PH response type lipoic acid microcapsule and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly discloses a pH response type lipoic acid microcapsule and a preparation method thereof. The microcapsule takes chitosan and sodium alginate as wall materials, wraps lipoic acid and lysine (the mass ratio is 1: 0.2), is prepared through an emulsification-crosslinking method, is small in particle size and good in absorption, and is used for intestinal targeted release of lipoic acid (alpha-lipoic acid). In-vitro release experiments show that the release rate in 2 hours in a gastric juice environment (pH 1.2) is lower than 10%, and the release rate in 4 hours in an intestinal juice environment (pH 6.8) is higher than 90%. According to the preparation, the stability and bioavailability of the lipoic acid are improved, and a new method is provided for innovation of pharmaceutical preparations.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, more particularly, it relates to a pH-responsive lipoic acid microcapsule and a preparation method thereof. BACKGROUND

[0002] Lipoic acid (chemical formula: C8H 14 O2S2) is a natural compound with antioxidant properties, widely used in the treatment of diabetes, liver disease and other related complications, especially diabetic peripheral neuropathy. More use of enteric capsule dosage form is considered to reduce gastrointestinal irritation and improve drug stability and absorption.

[0003] However, due to the short plasma half-life of lipoic acid, the current lipoic acid preparation has insufficient release accuracy, and needs to be administered multiple times a day and continuously taken to gradually repair and accumulate effect. The blood drug concentration of some patients fluctuates greatly, and is limited by gastric degradation and rapid absorption in the upper digestive tract, unstable absorption, low bioavailability, and poor patient compliance.

[0004] Therefore, how to optimize the release characteristics of lipoic acid, provide a new type of pH-responsive lipoic acid microcapsule preparation, so that it has high targeting, stability and bioavailability, and provide a new method for pharmaceutical preparation innovation, which has high research value for improving the quality of life of diabetic patients. SUMMARY

[0005] In order to improve the stability and bioavailability of lipoic acid, the present application provides a pH-responsive lipoic acid microcapsule and a preparation method thereof.

[0006] In a first aspect, the present application provides a preparation method of a pH-responsive lipoic acid microcapsule, which adopts the following technical scheme: comprising the following steps: S1: adding lipoic acid and lysine into a solvent, dispersing uniformly, heating and stirring to obtain a lipoic acid mixture; S2: dissolving sodium alginate in water, adding the lipoic acid mixture, stirring uniformly, dropping in a chitosan solution, centrifuging, washing and freeze-drying to obtain a pH-responsive lipoic acid microcapsule.

[0007] By adopting the above technical scheme, in gastric juice (pH 1.2), the amino group (-NH2) of chitosan is protonated (-NH3+), which enhances the electrostatic interaction with the carboxyl group (-COO-) of sodium alginate, forms a stable polyelectrolyte complex, and prevents the dissolution of the microcapsule. In intestinal juice (pH 6.8), chitosan is deprotonated, the stability of the complex is reduced, leading to the dissolution of the microcapsule and the release of lipoic acid and lysine. And lysine as a stabilizer may protect lipoic acid through the following mechanisms: the amino group of lysine may chelate metal ions to prevent metal-catalyzed oxidation; lysine may protect lipoic acid by neutralizing free radicals.

[0008] Preferably, TPGS vitamin E polyethylene glycol succinate is also added to the lipoic acid mixture, which has better absorption effect in the intestinal tract and higher utilization efficiency, and calcium chloride is also added dropwise in S2, which has better solidification effect.

[0009] In a specific embodiment, slow-release lipoic acid microparticles are also added to the lipoic acid mixture, and the preparation steps of the slow-release lipoic acid microparticles include: mixing lipoic acid with medium-chain triglyceride, heating and melting, adding vinylpyrrolidone-vinyl acetate copolymer to dissolve, ultrasonic emulsification, adding L-cysteine, heating and reacting under nitrogen protection, dialysis purification, and freeze-drying to obtain slow-release lipoic acid microparticles.

[0010] In a specific embodiment, cross-linked povidone is also added to the lipoic acid mixture.

