Lipoic acid injection composition applied to mesoderm and preparation method thereof

Abstract

The invention discloses a lipoic acid injection composition applied to mesoderm and a preparation method of the lipoic acid injection composition. The lipoic acid injection composition comprises lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator and an osmotic pressure regulator. The cyclodextrin is selected to dissolve the lipoic acid powder, the solubility of the lipoic acid is improved, the later-stage stability of the injection is improved by utilizing the wrapping property of the lipoic acid, meanwhile, the irritation to mesoderm caused by the cyclodextrin is reduced by adding the hyaluronic acid and the salt thereof, and the comfortable feeling of a user is obviously improved.

Description

Technical Field

[0001] This case is a divisional application of a case with an application date of February 15, 2023, an invention name of "A lipoic acid injection composition for mesoderm and its preparation method", and an application number of 2023101201295.

[0002] The present application relates to the field of biomedicine technology, and in particular to a lipoic acid injection composition for use in mesoderm, and also to a method for preparing the composition. Background Art

[0003] Lipoic acid is a natural product first isolated from pig liver. It can now be obtained through chemical synthesis. Lipoic acid is a cofactor of pyruvate dehydrogenase and is mostly found in the liver, kidneys and heart. Previously, its understanding has always been limited to its energy metabolism; now a large amount of research has shown the antioxidant effects of α-lipoic acid and its reduced dihydrolipoic acid, as well as its preventive and therapeutic effects in various diseases. Since α-lipoic acid has a very low redox potential and a small molecule, it is a natural metabolite. For this reason, many medical scientists have vigorously carried out research on the antioxidant and medical applications of α-lipoic acid, which has become a hot research topic. Lipoic acid is almost insoluble in water, with a solubility of only 1g / L (20°C) in water. If its injection solution is placed for a long time, the relevant substances will obviously exceed the standard, the color of the solution will become lighter, the pH value will decrease, and the stability will be poor.

[0004] In response to these problems, several technical solutions have been proposed at home and abroad. Some researchers have made it into a powder injection, but due to the poor water solubility of lipoic acid, it is difficult or difficult to re-dissolve, and its sterility assurance level is lower than the terminal sterilization level; some researchers have made it into an injection, adding excipients such as meglumine and ethylenediamine as its co-solvent, but the long-term stability of the obtained injection is not good, and the related substances continue to increase; some researchers have added the antioxidant sodium bisulfite to the injection, but the pH value of the injection prepared by this prescription continues to increase during long-term storage, and the stability cannot be guaranteed.

[0005] At present, most of the mesodermal drugs for improving skin color are the combination of hyaluronic acid and its derivatives, tranexamic acid or glutathione, as well as the combination of their respective raw material injections or the combination of lyophilized powder and injections. On the application side of the market, it is cumbersome for doctors to compound and use, and there is also a risk of contamination. Even if some products are first mixed with the respective raw material injections to prepare a composite, there is no direct use of powdered lipoic acid in mesodermal products.

[0006] For example, Chinese patent document CN201910704274.1 discloses a pharmaceutical composition for mesotherapy for reducing skin pigmentation and treating pain and its preparation method, mentioning that lipoic acid injection, non-lipoic acid powder, is added to the composition, and the stability problem of lipoic acid powder prepared into injection is not solved. At the same time, the production cost of directly using lipoic acid injection to prepare the composition is high. Chinese patent document CN101961312A discloses a lipoic acid composition, containing lipoic acid, a solubilizer and an antioxidant, etc., but does not indicate whether it can be applied to mesoderm and its safety.

[0007] The lipoic acid injection currently on the market is used to treat the paresthesia caused by diabetic peripheral neuropathy, and can be used for intravenous injection or intramuscular injection, but it is not injected in the mesoderm (subcutaneous), and subcutaneous injection is to inject the liquid medicine into the tissue between the skin and the muscle, and intramuscular injection is mostly used for injecting drugs with strong irritation, or drugs with a large dosage. It is shown that the irritation of lipoic acid is large, and there are fewer studies and applications in the field of mesoderm injection. How to dissolve lipoic acid well, reduce lipoic acid stimulation, make it suitable for mesoderm (subcutaneous) injection, and ensure that the stability of injection is a problem that those skilled in the art need to solve. Summary of the invention

[0008] Lipoic acid has poor solubility. The commonly used solution on the market is to add a large amount of alkali solution to dissolve it, but strong alkali can easily degrade the effective drug content. Therefore, the addition of cyclodextrin to the lipoic acid injection in the present application can avoid excessive addition of alkali, effectively avoiding the degradation of effective substances and excessive alkali causing more clinical irritation to patients. At the same time, hyaluronic acid or its salt is compounded to further reduce irritation.

