A drug for lowering blood sugar and / or treating diabetic complications

Abstract

The present invention discloses a drug for lowering blood sugar and / or ameliorating diabetic complications, belonging to the field of biomedicine. The drug for lowering blood sugar and / or ameliorating diabetic complications of the present invention comprises nanoparticles formed from lipoic acid and / or lipoic acid derivatives. These lipoic acid nanoparticles provide safe and long-term blood sugar control while simultaneously preventing / treating diabetic complications through the dual effects of lowering blood sugar and inhibiting oxidative stress, demonstrating promising clinical prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and in particular relates to a medicine for treating diabetes and its complications. Technical Background

[0002] Diabetes is a metabolic disorder characterized by hyperglycemia, affecting 425 million people worldwide. Glucose-lowering drugs such as metformin and acarbose are currently routinely used in the treatment of diabetic patients. However, diabetic patients often suffer from complications such as cardiovascular disease, obesity, kidney disease, eye disease, and peripheral neuropathy. These drugs, which simply lower blood sugar levels, are ineffective against these complications, and the condition of diabetic patients with these complications can worsen. Consequently, the development of glucose-lowering drugs with the potential to improve these complications is a clinical trend.

[0003] Currently, the main glucose-lowering drugs with the above characteristics in clinical practice are glucagon-like peptide 1 agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), which have shown some improvement in reducing the risk of cardiovascular and end-stage renal disease mortality. Unfortunately, the range of indications for these drugs is narrow, and whether they can effectively treat complications requires further clinical research. In addition, GLP-1RAs require daily subcutaneous injections, which have poor patient compliance, and long-term use can exacerbate the condition of patients with diabetic retinopathy. SGLT2i are prone to urinary and reproductive tract infections and have a high incidence of gastrointestinal events. Therefore, glucose-lowering drugs with the characteristics of improving diabetic complications are far from meeting clinical needs. Summary of the Invention

[0004] To address these issues, the present invention provides a novel drug for lowering blood sugar and / or ameliorating diabetic complications. This drug, primarily composed of nanoparticles formed from lipoic acid and / or lipoic acid derivatives, offers safe and long-term blood sugar control while effectively preventing or alleviating diabetic complications, demonstrating promising clinical application prospects.

[0005] The present invention includes the following technical solutions:

[0006] A lipoic acid nanoparticle with the function of lowering blood sugar and / or improving diabetic complications is provided. The lipoic acid nanoparticle is formed from a component containing lipoic acid and / or a lipoic acid derivative. The formation process may include various modifications or modifications to the nanoparticle. The lipoic acid derivative includes lipoic acid salt or a pharmaceutically acceptable modified product obtained by non-substantial modification of lipoic acid that does not affect its core function (including but not limited to grafting functional groups onto the lipoic acid molecule).

[0007] As an option, in the above lipoic acid nanoparticles, the lipoic acid and / or lipoic acid derivatives are cross-linked and polymerized via disulfide bonds.

[0008] As an alternative, in the above-mentioned lipoic acid nanoparticles, the nanoparticles can be formed by loading liposomes or polymers.

[0009] Alternatively, in the above-mentioned lipoic acid nanoparticles, the nanoparticles may be modified with polyethylene glycol.

[0010] Alternatively, the lipoic acid nanoparticles are formed by cross-linking small molecule lipoic acid monomers and / or lipoic acid derivatives via disulfide bonds. This allows for stable cross-linking without the need for additional cross-linking molecules, resulting in a single, controllable drug component. The cross-linked nanoparticles are structurally stable, facilitating long-term circulation in the blood.

[0011] As an option, in the above-mentioned lipoic acid nanoparticles, the hydrophilic group is outside the nanoparticles and the hydrophobic group is inside the nanoparticles, so that the lipoic acid nanoparticles can be dissolved in water without any cosolvent, and the solubility is much higher than that of lipoic acid monomer.

[0012] As an optional method, in the above-mentioned lipoic acid nanoparticles, the particle size of the lipoic acid nanoparticles is 10-300nm, which is much larger than the critical particle size for penetrating the capillary wall. Therefore, the lipoic acid nanoparticles can circulate in the body with the blood to the nerve tissues throughout the body, greatly prolonging the retention time in the body, allowing insulin-sensitive response and diabetic complication diseased tissues to effectively absorb lipoic acid, thereby improving the therapeutic effect.

