A lipoic acid injection composition applied to mesoderm and a preparation method thereof

Abstract

The application discloses a lipoic acid injection composition applied to mesoderm and a preparation method thereof, wherein the lipoic acid injection composition comprises lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator and an osmotic pressure regulator. The lipoic acid powder is dissolved by using the cyclodextrin, the solubility of the lipoic acid is improved, the post-stability of the injection is improved by using the wrapping property of the cyclodextrin, meanwhile, the irritation of the cyclodextrin to the mesoderm is reduced by adding hyaluronic acid and a salt thereof, and the comfortable feeling of a user is obviously improved.

Description

Technical Field

[0001] This case is a divisional application of the application filed on February 15, 2023, entitled "A Thioctic Acid Injection Composition for Application to Mesodermis and Its Preparation Method Thereof", with application number 2023101201295.

[0002] This application relates to the field of biomedical technology, specifically to a thioctic acid injection composition for use in mesoderm, and also to a method for preparing the above composition. Background Technology

[0003] Alpha-lipoic acid, initially isolated from pig liver, is now synthesized chemically. It is a cofactor of pyruvate dehydrogenase and is abundant in the liver, kidneys, and heart. Previously, its understanding was limited to its energy metabolism; however, extensive research has demonstrated the antioxidant effects of α-lipoic acid and its reduced form, dihydrolipoic acid, as well as its preventative and therapeutic effects in various diseases. Due to its low redox potential, small molecular size, and status as a naturally occurring metabolite, α-lipoic acid has become a hot research topic, attracting significant attention from medical scientists for its antioxidant and pharmaceutical applications. Alpha-lipoic acid is almost insoluble in water, with a solubility of only 1 g / L (20°C). Prolonged storage of its injection solution results in significant exceedances of related substances, a lighter color, a decreased pH, and poor stability.

[0004] To address these issues, several technical solutions have been developed both domestically and internationally. Some researchers have formulated it as a powder for injection, but due to the poor water solubility of thioctic acid, reconstitution is difficult or impossible, and its sterility level is lower than terminal sterilization. Other researchers have formulated it as an injection solution, adding excipients such as meglumine and ethylenediamine as co-solvents, but the resulting injection solution has poor long-term stability, with related substances continuously increasing in size. Still others have added the antioxidant sodium bisulfite to the injection solution, but the pH value of the solution prepared by this formulation continuously increases during long-term storage, and its stability cannot be guaranteed.

[0005] Currently, most mesotherapy drugs for improving skin tone involve the combined use of hyaluronic acid and its derivatives, tranexamic acid, or glutathione, or the combined use of their respective injectable solutions, or the combined use of lyophilized powder and injectable solutions. In the market, this results in cumbersome compounding procedures for doctors and also poses a risk of contamination. Even if some products first mix the individual injectable solutions to prepare a combination, there is no direct application of powdered thioctic acid to mesotherapy products.

[0006] For example, Chinese patent document CN201910704274.1 discloses a pharmaceutical composition and its preparation method for mesotherapy to reduce skin pigmentation and treat pain. It mentions adding thioctic acid injection solution to the composition, but not thioctic acid powder. This method fails to address the stability issues of thioctic acid powder in the preparation of the injection solution, and the production cost of directly using thioctic acid injection solution is high. Chinese patent document CN101961312A discloses a thioctic acid composition containing thioctic acid, solubilizers, and antioxidants, but does not specify whether it can be applied to mesotherapy or its safety.