[0009] The present application provides a lipoic acid injection composition for use in the mesoderm and a preparation method thereof, which solves the dissolution and stability problems of lipoic acid injection on the one hand, and on the other hand, applies lipoic acid injection to the mesoderm to solve the problems of poor permeability and slow effect of existing smear-type products, and quickly solves the problems of dark yellow and rough skin; at the same time, it solves the irritation and safety problems in mesoderm injection.

[0010] Specifically, this application adopts the following technical solutions:

[0011] 1. A lipoic acid injection composition for use in the mesoderm, comprising lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator, and an osmotic pressure regulator.

[0012] 2. The composition according to item 1, wherein the lipoic acid is in an amount of 0.1 to 10 parts by weight, preferably 0.5 to 5.0 parts by weight, relative to 100 parts by weight of the composition.

[0013] 3. The composition according to item 1 or 2, wherein the cyclodextrin is 0.05 to 5 parts by weight, preferably 0.1 to 1.5 parts by weight, relative to 100 parts by weight of the composition.

[0014] 4. The composition according to any one of items 1 to 3, wherein the stabilizer is present in an amount of 0.02 to 5 parts by weight, preferably 0.1 to 1.5 parts by weight, relative to 100 parts by weight of the composition.

[0015] 5. The composition according to any one of items 1 to 4, wherein the amount of the regulator is 0.05 to 5 parts by weight, preferably 0.2 to 2.0 parts by weight, relative to 100 parts by weight of the composition.

[0016] 6. The composition according to any one of items 1 to 5, wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, preferably, the cyclodextrin is β-cyclodextrin, and more preferably, it is hydroxypropyl-β-cyclodextrin.

[0017] 7. The composition according to any one of items 1 to 6, wherein the regulator is hyaluronic acid or a salt thereof, preferably the hyaluronic acid or a salt thereof is selected from one or more of sodium hyaluronate, potassium hyaluronate, zinc hyaluronate and calcium hyaluronate.

[0018] 8. The composition according to any one of items 1 to 7, wherein the molecular weight of the hyaluronic acid or its salt is 2500-3500 KDa, preferably 3000 KDa.

[0019] 9. The composition according to any one of items 1 to 8, wherein the mass ratio of lipoic acid, cyclodextrin and regulator is: 1: (0.05-0.5): (0.01-0.4), preferably: 1: (0.1-0.3): (0.02-0.2).

[0020] 10. The composition according to any one of items 1 to 9, wherein the mass ratio of lipoic acid, cyclodextrin and stabilizer is 1:(0.1-0.5):(0.2-2).

[0021] 11. A composition according to any one of items 1 to 10, wherein the stabilizer comprises carnosine and EDTA-2Na, and preferably, the mass ratio of carnosine to EDTA-2Na is 1:(0.5-2).

[0022] 12. The composition according to item 11, wherein the mass ratio of lipoic acid, carnosine and EDTA-2Na is (1-20):1:(0.1-5), preferably (2-10):1:(0.5-1).

[0023] 13. A composition according to any one of items 1 to 12, wherein the pH adjuster is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide or triethanolamine.

[0024] 14. The composition according to any one of items 1 to 13, wherein the pH adjuster is present in an amount of 0.001 to 1.0 parts by weight relative to 100 parts by weight of the composition.

[0025] 15. A method for preparing an injection composition for use in the mesoderm, comprising:

[0026] Dissolve cyclodextrin in injection water, add lipoic acid, stir until the solution is clear and transparent, adjust the pH value of the solution with a pH regulator, and adjust the osmotic pressure with an osmotic pressure regulator;

[0027] After aseptic filtration, a regulator is added, stirred evenly, and then sterilized to obtain the injection composition.

[0028] 16. The method according to item 15, wherein the preparation method is carried out at 40-50°C.

[0029] 17. The method according to item 15 or 16, wherein the pH value of the solution is adjusted to a range of 8.5 to 9.5 using a pH adjuster.