[0013] As an optional embodiment, in the above-mentioned lipoic acid nanoparticles, the surface potential of the lipoic acid nanoparticles is negative. The negative surface potential is beneficial to improving the stability of the lipoic acid nanoparticles in blood.

[0014] As an optional embodiment, in the above-mentioned lipoic acid nanoparticles, the surface potential of the lipoic acid nanoparticles is -100 mV to 0 mV.

[0015] The present invention also provides a method for preparing the lipoic acid nanoparticles, which comprises: cross-linking and polymerizing the disulfide bonds of lipoic acid monomers and / or lipoic acid derivatives to form lipoic acid nanoparticles through disulfide bond cross-linking polymerization.

[0016] As an optional manner, in the above-mentioned method for preparing lipoic acid nanoparticles, the uniform mixing method may be: ultrasonic oscillation mixing, vortex oscillation mixing, manual shaking mixing, preferably ultrasonic oscillation mixing.

[0017] As an optional manner, in the above-mentioned method for preparing lipoic acid nanoparticles, the method for breaking the disulfide bond of lipoic acid can be ultraviolet light breaking, ultrasonic breaking, thermal breaking, or mechanical stress breaking.

[0018] As an optional manner, in the above-mentioned method for preparing lipoic acid nanoparticles, the cross-linking polymerization method can be oxygen flow, mechanical stress, or catalysis.

[0019] The present invention also discloses an application of the lipoic acid nanoparticles, characterized in that the lipoic acid nanoparticles are used to prepare a drug for lowering blood sugar and / or improving diabetic complications. Alternatively, in the application, the lipoic acid nanoparticles are prepared into an injection, capsule, tablet, pill, or oral solution.

[0020] As an option, in the above application, the lipoic acid nanoparticles have good water solubility.

[0021] Alternatively, in the above application, lipoic acid nanoparticles are used in combination with other active ingredients.

[0022] As an optional manner, in the above application, the drug for improving diabetic complications achieves improvement of diabetic complications by the dual effects of lowering blood sugar and inhibiting oxidative stress.

[0023] As an option, in the above application, the complications of diabetes include one or more of diabetic nephropathy, diabetic eye disease, diabetic foot, diabetic cardiovascular disease, diabetic cerebrovascular disease and diabetic peripheral neuropathy.

[0024] The present invention also discloses a medicine for lowering blood sugar and / or improving diabetic complications, which is characterized by containing lipoic acid nanoparticles.

[0025] Alternatively, the aforementioned drug for lowering blood sugar and / or ameliorating diabetic complications may also contain other active ingredients. Furthermore, the other active ingredients may be other hypoglycemic drugs or other drugs that have the function of ameliorating diabetic complications, or other substances that can promote the efficacy of the drug for lowering blood sugar and / or ameliorating diabetic complications.

[0026] All features disclosed in this specification, or all steps in the disclosed methods or processes, except mutually exclusive features and / or steps, can be combined in any manner.

[0027] Beneficial effects of the present invention:

[0028] The nanomedicine described in this invention exhibits long-lasting and highly effective blood sugar-lowering efficacy, with the effect and duration, respectively, being 1.53 times and 3 times greater than those of metformin, a first-line clinical hypoglycemic drug. Furthermore, the nanomedicine overcomes the drawbacks of existing hypoglycemic drugs, which lack efficacy against complications, demonstrating excellent therapeutic effects on a wide range of diabetic complications and promising clinical prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Schematic diagram of lipoic acid nanoparticles for the treatment of diabetes and its complications;

[0030] Figure 2 is the hydrated particle size of lipoic acid nanoparticles after cross-linking;

[0031] Figure 3 Zeta potential of cross-linked stabilized lipoic acid nanoparticles;

[0032] Figure 4 To determine the dilution stability of cross-linked lipoic acid nanoparticles;

[0033] Figure 5 To determine the serum stability of cross-linked lipoic acid nanoparticles;

[0034] Figure 6 The changes of blood glucose, insulin content and insulin resistance index in each group of experimental diabetic mice;

[0035] Figure 7 Figure 2 shows the changes in blood glucose in experimental diabetic nephropathy mice in each group;