[0007] Currently available thioctic acid injections are used to treat sensory abnormalities caused by diabetic peripheral neuropathy. They can be administered intravenously or intramuscularly, but not subcutaneously (in the mesodermis). Subcutaneous injection involves injecting the drug into the tissue between the skin and muscle, while intramuscular injection is mostly used for highly irritating drugs or large doses. This indicates that thioctic acid is highly irritating, and its research and application in mesodermal injection are limited. How to effectively dissolve thioctic acid, reduce its irritation, make it suitable for mesodermal (subcutaneous) injection, and simultaneously ensure the stability of the injection solution is a problem that needs to be solved by those skilled in the art. 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 to dissolve it. However, strong alkali can easily degrade the content of the effective drug. Therefore, this application adds cyclodextrin to lipoic acid injection to avoid the excessive addition of alkali, effectively avoiding the degradation of the effective substance and the excessive alkali causing more clinical irritation to patients. At the same time, it is compounded with hyaluronic acid or its salt to further reduce irritation.

[0009] This application provides a thioctic acid injection composition for application to the mesoderm and its preparation method. On the one hand, it solves the problems of solubility and stability of thioctic acid injections; on the other hand, by applying the thioctic acid injection to the mesoderm, it addresses the issues of poor penetration and slow effectiveness of existing topical products, quickly resolving problems such as dull and rough skin. Simultaneously, it solves the irritation and safety issues associated with mesotherapy injections.

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

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

[0012] 2. The composition according to claim 1, wherein the thioctic acid is 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 1-3, wherein the stabilizer is 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 1-4, wherein the modifier 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 1-5, wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, preferably β-cyclodextrin, more preferably hydroxypropyl-β-cyclodextrin.

[0017] 7. The composition according to any one of items 1-6, 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 1-7, wherein the molecular weight of the hyaluronic acid or its salt is in the range of 2500-3500 kDa, preferably in the range of 3000 kDa.

[0019] 9. The composition according to any one of items 1-8, wherein the mass ratio of the lipoic acid, cyclodextrin and the 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 1-9, wherein the mass ratio of the lipoic acid, cyclodextrin and stabilizer is 1:(0.1-0.5):(0.2-2).

[0021] 11. The composition according to any one of items 1-10, wherein the stabilizer comprises carnosine and EDTA-2Na, 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. The composition according to any one of items 1-12, 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 1-13, wherein the pH adjuster is 0.001 to 1.0 parts by weight relative to 100 parts by weight of the composition.

[0025] 15. A method for preparing an injectable composition for application to the mesoderm, comprising,

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

[0027] After sterile filtration, a regulator is added, the mixture is 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 15-17, wherein the pH value of the sterilized injection composition is in the range of 7.0 to 7.3, and the osmotic pressure is 230 to 330 mOsmol / kg.

[0031] 19. Use of the injectable composition of any one of items 1-14 or the injectable composition prepared by any one of items 15-18 in terms of skin anti-oxidation, reduction of skin pigmentation, relief of skin roughness or relief of skin pain.

[0032] 20. Use of hyaluronic acid or its salts in relieving irritation from cyclodextrin.

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

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

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

[0036] Invention Effects

[0037] 1. The thioctic acid injection of this application uses cyclodextrin to dissolve thioctic acid powder, which improves the solubility of thioctic acid and enhances the later stability of the injection by utilizing its encapsulation properties. At the same time, the addition of hyaluronic acid and its salt reduces the irritation to the mesoderm caused by cyclodextrin, and the user's comfort is significantly improved.

[0038] 2. The lipoic acid injection of this application further adds carnosine to replace sodium bisulfite, which plays an antioxidant role in commonly approved lipoic acid injections. Compared to sodium bisulfite, which increases the safety risks of lipoic acid injections, the carnosine in this application not only effectively protects lipoic acid from oxidation at high temperatures but also synergistically works with lipoic acid to treat mesotherapy, significantly reducing safety risks. Carnosine, as a bioactive peptide, has buffering and regulating functions, as well as functions of scavenging free radicals, anti-oxidation, anti-aging, and preventing metabolic disorders. In clinical practice, carnosine can be formulated into injections, such as cerebrolysin, to treat brain nerve damage. Carnosine can also correct energy metabolism disorders by scavenging oxygen free radicals. Sodium bisulfite is an acidic corrosive substance; excessive doses can be corrosive to the eyes, skin, and mucous membranes, and can cause sensitization. To minimize irritation in various injections, the amount added is kept as low as possible, between 0.01% and 0.2%.