[0030] 18. The method according to any one of items 15 to 17, wherein the pH value of the injection composition obtained after sterilization is in the range of 7.0 to 7.3, and the osmotic pressure is in the range of 230 to 330 mOsmol / kg.

[0031] 19. Use of the injection composition described in any one of items 1 to 14 or the injection composition prepared by the method described in any one of items 15 to 18 for skin anti-oxidation, reducing skin pigmentation, alleviating skin roughness or alleviating pain in skin treatment.

[0032] 20. Use of hyaluronic acid or its salts in alleviating the irritation of cyclodextrin.

[0033] 21. Use of carnosine and EDTA-2Na in stabilizing lipoic acid.

[0034] 22. Use of carnosine and EDTA-2Na in preventing lipoic acid oxidation.

[0035] 23. Use of carnosine and EDTA-2Na in preventing fading of lipoic acid.

[0036] Effects of the Invention

[0037] 1. The lipoic acid injection of the present application uses cyclodextrin to dissolve lipoic acid powder, thereby improving the solubility of lipoic acid and utilizing its encapsulation property to improve the later stability of the injection. At the same time, the addition of hyaluronic acid and its salts reduces the irritation to the mesoderm caused by cyclodextrin, and the user's comfort feeling is significantly improved.

[0038] 2. The lipoic acid injection of the present application is further added with carnosine to replace the sodium bisulfite that plays an antioxidant role in the commonly approved lipoic acid injection on the market. Compared with sodium bisulfite, the safety risk of lipoic acid injection will increase. The antioxidant property of the carnosine of the present application not only effectively protects lipoic acid from being oxidized at high temperatures, but also can cooperate with lipoic acid to achieve the purpose of treating mesoderm, greatly reducing the safety risk. As a bioactive peptide, carnosine has the functions of buffering and adjusting the human body, as well as scavenging free radicals, anti-oxidation, anti-aging, and preventing metabolic disorders. Carnosine can be made into injections in the clinic, such as cerebroside carnosine, which can treat brain nerve damage. Carnosine can also correct the energy metabolism disorder of the human body by scavenging oxygen free radicals. Sodium bisulfite is an acidic corrosive product. Excessive dosage will be corrosive to the eyes, skin and mucous membranes, and have a sensitizing effect. In various injections, the amount added is as small as possible to reduce stimulation, at 0.01-0.2%.

[0039] 3. The lipoic acid injection of the present application uses carnosine and EDTA-2Na as stabilizers at the same time, and utilizes the antioxidant property of carnosine to effectively protect lipoic acid from being oxidized at high temperatures. At the same time, it can also synergize with lipoic acid to achieve the purpose of treating mesoderm. The combination of carnosine and EDTA-2Na can effectively solve the problem of lipoic acid fading under light.

[0040] 4. The lipoic acid injection of the present application is applied to the mesoderm. Because mesodermal injection is different from intramuscular injection, irritating substances cannot be used and the injection volume should not be too large. After adding carnosine and EDTA-2Na, the present application not only plays an antioxidant role, but also acts as a stabilizer, thereby reducing the amount of cyclodextrin used to stabilize lipoic acid, which not only reduces the irritation caused by cyclodextrin, but also does not affect the stability of lipoic acid injection, making it more suitable for mesoderm injection. DETAILED DESCRIPTION

[0041] The following is a description of the exemplary embodiments of the present application, including various details of the embodiments of the present application to facilitate understanding, which should be considered as merely exemplary. Therefore, it should be recognized by those of ordinary skill in the art that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present application. Similarly, for clarity and conciseness, the description of well-known functions and structures is omitted in the following description.

[0042] The present application provides a lipoic acid injection composition for use in the mesoderm, which comprises lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator, and an osmotic pressure regulator.

[0043] In a preferred embodiment, the lipoic acid is 0.1 to 10 parts by weight relative to 100 parts by weight of the composition, for example, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, 5 parts by weight, 5.5 parts by weight, 6 parts by weight, 6.5 parts by weight, 7 parts by weight, 7.5 parts by weight, 8 parts by weight, 8.5 parts by weight, 9 parts by weight, 9.5 parts by weight, and more preferably 0.5 to 5.0 parts by weight.

[0044] In a preferred embodiment, relative to 100 parts by weight of the composition, the cyclodextrin is 0.05 to 5 parts by weight, for example, it can be 0.1 parts by weight, 0.15 parts by weight, 0.2 parts by weight, 0.25 parts by weight, 0.3 parts by weight, 0.35 parts by weight, 0.4 parts by weight, 0.45 parts by weight, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, and more preferably 0.1 to 1.5 parts by weight.