[0011] By adopting the above technical scheme, the prepared pH-responsive microcapsules have a three-layer structure from outside to inside, which is chitosan-sodium alginate enteric capsule wall, lipoic acid intermediate layer with disintegration effect, and slow-release lipoic acid microparticles. After the microcapsules enter the intestinal tract and dissolve, the lipoic acid in the intermediate layer rapidly disintegrates to produce drug efficacy, and at the same time, with the occurrence of disintegration, the small slow-release lipoic acid microparticles are more uniformly distributed in the intestinal tract, and the contact absorption effect is better. After the lipoic acid in the intermediate layer is absorbed, the lipoic acid in the slow-release lipoic acid microparticles is released, and the blood drug concentration of the patient is more stable.

[0012] In a specific embodiment, the pH-responsive lipoic acid microcapsules include the following mass fractions of raw materials: lipoic acid 10-30 parts, L-lysine 1.0-4.5 parts, TPGS 0.5-3.0 parts; sodium alginate 2-8 parts, chitosan 1-5 parts, calcium chloride 1.5-4.5 parts, medium-chain triglyceride 5-8 parts, vinylpyrrolidone-vinyl acetate copolymer 0.5-1.0 parts, and L-cysteine 0.03-0.08 parts.

[0013] In a specific embodiment, the mass ratio of lipoic acid in the lipoic acid mixture to lipoic acid in the slow-release lipoic acid microparticles is 1:(1-2).

[0014] By adopting the above technical scheme, the pH-responsive lipoic acid microcapsules have more stable pH response effect and slow-release effect.

[0015] In a specific embodiment, the mass ratio of calcium chloride to cross-linked povidone is 2:(1.0-1.3).

[0016] By adopting the technical scheme, the precise design of the disintegrating agent realizes intelligent disintegration and uniform diffusion in the intestinal tract, while maintaining high stability and sustained-release characteristics of thioctic acid, and is suitable for thioctic acid preparation scenarios requiring intestinal targeted delivery. The microcapsule particle size facilitates cell uptake and drug delivery, and also reduces gastric irritation and side effects.

[0017] In a specific embodiment, the dialysis purification process uses a MWCO 500-2000Da membrane, and dialysis is performed at 4-10℃ for 12-36 hours.

[0018] By adopting the technical scheme, the purity and stability of the sustained-release thioctic acid microparticles are higher, and they are more suitable for intestinal absorption and utilization.

[0019] In a specific embodiment, the sustained-release thioctic acid microparticles include 2000Da membrane sustained-release microparticles and 500Da membrane sustained-release microparticles in a mass ratio of 1:(0.5-1.5), the 2000Da membrane sustained-release microparticles are selected from a MWCO 2000Da membrane and dialyzed at 10℃ for 10-12h, and the 500Da membrane sustained-release microparticles are selected from a MWCO 500Da membrane and dialyzed at 4℃ for 32-36 hours.

[0020] By adopting the technical scheme, the disintegration and sustained-release speed of thioctic acid is further adjusted, and the sustained-release thioctic acid microparticles with different cross-linking densities and layer thicknesses are matched to release smoothly in the absorption window of the small intestine, so that the blood drug concentration of the patient is more stable and the compliance is better.

[0021] In a specific embodiment, the mass ratio of thioctic acid to lysine is 1:(0.1-0.3), and the mass ratio of chitosan to sodium alginate is 1:(1.3-1.7).

[0022] In a second aspect, the application provides a pH-responsive thioctic acid microcapsule prepared by the preparation method of the pH-responsive thioctic acid microcapsule.

[0023] By adopting the technical scheme, it can be directly swallowed, or it can be made into an enteric-coated capsule and the like, which is beneficial to children and patients with swallowing difficulties, and can also be used together with chemotherapy drugs for synergistic anticancer and the like, In summary, the application has the following beneficial effects: The application provides a preparation method of pH-responsive lipoic acid microcapsules, the prepared microcapsules comprise a chitosan-sodium alginate enteric capsule wall, a lipoic acid intermediate layer with a disintegrating effect, and realize disintegration after reaching the intestine, rapidly reach an effective blood drug concentration, further prepare the microcapsules containing a slow-release lipoic acid microparticle inner layer, uniformly diffuse after disintegration, the slow-release lipoic acid microparticle continuously releases lipoic acid, and through matching of a small intestine absorption window, release and absorption are more stable. The problems of short lipoic acid half-life, insufficient release accuracy and low absorption rate are effectively solved. DETAILED DESCRIPTION

[0024] In order to further help understand the technical solutions of the present application, the following describes the technical solutions of the present application in a more specific manner by providing several specific implementation examples, and all the described examples are only partial examples of the present application, not all examples; The following specific examples can be combined with each other, and the same or similar concepts or processes in some examples can not be described again; and the reaction devices, monomer compounds and the like involved in the following examples are commercially available.