[0039] 3. The lipoic acid injection of this application uses carnosine and EDTA-2Na as stabilizers. The antioxidant properties of carnosine effectively protect lipoic acid from oxidation at high temperatures. At the same time, it can also work synergistically with lipoic acid to achieve the purpose of treating mesodermal lesions. The combination of carnosine and EDTA-2Na can effectively solve the problem of lipoic acid fading under light.

[0040] 4. The thioctic acid injection of this application is applied to the mesoderm. Since mesotherapy injection is different from intramuscular injection, highly irritating substances cannot be used, and the injection volume should not be too large. After adding carnosine and EDTA-2Na, the carnosine and EDTA-2Na not only play an antioxidant role, but also play a stabilizer role. This reduces the amount of cyclodextrin used to stabilize thioctic acid, which not only reduces the irritation caused by cyclodextrin, but also does not affect the stability of the thioctic acid injection, making it more suitable for mesotherapy injection. Detailed Implementation

[0041] The following description provides exemplary embodiments of this application, including various details to aid understanding, and should be considered merely exemplary. Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of this application. Similarly, for clarity and brevity, descriptions of well-known functions and structures are omitted in the following description.

[0042] This application provides a thioctic acid injection composition for use in mesoderm, comprising thioctic acid, cyclodextrin, stabilizer, regulator, pH regulator, and 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, or 9.5 parts by weight, and more preferably 0.5 to 5.0 parts by weight.

[0044] In a preferred embodiment, the cyclodextrin 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, or 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, 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, or 4.5 parts by weight, and more preferably 0.1 to 1.5 parts by weight.

[0046] In a preferred embodiment, the modifier 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, or 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, 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 thioctic acid injection composition of this application is intended for injection into the mesodermis of the skin. Thioctic acid has poor solubility, therefore, this application uses cyclodextrin to dissolve thioctic acid while ensuring its stability.

[0049] As used herein, the term "cyclodextrin" includes any known cyclodextrin, such as unsubstituted cyclodextrins containing 6-12 glucose units and / or their derivatives and / or mixtures thereof. Preferably, the cyclodextrins used in this 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. Cyclodextrin derivatives are primarily composed of molecules in which some of their OH groups are converted to OR groups, wherein R is an alkyl group having 1-6 carbon atoms, preferably 1-3 carbon atoms. More preferably, the cyclodextrin is a β-cyclodextrin, and more preferably hydroxypropyl-β-cyclodextrin.

[0050] However, considering the high irritation of lipoic acid, dissolving it with cyclodextrin would further increase the irritation. When injected into the mesodermis, it would cause pain and other irritating reactions in the user, causing discomfort. Therefore, this application uses a modifier to alleviate the irritation of the composition. The modifier is not limited and can be any modifier that can be applied to the mesodermis and alleviate the irritation of the composition to the mesodermis. In a preferred embodiment, the modifier is hyaluronic acid or a salt thereof.

[0051] The hyaluronic acid refers to a biopolymer material composed of linearly linked repeating units N-acetyl-D-glucosamine and D-glucuronic acid. The hyaluronic acid or its salts include hyaluronic acid itself, its salts, or combinations thereof. Examples of hyaluronic acid salts include, but are not limited to: inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, gold hyaluronate, and cobalt hyaluronate; and organic salts such as tetrabutylammonium hyaluronate. In this application, hyaluronic acid itself or its salts may be used alone, or combinations of two or more hyaluronic acids or their salts may be used.

