Long-acting injection preparation based on alpha-lipoic acid derivative as well as preparation method and application of long-acting injection preparation

Abstract

The invention provides a long-acting injection preparation based on an alpha-lipoic acid derivative and a preparation method and application thereof, and the preparation method of the long-acting injection preparation comprises the following steps: taking alpha-lipoic acid as a carboxylic acid donor and n-hexylamine as a primary amine donor, and carrying out reaction in a system of EDC and NHS to generate N-hexyl lipoic amide; n-hexyl lipoic amide and alpha-lipoic acid are dissolved in dimethyl sulfoxide according to the mass ratio of 1: 1 for a reaction, and the long-acting injection preparation is obtained. The long-acting injection preparation can realize in-situ phase change and drug long-acting slow release through solvent diffusion response, has good injectability and biocompatibility, can be used as a drug delivery carrier, and is used for long-term treatment of chronic metabolic diseases.

Description

Technical Field

[0001] This invention belongs to the field of biomedical engineering technology, and particularly relates to a long-acting injectable formulation based on α-lipoic acid derivatives, its preparation method, and its application. Background Technology

[0002] Alpha-lipoic acid (ALA), a natural antioxidant, has shown great potential in the field of intelligent drug delivery due to its unique five-membered ring disulfide bond structure. This molecule exhibits reduction sensitivity, excellent self-assembly ability, and good biocompatibility, while its strong antioxidant activity can directly protect drug activity and reduce oxidative damage to tissues. Despite ALA's multiple advantages in drug delivery system construction, several bottlenecks remain in its large-scale preparation, formulation stability, and clinical translation. Currently, designing and synthesizing novel ALA derivatives and optimizing their dynamic covalent chemical properties have become the main research strategies for expanding its drug delivery applications.

[0003] Long-acting injectable formulations (LAIs) represent a significant frontier in drug delivery, combining the convenience of injection with the sustained-release properties of long-acting drugs. This allows for on-demand, targeted, and controlled drug release within the body, maximizing therapeutic efficacy, reducing side effects, and significantly improving patient adherence. Solvent diffusion-responsive phase transitions (LAIs) are a mild and efficient physical gelation mechanism that can form solid or high-strength gels without complex chemical modifications or additional cross-linking agents. The stable gel structure avoids the risk of drug denaturation caused by environmental changes such as temperature and pH, and exhibits good compatibility with bioactive molecules such as proteins and peptides. Therefore, developing LAIs based on solvent diffusion-responsive phase transitions is beneficial for advancing intelligent drug delivery systems within the framework of precision medicine and holds promise as a crucial platform for ultra-long-acting sustained-release drug delivery.

[0004] However, traditional long-acting injectable formulations generally suffer from problems such as complex formulation processes, poor injection performance, high risk of drug burst release, limited applicable drug loading types, and poor patient compliance. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies. To address these shortcomings, this invention provides a long-acting injectable formulation based on α-lipoic acid derivatives, its preparation method, and its applications. This long-acting injectable formulation based on α-lipoic acid derivatives can achieve in-situ phase transition and form drug aggregates through solvent diffusion response, thereby efficiently encapsulating the target drug and achieving long-acting sustained release. This formulation exhibits excellent injection performance, a wide range of drug loading applications, a simple preparation process, and is easy to scale up. It is expected to overcome the limitations of existing drug delivery systems, improve patient compliance and clinical treatment efficacy, and can serve as a novel drug delivery matrix for metabolic diseases such as obesity and diabetes.

[0006] To address the aforementioned technical problems, the present invention provides a method for preparing the long-acting injectable formulation, the method comprising the following steps: S1. Using α-lipoic acid as a carboxylic acid donor and n-hexylamine as a primary amine donor, the reaction is carried out in a system of EDC and NHS to generate N-n-hexyllipoamide. S2. N-hexylthiocamide and α-lipoic acid are dissolved in dimethyl sulfoxide and reacted to obtain a long-acting injectable formulation.

[0007] In the above preparation method, the reaction temperature in S1 is 20℃~50℃, and the reaction time is 12 h.

[0008] In the above preparation method, the mass ratio of N-hexylthiocamide to α-lipoic acid in S2 is 1:1.

[0009] In the above preparation method, the reaction temperature in S2 is 20℃~50℃, and the reaction time is 4h~24h.

[0010] In the above preparation method, the organic solvent in step S2 is one or more of chloroform, dichloromethane, ethanol, isopropanol, propylene glycol, and dimethyl sulfoxide.