[0025] The following specific examples can be combined with each other, and the same or similar concepts or processes in some examples can not be described again.

[0026] The following examples are further illustrations of the present application, and the present application is not limited thereto.

[0027] Cross-linked povidone was purchased from Anshan Haize Pharmaceutical Auxiliary Co., Ltd. XL-10; medium-chain triglyceride was purchased from Bari Xincai Glyceride GB2760, production batch number 6364HNLC; sodium alginate was purchased from Hongfa Chemical 23028; chitosan was purchased from Shandong Gushuo; TPGS was purchased from Shenzhen Haodihuatuo Biological Technology Co., Ltd., and the molecular weight was about 1513 g / mol; ethylene pyrrolidone-vinyl acetate copolymer was purchased from Macklin P708192 (7:3); L-cysteine was purchased from Nanjing Bumoda Biological Technology Co., Ltd. EXAMPLE

[0028] Example 1 Raw material preparation: lipoic acid 18 g, L-lysine 3.6 g; sodium alginate 3 g, chitosan 2 g.

[0029] Preparation steps: S1: add lysine into 100 ml of water, stir at 500 rpm for 5 minutes, add lipoic acid, and high-speed shear at 12000 rpm for 12 minutes to obtain a lipoic acid mixture; S2: Dissolve sodium alginate in 80 ml water, 40 °C constant temperature water bath, 600 rpm magnetic stirring for 30 minutes, add the mixture of thioctic acid, 600 rpm continue to stir for 20 minutes to get sodium alginate mixture; S3: Add chitosan to 100 ml of 1wt% acetic acid solution, 30 °C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, slowly drop into the sodium alginate mixture, 30 minutes drop, 30 °C under 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze drying to get pH responsive thioctic acid microcapsule.

[0030] Example 2 Raw material preparation: thioctic acid 18 g, L-lysine 3.6 g, TPGS 3.0 g; sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g.

[0031] Preparation steps: S1: Add lysine to 100 ml water, 500 rpm stirring for 5 minutes, add TPGS, 45 °C 800 rpm stirring for 15 minutes, add thioctic acid, 12000 rpm high speed shearing for 12 minutes, get thioctic acid mixture; S2: Dissolve sodium alginate in 80 ml water, 40 °C constant temperature water bath, 600 rpm magnetic stirring for 30 minutes, add the mixture of thioctic acid, 600 rpm continue to stir for 20 minutes to get sodium alginate mixture; S3: Add calcium chloride to 200 ml water, 800 rpm magnetic stirring for 10 minutes, slowly drop into the sodium alginate mixture, 30 minutes drop, continue to stir for 30 minutes, centrifugal to get sodium alginate microspheres; S4: Add chitosan to 100 ml of 1wt% acetic acid solution, 30 °C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, add sodium alginate microspheres, 30 °C under 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze drying to get pH responsive thioctic acid microcapsule.

[0032] Example 3 Raw material preparation: thioctic acid 18 g, L-lysine 2 g, TPGS 3.0 g; sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g.

[0033] Preparation steps: S1: Add lysine to 100 ml water, 500 rpm stirring for 5 minutes, add TPGS, 45 °C 800 rpm stirring for 15 minutes, add thioctic acid, 12000 rpm high speed shearing for 12 minutes, get thioctic acid mixture; S2: The sodium alginate was dissolved in 80 ml of water, 40°C constant temperature water bath, 600 rpm magnetic stirring for 30 minutes, the mixture of lipoic acid was added, 600 rpm continued to stir for 20 minutes to get the sodium alginate mixture; S3: The calcium chloride was added to 200 ml of water, 800 rpm magnetic stirring for 10 minutes, slowly drop into the sodium alginate mixture, 30 minutes drop, continue to stir for 30 minutes, centrifugal to get the sodium alginate microspheres; S4: The chitosan was added to 100 ml of 1 wt% acetic acid solution, 30°C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, the sodium alginate microspheres were added, 30°C under 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze drying to get the pH responsive lipoic acid microcapsule.

[0034] Example 4 Raw material preparation: lipoic acid 18 g, L-lysine 3.6 g, TPGS 2.0 g; sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g. Medium chain triglyceride 6 g, vinyl pyrrolidone-vinyl acetate copolymer 0.7 g, L-cysteine 0.05 g.

