystine and cysteine.

[0015] 7. The use according to item 1 or 2,

[0016] The vitamins are selected from one or more of vitamin B1, vitamin B2, niacinamide, vitamin B6, vitamin B12, folic acid, biotin, calcium pantothenate and vitamin C.

[0017] 8. An injectable hyaluronic acid gel comprising: cross-linked hyaluronic acid or its salt, oligopeptides, vitamins and / or amino acids.

[0018] 9. The injectable hyaluronic acid gel according to item 8,

[0019] The oligopeptide is anserine, oligopeptide 1, glutathione or carnosine, preferably anserine or oligopeptide 1.

[0020] 10. The injectable hyaluronic acid gel according to item 8,

[0021] The amino acids are selected from one or more of glycine, proline, hydroxyproline, lysine, lysine hydrochloride, isoleucine, leucine, serine, alanine, aspartic acid, tyrosine, glutamic acid, phenylalanine, arginine, valine, threonine, histidine, tryptophan, methionine, cystine and cysteine.

[0022] 11. The injectable hyaluronic acid gel according to item 8,

[0023] The vitamins are selected from one or more of vitamin B1, vitamin B2, niacinamide, vitamin B6, vitamin B12, folic acid, biotin, calcium pantothenate and vitamin C.

[0024] 12. The injectable hyaluronic acid gel according to item 8,

[0025] Relative to 1 part by weight of the oligopeptide, the cross-linked hyaluronic acid or its salt is (1 to 25) parts by weight, preferably (2 to 10) parts by weight;

[0026] Preferably,

[0027] Relative to 1 part by weight of the oligopeptide, the amino acid is (0.001 to 5) parts by weight, preferably (0.05 to 2.5) parts by weight;

[0028] More preferably,

[0029] The vitamin is present in an amount of (0.001 to 5) parts by weight, preferably (0.0015 to 2.5) parts by weight, relative to 1 part by weight of the oligopeptide.

[0030] 13. The injectable hyaluronic acid gel according to item 8 further comprises excipients and active ingredients.

[0031] Technical Effects

[0032] (1) The addition of oligopeptides, in addition to being nutrients themselves, can also stabilize vitamins and / or amino acids, preventing the vitamin and / or amino acid content from decreasing during storage.

[0033] (2) The addition of oligopeptide components can also improve the pH stability of the injectable hyaluronic acid gel containing vitamins and / or amino acids and prevent the pH of the injectable hyaluronic acid gel from changing during placement.

[0034] (3) With cross-linked hyaluronic acid gel as the matrix and compounded with vitamins and / or amino acids, the ingredients work synergistically to replenish water and moisturize, stimulate fibroblast activity, and increase fibroblast synthesis substrates, thereby improving skin quality. DETAILED DESCRIPTION

[0035] The present application is further described below in conjunction with examples. It should be understood that the examples are only used to further describe and illustrate the present application and are not used to limit the present application.

[0036] Unless otherwise defined, the technical and scientific terms in this specification have the same meaning as those generally understood by those skilled in the art. Although similar or identical methods and materials as described herein may be used in experiments or practical applications, materials and methods are described herein below. In the event of a conflict, the present specification including the definitions therein shall prevail. In addition, materials, methods and examples are provided for illustration only and are not restrictive. The present application is further described below in conjunction with specific embodiments, but is not intended to limit the scope of the present application.

[0037] The present application provides an application of an oligopeptide in improving the stability of vitamins and / or amino acids. In some embodiments of the present application, the oligopeptide can improve the content stability of vitamins and / or amino acids.

[0038] The present application provides an application of an oligopeptide in improving the pH stability of an injectable hyaluronic acid gel containing vitamins and / or amino acids.

[0039] In this application, oligopeptide refers to a classification of polypeptides, and the molecular weight range is generally below 1000 Daltons, also known as small peptides, oligopeptides, oligopeptides or small molecule active peptides, compounds formed by the condensation of 2 to 10 amino acids. Those exceeding are called polypeptides, and polypeptides with more than 50 amino acids are called proteins. The difference from other peptides is that it can be directly absorbed in the human body without digestion. Oligopeptides can be divided into: oligopeptide-1, oligopeptide-3, oligopeptide-5, etc., and oligopeptide-6 is also called hexapeptide or hexapeptide.

[0040] Vitamins and amino acids are easily degraded under the influence of active oxygen, light, high temperature and other factors in water, resulting in reduced content, changes in pH value, changes in solution color, etc.

[0041] In the present application, the storage state of vitamins in solution is unstable, and the stability of the content will decrease over time. Adding a certain amount of oligopeptides to the vitamin solution in proportion can maintain the stability of the vitamins in the solution and prevent the content from decreasing.

[0042] In the present application, the storage state of amino acids in solution is unstable. As time goes by, the stability of the content will decrease. Adding a certain amount of oligopeptides in proportion to the amino acid solution can maintain the stability of the amino acids in the solution and prevent the content from decreasing.

[0043] In the present application, the injectable hyaluronic acid gel containing vitamins and / or amino acids is unstable during storage, and the pH value may decrease over time. Adding certain oligopeptides in proportion to the injectable hyaluronic acid gel containing vitamins and / or amino acids can prevent the pH value of the injectable hyaluronic acid gel from decreasing.

[0044] In some embodiments of the present application, the oligopeptide is anserine, oligopeptide 1, glutathione or carnosine, preferably anserine or oligopeptide 1.

[0045] In the present application, anserine (β-alanyl-1-methyl-L-histidine, Anserine) is a highly stable water-soluble dipeptide that relieves hyperuricemia by promoting uric acid excretion, and is naturally present in the skeletal muscle tissue and brain tissue of vertebrates.