[0045] In a preferred embodiment, the stabilizer is 0.02 to 5 parts by weight relative to 100 parts by weight of the composition, for example, it can be 0.04 parts by weight, 0.06 parts by weight, 0.08 parts by weight, 0.1 parts by weight, 0.15 parts by weight, 0.2 parts by weight, 0.25 parts by weight, 0.3 parts by weight, 0.35 parts by weight, 0.4 parts by weight, 0.45 parts by weight, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, and more preferably 0.1 to 1.5 parts by weight.

[0046] In a preferred embodiment, the amount of the regulator is 0.05 to 5 parts by weight relative to 100 parts by weight of the composition, for example, 0.1 parts by weight, 0.15 parts by weight, 0.2 parts by weight, 0.25 parts by weight, 0.3 parts by weight, 0.35 parts by weight, 0.4 parts by weight, 0.45 parts by weight, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, and more preferably 0.2 to 2.0 parts by weight.

[0047] In a preferred embodiment, the pH adjuster is 0.001 to 1.0 parts by weight relative to 100 parts by weight of the composition, for example, it can be 0.005 parts by weight, 0.01 parts by weight, 0.02 parts by weight, 0.03 parts by weight, 0.05 parts by weight, 0.1 parts by weight, 0.15 parts by weight, 0.2 parts by weight, 0.25 parts by weight, 0.3 parts by weight, 0.35 parts by weight, 0.4 parts by weight, 0.45 parts by weight, 0.5 parts by weight, 0.55 parts by weight, 0.6 parts by weight, 0.65 parts by weight, 0.7 parts by weight, 0.75 parts by weight, 0.8 parts by weight, or 0.9 parts by weight.

[0048] The lipoic acid injection composition of the present application is used for injection into the mesoderm of the skin. The solubility of lipoic acid is poor, so cyclodextrin is used in the present application to dissolve lipoic acid and ensure the stability of lipoic acid.

[0049] The term "cyclodextrin" as used herein includes any of the known cyclodextrins, such as unsubstituted cyclodextrins containing 6-12 glucose units and / or their derivatives and / or mixtures thereof. Preferably, the cyclodextrins used in the present application are highly water-soluble α-cyclodextrins and / or their derivatives, β-cyclodextrins and / or their derivatives, and γ-cyclodextrins and / or their derivatives, and / or mixtures thereof. The derivatives of cyclodextrins are mainly composed of molecules in which some OH groups are converted into OR groups, wherein R is an alkyl group having 1-6 carbon atoms, preferably 1-3 carbon atoms. Further preferably, the cyclodextrin is β-cyclodextrin, further preferably hydroxypropyl-β-cyclodextrin.

[0050] However, considering that lipoic acid is highly irritating, using cyclodextrin to dissolve lipoic acid will further increase the irritation. When used for injection into the mesoderm of the skin, it will cause irritating reactions such as pain to the user, causing discomfort to the user. Therefore, the present application uses a regulator to alleviate the irritation of the composition. The regulator is not limited and can be any regulator that is applied to the mesoderm and can alleviate the irritation of the composition to the mesoderm. In a preferred embodiment, the regulator is hyaluronic acid or a salt thereof.

[0051] The hyaluronic acid refers to a biopolymer material consisting of linearly connected repeating units N-acetyl-D-glucosamine and D-glucuronic acid. The hyaluronic acid or its salt includes hyaluronic acid itself, its salt or its combination. The example of hyaluronate includes but is not limited to: inorganic salts, such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, gold hyaluronate, cobalt hyaluronate; and organic salts, such as tetrabutylammonium hyaluronate. In the present application, hyaluronic acid itself or its salt can be used alone, or a combination of two or more hyaluronic acids or their salts can be used.

[0052] The hyaluronic acid or its salt described in the present application is not limited. In a preferred embodiment, the hyaluronate is a water-soluble salt of hyaluronic acid, and more preferably is one or more of sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, and calcium hyaluronate.

[0053] The molecular weight of the hyaluronic acid or its salt described in the present application is not limited. In a preferred embodiment, the molecular weight of the hyaluronic acid or its salt is 2500-3500 KDa, for example, it can be 2600 KDa, 2700 KDa, 2800 KDa, 2900 KDa, 3000 KDa, 3100 KDa, 3200 KDa, 3300 KDa, 3400 KDa, and the preferred molecular weight is 3000 KDa.