[0035] Preparation steps: S1: 10 g of lipoic acid was mixed with medium chain triglyceride, 60°C melting, vinyl pyrrolidone-vinyl acetate copolymer was added, 500 W ultrasonic emulsification for 5 minutes, L-cysteine was added, stirred evenly, heated to 70°C under nitrogen protection for 2 hours, MWCO 1000 Da membrane, 4°C water dialysis purification for 24 hours, freeze-drying to get the sustained-release lipoic acid microparticles.

[0036] S2: Lysine was added to 100 ml of water, 500 rpm stirring for 5 minutes, TPGS was added, 45°C 800 rpm stirring for 15 minutes, 8 g of lipoic acid was added, 12000 rpm high speed shearing for 12 minutes, the sustained-release lipoic acid microparticles were added, 600 rpm stirring for 25 minutes to get the lipoic acid mixture; S3: The sodium alginate was dissolved in 80 ml of water, 40°C constant temperature water bath, 600 rpm magnetic stirring for 30 minutes, the mixture of lipoic acid was added, 600 rpm continued to stir for 20 minutes to get the sodium alginate mixture; S4: The calcium chloride was added to 200 ml of water, 800 rpm magnetic stirring for 10 minutes, slowly drop into the sodium alginate mixture, 30 minutes drop, continue to stir for 30 minutes, centrifugal to get the sodium alginate microspheres; S5: The chitosan was added to 100 ml of 1 wt% acetic acid solution, 30°C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, the sodium alginate microspheres were added, 30°C under 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze drying to get the pH responsive lipoic acid microcapsule.

[0037] Example 5 Raw material preparation: lipoic acid 18 g, L-lysine 3.6 g, TPGS 2.0 g, cross-linked povidone 2.0 g; sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g. Medium-chain triglyceride 6 g, vinylpyrrolidone-vinyl acetate copolymer 0.7 g, L-cysteine 0.05 g.

[0038] Preparation steps: S1: Mix 8 g of lipoic acid with medium-chain triglyceride, melt at 60°C, add vinylpyrrolidone-vinyl acetate copolymer, emulsify with 500W ultrasound for 5 minutes, add L-cysteine, stir evenly, heat to 70°C under nitrogen protection for 2 hours, purify with MWCO 1000 Da membrane, 4°C water dialysis for 24 hours, and freeze-dry to obtain sustained-release lipoic acid microparticles.

[0039] S2: Add lysine to 100 ml of water, stir at 500 rpm for 5 minutes, add TPGS, stir at 45°C and 800 rpm for 15 minutes, add 10 g of lipoic acid, high-speed shear at 12000 rpm for 12 minutes, add the sustained-release lipoic acid microparticles, stir at 600 rpm for 25 minutes to obtain a lipoic acid mixture; S3: Dissolve sodium alginate in 80 ml of water, stir at 600 rpm in a 40°C constant temperature water bath for 30 minutes, add the lipoic acid mixture, continue to stir at 600 rpm for 20 minutes to obtain a sodium alginate mixture; S4: Add calcium chloride to 200 ml of water, stir at 800 rpm for 10 minutes, slowly drop the sodium alginate mixture, drop for 30 minutes, continue to stir for 30 minutes, and centrifuge to obtain sodium alginate microspheres; S5: Add chitosan to 100 ml of 1 wt% acetic acid solution, stir at 800 rpm in a 30°C constant temperature water bath for 60 minutes, add the sodium alginate microspheres, stir at 500 rpm at 30°C for 90 minutes, centrifuge, wash with pure water, and freeze-dry to obtain pH-responsive lipoic acid microcapsules.

[0040] Example 6 Raw material preparation: lipoic acid 18 g, L-lysine 3.6 g, TPGS 2.0 g, cross-linked povidone 2.0 g; sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g. Medium-chain triglyceride 6 g, vinylpyrrolidone-vinyl acetate copolymer 0.7 g, L-cysteine 0.05 g.

[0041] Preparation steps: S1 : 10 g of lipoic acid was mixed with medium-chain triglyceride, melted at 60°C, and then 500W ultrasonic emulsification was performed for 5 minutes. L-cysteine was added, stirred uniformly, and then heated to 70°C under nitrogen protection for 2 hours. Purification was performed by MWCO 1000 Da membrane and water dialysis at 4°C for 24 hours. Lipoic acid microspheres were obtained by freeze-drying.