[0052] The hyaluronic acid or its salts described in this application are not limited. In a preferred embodiment, the hyaluronic acid salt is a water-soluble salt of hyaluronic acid, and is more preferably 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 this application is not limited. In a preferred embodiment, the molecular weight of the hyaluronic acid or its salt is in the range of 2500-3500 kDa, for example, 2600 kDa, 2700 kDa, 2800 kDa, 2900 kDa, 3000 kDa, 3100 kDa, 3200 kDa, 3300 kDa, 3400 kDa, and preferably 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, 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 to hyaluronic acid or a salt thereof is 1:(0.05-0.5):(0.01-0.4), for example, 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 this application incorporates a pH adjuster to regulate its pH value, making it suitable for injection into mesotherapy and avoiding skin discomfort and irritation. It also promotes the dissolution of thioctic acid to some extent. The pH adjuster is not limited; any commonly used pH adjuster in the art can be used. In a preferred embodiment, the pH adjuster is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide, or triethanolamine.

[0057] The composition of this application incorporates an osmotic pressure regulator to adjust the osmotic pressure of the composition, making it suitable for injection into the mesodermis and avoiding skin discomfort and intolerance. The osmotic pressure regulator is not limited; any commonly used osmotic pressure regulator in the art can be used. In a preferred embodiment, the osmotic pressure regulator is sodium chloride.

[0058] To further alleviate the irritation of the composition of this application and to better apply it to mesotherapy injection, another stabilizer is added. This stabilizer reduces the conventional amount of cyclodextrin used while ensuring that the cyclodextrin can dissolve lipoic acid, and simultaneously ensures 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, 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 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 buffering and regulating functions in the human body, as well as functions of scavenging free radicals, anti-oxidation, anti-aging, and preventing metabolic disorders. Carnosine can be formulated into injectable preparations in clinical practice, such as cerebrolysin carnosine, which can treat damage to brain nerves. Carnosine can also correct energy metabolism disorders in the human body by scavenging oxygen free radicals. This application uses carnosine as a stabilizer, utilizing its antioxidant properties to effectively protect lipoic acid from oxidation at high temperatures. It can also synergistically work with lipoic acid to achieve the purpose of treating mesodermal damage. Furthermore, 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, 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, or 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] This application also provides a method for preparing an injectable composition for use in mesoderm, comprising: dissolving cyclodextrin in water for injection, adding thioctic acid, stirring until the solution is clear and transparent, adjusting the pH value of the solution with a pH adjuster, adjusting the osmotic pressure with an osmotic pressure adjuster; aseptically filtering, adding the adjuster, stirring evenly, and then sterilizing to obtain the injectable composition.

[0063] In a preferred embodiment of the above preparation method, the preparation method is carried out at 40-50°C, for example, at 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 to a range of 8.5 to 9.5 using a pH adjuster, for example, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, or 9.4.

[0065] In a preferred embodiment of the above preparation method, the pH value of the sterilized injection composition is in the range of 7.0 to 7.3, for example, 7.1 or 7.2, and the osmotic pressure is 230 to 330 mOsmol / kg, for example, 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] This application provides the use of the mesotherapy injection composition of this application as described above, or the mesotherapy injection composition prepared by any of the methods of preparing the mesotherapy injection composition of this application as described above, in terms of skin anti-oxidation, reduction of skin pigmentation, relief of skin roughness, or relief of skin pain.

[0067] This application also provides the use of hyaluronic acid or its salts in relieving the irritation caused by cyclodextrin.

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

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

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

[0071] This application provides a thioctic acid injection composition for use in mesotherapy, ensuring the stability of thioctic acid. Accelerated experiments have verified that under accelerated conditions of 50°C for 6 months, the appearance of the thioctic acid injection composition showed no significant change, remaining a slightly yellow and transparent liquid. The pH value and osmotic pressure were within the standard range, and the content of thioctic acid did not decrease significantly, remaining within the standard range. The stability is excellent, ensuring that the composition can effectively exert its effects of skin anti-oxidation, reducing skin pigmentation, relieving skin roughness, or alleviating skin pain.

[0072] Human trials have demonstrated that the thioctic acid injection composition of this application significantly improves the dull, yellow, dry, and lackluster skin tone of the subjects. Furthermore, subject feedback indicates that the composition of this application is not significantly irritating and provides good comfort.