[0036] Figure 8 The urine protein / creatinine ratio, serum CRE, renal HE, PAS and podocyte pathological changes of experimental diabetic nephropathy mice in each group;

[0037] Figure 9 The changes of MDA content, SOD activity and gene transcription levels of inflammatory factors TNF-α, IL-6 and IL-1β in kidney tissues of experimental diabetic nephropathy mice in each group;

[0038] Figure 10 The changes in thermal pain thresholds of experimental diabetic peripheral neuropathy mice in each group;

[0039] Figure 11 The changes in mechanical thresholds of mice with experimental diabetic peripheral neuropathy in each group;

[0040] Figure 12 The Na levels in erythrocytes (a) and sciatic nerves (b) of mice with experimental diabetic peripheral neuropathy in each group + -K + -Changes in ATPase activity;

[0041] Figure 13 The changes of MDA and GSH contents and SOD activity in the sciatic nerve of mice with experimental diabetic peripheral neuropathy in each group;

[0042] Figure 14 The changes of TNF-α, IL-6 and IL-1β levels in the sciatic nerve of mice with experimental diabetic peripheral neuropathy in each group;

[0043] Figure 15 The changes in the morphological structure of the sciatic nerve in each group of mice with experimental diabetic peripheral neuropathy. DETAILED DESCRIPTION

[0044] The following further details the above content of the present invention through the specific implementation of the examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. Any modifications made without departing from the spirit and principles of the present invention, as well as equivalent substitutions or improvements made based on common technical knowledge and customary means in the art, are intended to be included within the scope of protection of the present invention.

[0045] Example 1

[0046] 1. Preparation of Lipoic Acid Nanovesicles

[0047] 210 mg of lipoic acid (LA) and 43.5 mg of the template molecule 1,4,7-triazanonane were dissolved in 3.5 mL of dimethyl sulfoxide (DMSO) and shaken for 4 hours to form a supra-amphiphile solution. This supra-amphiphile solution was then slowly added dropwise to 300 mL of deionized water under ultrasonication to form a stock solution of LA-1,4,7-triazanonane-constructed LA nanovesicles. The stock solution was irradiated with 365 nm UV light for 4 hours to induce disulfide self-crosslinking of LA. The pH was adjusted to approximately 9.0 with NaOH, and the solution was extracted three times with dichloromethane to remove 1,4,7-triazanonane. The supernatant was then neutralized with dilute HCl and dialyzed against deionized water for 48 hours (spectrum / pore, MWCO 2000) to prepare cross-linked LA nanovesicles.

[0048] Size and potential detection of cross-linked lipoic acid nanoparticles:

[0049] 2 mL of the cross-linked lipoic acid nanoparticles prepared above were placed in a 3.5 mL standard quartz dish and their size and zeta potential were measured using a dynamic light scattering (DLS) instrument. The results showed that the particle size of the cross-linked lipoic acid nanoparticles was about 130 nm and the zeta potential was -12.2 mV. Figure 2 and Figure 3 .

[0050] Stability testing of cross-linked lipoic acid nanoparticles:

[0051] (1) Dilution stability: The cross-linked lipoic acid nanoparticle solution prepared above was diluted with RO water to 2000 / 1000 / 500 / 250 / 125 / 63 / 32 / 16 / 8 μM (expressed as LA concentration), and the particle size of the lipoic acid nanoparticles after each dilution was measured. The results are as follows: Figure 4 As shown in the figure, even when the lipoic acid nanoparticle solution was diluted to 8 μM, its size remained close to the initial size, indicating that the prepared cross-linked lipoic acid nanoparticles have good dilution stability. (2) Serum stability: 4.5 mL of the above cross-linked lipoic acid nanoparticles were incubated with 0.5 mL of fetal bovine serum, and the particle size of the nanoparticles was measured at different time points. The results are shown in the figure. Figure 5 As shown, the cross-linked lipoic acid nanoparticles did not significantly change in size during the 12-hour serum incubation, indicating that the prepared cross-linked lipoic acid nanoparticles have excellent serum stability. The above results show that the lipoic acid nanoparticles prepared by the method of the present invention have good stability, are conducive to long-term storage, allow for large-scale production, and reduce synthesis costs.

