A lipoic acid composition and a method for preparing the same

Abstract

The application provides a lipoic acid composition and a preparation method thereof, and belongs to the technical field of medicines.The lipoic acid composition contains lipoic acid, poloxamer and a random copolymer of ethylene oxide and propylene oxide, and the mass ratio of the lipoic acid, the poloxamer and the random copolymer of ethylene oxide and propylene oxide is 7-10:3-5:1-2.The lipoic acid composition can improve the bioavailability of the prepared lipoic acid composition, can be directly orally administered, greatly simplifies the difficulty of administration, avoids injection and other administration modes, reduces the pain of patients, improves the safety of the production process and ensures the safety of drug use, and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a thioctic acid composition and its preparation method. Background Technology

[0002] Lipoic acid is a naturally occurring antioxidant. It is also known as thioctic acid, 1,2-dimercapto-3-pentanoic acid, 1,2-dimercapto-3-valoxalic acid, and 6,8-lipoic acid.

[0003] Alpha-lipoic acid is primarily a vitamin-like drug used for the treatment and maintenance of acute and chronic hepatitis, cirrhosis, hepatic coma, fatty liver, diabetes, and other conditions. Alpha-lipoic acid preparations were first marketed in Germany in the 1980s for the treatment of diabetic neurological symptoms.

[0004] Simultaneously, lipoic acid and its reduced form, dihydrolipoic acid (DHLA), possess antioxidant properties. It also protects membranes by interacting with vitamin C and glutathione, which can subsequently reuse vitamin E. In addition to its antioxidant activity, DHLA can act as an oxidative enhancer in the iron reduction process. The use of lipoic acid has been shown to be beneficial for many diseases such as ischemia-reperfusion injury (IRI), diabetes, cataract formation, HIV activation, neurodegeneration, and radiation damage. Furthermore, lipoic acid can act as a redox regulator of proteins such as myosin, prolactin, thioredoxin, and NF-κB transcription factor.

[0005] Lipoic acid also possesses other activities. For example, DHLA has been found to be an anti-inflammatory agent in vitro, simultaneously interfering with the release of NO from inflamed macrophages and protecting target cells from attack by oxygen free radicals. Lipoic acid is also a coenzyme for certain enzymes. It is a coenzyme for the α-ketoacid dehydrogenase complex, branched-chain α-ketoacid dehydrogenase complex, and glycine cleavage system, in which a complex of multiple enzymes, including lipoic acid, is formed, breaking down pyruvate molecules generated in early metabolism to form a slightly smaller, higher-energy molecule called acetyl-CoA. This produces molecules that can enter a series of reactions that complete the conversion of food into energy, either the citric acid cycle or the Klebsiella cycle. Essentially, lipoic acid promotes basal glucose transport and has an active role in insulin, which promotes glucose absorption.

[0006] Under physiological conditions, lipoic acid exists as a lipoamide in at least five proteins, where it is covalently linked to a lysine residue. Four of these proteins are the α-ketoacid dehydrogenase complex, pyruvate dehydrogenase complex, branched-chain ketoacid dehydrogenase complex, and α-ketoglutarate dehydrogenase complex. A protein containing three lipoamide residues is present in the E2 enzyme dihydrolipoic acid acyltransferase, which differs from each complex and is specific to the culture medium of the complex. One lipoic acid residue is present in protein X, which is identical across all complexes. A fifth lipoamide residue is present in the glycine cleavage system.

[0007] The main marketed dosage forms of lipoic acid are injections and oral solutions. In practical applications, lipoic acid injections suffer from numerous drawbacks due to its easy oxidation, photosensitivity, and low melting point. These drawbacks result in a high variety and concentration of impurities, especially oxidation products. Therefore, it is essential to reduce the content and types of impurities by implementing specific process controls and stabilizing the oxygen content of the formulation to ensure its quality and safety. However, the oral solution of this drug exhibits a strong first-pass effect and a very rapid metabolic rate, preventing the drug from maintaining an effective concentration range in the body for an extended period. Even repeated administration cannot achieve a steady-state blood concentration. In contrast, intravenous infusion of lipoic acid can achieve very high blood concentrations that can be maintained for a longer period, thus significantly enhancing insulin sensitivity, increasing glucose metabolism, improving DPN, and effectively treating diabetes. However, considering the severity of long-term oxidative damage in diabetic neuropathy, the lack of more effective treatment options, and the convenience of oral lipoic acid formulations, developing novel oral tablets remains an important approach. Summary of the Invention

[0008] The purpose of this invention is to provide a thioctic acid composition and its preparation method, which can improve the bioavailability of the obtained thioctic acid composition, allow for direct oral administration, greatly simplify the administration process, avoid injection and other methods of administration, reduce patient suffering, improve the safety of the production process and ensure the safety of medication, and has broad application prospects.