[0073] Example

[0074] Examples 1-8 and Comparative Examples 1 and 2 were prepared with thioctic acid injection according to the following method. The types and amounts of each raw material are shown in Table 1.

[0075] 1) At a temperature of 40-50℃, first dissolve hydroxypropyl-β-cyclodextrin quickly, then add thioctic acid and 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 until homogeneous.

[0076] 2) After aseptic filtration, add the regulator and replenish the solvent; stir evenly and then sterilize. The pH range of the sterilized product is 7.0-7.3, and the osmotic pressure is 230-330 mOsmol / kg.

[0077] During the preparation process, aseptic filtration is used to remove impurities and bacteria that may be introduced by small molecules, employing a 0.22-0.45µm filter membrane. Considering that the regulator is a large polymer (hyaluronic acid and its salts), which cannot pass through a 0.22-0.45µm pore size, moist heat sterilization is used to aseptically process the product. To maximize the preservation of the active ingredient activity of the injection solution, sterilization conditions required for bioload are used: 121℃ for 8 minutes or 115℃ for 30 minutes.

[0078] Table 1. Raw materials and amounts used in the examples and comparative examples.

[0079]

[0080]

[0081] Evaluation of the stabilization effect in Experiment Example 1

[0082] To evaluate the stability of the injection solution under accelerated conditions at 50°C, in accordance with the "Guiding Principles for Registration Application Materials on Shelf Life of Passive Implantable Medical Devices" and the "Guiding Principles for Stability Testing of Raw Materials and Preparations" (2020 Edition of the Pharmacopoeia of the People's Republic of China, Part IV-9001), we conducted stability tests on three groups of products to evaluate changes in quality requirements during storage under different temperature conditions. The quality evaluation was based on the "Quality Evaluation Study of Thioctic Acid Injection Preparations".

[0083] Table 2 Comparison of data between Example 2 and the control group

[0084]

[0085]

[0086] According to the requirements of the 2020 edition of the Pharmacopoeia of the People's Republic of China, Part IV-9001, Guidelines for Stability Testing of Raw Materials and Preparations, accelerating the process at 50°C for 4 months is approximately equivalent to 2 years of storage at room temperature (25°C), and accelerating it at 50°C for 6 months is approximately equivalent to 3 years of storage at room temperature (25°C). As shown in Table 2, Example 2 of this application meets all indicators after 6 months of acceleration, meaning it meets the standard within a 3-year shelf life. However, Comparative Example 1, which did not include the stabilizers carnosine and disodium EDTA, could not achieve the 3-year shelf life (appearance, lipoic acid content, and pH were all substandard). Comparative Example 2, which replaced the stabilizer with sodium bisulfite, also failed to achieve the 3-year shelf life. This indicates that the addition of the stabilizers in this application is more effective in ensuring the later-stage stability of the cyclodextrin product. In Example 8, only carnosine was added as a stabilizer, without disodium EDTA. The stability was slightly worse, indicating that in this application, the simultaneous addition of carnosine and disodium EDTA as stabilizers has a better stabilizing effect on the composition. The two have a synergistic effect, which is better than the effect of using the stabilizer (carnosine) alone.

[0087] Example 2: Human safety and efficacy evaluation

[0088] Sixty volunteers were selected, aged 20-55, and divided into two groups for comparison between Examples 3 and 4, and Examples 3 and 5. Volunteers were required to have dull, yellowish, dry, and lackluster skin. The left and right sides of the face were injected using the Dermasa 2nd Generation Aqua Injection Device (nine needles). One group received Examples 3 (left face) and Examples 4 (right face), while the other group received Examples 3 (left face) and Examples 5 (right face), with an injection depth of 0.8-1.2 mm. Before injection, the face was cleansed and a VISA (Canfiled 6th Generation VISA) photo was taken. A layer of numbing cream was then applied to the face, and removed after 30 minutes. The composition of the invention was injected under aseptic conditions. After the injection, a refrigerated sterile medical device-grade facial mask was applied for 20-30 minutes.