[0042] S2: Lysine was added to 100 ml of water, stirred at 500 rpm for 5 minutes, and then TPGS was added. Stirring was performed at 45°C and 800 rpm for 15 minutes. 8 g of lipoic acid and cross-linked povidone were added, and high-speed shearing was performed at 12000 rpm for 12 minutes. Lipoic acid microspheres were added, and stirring was performed at 600 rpm for 25 minutes to obtain a lipoic acid mixture; S3: Sodium alginate was dissolved in 80 ml of water in a 40°C constant-temperature water bath, and magnetic stirring was performed at 600 rpm for 30 minutes. The lipoic acid mixture was added, and stirring was continued at 600 rpm for 20 minutes to obtain a sodium alginate mixture;

[0043] Example 7 Raw material preparation: lipoic acid 18 g, L-lysine 3.6 g, TPGS 2.0 g, cross-linked povidone 1.0 g, sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g, medium-chain triglyceride 6 g, vinyl pyrrolidone-vinyl acetate copolymer 0.7 g, and L-cysteine 0.05 g.

[0044] Preparation steps: S1 : 10 g of lipoic acid was mixed with medium-chain triglyceride, melted at 60°C, and then 500W ultrasonic emulsification was performed for 5 minutes. L-cysteine was added, stirred uniformly, and then heated to 70°C under nitrogen protection for 2 hours. Purification was performed by MWCO 1000 Da membrane and water dialysis at 4°C for 24 hours. Lipoic acid microspheres were obtained by freeze-drying.

[0045] S2: Lysine was added to 100 ml of water, stirred at 500 rpm for 5 minutes, and then TPGS was added. Stirring was performed at 45°C and 800 rpm for 15 minutes. 8 g of lipoic acid and cross-linked povidone were added, and high-speed shearing was performed at 12000 rpm for 12 minutes. Lipoic acid microspheres were added, and stirring was performed at 600 rpm for 25 minutes to obtain a lipoic acid mixture;​​ S3: Dissolve sodium alginate in 80 ml water, 40°C constant temperature water bath, 600 rpm magnetic stirring for 30 minutes, add the thioctic acid mixture, continue to stir at 600 rpm for 20 minutes to get sodium alginate mixture; S4: Add calcium chloride to 200 ml water, 800 rpm magnetic stirring for 10 minutes, slowly drop into the sodium alginate mixture, drop for 30 minutes, continue to stir for 30 minutes, centrifugal to get sodium alginate microspheres; S5: Add chitosan to 100 ml 1wt% acetic acid solution, 30°C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, add sodium alginate microspheres, 30°C under 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze-drying to get pH responsive thioctic acid microcapsule.

[0046] Example 8 Raw material preparation: thioctic acid 18g, L-lysine 3.6g, TPGS 2.0g, cross-linked polyvinylpyrrolidone 3.0g; sodium alginate 3g, chitosan 2g, calcium chloride 4.0g. Medium chain triglyceride 6g, vinylpyrrolidone-vinyl acetate copolymer 0.7g, L-cysteine 0.05g.

[0047] Preparation steps: S1: Mix 10g thioctic acid with medium chain triglyceride, melt at 60°C, add vinylpyrrolidone-vinyl acetate copolymer, 500W ultrasonic emulsification for 5 minutes, add L-cysteine, stir evenly, heat to 70°C under nitrogen protection for 2 hours, MWCO 1000Da membrane, 4°C water dialysis purification for 24 hours, freeze-drying to get slow-release thioctic acid microparticles.

[0048] S2: Add lysine to 100 ml water, 500 rpm stirring for 5 minutes, add TPGS, 45°C 800 rpm stirring for 15 minutes, add 8g thioctic acid and cross-linked polyvinylpyrrolidone, 12000 rpm high speed shearing for 12 minutes, add slow-release thioctic acid microparticles, 600 rpm stirring for 25 minutes to get thioctic acid mixture; S3: Dissolve sodium alginate in 80 ml water, 40°C constant temperature water bath, 600 rpm magnetic stirring for 30 minutes, add the thioctic acid mixture, continue to stir at 600 rpm for 20 minutes to get sodium alginate mixture; S4: Add calcium chloride to 200 ml water, 800 rpm magnetic stirring for 10 minutes, slowly drop into the sodium alginate mixture, drop for 30 minutes, continue to stir for 30 minutes, centrifugal to get sodium alginate microspheres; S5: chitosan was added to 100 ml of 1 wt% acetic acid solution, 30 °C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, adding sodium alginate microspheres, 30 °C 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze-drying to get pH responsive lipoic acid microcapsules.