[0052] Example 2

[0053] Preparation of lipoic acid nanomicelles

[0054] 300 mg of LA was added to 150 mL of deionized water. A 1 M aqueous NaOH solution was added dropwise with stirring until the LA was completely dissolved. The LA solution was then titrated to neutrality with a 1 M HCl solution. The solution was freeze-dried to obtain sodium lipoate powder. 41.2 mg of sodium lipoate was weighed and dissolved in 1 mL of deionized water. Ultrasonic emulsification was used to form lipoic acid nanoparticles. The resulting nanoparticles were irradiated with 365 nm ultraviolet light to induce self-crosslinking of lipoic acid disulfide bonds. The reaction was continued for 2.5 hours. After dialysis for 48 hours, cross-linked lipoic acid nanomicelles with a size of approximately 15 nm and a zeta potential of approximately -33 mV were obtained.

[0055] Example 3

[0056] Preparation of lipoic acid nanoaggregates

[0057] 41.2 mg of lipoic acid was dissolved in 1 mL of N,N-dimethylformamide (DMF) and shaken on an oscillator for 2 hours to obtain a 0.2 M lipoic acid stock solution. 50 μL of this stock solution was added to 5 mL of deionized water under ultrasonic conditions to produce lipoic acid nanoparticles. The resulting nanoparticles were irradiated with 365 nm UV light to induce self-crosslinking of lipoic acid disulfide bonds. The reaction was continued for 2.5 hours. After dialysis for 48 hours, cross-linked lipoic acid aggregates with a size of approximately 80 nm and a zeta potential of approximately -30 mV were obtained.

[0058] Example 4

[0059] In this example, db / db mice were used as a type 2 diabetes model to evaluate the efficacy of lipoic acid nanoparticles on diabetes and compared with LA monomer and metformin hydrochloride, a first-line clinical hypoglycemic drug.

[0060] The lipoic acid nanoparticles prepared in Example 1 were dispersed in physiological saline to prepare a 10 mg / mL solution, which was then administered to mice by gavage at a dose of 100 mg / kg.

[0061] 1. Experimental Materials and Methods

[0062] S1. Instruments and reagents:

[0063] Blood glucose monitor, Sinocare Biosensing Co., Ltd.;

[0064] Insulin (Insulin), Shanghai Beyotime Biotechnology Co., Ltd.;

[0065] Mouse insulin ELISA detection kit, Jiangsu Jingmei Biotechnology Co., Ltd.;

[0066] S2. Experimental Materials and Animal Treatment

[0067] Eight-week-old male C57BL / KsJ db / db mice, SPF grade, were provided by Jiangsu Jicui Yaokang Biotechnology Co., Ltd., Changzhou Branch, with a certificate number of 202012449. Initial weight was 44 ± 2 g. After one week of adaptive feeding, 24 C57BL / KsJ db / db mice were randomly divided into four groups (n=6) based on body weight and blood glucose: the db / db model group, the db / db + lipoic acid nanoparticle group (100 mg / kg), the db / db + lipoic acid monomer group (100 mg / kg), and the db / db + metformin group (120 mg / kg). Six w / w male mice from the same littermate served as the vehicle control group. Different doses of drugs were administered orally at a volume of 10 ml / kg: lipoic acid monomer and metformin were administered once daily, and the lipoic acid nanoparticle group was administered every three days for one month. The vehicle control and model groups were given an equal volume of normal saline by gavage. After a single dose, the blood glucose level of the mice was continuously monitored for 3 days. During the 1-month treatment cycle, the blood glucose level of the mice was tested every 3 days. 2 hours after the end of the 30th day of administration, the blood glucose level of the mice was tested, and the blood glucose level difference between the model and normal control groups was used as the base to calculate the percentage of blood glucose reduction by the drug. The mice were killed by enucleation and bleeding, and serum samples were collected by centrifugation at room temperature. The serum insulin level was tested using a mouse insulin ELISA kit, and the insulin resistance index was calculated. The difference between the model and normal control groups was used as the base to calculate the percentage of serum insulin level and insulin resistance index reduced by the drug.

[0068] S3. Statistical methods

[0069] The quantitative experimental results are expressed as mean ± variance SPSS version 19.0 Statistical Software (Chicago, IL, USA) was used to compare differences among the groups using one-way analysis of variance. Pairwise comparisons between groups were performed using the Turkey post hoc method when P < 0.05, and differences were considered statistically significant.