[0009] The technical solution of this invention is implemented as follows:

[0010] The present invention provides a thioctic acid composition comprising thioctic acid, poloxamer, and an ethylene oxide-propylene oxide random copolymer, wherein the mass ratio of the thioctic acid, poloxamer, and the ethylene oxide-propylene oxide random copolymer is 7-10:3-5:1-2.

[0011] As a further improvement of the present invention, the poloxamer includes poloxamer 188 and poloxamer 407 in a mass ratio of 5-7:2.

[0012] As a further improvement of the present invention, the average molecular weight of poloxamer 188 is 7680-9510, the average molecular weight of poloxamer 407 is 9840-14600, and the average molecular weight of the ethylene oxide-propylene oxide random copolymer is 10000-12000.

[0013] As a further improvement of the invention, it also includes pharmaceutically acceptable excipients for molding.

[0014] As a further improvement of the present invention, the excipients are selected from any one or a combination of two or more of fillers, disintegrants, and lubricants; the fillers are selected from any one or a combination of two or more of lactose, mannitol, starch, pregelatinized starch, microcrystalline cellulose, and sorbitol; the disintegrants are selected from any one or a combination of two or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose; and the lubricants are selected from any one or a combination of two or more of magnesium stearate, talc, and sodium stearate fumarate.

[0015] The present invention further protects a method for preparing the above-mentioned thioctic acid composition, comprising the following steps:

[0016] S1. Ball mill the lipoic acid until uniform to obtain pretreated lipoic acid;

[0017] S2. Dissolve poloxamer in an aqueous ethanol solution and mix it evenly with an ethylene oxide-propylene oxide random copolymer to obtain a mixture. Spray the mixture evenly onto the pretreated thioctic acid surface from step S1 to obtain a thioctic acid composition.

[0018] As a further improvement of the present invention, the ball milling time in step S1 is 2-3 hours.

[0019] As a further improvement of the present invention, the concentration of ethanol in the aqueous ethanol solution in step S2 is 40-60 wt%, and the solution is heated to 50-60°C and stirred during the dissolution process.

[0020] As a further improvement of the present invention, the method of uniformly spraying the mixture onto the pretreated thioctic acid surface in step S2 is to use fluidized bed treatment.

[0021] The present invention further protects the use of the above-mentioned lipoic acid composition in the preparation of an antioxidant drug for diabetes.

[0022] The present invention has the following beneficial effects: The fluidized bed equipment used in the present invention can be used for coating azisartan powder to prepare azisartan granules, and can also be used for drying, so that most of the ethanol and water evaporate, avoiding the degradation of excipients and raw materials in a high humidity and high temperature environment.

[0023] The present invention relates to poloxamer 188 and poloxamer 407, both of which are water-soluble polymers that can improve the viscosity and cohesiveness of aqueous solutions. At the same time, they can improve the bioavailability of the prepared thioctic acid composition, allowing for direct oral administration, greatly simplifying the administration process, avoiding injection and other methods, reducing patient suffering, improving the safety of the production process and ensuring the safety of medication, and having broad application prospects. Implementation

[0024] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] The average molecular weight of poloxamer 188 is 8250, the average molecular weight of poloxamer 407 is 12600, and the average molecular weight of the ethylene oxide-propylene oxide random copolymer is 11000. Example

[0026] This embodiment provides a thioctic acid composition containing thioctic acid, poloxamer, and an ethylene oxide-propylene oxide random copolymer. The poloxamer comprises poloxamer 188 and poloxamer 407 in a mass ratio of 5:2.