[0049] Example 9 Raw material preparation: lipoic acid 18 g, L-lysine 3.6 g, TPGS 2.0 g, cross-linked povidone 2.0 g; sodium alginate 3 g, chitosan 2 g, calcium chloride 4.0 g. Medium chain triglyceride 6 g, vinyl pyrrolidone-vinyl acetate copolymer 0.7 g, L-cysteine 0.05 g.

[0050] Preparation steps: S1: 10 g of lipoic acid was mixed with medium chain triglyceride, melted at 60 °C, vinyl pyrrolidone-vinyl acetate copolymer was added, and emulsified at 500 W for 5 minutes. L-cysteine was added and stirred evenly. Nitrogen protection was used to heat to 70 °C for 2 hours. The mixture was evenly divided into two parts with equal mass, and purified by dialysis in water at 10 °C for 12 hours using MWCO 2000 Da membrane, and dialysis in water at 4 °C for 36 hours using MWCO 500 Da membrane. Freeze-drying and mixing evenly obtained mixed sustained-release lipoic acid microparticles.

[0051] S2: Lysine was added to 100 ml of water and stirred at 500 rpm for 5 minutes. TPGS was added and stirred at 45 °C and 800 rpm for 15 minutes. 8 g of lipoic acid and cross-linked povidone were added and sheared at high speed for 12 minutes. The sustained-release lipoic acid microparticles were added and stirred at 600 rpm for 25 minutes to obtain a lipoic acid mixture. S3: Sodium alginate was dissolved in 80 ml of water in a 40 °C constant temperature water bath, and stirred at 600 rpm for 30 minutes. The lipoic acid mixture was added and stirred at 600 rpm for 20 minutes to obtain a sodium alginate mixture. S4: Calcium chloride was added to 200 ml of water and stirred at 800 rpm for 10 minutes. The sodium alginate mixture was slowly added dropwise, and the stirring was continued for 30 minutes. Centrifugation obtained sodium alginate microspheres. S5: Chitosan was added to 100 ml of 1 wt% acetic acid solution, 30 °C constant temperature water bath, 800 rpm magnetic stirring for 60 minutes, adding sodium alginate microspheres, 30 °C 500 rpm magnetic stirring for 90 minutes, centrifugal, pure water washing, freeze-drying to get pH responsive lipoic acid microcapsules.

[0052] Comparative example Comparative example 1 Raw material preparation: lipoic acid 18 g; sodium alginate 3 g, chitosan 2 g.

[0053] Preparation steps: S1: lipoic acid was added to 100 ml of water, and high-speed shearing was performed at 12000 rpm for 12 minutes to obtain a lipoic acid mixture; S2: sodium alginate was dissolved in 80 ml of water in a 40°C constant-temperature water bath, and magnetic stirring was performed at 600 rpm for 30 minutes, and then the lipoic acid mixture was added, and stirring was continued at 600 rpm for 20 minutes to obtain a sodium alginate mixture; S3: chitosan was added to 100 ml of 1 wt% acetic acid solution in a 30°C constant-temperature water bath, and magnetic stirring was performed at 800 rpm for 60 minutes, and then the sodium alginate mixture was slowly added dropwise, and the dropping was completed in 30 minutes, and then magnetic stirring was performed at 500 rpm for 90 minutes at 30°C, and then centrifugation, pure water washing, and freeze-drying were performed to obtain pH-responsive lipoic acid microcapsules.

[0054] Performance detection test I. The prepared samples were respectively added to freshly prepared 100 mL artificial gastric juice (pH = 1.2) and artificial small intestinal juice (pH = 6.8), and reaction was performed in a constant-temperature water bath shaker at 37°C ± 1°C and 60 rpm, 1 mL of simulated gastric juice / small intestinal juice was taken out every 2 hours, 1 mL of simulated gastric juice / small intestinal juice was supplemented at the same time, the lipoic acid content in the simulated gastric juice / small intestinal juice was measured, and the cumulative release rate was calculated. Release rate (%) = released lipoic acid mass / (added microcapsule weight x drug loading).

[0055] The results are summarized in Table 1.