[0046] In the present application, oligopeptide-1 is a synthetic polypeptide composed of glycine, histidine and lysine. It is a white solid powder that is easily soluble in water. When used in the medical field, it can promote the repair and regeneration of damaged epidermis. As a skin care ingredient, it can increase the synthesis of proteins, especially dermal collagen and elastin, thereby helping the skin to improve metabolism and increase the skin's repair ability.

[0047] In some embodiments of the present application, relative to 1 part by weight of the oligopeptide, the amino acid is (0.001 to 5) parts by weight, preferably (0.05 to 2.5) parts by weight, and more preferably (0.1 to 2) parts by weight;

[0048] For example, relative to 1 part by weight of the oligopeptide, the amino acid can be 0.001 part by weight, 0.002 part by weight, 0.004 part by weight, 0.006 part by weight, 0.008 part by weight, 0.01 part by weight, 0.05 part by weight, 0.1 part by weight, 0.2 part by weight, 0.3 part by weight, 0.4 part by weight, 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1.0 part by weight, 1.1 part by weight, 1.2 part by weight, 1.3 part by weight, 1.4 part by weight, 1.5 part by weight, 1.6 part by weight, 1.7 part by weight, 1.8 part by weight, 1.9 part by weight, 2.0 part by weight. 3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight or any range therebetween.

[0049] In some embodiments of the present application, relative to 1 part by weight of the oligopeptide, the vitamin is (0.001 to 5) parts by weight, preferably (0.0015 to 2.5) parts by weight, and more preferably (0.002 to 0.2) parts by weight;

[0050] For example, relative to 1 part by weight of the oligopeptide, the vitamin can be 0.001 part by weight, 0.0015 part by weight, 0.002 part by weight, 0.004 part by weight, 0.006 part by weight, 0.008 part by weight, 0.01 part by weight, 0.05 part by weight, 0.1 part by weight, 0.2 part by weight, 0.3 part by weight, 0.4 part by weight, 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1.0 part by weight, 1.1 part by weight, 1.2 part by weight, 1.3 part by weight, 1.4 part by weight, 1.5 part by weight, 1.6 part by weight, 1.7 part by weight, 1.8 part by weight, 1.9 part by weight, 2.0 parts by weight, 2.1 parts by weight, 2.2 parts by weight, 2.3 parts by weight, 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight or any range therebetween.

[0051] The term amino acid is intended to refer to naturally occurring amino acids and non-naturally occurring amino acids and amino acid analogs and mimetics. Naturally occurring amino acids include the 20 (L)-amino acids utilized during protein biosynthesis as well as other amino acids, such as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, homocysteine, citrulline and ornithine. Non-naturally occurring amino acids include, for example, (D)-amino acids, norleucine, norvaline, p-fluorophenylalanine, ethionine and similar amino acids, which are known to those skilled in the art. Amino acid analogs include modified forms of naturally occurring amino acids and non-naturally occurring amino acids. These modifications may include, for example, substitution or replacement of chemical groups and moieties on the amino acids, or derivatization of the amino acids. Amino acid mimetics include, for example, organic structures that functionally exhibit similar properties, such as charge and charge spacing characteristics of reference amino acids. For example, an organic structure that mimics arginine (Arg or R) will have a positively charged moiety that is located in a similar molecular space and has the same degree of mobility as the ε-amino group of the side chain of the naturally occurring Arg amino acid. Mimetics also include constrained structures to maintain optimal spacing and charge interactions of amino acids or amino acid functional groups. Those skilled in the art know or can determine what structures constitute functionally equivalent amino acid analogs and amino acid mimetics.

[0052] In some embodiments of the present application, the amino acid is selected from one or more of glycine, proline, hydroxyproline, lysine, lysine hydrochloride, isoleucine, leucine, serine, alanine, aspartic acid, tyrosine, glutamic acid, phenylalanine, arginine, valine, threonine, histidine, tryptophan, methionine, cystine and cysteine. Preferably, the amino acid is selected from one or more of alanine, glycine, threonine, arginine, lysine, lysine hydrochloride, proline, valine, isoleucine and leucine.

[0053] In some embodiments of the present application, the vitamin is selected from one or more of vitamin B1, vitamin B2, niacinamide, vitamin B6, vitamin B12, folic acid, biotin, calcium pantothenate and vitamin C.

[0054] Vitamin B is a water-soluble vitamin. Vitamin B1 (thiamine) can inhibit the activity of cholinesterase. When vitamin B1 is deficient, the activity of this enzyme is too high, and acetylcholine (one of the neurotransmitters) is destroyed in large quantities, affecting nerve conduction, which may affect gastrointestinal motility and the secretion of digestive juices. Thiamine is usually made into a more stable form such as hydrochloride or nitrate for use. Vitamin B2 (riboflavin 1) constitutes many important coenzymes, participates in metabolism and energy release, and helps growth. It can maintain and improve the health of epithelial tissues, such as the mucosal tissue of the digestive tract. Vitamin B3 (niacin) constitutes a coenzyme of dehydrogenase in the body. Vitamin B3 is the most needed vitamin in the B vitamins. It is not only a vitamin that maintains the health of the digestive system, but also can relieve gastrointestinal disorders. Niacin is converted into nicotinamide in the human body. Nicotinamide is a component of coenzyme I and coenzyme II, and participates in lipid metabolism, the oxidation process of tissue respiration and the anaerobic decomposition of carbohydrates in the body. Vitamin B6 includes pyridoxine, pyridoxal and pyridoxamine, which can be converted into each other. Deoxyadenosylcobalamin is the main form of vitamin B12 in the body. Its role is often related to that of folic acid. Folic acid has a variety of coenzyme forms in cells. The side chain carboxyl group of biotin can be connected to the lysine residue of the enzyme through an amide bond. Biotin is a carboxyl carrier and is also involved in the metabolism of vitamin B12, folic acid and pantothenic acid.