[0054] In a preferred embodiment, the mass ratio of lipoic acid, cyclodextrin and regulator is: 1: (0.05-0.5): (0.01-0.4), for example, it can be 1: 0.05: 0.01, 1: 0.1: 0.01, 1: 0.2: 0.01, 1: 0.3: 0.01, 1: 0.4: 0.01, 1: 0.05: 0.02, 1: 0.05: 0.02, 1: 0.1: 0.02, 1: 0.2: 0.02, 1: 0.3: 0.02, 1: 0.4: 0.02, 1: 0.05: 0.02, 1: 0.05: 0.1, 1: 0.1: 0.1, 1: 0.2: 0.1, 1: 0.3: 0 .1, 1:0.4:0.1, 1:0.5:0.1, 1:0.05:0.2, 1:0.1:0.2, 1:0.2:0.2, 1:0.3:0.2, 1:0.4:0.2, 1:0.5:0.2, 1:0.05:0.3, 1:0.1:0.3, 1:0.2:0.3, 1:0.3:0.3, 1:0.4:0.3, 1:0.5:0.3, 1:0.05:0.4, 1:0.1:0.4, 1:0.2:0.4, 1:0.3:0.4, 1:0.4:0.4, 1:0.5:0.4, preferably: 1:(0.1~0.3):(0.02-0.2).

[0055] In a preferred embodiment, the regulator is hyaluronic acid or a salt thereof, and the mass ratio of lipoic acid, cyclodextrin and hyaluronic acid or a salt thereof is: 1: (0.05-0.5): (0.01-0.4), for example, it can be 1: 0.05: 0.01, 1: 0.1: 0.01, 1: 0.2: 0.01, 1: 0.3: 0.01, 1: 0.4: 0.01, 1: 0.05: 0.02, 1: 0.05: 0.02, 1: 0.1: 0.02, 1: 0.2: 0.02, 1: 0.3: 0.02, 1: 0.4: 0.02, 1: 0.05: 0.02, 1: 0.05: 0.1, 1: 0.1: 0.1, 1: 0.2: 0. 1, 1:0.3:0.1, 1:0.4:0.1, 1:0.5:0.1, 1:0.05:0.2, 1:0.1:0.2, 1:0.2:0.2, 1:0.3:0.2, 1:0.4:0.2, 1:0.5:0.2, 1:0.05:0.3, 1:0.1:0.3, 1:0.2:0.3, 1:0.3:0.3, 1:0.4:0.3, 1:0.5:0.3, 1:0.05:0.4, 1:0.1:0.4, 1:0.2:0.4, 1:0.3:0.4, 1:0.4:0.4, 1:0.5:0.4, preferably: 1:(0.1~0.3):(0.02-0.2).

[0056] The composition of the present application is added with a pH adjusting agent to adjust the pH value of the composition, adapt to the injection use of the mesoderm, avoid discomfort and discomfort of the skin, and promote the dissolution of lipoic acid to a certain extent. The pH adjusting agent is not limited, and any pH adjusting agent commonly used in the art can be used. In a preferred embodiment, the pH adjusting agent is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide or triethanolamine.

[0057] The composition of the present application adds an osmotic pressure regulator to adjust the osmotic pressure of the composition to adapt to the injection of the mesoderm and avoid skin discomfort and maladaptation. The osmotic pressure regulator is not limited, and any osmotic pressure regulator commonly used in the art can be used. In a preferred embodiment, the osmotic pressure regulator is sodium chloride.

[0058] In order to further alleviate the irritation of the composition of the present application and to better apply it to the injection of the mesoderm, the present application adds another stabilizer to reduce the conventional amount of cyclodextrin while ensuring that cyclodextrin can dissolve lipoic acid, and use another stabilizer to ensure the stability of lipoic acid. In a preferred embodiment, the mass ratio of lipoic acid, cyclodextrin and stabilizer is 1: (0.1-0.5): (0.2-2), for example, it can be 1:0.1:0.2, 1:0.2:0.2, 1:0.3:0.2, 1:0.4:0.2, 1:0.5:0.2, 1:0.1:0.3, 1:0.2:0.3, 1:0.3:0.3, 1:0.4:0.3, 1:0.5:0.3, 1:0.1:0.5, 1:0 .2:0.5, 1:0.3:0.5, 1:0.4:0.5, 1:0.5:0.5, 1:0.1:1, 1:0.2:1, 1:0.3:1, 1:0.4:1, 1:0.5:1, 1:0.1:1.5, 1:0.2:1.5, 1:0.3:1.5, 1:0.4:1.5, 1:0.5:1.5, 1:0.1:2, 1:0.2:2, 1:0.3:2, 1:0.4:2, 1:0.5:2.