[0027] The preparation method includes the following steps:

[0028] S1. Ball mill 7 parts by weight of lipoic acid for 2 hours to obtain pretreated lipoic acid;

[0029] S2. Add 3 parts by weight of poloxamer to 50 parts by weight of 40 wt% ethanol aqueous solution, heat to 50°C, stir to dissolve, and mix with 1 part by weight of ethylene oxide and propylene oxide random copolymer to obtain a mixture. Use fluidized bed treatment to spray the mixture evenly onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition. Example

[0030] This embodiment provides a thioctic acid composition containing thioctic acid, poloxamer, and an ethylene oxide-propylene oxide random copolymer. The poloxamer comprises poloxamer 188 and poloxamer 407 in a mass ratio of 7:2.

[0031] The preparation method includes the following steps:

[0032] S1. Ball mill 10 parts by weight of thioctic acid for 3 hours to obtain pretreated thioctic acid;

[0033] S2. Add 5 parts by weight of poloxamer to 50 parts by weight of 60 wt% ethanol aqueous solution, heat to 60°C, stir to dissolve, and mix with 2 parts by weight of ethylene oxide and propylene oxide random copolymer to obtain a mixture. Use fluidized bed treatment to spray the mixture evenly onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition. Example

[0034] This embodiment provides a thioctic acid composition containing thioctic acid, poloxamer, and an ethylene oxide-propylene oxide random copolymer. The poloxamer comprises poloxamer 188 and poloxamer 407 in a mass ratio of 6:2.

[0035] The preparation method includes the following steps:

[0036] S1. 8.5 parts by weight of thioctic acid were ball-milled for 2.5 hours to obtain pretreated thioctic acid;

[0037] S2. Add 4 parts by weight of poloxamer to 50 parts by weight of 50 wt% ethanol aqueous solution, heat to 55°C, stir to dissolve, and mix evenly with 1.5 parts by weight of ethylene oxide and propylene oxide random copolymer to obtain a mixture. Use fluidized bed treatment to spray the mixture evenly onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition. Example

[0038] The difference from Example 3 is that poloxamer is a single poloxamer 188.

[0039] This embodiment provides a thioctic acid composition containing thioctic acid, poloxamer, and a random copolymer of ethylene oxide and propylene oxide.

[0040] The preparation method includes the following steps:

[0041] S1. 8.5 parts by weight of thioctic acid were ball-milled for 2.5 hours to obtain pretreated thioctic acid;

[0042] S2. Add 4 parts by weight of poloxamer 188 to 50 parts by weight of 50 wt% ethanol aqueous solution, heat to 55°C, stir to dissolve, and mix evenly with 1.5 parts by weight of ethylene oxide and propylene oxide random copolymer to obtain a mixture. Use fluidized bed treatment to spray the mixture evenly onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition. Example

[0043] The difference from Example 3 is that poloxamer is a single poloxamer 407.

[0044] This embodiment provides a thioctic acid composition containing thioctic acid, poloxamer, and a random copolymer of ethylene oxide and propylene oxide.

[0045] The preparation method includes the following steps:

[0046] S1. 8.5 parts by weight of thioctic acid were ball-milled for 2.5 hours to obtain pretreated thioctic acid;

[0047] S2. Add 4 parts by weight of poloxamer 407 to 50 parts by weight of 50 wt% ethanol aqueous solution, heat to 55°C, stir to dissolve, and mix evenly with 1.5 parts by weight of ethylene oxide and propylene oxide random copolymer to obtain a mixture. Use fluidized bed treatment to spray the mixture evenly onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition.

[0048] Comparative Example 1

[0049] The difference compared to Example 3 is that poloxamer was not added.

[0050] This embodiment provides a thioctic acid composition containing thioctic acid and a random copolymer of ethylene oxide and propylene oxide.

[0051] The preparation method includes the following steps:

[0052] S1. 8.5 parts by weight of thioctic acid were ball-milled for 2.5 hours to obtain pretreated thioctic acid;

[0053] S2. Mix 50 parts by weight of 50 wt% ethanol aqueous solution with 1.5 parts by weight of ethylene oxide and propylene oxide random copolymer to obtain a mixture. Use a fluidized bed to treat the mixture and spray it evenly onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition.

[0054] Comparative Example 2

[0055] The difference compared to Example 3 is that no ethylene oxide-propylene oxide random copolymer was added.

[0056] This embodiment provides a thioctic acid composition containing thioctic acid, poloxamer, and an ethylene oxide-propylene oxide random copolymer. The poloxamer comprises poloxamer 188 and poloxamer 407 in a mass ratio of 6:2.