[0055] "Riboflavin" is used interchangeably with "vitamin B2" and includes riboflavin and its esters, particularly riboflavin-5'-phosphate.

[0056] The term "vitamin C" is water-soluble (its aqueous solution is acidic) and is a very strong antioxidant. It can also protect other antioxidants, such as vitamin A, vitamin E, and unsaturated fatty acids, and defend the body from free radical damage. The strength of the blood vessel wall is closely related to vitamin C. Capillaries are the smallest of all blood vessels, and the wall may be only as thick as a cell. Its strength and elasticity are determined by collagen, which is responsible for connecting cells and has a cement effect. The presence of vitamin C helps the skin maintain elasticity and vitality. The term "vitamin C" used interchangeably with "ascorbic acid" also includes its pharmaceutically acceptable salts (such as sodium ascorbate and calcium ascorbate) and its pharmaceutically acceptable esters (especially ascorbyl palmitate).

[0057] The present application also provides an injectable hyaluronic acid gel, which comprises: cross-linked hyaluronic acid or its salt, oligopeptides, vitamins and / or amino acids.

[0058] Hydrogel is a gel that uses water as a dispersion medium. It is a cross-linked polymer that can swell in water by introducing a part of hydrophobic groups into a water-soluble polymer with a cross-linked structure. It has high water absorption and high water retention, and has good biocompatibility and water permeability. Injectable hydrogel refers to a hydrogel that can be injected and implanted in the human body. Since it directly enters the human tissue to play the expected role, it must be ensured that the viscoelasticity of the injectable hydrogel meets the expected use, is sterile, and has a certain fluidity for injection.

[0059] Injectable gels can include any suitable biological or synthetic gel. For example, gels can include hyaluronic acid, alginate, cross-linked alginate, collagen, fibrin glue, fibrin clot, poly-(N-isopropylacrylamide), agarose, chitin, chitosan, cellulose, polysaccharides, poly-(oxyalkylenes), copolymers of poly-(oxyethylenes)-poly-(oxypropylenes), poly-(vinyl alcohol), polyacrylates, matrigel or its blends.

[0060] The oligopeptides have been described above and will not be described again here.

[0061] Vitamins have been described above and will not be repeated here.

[0062] Amino acids have been described above and will not be described again here.

[0063] In the present application, cross-linked hyaluronic acid or its salt refers to cross-linked hyaluronic acid or its salt obtained by cross-linking hyaluronic acid or its salt with a cross-linking agent. Cross-linked hyaluronic acid or its salt is more stable in molecular structure, lasts longer, and decomposes more slowly.

[0064] Hyaluronic acid or its salt is mixed with a cross-linking agent in an alkaline solution to carry out a cross-linking reaction, and the cross-linking agent is eluted with a buffer solution to terminate the cross-linking reaction, and the cross-linked hyaluronic acid or its salt is obtained after homogenization.

[0065] In some embodiments, the cross-linked hyaluronic acid or a salt thereof is slightly cross-linked hyaluronic acid or a salt thereof.

[0066] In the slightly cross-linked hyaluronic acid or its salt, the mass ratio of hyaluronic acid or its salt to the cross-linking agent is 100:(1-2);

[0067] For example, in the slightly cross-linked hyaluronic acid or its salt, the mass ratio of hyaluronic acid or its salt to the cross-linking agent can be 100:1, 100:1.1, 100:1.2, 100:1.3, 100:1.4, 100:1.5, 100:1.6, 100:1.7, 100:1.8, 100:1.9, 100:2 or any range therebetween.

[0068] In some embodiments of the present application, the hyaluronate is selected from one or more of the sodium salt, potassium salt, zinc salt, calcium salt, and magnesium salt of hyaluronic acid, preferably the sodium salt of hyaluronic acid.

[0069] In some embodiments of the present application, the hyaluronate is sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, zinc hyaluronate, or bismuth hyaluronate.

[0070] In some embodiments of the present application, the molecular weight of hyaluronic acid or its salt is 500kDa-3000kDa; for example, the molecular weight of hyaluronic acid or its salt is 500kDa, 600kDa, 700kDa, 800kDa, 900kDa, 1000kDa, 1100kDa, 1200kDa, 1300kDa, 1400kDa, 1500kDa, 1600kDa, 1700kDa, 1800kDa, 1900kDa, 2000kDa, 2100kDa, 2200kDa, 2300kDa, 2400kDa, 2500kDa, 2600kDa, 2700kDa, 2800kDa, 2900kDa, 3000kDa or any range therebetween.

[0071] In some embodiments of the present application, in the slightly cross-linked hyaluronic acid or its salt, the cross-linking agent is carbodiimide, divinyl sulfone, ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether or polyglycerol polyglycidyl ether, preferably 1,4-butanediol diglycidyl ether.

[0072] In some embodiments of the present application, relative to 1 part by weight of the oligopeptide, the cross-linked hyaluronic acid is (1 to 25) parts by weight, preferably (2 to 10) parts by weight;

[0073] For example, relative to 1 part by weight of the oligopeptide, the cross-linked hyaluronic acid can be 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight, 14 parts by weight, 15 parts by weight, 16 parts by weight, 17 parts by weight, 18 parts by weight, 19 parts by weight, 20 parts by weight, 21 parts by weight, 22 parts by weight, 23 parts by weight, 24 parts by weight, 25 parts by weight or any range therebetween.

[0074] In some embodiments of the present application, the gel further comprises auxiliary materials and active ingredients.

[0075] The excipients are acceptable excipients for preparing injectable hyaluronic acid gels, and those skilled in the art can select them conventionally in the prior art, such as acid-base regulators, osmotic fluid regulators, preservatives, thickeners, etc. The active ingredients are acceptable active ingredients for preparing injectable hyaluronic acid gels, and those skilled in the art can select them conventionally in the prior art, such as moisturizing ingredients, anti-wrinkle ingredients, whitening ingredients, anti-aging ingredients, antibacterial ingredients, anti-inflammatory ingredients, anesthetics, etc.