[0070] 2. Experimental results

[0071] S1. Effects of lipoic acid nanoparticles on blood glucose in experimental diabetic mice

[0072] To investigate the therapeutic effects of lipoic acid nanoparticles on type 2 diabetes, we administered lipoic acid monomers (100 mg / kg), lipoic acid nanoparticles (100 mg / kg), and metformin (120 mg / kg) to db / db mice via oral gavage. W / w mice were gavaged with the solvent as a control. Continuous blood glucose monitoring after a single dose showed no significant difference in blood glucose levels between the LA monomer group and the model group (p>0.05). The metformin group only exhibited a hypoglycemic effect within 24 hours (p<0.05), while the lipoic acid nanoparticle group maintained a hypoglycemic effect for up to 72 hours, with the lowest blood glucose level reaching 8.4 mmol / L, a 21.50% decrease compared to the lowest blood glucose level observed with metformin. Figure 6 A) Experimental results show that lipoic acid nanoparticles can effectively and long-term reduce blood glucose levels in diabetic mice.

[0073] During the one-month treatment period, blood sugar test results were as follows: Figure 6 B. The blood glucose level of the LA monomer treatment group remained close to the initial blood glucose level of diabetic mice, with no hypoglycemic effect (p>0.05). Although the metformin group could reduce blood glucose by 50.28% (p<0.05), it required daily administration. However, when lipoic acid nanoparticles were administered once every three days, the blood glucose level of mice was reduced by 76.84% (p<0.01), which was 1.53 times that of the metformin treatment group, indicating that it has a significantly better hypoglycemic effect than the first-line clinical drugs. * P<0.05); significant differences among the lipoic acid monomer group, lipoic acid nanoparticle group and db / db mouse group ( # P<0.05, ## P<0.01); significant differences among the lipoic acid nanoparticle group, lipoic acid monomer group and metformin group ( & P<0.05).

[0074] Effects of S2 and lipoic acid nanoparticles on serum insulin content and sensitivity in diabetic mice

[0075] Serum insulin content detection and insulin resistance index analysis Figure 6 As shown in C and D, the serum insulin levels and insulin resistance index of mice in the db / db model group were significantly higher than those in the w / w control group (p < 0.05), indicating severe insulin resistance in diabetic mice. Compared with the diabetic group, the serum insulin levels and insulin resistance index of the LA monomer group were not significantly different from those in the model group (p > 0.05). Metformin, a clinical antidiabetic drug that lowers blood glucose by increasing peripheral tissue sensitivity to insulin, reduced serum insulin levels by 34.69% (p < 0.05) and the insulin resistance index by 53.68% (p < 0.05) in diabetic mice after treatment. Notably, treatment with lipoic acid nanoparticles reduced serum insulin levels by 73.47% (p < 0.01) and the insulin resistance index by 79.84% (p < 0.01), representing 2.1 and 1.5 times the effects of metformin, respectively (p < 0.05). These results demonstrate that lipoic acid nanoparticles have a more potent insulin-sensitizing effect than first-line clinical drugs. The significant difference analysis between metformin group (120mg / kg), lipoic acid nanoparticle group (100mg / kg) and db / db mice group ( * P<0.05, ** P<0.01, # P<0.05, ## P<0.01).

[0076] In the above examples, the vesicles were replaced with micelles and aggregates, respectively, and similar experimental results were obtained, indicating that the various forms of lipoic acid nanoparticles prepared by the present invention all have the effect of long-term and high-efficiency lowering of blood sugar levels.

[0077] Example 5

[0078] Experiment 1:

[0079] 10 mL of the lipoic acid nanovesicle aqueous solution (10 mg / mL) prepared in Example 1 was taken, 8.3 mg of metformin hydrochloride was added thereto, and the mixture was mixed to obtain a lipoic acid nanoparticle / metformin physical mixture.