[0059] The type of the stabilizer is not limited, and can be any one or more stabilizers commonly used in the art. In a preferred embodiment, the stabilizer includes carnosine and EDTA-2Na. Carnosine, as a bioactive peptide, has the functions of buffering and adjusting the human body, as well as scavenging free radicals, anti-oxidation, anti-aging, and preventing metabolic disorders. Carnosine can be made into an injection in the clinic, such as cerebroside carnosine, which can treat brain nerve damage. Carnosine can also correct the energy metabolism disorder of the human body by scavenging oxygen free radicals. The present application uses carnosine as a stabilizer, and its antioxidant property is used to effectively protect lipoic acid from being oxidized at high temperatures. It can also cooperate with lipoic acid in anti-oxidation to treat mesoderm. In addition, the combination with EDTA-2Na can effectively solve the problem of lipoic acid fading under light.

[0060] In a preferred embodiment, the stabilizer is carnosine and EDTA-2Na, and the mass ratio of lipoic acid, cyclodextrin and (carnosine and EDTA-2Na) is 1: (0.1-0.5): (0.2-2), for example, it can be 1: 0.1: 0.2, 1: 0.2: 0.2, 1: 0.3: 0.2, 1: 0.4: 0.2, 1: 0.5: 0.2, 1: 0.1: 0.3, 1: 0.2: 0.3, 1: 0.3: 0.3, 1: 0.4: 0.3, 1: 0.5: 0.3 , 1:0.1:0.5, 1:0.2:0.5, 1:0.3:0.5, 1:0.4:0.5, 1:0.5:0.5, 1:0.1:1, 1:0.2:1, 1:0.3:1, 1:0.4:1, 1:0.5:1, 1:0.1:1.5, 1:0.2:1.5, 1:0.3:1.5, 1:0.4:1.5, 1:0.5:1.5, 1:0.1:2, 1:0.2:2, 1:0.3:2, 1:0.4:2, 1:0.5:2.

[0061] In a preferred embodiment, the mass ratio of carnosine to EDTA-2Na is 1:(0.5-2), for example, it can be 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, or 1:1.9.

[0062] The present application also provides a method for preparing an injection composition for use in the mesoderm, which comprises dissolving cyclodextrin in injection water, adding lipoic acid, stirring until the solution is clear and transparent, adjusting the pH value of the solution with a pH regulator, and adjusting the osmotic pressure with an osmotic pressure regulator; adding the regulator after sterile filtration, stirring evenly and then sterilizing to obtain the injection composition.

[0063] In the above preparation method, a preferred embodiment is that the preparation method is carried out at 40-50°C, for example, 41°C, 42°C, 43°C, 44°C, 45°C, 45°C, 46°C, 47°C, 48°C, or 49°C.

[0064] In the above preparation method, in a preferred embodiment, the pH value of the solution is adjusted by a pH adjuster to a range of 8.5 to 9.5, for example, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, or 9.4.

[0065] In the above preparation method, a preferred embodiment, the pH value of the injection composition obtained after sterilization is in the range of 7.0 to 7.3, for example, it can be 7.1 or 7.2, and the osmotic pressure is 230 to 330 mOsmol / kg, for example, it can be 240 mOsmol / kg, 250 mOsmol / kg, 260 mOsmol / kg, 270 mOsmol / kg, 280 mOsmol / kg, 290 mOsmol / kg, 300 mOsmol / kg, 310 mOsmol / kg, or 320 mOsmol / kg.

[0066] The present application provides the use of the mesodermal injection composition of the present application as described above or the mesodermal injection composition prepared by any one of the preparation methods for preparing the mesodermal injection composition provided by the present application as described above in skin anti-oxidation, reducing skin pigmentation, alleviating skin roughness or alleviating skin treatment pain.

[0067] The present application also provides use of hyaluronic acid or a salt thereof in alleviating the irritation of cyclodextrin.