[0076] In some embodiments of the present application, the gel further comprises active ingredient polynucleotides and / or polydeoxyribonucleotides.

[0077] In some embodiments of the present application, the polynucleotide is (0.5-10) parts by weight relative to 1 part by weight of the oligopeptide;

[0078] For example, relative to 1 part by weight of the oligopeptide, the polynucleotide can be 0.5 parts by weight, 0.6 parts by weight, 0.7 parts by weight, 0.8 parts by weight, 0.9 parts by weight, 1.0 parts by weight, 1.1 parts by weight, 1.2 parts by weight, 1.3 parts by weight, 1.4 parts by weight, 1.5 parts by weight, 1.6 parts by weight, 1.7 parts by weight, 1.8 parts by weight, 1.9 parts by weight, 2.0 parts by weight, 2.1 parts by weight, 2.2 parts by weight, 2.3 parts by weight, 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, .4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight , 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 6.8 parts by weight, 6.9 parts by weight, 7.0 parts by weight, 7.1 parts by weight, 7.2 parts by weight, 7.3 parts by weight, 7.4 parts by weight, 7.5 parts by weight, 7.6 parts by weight, 7.7 parts by weight, 7.8 parts by weight, 7.9 parts by weight. parts by weight, 8.0 parts by weight, 8.1 parts by weight, 8.2 parts by weight, 8.3 parts by weight, 8.4 parts by weight, 8.5 parts by weight, 8.6 parts by weight, 8.7 parts by weight, 8.8 parts by weight, 8.9 parts by weight, 9.0 parts by weight, 9.1 parts by weight, 9.2 parts by weight, 9.3 parts by weight, 9.4 parts by weight, 9.5 parts by weight, 9.6 parts by weight, 9.7 parts by weight, 9.8 parts by weight, 9.9 parts by weight, 10 parts by weight or any range therebetween.

[0079] In some embodiments of the present application, the polydeoxyribonucleotide is (0.5-10) parts by weight relative to 1 part by weight of the oligopeptide;

[0080] For example, relative to 1 part by weight of the oligopeptide, the polydeoxyribonucleotide can be 0.5 parts by weight, 0.6 parts by weight, 0.7 parts by weight, 0.8 parts by weight, 0.9 parts by weight, 1.0 parts by weight, 1.1 parts by weight, 1.2 parts by weight, 1.3 parts by weight, 1.4 parts by weight, 1.5 parts by weight, 1.6 parts by weight, 1.7 parts by weight, 1.8 parts by weight, 1.9 parts by weight, 2.0 parts by weight, 2.1 parts by weight, 2.2 parts by weight, 2.3 parts by weight, , 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 6.8 parts by weight, 6.9 parts by weight, 7.0 parts by weight, 7.1 parts by weight, 7.2 parts by weight, 7.3 parts by weight, 7.4 parts by weight, 7.5 parts by weight, 7.6 parts by weight, 7.7 parts by weight, 7.8 parts by weight, 7. 9 parts by weight, 8.0 parts by weight, 8.1 parts by weight, 8.2 parts by weight, 8.3 parts by weight, 8.4 parts by weight, 8.5 parts by weight, 8.6 parts by weight, 8.7 parts by weight, 8.8 parts by weight, 8.9 parts by weight, 9.0 parts by weight, 9.1 parts by weight, 9.2 parts by weight, 9.3 parts by weight, 9.4 parts by weight, 9.5 parts by weight, 9.6 parts by weight, 9.7 parts by weight, 9.8 parts by weight, 9.9 parts by weight, 10 parts by weight or any range therebetween.

[0081] In some embodiments of the present application, the injectable hyaluronic acid gel is prepared by sterilizing a composite gel including the cross-linked hyaluronic acid or its salt and the oligopeptide.

[0082] In some embodiments of the present application, the cross-linked hyaluronic acid or its salt gel is prepared by mixing hyaluronic acid or its salt with a cross-linking agent in an alkaline solution to carry out a cross-linking reaction, eluting the cross-linking agent with a buffer solution to terminate the cross-linking reaction, and obtaining a cross-linked hyaluronic acid or its salt gel after homogenization; mixing: uniformly mixing the cross-linked hyaluronic acid or its salt gel with a nutrient solution containing oligopeptides to obtain a composite gel; sterilization: canning the composite gel and sterilizing it with wet heat to obtain an injectable hyaluronic acid or its salt composite gel.

[0083] In some embodiments of the present application, the cross-linked hyaluronic acid or its salt gel is prepared by: mixing hyaluronic acid or its salt with a cross-linking agent in an alkaline solution to carry out a cross-linking reaction, eluting the cross-linking agent with a buffer solution to terminate the cross-linking reaction, and obtaining a cross-linked hyaluronic acid or its salt gel after homogenization; mixing: uniformly mixing the cross-linked hyaluronic acid or its salt gel with a solution containing oligopeptides, vitamins, amino acids, polynucleotides and / or polydeoxyribonucleotides to obtain a composite gel; sterilization: canning the composite gel and sterilizing it with wet heat to obtain an injectable hyaluronic acid or its salt composite gel.

[0084] Since injectable hyaluronic acid gel is directly injected into the human body, it needs to be sterilized during the preparation process. After sterilization, the cross-linked hyaluronic acid or its salts are susceptible to degradation under the influence of active oxygen, light, high temperature and other factors in water, resulting in reduced content, changes in pH value, changes in solution color, etc. Therefore, the storage state of vitamins and amino acids in solution is unstable. As time goes by, the pH stability and content stability will decrease. Adding a certain amount of oligopeptides in proportion to the vitamin solution can maintain the stability of vitamins and amino acids in the solution and prevent the pH and content from decreasing.