[0056] Table 1 It can be seen from Examples 1-3 and Comparative Example 1 in combination with Table 1 that, by embedding lipoic acid and a certain mass ratio of lysine in sodium alginate, chitosan, and calcium chloride, the prepared pH-responsive lipoic acid microcapsules are stably embedded in gastric juice and stably released in intestinal juice, and the absorption effect of patients is better.

[0057] It can be seen from Examples 2, 4-5 in combination with Table 1 that, by adding a certain mass of slow-release lipoic acid microparticles and limiting the mass ratio of lipoic acid in the microparticles and the lipoic acid mixture, the release is more stable.

[0058] It can be seen from Examples 4, 6-8 in combination with Table 1 that, by adding a certain mass of cross-linked povidone and limiting the mass ratio, the release of lipoic acid is more sufficient, and the bioavailability is better.

[0059] It can be seen from Examples 6, 9 in combination with Table 1 that, by limiting the preparation process parameters of the slow-release lipoic acid microparticles, the release of lipoic acid is more sufficient, and the bioavailability is better.

[0060] The embodiments are only illustrative of the present application, and are not intended to limit the present application, and those skilled in the art can make modifications to the embodiments without creative contribution after reading the specification, but as long as the modifications are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A method for preparing pH-responsive lipoic acid microcapsules, characterized in that, Includes the following steps: S1: Add lipoic acid and lysine to a solvent, disperse evenly, and heat and stir to obtain a lipoic acid mixture; S2: Dissolve sodium alginate in water, add lipoic acid mixture, stir well, add chitosan solution, centrifuge, wash and freeze dry to obtain pH-responsive lipoic acid microcapsules.

2. The method for preparing pH-responsive lipoic acid microcapsules according to claim 1, characterized in that, The lipoic acid mixture also contains slow-release lipoic acid microparticles. The preparation steps of the slow-release lipoic acid microparticles include: mixing lipoic acid with medium-chain triglycerides, heating and melting, adding vinylpyrrolidone-vinyl acetate copolymer to dissolve, ultrasonic emulsifying, adding L-cysteine, heating and reacting under nitrogen protection, dialysis purification, and freeze-drying to obtain slow-release lipoic acid microparticles.

3. The method for preparing pH-responsive lipoic acid microcapsules according to claim 2, characterized in that, The pH-responsive lipoic acid microcapsules comprise the following raw materials in parts by weight: 10-30 parts lipoic acid, 1.0-4.5 parts L-lysine, 0.5-3.0 parts TPGS; 2-8 parts sodium alginate, 1-5 parts chitosan, 1.5-4.5 parts calcium chloride, 5-8 parts medium-chain triglycerides, 0.5-1.0 parts vinylpyrrolidone-vinyl acetate copolymer, and 0.03-0.08 parts L-cysteine.

4. The method for preparing pH-responsive lipoic acid microcapsules according to claim 2, characterized in that, The mass ratio of lipoic acid in the lipoic acid mixture to that in the slow-release lipoic acid microparticles is 1:(1-2).

5. The method for preparing pH-responsive lipoic acid microcapsules according to claim 2, characterized in that, Cross-linked polyvinyl ketone was also added to the thioctic acid mixture.

6. The method for preparing pH-responsive lipoic acid microcapsules according to claim 5, characterized in that, The mass ratio of calcium chloride to crosslinked polyvinyl chloride is 2:(1.0-1.3).

7. The method for preparing pH-responsive lipoic acid microcapsules according to claim 2, characterized in that, The dialysis purification process uses an MWCO 500-2000Da membrane and dialysis at 4-10℃ for 12-36 hours.

8. The method for preparing pH-responsive lipoic acid microcapsules according to claim 2, characterized in that, The sustained-release lipoic acid microparticles include 2000Da membrane sustained-release microparticles and 500Da membrane sustained-release microparticles in a mass ratio of 1:(0.5-1.5). The 2000Da membrane sustained-release microparticles are made of MWCO 2000Da membrane and are dialyzed at 10°C for 10-12 hours. The 500Da membrane sustained-release microparticles are made of MWCO 500Da membrane and are dialyzed at 4°C for 32-36 hours.

9. The method for preparing pH-responsive lipoic acid microcapsules according to claim 1, characterized in that, The mass ratio of lipoic acid to lysine in the lipoic acid mixture is 1:(0.1-0.3); the mass ratio of chitosan to sodium alginate is 1:(1.3-1.7).

10. A pH-responsive lipoic acid microcapsule, characterized in that, The lipoic acid microcapsules were prepared using any one of the preparation methods of claims 1-9.

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