[0089] Observation indicators: Skin tone improvement is divided into five levels: significant improvement, relatively significant improvement, no significant improvement, relatively significant deterioration, and significant deterioration. Based on injection comfort, the product is divided into four levels: very satisfied, satisfied, average, and unsatisfactory.

[0090] Two weeks later, a follow-up visit was conducted. A VISA photo was taken after facial cleansing, and the skin tone improvement was compared with the pre-treatment VISA photo. The results are shown in Table 3. Volunteers were also asked to self-evaluate their skin tone improvement and comfort (pain level). The evaluation results are shown in Table 4.

[0091] Table 3. Results of skin tone improvement captured by VISA.

[0092]

[0093] Table 4 Volunteer Self-Assessment

[0094]

[0095] As shown in Tables 3 and 4, Example 3 was slightly better than Example 4 in terms of efficacy and had a higher satisfaction (pain level) score, indicating that hyaluronic acid, in addition to alleviating the irritation of hydroxypropyl-β-cyclodextrin, also verified its regulatory effect on skin texture. Example 5 was better than Example 3, but it also caused irritation and had a lower comfort level than Example 3, although the satisfaction rate was still above 96%. No adverse reactions related to the product were observed, indicating good safety.

[0096] Although the embodiments of this application have been described above in conjunction with the specific embodiments described, this application is not limited to the specific embodiments and application fields described above. The specific embodiments described above are merely illustrative and instructive, and not restrictive. Those skilled in the art can make many other forms based on the teachings of this specification and without departing from the scope of protection of the claims of this application, and these are all within the scope of protection of this application.

Claims

1. Use of hyaluronic acid or its salts for non-therapeutic purposes in relieving irritation from a thioctic acid injection composition applied to mesoderm; in, The lipoic acid injection composition includes lipoic acid, cyclodextrin, stabilizer, hyaluronic acid or its salt, pH adjuster, and osmotic pressure adjuster; The stabilizer is 1 to 5 parts by weight relative to 100 parts by weight of the composition; the stabilizer includes carnosine and EDTA-2Na; Wherein, relative to 100 parts by weight of the composition, the thioctic acid is 0.1 to 10 parts by weight; The mass ratio of lipoic acid, cyclodextrin and hyaluronic acid or its salt is 1:(0.05~0.5):(0.01~0.4).

2. Non-therapeutic uses of carnosine and EDTA-2Na in stabilizing lipoic acid.

3. The use according to claim 2, wherein the carnosine and EDTA-2Na stabilize lipoic acid in a lipoic acid injection composition applied to mesoderm.

4. The use according to claim 3, wherein, The thioctic acid injection composition includes thioctic acid, cyclodextrin, stabilizer, hyaluronic acid or its salt, pH adjuster, and osmotic pressure adjuster.

5. Non-therapeutic uses of carnosine and EDTA-2Na in preventing the oxidation of lipoic acid.

6. The use according to claim 5, wherein the carnosine and EDTA-2Na prevent lipoic acid oxidation in a lipoic acid injection composition applied to mesoderm.

7. The use according to claim 6, wherein, The thioctic acid injection composition includes thioctic acid, cyclodextrin, stabilizer, hyaluronic acid or its salt, pH adjuster, and osmotic pressure adjuster.

8. Uses of carnosine and EDTA-2Na in preventing the fading of lipoic acid.

9. The use according to claim 8, wherein the carnosine and EDTA-2Na prevent lipoic acid from fading in a lipoic acid injection composition applied to mesoderm.

10. The use according to claim 9, wherein, The thioctic acid injection composition includes thioctic acid, cyclodextrin, stabilizer, hyaluronic acid or its salt, pH adjuster, and osmotic pressure adjuster.