[0085] Example 1

[0086] Take 0.02g of 1,4-butanediol diglycidyl ether (BDDE) and mix it evenly with 5mL of 1wt% sodium hydroxide solution, then add 1.0g of sodium hyaluronate and stir to dissolve it evenly. The above reactants are sealed, left to react at 3°C ​​for 15h, then left to react at 50°C for 3h, and finally left to react at 20°C for 15h. The reactants are dialyzed, swollen, and homogenized in phosphate sodium chloride buffer to obtain a cross-linked sodium hyaluronate gel with a content of 2mg / mL; a composite solution is added to the cross-linked sodium hyaluronate gel at a volume ratio of 1:1, wherein the oligopeptide in the composite solution is oligopeptide 1 and the content of oligopeptide 1 is 2mg / mL, the content of vitamin B2 is 0.2mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 10:1, and mixed evenly to obtain a composite gel, in which the content of oligopeptide 1 is 1mg / mL, the content of vitamin B2 is 0.1mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 10:1.

[0087] Amino acid content determination method: Use an amino acid automatic analyzer and call the instrument's built-in sample test method for testing. The reference substances of each amino acid are purchased from the China National Institute for Food and Drug Control. Prepare a certain concentration of amino acid reference substance solution, take 20μL of blank control solution, reference substance solution, and test sample solution and inject them into the amino acid analyzer, record the chromatogram, calculate the content of each amino acid in the test sample by the external standard method, deduct the inherent content in the skin, and multiply by the corresponding dilution factor to obtain the result.

[0088] Vitamin content determination method: The detection methods of vitamin B1, vitamin B2, vitamin B6, niacinamide and folic acid content refer to the HPLC method of Wang Degang et al. (Wang Degang, Yan Huiru, Ma Ping, Liu Junhua. HPLC determination of five B vitamins in multi-element effervescent tablets [J]. Journal of Drug Analysis. 2010, 30(7): 1271-1275); the detection method of vitamin B12 refers to the HPLC method of Xu Shuo et al. (Xu Shuo, Jin Pengfei, Kuang Yongmei, et al. HPLC determination of trace folic acid, vitamin B12 and biotin in complex vitamin B tablets [J]. Journal of Drug Analysis. 2018, 38(6): 1091-1097); the detection method of vitamin C refers to the HPLC method of Chen Xijuan (Chen Xijuan, Xincai County Food and Drug Inspection Institute, Henan Province (463500). Analysis of vitamin C content in vitamin C tablets by high performance liquid chromatography [J]. Drug Inspection. 2019: 180).

[0089] pH determination method: dilute the gel with freshly boiled and cooled purified water in equal proportions, and then determine the pH using an acidometer.

[0090] Example 2

[0091] The only difference between Example 2 and Example 1 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of vitamin B2 is 0.2 mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 5:1.

[0092] Example 3

[0093] The only difference between Example 3 and Example 1 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of vitamin B2 is 2 mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 1:2.

[0094] Example 4

[0095] The only difference between Example 4 and Example 1 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of vitamin B2 is 0.002 mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 500:1.

[0096] Example 5

[0097] The only difference between Example 5 and Example 1 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of vitamin B2 is 0.001 mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 1000:1.

[0098] Example 6

[0099] The only difference between Example 6 and Example 1 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of vitamin B2 is 3 mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 1:3.

[0100] Example 7

[0101] The only difference between Example 7 and Example 1 is that, in the composite solution, the content of oligopeptide 1 is 2 mg / mL, the content of vitamin B2 is 0.2 mg / mL, the content of glycine is 2 mg / mL, the mass ratio of oligopeptide 1 to vitamin B2 is 10:1, and they are mixed evenly to obtain a composite gel, in which the content of oligopeptide 1 is 1 mg / mL, the content of vitamin B2 is 0.1 mg / mL, the content of glycine is 1 mg / mL, and the mass ratio of oligopeptide 1 to vitamin B2 is 10:1.

[0102] Example 8

[0103] The only difference between Example 8 and Example 1 is that in the composite solution, the oligopeptide is anserine, and the content of anserine is 2 mg / mL, the content of vitamin B2 is 0.2 mg / mL, and the mass ratio of anserine to vitamin B2 is 10:1. The mixture is mixed evenly to obtain a composite gel, in which the content of anserine is 1 mg / mL, the content of vitamin B2 is 0.1 mg / mL, and the mass ratio of anserine to vitamin B2 is 10:1.

[0104] Example 9

[0105] The only difference between Example 9 and Example 8 is that in the composite gel, the content of anserine is 1 mg / mL, the content of vitamin B2 is 0.2 mg / mL, and the mass ratio of anserine to vitamin B2 is 5:1.

[0106] Example 10

[0107] The only difference between Example 10 and Example 8 is that in the composite gel, the content of anserine is 1 mg / mL, the content of vitamin B2 is 2 mg / mL, and the mass ratio of anserine to vitamin B2 is 1:2.

[0108] Embodiment 11

[0109] The only difference between Example 11 and Example 8 is that in the composite gel, the content of anserine is 1 mg / mL, the content of vitamin B2 is 0.002 mg / mL, and the mass ratio of anserine to vitamin B2 is 500:1.

[0110] Example 12

[0111] The only difference between Example 12 and Example 8 is that in the composite gel, the content of anserine is 1 mg / mL, the content of vitamin B2 is 0.001 mg / mL, and the mass ratio of anserine to vitamin B2 is 1000:1.

[0112] Embodiment 13

[0113] The only difference between Example 13 and Example 8 is that in the composite gel, the content of anserine is 1 mg / mL, the content of vitamin B2 is 3 mg / mL, and the mass ratio of anserine to vitamin B2 is 1:3.