[0068] The present application further provides the use of carnosine and EDTA-2Na in stabilizing lipoic acid.

[0069] The present application further provides the use of carnosine and EDTA-2Na in preventing lipoic acid oxidation.

[0070] The present application further provides the use of carnosine and EDTA-2Na in preventing lipoic acid from fading.

[0071] The present application provides a lipoic acid injection composition for use in the mesoderm, which ensures the stability of lipoic acid. Accelerated experiments have verified that under conditions of acceleration at 50°C for 6 months, the appearance of the lipoic acid injection composition has no obvious change, and it is more of a slightly yellowish transparent liquid. The pH value and osmotic pressure are both within the standard range, and the lipoic acid content has no obvious decrease, and is still within the standard range. The stability is very good, which also ensures that the composition can normally exert the effects of skin anti-oxidation, reduce skin pigmentation, relieve skin roughness or relieve skin treatment pain.

[0072] Human experiments have shown that the lipoic acid injection composition of the present application has a very obvious effect of improving the dull, yellow, dry and dull skin tone of the subjects, and according to the feedback from the subjects, the composition of the present application has no obvious irritation and has good comfort.

[0073] Example

[0074] Examples 1-8 and Comparative Examples 1 and 2 were used to prepare lipoic acid injections according to the following method. Parameters such as the types and amounts of various raw materials are shown in Table 1.

[0075] 1) At a temperature of 40-50° C., first quickly dissolve hydroxypropyl-β-cyclodextrin, then add lipoic acid, stir until the solution is clear and transparent, adjust the pH range to 8.5-9.5 with a pH adjuster, then add a stabilizer and an osmotic pressure regulator, and stir evenly;

[0076] 2) After aseptic filtration, a regulator is added and the solvent is supplemented; after stirring evenly, sterilization is performed. After sterilization, the pH range of the product is 7.0-7.3, and the osmotic pressure is 230-330 mOsmol / kg.

[0077] During the preparation process, sterile filtration is used to remove impurities and bacteria that may be introduced by small molecules, and 0.22-0.45um filter membrane is used for filtration. Considering that the regulator is a macromolecular polymer (hyaluronic acid and its salts), it cannot pass through the pore size of 0.22-0.45um, so the product is sterilized by wet heat sterilization. In order to maximize the activity of the effective substance of the injection, the sterilization conditions required by the bioload are used, 121℃, 8min or 115℃, 30min

[0078] Table 1 Raw materials and dosage of Examples and Comparative Examples

[0079]

[0080]

[0081] Test Example 1 Evaluation of stabilization effect

[0082] To evaluate the stability of the injection at the accelerated condition of 50°C, we conducted stability tests on three groups of products according to the requirements of the Guidance on Registration and Application Materials for Shelf Validity Period of Passive Implantable Medical Devices and the Guidance on Stability Testing of Raw Materials and Preparations of Part IV-9001 of the 2020 edition of the Pharmacopoeia of the People's Republic of China, and evaluated the changes in quality requirements during storage and under different temperature and environmental conditions. The quality evaluation refers to the Quality Evaluation Study of Lipoic Acid Injection Preparations.

[0083] Table 2 Data comparison between Example 2 and the control group

[0084]

[0085]

[0086] According to the requirements of the Pharmacopoeia of the People's Republic of China 2020 Edition IV-9001 Guidelines for Stability Tests of Raw Materials and Preparations, 4 months are accelerated at 50 ° C, which is approximately equal to 2 years of storage time at room temperature (25 ° C), and 6 months are accelerated at 50 ° C, which is approximately equal to 3 years of storage time at room temperature (25 ° C). As can be seen from Table 2, Example 2 of the present application is qualified in all indicators in the accelerated time of 6 months, that is, it meets the standards within a shelf life of 3 years, while the stabilizer carnosine and disodium ethylenediaminetetraacetic acid are not added in Comparative Example 1, and the shelf life of 3 years cannot be achieved (appearance is unqualified, lipoic acid content is unqualified, pH is unqualified), and the stabilizer is replaced with sodium bisulfite in Comparative Example 2, and the shelf life of 3 years cannot be achieved, indicating that the addition of the stabilizer of the present application can better assist cyclodextrin in ensuring the stability of the product in the later stage. In Example 8, only carnosine was added as the stabilizer, but disodium edetate was not added, and the accelerated stability was slightly worse, indicating that in the present application, adding both the stabilizer carnosine and disodium edetate simultaneously had a better stabilizing effect on the composition, and the two had a synergistic effect, which was better than the effect of using the single stabilizer (carnosine).