11. The use according to claim 1, 2, 5 or 8, wherein the mass ratio of carnosine to EDTA-2Na is 1:(0.5~2).

12. The use according to claim 4, 7 or 10, wherein, The thioctic acid is 0.1 to 10 parts by weight relative to 100 parts by weight of the composition.

13. The use according to claim 12, wherein, The thioctic acid is 0.5 to 5.0 parts by weight relative to 100 parts by weight of the composition.

14. The use according to claim 1, 4, 7 or 10, wherein, The cyclodextrin is 0.05 to 5 parts by weight relative to 100 parts by weight of the composition.

15. The use according to claim 14, wherein, The cyclodextrin is 0.1 to 1.5 parts by weight relative to 100 parts by weight of the composition.

16. The use according to claim 4, 7 or 10, wherein, The stabilizer is 0.02 to 5 parts by weight relative to 100 parts by weight of the composition.

17. The use according to claim 16, wherein, The stabilizer is 0.1 to 1.5 parts by weight relative to 100 parts by weight of the composition.

18. The use according to claim 1, 4, 7 or 10, wherein, The hyaluronic acid or its salt is 0.05 to 5 parts by weight relative to 100 parts by weight of the composition.

19. The use according to claim 18, wherein, The hyaluronic acid or its salt is 0.2 to 2.0 parts by weight relative to 100 parts by weight of the composition.

20. The use according to claim 1, 4, 7 or 10, wherein, The cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

21. The use according to claim 20, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.

22. The use according to claim 1, 4, 7 or 10, wherein, The hyaluronic acid or its salt is selected from one or more of sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, and calcium hyaluronate.

23. The use according to claim 1, 4, 7 or 10, wherein, The molecular weight of the hyaluronic acid or its salt is between 2500 and 3500 kDa.

24. The use according to claim 23, wherein, The hyaluronic acid or its salt has a molecular weight of 3000 kDa.

25. The use according to claim 4, 7 or 10, wherein, The mass ratio of lipoic acid, cyclodextrin and hyaluronic acid or its salt is 1:(0.05~0.5):(0.01-0.4).

26. The use according to claim 25, wherein, The mass ratio of lipoic acid, cyclodextrin and hyaluronic acid or its salt is 1:(0.1~0.3):(0.02-0.2).

27. The use according to claim 1, 4, 7 or 10, wherein, The mass ratio of lipoic acid, cyclodextrin, and stabilizer is 1:(0.1~0.5):(0.2~2).

28. The use according to claim 4, 7 or 10, wherein, The mass ratio of lipoic acid, carnosine and EDTA-2Na is (1~20):1:(0.1~5).

29. The use according to claim 28, wherein, The mass ratio of lipoic acid, carnosine, and EDTA-2Na is (2~10):1:(0.5~1).

30. The use according to claim 1, 4, 7 or 10, wherein, The pH adjuster is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide, or triethanolamine.

31. The use according to claim 1, 4, 7 or 10, wherein, The pH adjuster is 0.001 to 1.0 parts by weight relative to 100 parts by weight of the composition.

32. The method for preparing the thioctic acid injection composition applied to the mesodermis according to claim 1, 4, 7 or 10. include, Dissolve cyclodextrin in water for injection, add thioctic acid, stir until the solution is clear and transparent, adjust the pH value of the solution with a pH adjuster, add a stabilizer, and adjust the osmotic pressure with an osmotic pressure adjuster. After sterile filtration, hyaluronic acid or its salt is added, stirred evenly, and then sterilized to obtain the thioctic acid injection composition.

33. The use according to claim 32, wherein, The preparation method is carried out at 40~50℃.

34. The use according to claim 32, wherein, The pH of the solution is adjusted to a range of 8.5 to 9.5 using a pH adjuster.

35. The use according to claim 32, wherein, After sterilization, the pH value of the injection composition is in the range of 7.0 to 7.3, and the osmotic pressure is 230 to 330 mOsmol / kg.

Images