[0114] Embodiment 14

[0115] The only difference between Example 14 and Example 8 is that, in the composite solution, the content of anserine is 2 mg / mL, the content of vitamin B2 is 0.2 mg / mL, the content of glycine is 2 mg / mL, the mass ratio of anserine to vitamin B2 is 10:1, and they are mixed evenly to obtain a composite gel, in which the content of anserine is 1 mg / mL, the content of vitamin B2 is 0.1 mg / mL, the content of glycine is 1 mg / mL, and the mass ratio of anserine to vitamin B2 is 10:1.

[0116] Embodiment 15

[0117] The only difference between Example 15 and Example 1 is that, in the composite solution, the oligopeptide is carnosine, the content of carnosine is 2 mg / mL, the content of vitamin B2 is 0.2 mg / mL, the mass ratio of carnosine to vitamin B2 is 10:1, and mixing is uniform to obtain a composite gel, in which the content of carnosine is 1 mg / mL, the content of vitamin B2 is 0.1 mg / mL, and the mass ratio of carnosine to vitamin B2 is 10:1.

[0118] Example 16

[0119] The only difference between Example 16 and Example 1 is that in the composite solution, the oligopeptide is glutathione and the content of glutathione is 2 mg / mL, the content of vitamin B2 is 0.2 mg / mL, and the mass ratio of glutathione to vitamin B2 is 10:1. The mixture is mixed evenly to obtain a composite gel, in which the content of glutathione is 1 mg / mL, the content of vitamin B2 is 0.1 mg / mL, and the mass ratio of glutathione to vitamin B2 is 10:1.

[0120] Embodiment 17

[0121] The only difference between Example 17 and Example 1 is that the vitamin used in the composite solution is vitamin B6.

[0122] Comparative Example 1

[0123] The only difference between Comparative Example 1 and Example 1 is that the composite gel does not contain oligopeptides and the content of vitamin B2 is 0.1 mg / mL.

[0124] Comparative Example 2

[0125] The only difference between Comparative Example 2 and Example 1 is that the composite gel does not contain oligopeptides and vitamins.

[0126] The parameters of Examples 1-17 and Comparative Examples 1-2 are shown in Table 1.

[0127] Table 1

[0128] Oligopeptide mg / mL Vitamin mg / mL Glycine mg / mL Example 1 Oligopeptide 1 / 1 Vitamin B2 / 0.1 --- Example 2 Oligopeptide 1 / 1 Vitamin B2 / 0.2 --- Example 3 Oligopeptide 1 / 1 Vitamin B2 / 2 --- Example 4 Oligopeptide 1 / 1 Vitamin B2 / 0.002 --- Example 5 Oligopeptide 1 / 1 Vitamin B2 / 0.001 --- Example 6 Oligopeptide 1 / 1 Vitamin B2 / 3 --- Example 7 Oligopeptide 1 / 1 Vitamin B2 / 0.1 1mg / mL Example 8 Anserine / 1 Vitamin B2 / 0.1 --- Example 9 Anserine / 1 Vitamin B2 / 0.2 --- Example 10 Anserine / 1 Vitamin B2 / 2 --- Embodiment 11 Anserine / 1 Vitamin B2 / 0.002 --- Example 12 Anserine / 1 Vitamin B2 / 0.001 --- Embodiment 13 Anserine / 1 Vitamin B2 / 3 --- Embodiment 14 Anserine / 1 Vitamin B2 / 0.1 1mg Embodiment 15 Carnosine / 1 Vitamin B2 / 0.1 --- Example 16 Glutathione / 1 Vitamin B2 / 0.1 --- Embodiment 17 Oligopeptide 1 / 1 Vitamin B6 / 0.1 --- Comparative Example 1 --- 0.1 --- Comparative Example 2 --- --- ---

[0129] Embodiment 18

[0130] Take 0.02 g of 1,4-butanediol diglycidyl ether (BDDE) and mix it evenly with 5 mL of 1 wt% sodium hydroxide solution, then add 1.0 g of sodium hyaluronate and stir to make it evenly dissolved. Seal the above reactants, let them stand at 3°C ​​for 15 hours, then let them stand at 50°C for 3 hours, and finally let them stand at 20°C for 15 hours. The reactants were dialyzed, swollen, and homogenized in a phosphate sodium chloride buffer to obtain a cross-linked sodium hyaluronate gel with a content of 2 mg / mL; a composite solution was added to the cross-linked sodium hyaluronate gel at a volume ratio of 1:1, wherein in the composite solution, the oligopeptide was oligopeptide 1 and the content of oligopeptide 1 was 2 mg / mL, the amino acid was lysine hydrochloride and the content of lysine hydrochloride was 0.2 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride was 10:1; the mixtures were mixed evenly to obtain a composite gel, wherein in the composite gel, the content of oligopeptide 1 was 1 mg / mL, the content of lysine hydrochloride was 0.1 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride was 10:1.

[0131] Amino acid content determination method: Use an amino acid automatic analyzer and call the instrument's built-in sample test method for testing. The reference substances of each amino acid are purchased from the China National Institute for Food and Drug Control. Prepare a certain concentration of amino acid reference substance solution, take 20μL of blank control solution, reference substance solution, and test sample solution and inject them into the amino acid analyzer, record the chromatogram, calculate the content of each amino acid in the test sample by the external standard method, deduct the inherent content in the skin, and multiply by the corresponding dilution factor to obtain the result.