[0087] Test Example 2 Human Safety and Efficacy Evaluation

[0088] 60 volunteers were selected, and by comparing Example 3 with Example 4, Example 3 with Example 5, 60 volunteers aged between 20 and 55 were selected and divided into two groups. Volunteers were required to have dark, yellow, dry and dull skin. The left and right faces were injected with Demasha 2nd generation water light injection instrument (nine needles), one group was injected with Example 3 (left face) and Example 4 (right face), and the other group was injected with Example 3 (left face) and Example 5 (right face), with an injection depth of 0.8-1.2mm. Wash the face before injection and take VISA (the sixth generation VISIA of Canfiled), then apply a layer of anesthetic cream on the face, remove the anesthetic cream after 30 minutes, and inject the embodiment invention composition aseptically. After the injection, apply a refrigerated sterile medical mask for 20-30 minutes.

[0089] Observation indicators: Skin color improvement is divided into five levels: obvious improvement, relatively obvious improvement, no obvious improvement, relatively obvious deterioration, and obvious deterioration. The products are divided into four levels according to the comfort of injection: very satisfied, satisfied, average, and dissatisfied.

[0090] Two weeks later, the volunteers were asked to wash their faces and take VISA photos. The improvement of skin color was compared with the VISA photos before the photo was taken. The results are shown in Table 3. At the same time, the volunteers were asked to self-evaluate the improvement of skin color and comfort (pain level). The evaluation results are shown in Table 4.

[0091] Table 3 Skin color improvement results of VISA shooting

[0092]

[0093] Table 4 Volunteers' self-evaluation

[0094]

[0095] As can be seen from Tables 3 and 4, Example 3 is better than Example 4 in terms of effect, and has a high score in satisfaction (pain level), indicating that hyaluronic acid not only alleviates the irritation of hydroxypropyl-β-cyclodextrin, but also verifies that hyaluronic acid has a regulating effect on skin quality. Example 5 is better than Example 3, but also brings irritation. The comfort level is lower than that of Example 3, but the satisfaction level is also above 96%. There are no adverse reactions related to the product, and it has good safety.

[0096] Although the embodiments of the present application are described above, the present application is not limited to the above specific embodiments and application fields, and the above specific embodiments are merely illustrative and instructive, rather than restrictive. A person of ordinary skill in the art can make many forms under the guidance of this specification and without departing from the scope of protection of the claims of the present application, all of which belong to the protection of the present application.

Claims

1. Use of hyaluronic acid or its salt in alleviating the irritation of cyclodextrin.

2. Use of carnosine and EDTA-2Na in stabilizing lipoic acid.

3. Use of carnosine and EDTA-2Na in preventing lipoic acid oxidation.

4. Use of carnosine and EDTA-2Na in preventing lipoic acid from fading.

5. The use according to any one of claims 1 to 4, wherein the hyaluronic acid or its salt in the lipoic acid injection composition applied to the mesoderm alleviates the stimulation of cyclodextrin; wherein, The lipoic acid injection composition comprises lipoic acid, cyclodextrin, a stabilizer, hyaluronic acid or its salt, a pH regulator, and an osmotic pressure regulator.

6. The use according to claim 5, wherein The lipoic acid is contained in an amount of 0.1 to 10 parts by weight, preferably 0.5 to 5.0 parts by weight, relative to 100 parts by weight of the composition.

7. The use according to claim 5 or 6, wherein The cyclodextrin is present in an amount of 0.05 to 5 parts by weight, preferably 0.1 to 1.5 parts by weight, relative to 100 parts by weight of the composition.

8. The use according to any one of claims 5 to 7, wherein The stabilizer is present in an amount of 0.02 to 5 parts by weight, preferably 0.1 to 1.5 parts by weight, relative to 100 parts by weight of the composition.

9. The use according to any one of claims 5 to 8, wherein The hyaluronic acid or a salt thereof is contained in an amount of 0.05 to 5 parts by weight, preferably 0.2 to 2.0 parts by weight, based on 100 parts by weight of the composition.

10. The use according to any one of claims 5 to 9, wherein The cyclodextrin is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. Preferably, the cyclodextrin is β-cyclodextrin, and more preferably hydroxypropyl-β-cyclodextrin.

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