[0011] Based on a general technical concept, the present invention also provides a long-acting injectable formulation prepared by the preparation method described above.

[0012] Based on a general technical concept, the present invention provides an application of the aforementioned long-acting injectable formulation in the preparation of a drug delivery carrier.

[0013] Further, the method of the above application includes: mixing the long-acting injectable formulation with a drug to form an injectable formulation, thereby achieving long-acting sustained release of the drug.

[0014] Furthermore, in the above-described applications, the drug includes one of the following: polypeptide drugs, protein drugs, and small molecule drugs. More specifically, the drug is smegglutinin.

[0015] Compared with the prior art, the advantages of the present invention are as follows: (1) This invention provides a long-acting injectable formulation based on α-lipoic acid derivatives, wherein the hydrophobically modified α-lipoic acid derivatives and α-lipoic acid solid are co-dissolved in solvents such as chloroform, dichloromethane, ethanol, isopropanol, propylene glycol or dimethyl sulfoxide, which can achieve in-situ phase change and long-acting sustained release of the drug through solvent diffusion response. The formulation has both good injectability and biocompatibility.

[0016] (2) The preparation method of the long-acting injectable formulation based on α-lipoic acid derivative provided by the present invention is simple in process, easy in synthesis steps, and easy to operate and prepare on a large scale.

[0017] (3) This invention further provides the application of a long-acting injectable formulation based on α-lipoic acid derivatives in the preparation of drugs for treating obesity. This long-acting injectable formulation exhibits excellent injection performance, stable solvent diffusion response, and can form a drug reservoir in situ within the body, making it suitable for long-term treatment of chronic metabolic diseases. It possesses significant long-acting sustained-release characteristics, maintaining stable blood drug concentrations over a longer period, effectively reducing injection frequency and significantly improving patient compliance. This invention can encapsulate a wide range of drug types, including peptide drugs, protein drugs, and small molecule drugs, demonstrating good versatility in application. Attached Figure Description

[0018] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0019] Figure 1 This is a schematic diagram illustrating the synthesis of the hydrophobically modified α-lipoic acid derivative in Example 1 of the present invention.

[0020] Figure 2 This is the result of the injectability study of the long-acting injectable formulations of N-hexylthiocamide and α-lipoic acid in Experiment 1 of this invention.

[0021] Figure 3 This is a schematic diagram of the long-acting injectable formulation constructed from N-hexylthiocamide and α-lipoic acid in Example 2 of the present invention.

[0022] Figure 4 This refers to the solvent diffusion response phase transition of the long-acting injectable formulations of N-hexyl thiocamide and α-lipoic acid in Experiment 2 of this invention.

[0023] Figure 5 This is the in-situ drug concentration change curve of the long-acting injectable formulation of N-hexyl lipoamide and α-lipoic acid loaded with semaglutide in mice after subcutaneous injection in Experiment 3 of this invention. Detailed Implementation

[0024] The present invention will be further described below with reference to specific preferred embodiments, but this does not limit the scope of protection of the present invention.

[0025] The materials, reagents, and instruments used in the following examples are all commercially available. Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art.

[0026] Example 1 A long-acting injectable formulation of an α-lipoic acid derivative of the present invention, the synthetic route of which is described below. Figure 1 Specifically, it includes the following steps; (1) Synthesis of n-hexylamine-modified α-lipoic acid: n-hexylamine and α-lipoic acid were reacted in the presence of carbodiimide (EDC) and N-hydroxysuccinimide (NHS) for 12 hours (at room temperature). After removing unreacted small molecules by dialysis, the mixture was lyophilized to obtain N-n-hexyllipoamide solid.

[0027] (2) N-hexyl thioctin solid and α-lipoic acid solid were dissolved in dimethyl sulfoxide in a mass ratio of 1:1 (the reaction temperature was room temperature to 50°C and the reaction time was 4 to 24 h, depending on the temperature) to obtain a long-acting injectable formulation with a final concentration of 200 mg / ml.

[0028] Experiment 1: To investigate the injectability of long-acting injectable formulations of α-lipoic acid derivatives.

[0029] Figure 2 For the investigation of the injectability of long-acting injectable formulations, it can be seen from the figure that the long-acting injectable formulations of N-hexyl thiocamide and α-lipoic acid are clear and have low viscosity, and can pass through the syringe needle, thus exhibiting good injectability.