[0132] Vitamin content determination method: The detection methods of vitamin B1, vitamin B2, vitamin B6, niacinamide and folic acid content refer to the HPLC method of Wang Degang et al. (Wang Degang, Yan Huiru, Ma Ping, Liu Junhua. HPLC determination of five B vitamins in multi-element effervescent tablets [J]. Journal of Drug Analysis. 2010, 30(7): 1271-1275); the detection method of vitamin B12 refers to the HPLC method of Xu Shuo et al. (Xu Shuo, Jin Pengfei, Kuang Yongmei, et al. HPLC determination of trace folic acid, vitamin B12 and biotin in complex vitamin B tablets [J]. Journal of Drug Analysis. 2018, 38(6): 1091-1097); the detection method of vitamin C refers to the HPLC method of Chen Xijuan (Chen Xijuan, Xincai County Food and Drug Inspection Institute, Henan Province (463500). Analysis of vitamin C content in vitamin C tablets by high performance liquid chromatography [J]. Drug Inspection. 2019: 180).

[0133] pH determination method: dilute the gel with freshly boiled and cooled purified water in equal proportions, and then determine the pH using an acidometer.

[0134] Embodiment 19

[0135] The only difference between Example 19 and Example 18 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of lysine hydrochloride is 1 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride is 1:1.

[0136] Embodiment 20

[0137] The only difference between Example 20 and Example 18 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of lysine hydrochloride is 2 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride is 1:2.

[0138] Embodiment 21

[0139] The only difference between Example 21 and Example 18 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of lysine hydrochloride is 0.002 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride is 500:1.

[0140] Embodiment 22

[0141] The only difference between Example 22 and Example 18 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of lysine hydrochloride is 0.001 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride is 1000:1.

[0142] Embodiment 23

[0143] The only difference between Example 23 and Example 18 is that in the composite gel, the content of oligopeptide 1 is 1 mg / mL, the content of lysine hydrochloride is 3 mg / mL, and the mass ratio of oligopeptide 1 to lysine hydrochloride is 1:3.

[0144] Embodiment 24

[0145] The only difference between Example 24 and Example 18 is that in the composite gel, the oligopeptide is anserine, the content of anserine is 1 mg / mL, the content of lysine hydrochloride is 0.1 mg / mL, and the mass ratio of anserine to lysine hydrochloride is 10:1.

[0146] Embodiment 25

[0147] The only difference between Example 25 and Example 18 is that in the composite gel, the oligopeptide is anserine, the content of anserine is 1 mg / mL, the content of lysine hydrochloride is 1 mg / mL, and the mass ratio of anserine to lysine hydrochloride is 1:1.

[0148] Embodiment 26

[0149] The only difference between Example 26 and Example 18 is that in the composite gel, the oligopeptide is anserine, the content of anserine is 1 mg / mL, the content of lysine hydrochloride is 2 mg / mL, and the mass ratio of anserine to lysine hydrochloride is 1:2.

[0150] Embodiment 27

[0151] The only difference between Example 27 and Example 18 is that in the composite gel, the oligopeptide is anserine, the content of anserine is 1 mg / mL, the content of lysine hydrochloride is 0.002 mg / mL, and the mass ratio of anserine to lysine hydrochloride is 500:1.

[0152] Embodiment 28

[0153] The only difference between Example 28 and Example 18 is that in the composite gel, the oligopeptide is anserine, the content of anserine is 1 mg / mL, the content of lysine hydrochloride is 0.001 mg / mL, and the mass ratio of anserine to lysine hydrochloride is 1000:1.

[0154] Embodiment 29

[0155] The only difference between Example 29 and Example 18 is that in the composite gel, the oligopeptide is anserine, the content of anserine is 1 mg / mL, the content of lysine hydrochloride is 3 mg / mL, and the mass ratio of anserine to lysine hydrochloride is 1:3.

[0156] Embodiment 30

[0157] The only difference between Example 30 and Example 18 is that in the composite gel, the oligopeptide is carnosine, the content of carnosine is 1 mg / mL, the content of lysine hydrochloride is 1 mg / mL, and the mass ratio of carnosine to lysine hydrochloride is 1:1.

[0158] Embodiment 31

[0159] The only difference between Example 31 and Example 18 is that in the composite gel, the oligopeptide is glutathione, the content of glutathione is 1 mg / mL, the content of lysine hydrochloride is 1 mg / mL, and the mass ratio of glutathione to lysine hydrochloride is 1:1.

[0160] Comparative Example 3

[0161] The only difference between Comparative Example 3 and Example 18 is that the composite gel does not contain oligopeptides and the content of lysine hydrochloride is 1 mg / mL.

[0162] The parameters of Examples 18-31 and Comparative Examples 2-3 are shown in Table 2.

[0163] Table 2

[0164] Oligopeptide mg / mL Vitamin B6mg / mL Lysine hydrochloride mg / mL Embodiment 18 Oligopeptide 1 / 1 --- 0.1 Embodiment 19 Oligopeptide 1 / 1 --- 1 Embodiment 20 Oligopeptide 1 / 1 --- 2 Embodiment 21 Oligopeptide 1 / 1 --- 0.002 Embodiment 22 Oligopeptide 1 / 1 --- 0.001 Embodiment 23 Oligopeptide 1 / 1 --- 3 Embodiment 24 Anserine / 1 --- 0.1 Embodiment 25 Anserine / 1 --- 1 Embodiment 26 Anserine / 1 --- 2 Embodiment 27 Anserine / 1 --- 0.002 Embodiment 28 Anserine / 1 --- 0.001 Embodiment 29 Anserine / 1 --- 3 Embodiment 30 Carnosine / 1 --- 1 Embodiment 31 Glutathione / 1 --- 1 Comparative Example 2 --- --- --- Comparative Example 3 --- --- 1

[0165] Table 3

[0166]

[0167] As can be seen from Table 3, when no oligopeptide was added to Comparative Example 1, after 6 months, both the vitamin content and the pH of the gel were greatly reduced. In Comparative Example 2, no oligopeptide and vitamin were added, and the pH of the gel did not change, indicating that the change in the pH of the gel was caused by the addition of vitamins. After adding a certain amount of oligopeptide to Examples 1-17, the changes in the vitamin content and the pH of the solution were significantly reduced compared to Comparative Example 1.