[0057] The preparation method includes the following steps:

[0058] S1. 8.5 parts by weight of thioctic acid were ball-milled for 2.5 hours to obtain pretreated thioctic acid;

[0059] S2. Add 4 parts by weight of poloxamer to 50 parts by weight of 50 wt% ethanol aqueous solution, heat to 55°C, stir to dissolve, and obtain a mixture. Use fluidized bed treatment to uniformly spray the mixture onto the pretreated thioctic acid surface in step S1 to obtain a thioctic acid composition.

[0060] Test Example 1

[0061] The lipoic acid compositions prepared in Examples 1-5 and Comparative Examples 1-2 were analyzed according to the dissolution test method (Chinese Pharmacopoeia 2010 Edition, Part II, Appendix XC, Method II). Dissolution media included 900 ml of water, 0.1 mol / L HCl solution (pH=1.0), acetate buffer (pH=4.0), and phosphate buffer (pH=6.8). The dissolution speed was 100 r / min. Appropriate amounts of solution were taken at different dissolution time points, filtered, and the filtrate was analyzed by high-performance liquid chromatography (Chinese Pharmacopoeia 2000 Edition, Part II, Appendix VD). An appropriate amount of reference reagent (Weineng, Jiangsu Wanhe Pharmaceutical Co., Ltd., batch number: 210710) was accurately weighed, dissolved in dissolution media, and prepared as a reference solution. The results were analyzed using the same method. The results are shown in Tables 1-4.

[0062] Table 1: Using water as a solvent

[0063]

[0064] Table 2: Using 0.1 mol / L HCl solution at pH=1.0 as solvent

[0065]

[0066] Table 3: Using acetate buffer solution at pH 4.0 as the solvent

[0067]

[0068] Table 4: Using phosphate buffer solution at pH 6.8 as the solvent

[0069]

[0070] As can be seen from the table above, the thioctic acid compositions prepared by the methods in Examples 1-5 of this invention have excellent solubility in various solvents.

[0071] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A lipoic acid composition, characterized in that, The product contains thioctic acid, poloxamer, and an ethylene oxide-propylene oxide random copolymer, wherein the mass ratio of thioctic acid, poloxamer, and the ethylene oxide-propylene oxide random copolymer is 7-10:3-5:1-2. The poloxamer is selected from poloxamer 188 and poloxamer 407 in a mass ratio of 5-7:

2.

2. The thioctic acid composition according to claim 1, characterized in that, The average molecular weight of poloxamer 188 is 7680-9510, the average molecular weight of poloxamer 407 is 9840-14600, and the average molecular weight of the ethylene oxide-propylene oxide random copolymer is 10000-12000.

3. The thioctic acid composition according to claim 1, characterized in that, It also contains pharmaceutically acceptable excipients for molding, wherein the excipients are selected from any one or a combination of two or more of fillers, disintegrants, and lubricants.

4. The thioctic acid composition according to claim 3, characterized in that, The filler is selected from any one or a combination of two or more of lactose, mannitol, starch, pregelatinized starch, microcrystalline cellulose, and sorbitol; the disintegrant is selected from any one or a combination of two or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose; the lubricant is selected from any one or a combination of two or more of magnesium stearate, talc, and sodium stearate fumarate.

5. A method for preparing the thioctic acid composition according to any one of claims 1-4, characterized in that, Includes the following steps: S1. Ball mill the lipoic acid until uniform to obtain pretreated lipoic acid; S2. Dissolve poloxamer in an aqueous ethanol solution and mix it evenly with an ethylene oxide-propylene oxide random copolymer to obtain a mixture. Spray the mixture evenly onto the pretreated thioctic acid surface from step S1 to obtain a thioctic acid composition.

6. The preparation method according to claim 5, characterized in that, The ball milling time in step S1 is 2-3 hours; the concentration of ethanol in the ethanol-water solution in step S2 is 40-60 wt%, and the dissolution process is heated to 50-60°C and stirred to dissolve; the method of uniformly spraying the mixture onto the pretreated thioctic acid surface in step S2 is by using fluidized bed treatment.

7. The use of the lipoic acid composition according to any one of claims 1-4 in the preparation of an antioxidant medicament for diabetes.

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