[0030] Example 2 The application of the long-acting injectable formulation of Example 1 in the preparation of a therapeutic weight loss drug includes: adding smegglutide to the long-acting injectable formulation of Example 1, with a final concentration of smegglutide of 10 mg / ml, and injecting it into the body.

[0031] Figure 3 The injection principle of this long-acting injectable formulation involves injecting the target drug, semaglutide, into the body, where the dimethyl sulfoxide solvent diffuses to form aggregates. As the aggregates degrade in vivo, semaglutide is released, achieving a long-acting sustained release. The release half-life of semaglutide is extended by 3.1 times.

[0032] Experiment 2: Investigating the solvent diffusion response phase transition of long-acting injectable formulations.

[0033] Figure 4 The graph shows the phase transition changes in the solvent diffusion response of the long-acting injectable formulation. Figure A shows that the long-acting injectable formulation rapidly gels at room temperature with the diffusion of ethanol in PBS. After gelation, the addition of dimethyl sulfoxide does not degrade the colloid, demonstrating the successful ring-opening polymerization of disulfide bonds. Figure B shows that the addition of Rhodamine B to the long-acting injectable formulation effectively encapsulates the Rhodamine B dye. The addition of dimethyl sulfoxide after gelation does not degrade the colloid, demonstrating the successful ring-opening polymerization of disulfide bonds.

[0034] Experiment 3: Animal Experiment.

[0035] In the experimental group, 100 µL of the long-acting injectable formulation from Example 1 was mixed with 0.1 mg of semaglutide and subcutaneously injected into 20 g male Balb / c mice to form an in situ drug reservoir, and drug concentration changes were monitored. In the control group, 100 µL of dimethyl sulfoxide was mixed with 0.1 mg of semaglutide and subcutaneously injected into 20 g male Balb / c mice, and drug concentration changes were monitored.

[0036] Figure 5 The graph shows the in-situ drug concentration changes in mice after subcutaneous injection of the long-acting injectable formulation of N-hexyllipoamide and α-lipoic acid encapsulated with semaglutide and the control group. As can be seen from the graph, the pharmacokinetic half-life increased from 0.65 days to 2.01 days. No obvious redness or swelling was observed at the injection site, and blood and major organ indicators remained normal.

[0037] In this embodiment, in addition to semaglutide, other drugs can be added to the long-acting injectable formulation, such as peptide drugs, protein drugs, and small molecule drugs, to achieve the effect of long-acting injection. The specific encapsulation principle is that the drug can be co-soluble with the matrix material in the solvent and can gel in response to water. Therefore, any drug that can be co-soluble with the matrix material in the solvent (except water) can achieve long-acting sustained release.

[0038] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention using the methods and techniques disclosed above, or modify them into equivalent embodiments with equivalent changes, without departing from the spirit and technical essence of the present invention. Therefore, any simple modifications, equivalent substitutions, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solutions of the present invention shall still fall within the protection scope of the technical solutions of the present invention.

Claims

1. A method for preparing a long-acting injectable formulation based on an α-lipoic acid derivative, characterized in that, The preparation method includes the following steps: S1. Using α-lipoic acid as a carboxylic acid donor and n-hexylamine as a primary amine donor, the reaction is carried out in a system of EDC and NHS to generate N-n-hexyllipoamide. S2. The N-hexylthiocamide and α-lipoic acid are dissolved in an organic solvent and reacted to obtain a long-acting injectable formulation.

2. The preparation method according to claim 1, characterized in that, The reaction temperature in S1 is 20℃~50℃, and the reaction time is 12 h.

3. The preparation method according to claim 1, characterized in that, The mass ratio of N-hexylthiocamide to α-lipoic acid in S2 is 1:

1.

4. The preparation method according to claim 1, characterized in that, The reaction temperature in S2 is 20℃~50℃, and the reaction time is 4 h~24 h.

5. The preparation method according to claim 1, characterized in that, The organic solvent in S2 is one or more of chloroform, dichloromethane, ethanol, isopropanol, propylene glycol, and dimethyl sulfoxide.

6. A long-acting injectable formulation prepared by any one of claims 1 to 5.

7. The use of the long-acting injectable formulation of claim 6 in the preparation of a drug delivery carrier.

8. The application according to claim 7, characterized in that, The application method includes: The long-acting injectable formulation is mixed with the drug to form an injectable formulation, thereby achieving long-acting sustained release of the drug.

9. The application according to claim 8, characterized in that, The drug includes one of the following: polypeptide drugs, protein drugs, and small molecule drugs.

10. The application according to claim 8, characterized in that, The drug in question is smegglutide.

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