[0168] Table 4

[0169]

[0170] As can be seen from Table 4, when no oligopeptide was added to Comparative Example 3, after 6 months, both the amino acid content and the solution pH were greatly reduced. In Comparative Example 2, no oligopeptide and amino acid were added, and the pH of the gel did not change, indicating that the change in the pH of the gel was caused by the addition of amino acids. After adding a certain amount of oligopeptide to Examples 7, 14, 18-31, the changes in vitamin content and solution pH were significantly reduced compared to Comparative Example 1.

[0171] Embodiment 32

[0172] Take 0.01 g of BDDE and 5 mL of 1 wt% sodium hydroxide solution and mix them evenly, then add 1.0 g of sodium hyaluronate and stir to make it evenly dissolved. Seal the above reactants, place them at 3°C ​​for 15 hours, then place them at 50°C for 3 hours, and finally place them at 20°C for 15 hours. The final reaction product was dialyzed, swollen and homogenized in a phosphate sodium chloride buffer to obtain a cross-linked sodium hyaluronate gel with a content of 20 mg / mL; a composite solution was added to the cross-linked sodium hyaluronate gel at a volume ratio of 1:1, wherein the composite solution contained 2 mg / mL of anserine, 0.02 mg / mL of nicotinamide, 0.02 mg / mL of vitamin B6, 0.1 mg / mL of proline, 0.1 mg / mL of glycine, 0.1 mg / mL of lysine hydrochloride, 1.2 mg / mL of polynucleotide and 15 mg / mL of polydeoxyribonucleotide, and the mixture was mixed evenly to obtain a composite gel. In the composite gel, the content of cross-linked sodium hyaluronate gel is 10 mg / mL, the content of anserine is 1 mg / mL, the content of nicotinamide is 0.01 mg / mL, the content of vitamin B6 is 0.01 mg / mL, the content of proline is 0.05 mg / mL, the content of glycine is 0.05 mg / mL, the content of lysine hydrochloride is 0.05 mg / mL, the content of polynucleotide is 0.6 mg / mL, and the content of polydeoxyribonucleotide is 7.5 mg / mL. The composite gel is canned and sterilized by wet heat to obtain an injectable hyaluronic acid or its salt composite gel.

[0173] The parameters of Example 32 are shown in Table 5.

[0174] Table 5

[0175]

[0176] Although the present invention has been disclosed as above by way of embodiments, it is not intended to limit the present invention. Any person having ordinary knowledge in the technical field may make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be determined by the scope of the patent application attached hereto.

Claims

1. Application of an oligopeptide in improving the content stability of vitamins and / or amino acids in injectable hyaluronic acid gel; The oligopeptide is anserine, oligopeptide 1, glutathione or carnosine; Relative to 1 part by weight of the oligopeptide, the amino acid is (0.001-3) parts by weight and / or the vitamin is (0.001-3) parts by weight.

2. Use of an oligopeptide in improving the pH stability of an injectable hyaluronic acid gel containing vitamins and / or amino acids; The oligopeptide is anserine, oligopeptide 1, glutathione or carnosine; Relative to 1 part by weight of the oligopeptide, the amino acid is (0.001-3) parts by weight and / or the vitamin is (0.001-3) parts by weight.

3. The use according to claim 1 or 2, wherein: The oligopeptide is anserine or oligopeptide 1.

4. The use according to claim 1 or 2, wherein: The amino acid is in an amount of (0.05-2.5) parts by weight relative to 1 part by weight of the oligopeptide.

5. The use according to claim 1 or 2, wherein: Relative to 1 part by weight of the oligopeptide, the vitamin is (0.0015-2.5) parts by weight.

6. The use according to claim 1 or 2, wherein: The amino acids are selected from one or more of glycine, proline, hydroxyproline, lysine, lysine hydrochloride, isoleucine, leucine, serine, alanine, aspartic acid, tyrosine, glutamic acid, phenylalanine, arginine, valine, threonine, histidine, tryptophan, methionine, cystine and cysteine.

7. The use according to claim 1 or 2, wherein: The vitamins are selected from one or more of vitamin B1, vitamin B2, niacinamide, vitamin B6, vitamin B12, folic acid, biotin, calcium pantothenate and vitamin C.

8. An injectable hyaluronic acid gel comprising: Cross-linked hyaluronic acid or its salt, oligopeptide, vitamin and / or amino acid; the oligopeptide is anserine or oligopeptide 1; Relative to 1 part by weight of the oligopeptide, the amino acid is (0.05-2.5) parts by weight and / or the vitamin is (0.002-2) parts by weight; The cross-linked hyaluronic acid or its salt is (1-25) parts by weight relative to 1 part by weight of the oligopeptide.

9. The injectable hyaluronic acid gel according to claim 8, wherein The amino acids are selected from one or more of glycine, proline, hydroxyproline, lysine, lysine hydrochloride, isoleucine, leucine, serine, alanine, aspartic acid, tyrosine, glutamic acid, phenylalanine, arginine, valine, threonine, histidine, tryptophan, methionine, cystine and cysteine.

10. The injectable hyaluronic acid gel according to claim 8, wherein The vitamins are selected from one or more of vitamin B1, vitamin B2, niacinamide, vitamin B6, vitamin B12, folic acid, biotin, calcium pantothenate and vitamin C.

11. The injectable hyaluronic acid gel according to claim 8, wherein The cross-linked hyaluronic acid or its salt is (2-10) parts by weight relative to 1 part by weight of the oligopeptide.

12. The injectable hyaluronic acid gel according to claim 8, wherein It also includes excipients and active ingredients.

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