[0080] The method for preparing vesicles was referred to as described in Example 1, except that deionized water was replaced with an aqueous solution containing 25.0 mg of metformin hydrochloride to prepare metformin hydrochloride-loaded lipoic acid nanovesicles. Referring to the method described in Example 4, the therapeutic effects of the physical mixture described in this example and the lipoic acid nanovesicles loaded with metformin hydrochloride on diabetes were verified respectively. The results showed that after physical mixing, the hypoglycemic effect was stronger than that of metformin hydrochloride and lipoic acid nanoparticles alone; after treatment with metformin hydrochloride loaded with lipoic acid nanoparticles, the therapeutic effect was further increased compared to the physical mixing method, while reducing the dosage of the active ingredient, the therapeutic effect was synergistically enhanced.

[0081] Experiment 2:

[0082] The method described in Experiment 1 of this example was used, except that metformin hydrochloride was replaced with acarbose. The method described in Example 4 was used to verify the therapeutic efficacy of acarbose-loaded lipoic acid nanovesicles for diabetes. The results showed that acarbose-loaded lipoic acid nanoparticles exhibited significantly enhanced therapeutic efficacy compared to acarbose or lipoic acid nanoparticles alone, generally consistent with the conclusions of Experiment 1.

[0083] Take 10mL of the lipoic acid nano-aggregate aqueous solution (10mg / mL) prepared in Example 3, add 25mg of pioglitazone thereto, fully mix under ultrasonic conditions and dialyze for 48h to prepare the lipoic acid nano-aggregate loaded with pioglitazone. With reference to the method described in Example 4, verify the therapeutic effect of the lipoic acid nano-aggregate loaded with pioglitazone on diabetes. The result shows: after the lipoic acid nano-aggregate is loaded with pioglitazone, the therapeutic effect is significantly enhanced compared with independent pioglitazone and lipoic acid nanoparticles, which is basically consistent with the experimental conclusion of Experiment 1.

[0084] Example 6

[0085] In this example, db / db mice were used as a diabetic nephropathy model to evaluate the therapeutic effect of the lipoic acid nanoparticles prepared in Example 1 on diabetic nephropathy mice, and the results were compared with those of LA monomers.

[0086] 1. Experimental Materials and Methods

[0087] S1. Instruments and reagents:

[0088] Blood glucose monitor, Sinocare Biosensing Co., Ltd.;

[0089] Mouse albumin ELISA kit, Shanghai Tongwei Industrial Co., Ltd.;

[0090] Creatinine (CRE) assay kit, Nanjing Jiancheng Bioengineering Institute;

[0091] Urea nitrogen (BUN) test kit, Nanjing Jiancheng Bioengineering Institute;

[0092] Malondialdehyde (MDA) assay kit, Nanjing Jiancheng Bioengineering Institute;

[0093] Superoxide dismutase (SOD) test kit, Beijing Solebow Technology Co., Ltd.;

[0094] RNApure high-purity total RNA rapid extraction kit (spin column type), Beijing Biotech Biotechnology Co., Ltd.;

[0095] cDNA synthesis kit, Shanghai Biotech Biotechnology Co., Ltd.;

[0096] RT-PCR kit, Beijing Solebow Technology Co., Ltd.;

[0097] S2. Experimental Materials and Animal Treatment

[0098] Ten-week-old male C57BL / KsJ db / db mice, SPF grade, were provided by Jiangsu Jicui Yaokang Biotechnology Co., Ltd., Changzhou Branch, with a certificate number of 202012449. Initial weight was 44 ± 2 g, and they were acclimated for two weeks. They were randomly divided into three groups based on body weight and blood glucose: a db / db model group, a db / db + lipoic acid nanoparticle group (30 mg / kg), and a db / db + lipoic acid monomer group (30 mg / kg). Six w / w male mice of the same age and littermate served as the vehicle control group. Different doses of the drug were administered intraperitoneally at a volume of 10 mL / kg once daily for four consecutive weeks. The control and model groups received an equal volume of normal saline intraperitoneally. During the treatment period, blood glucose levels were measured every three days. The difference in blood glucose between the model and normal control groups was used as the basis for calculating the percentage of blood glucose reduction achieved by the drug to determine the drug's hypoglycemic effect. Two hours after administration at the end of the fourth week, the blood glucose levels of the experimental animals were tested, and the mice were killed by enucleation and bleeding. Blood samples were collected and centrifuged at 3000 rpm at room temperature for 15 minutes to separate serum samples. The levels of creatinine (CER) and urea nitrogen (BUN) in the mouse serum were measured according to the instructions of the creatinine (CER) and urea nitrogen (BUN) kits. At the same time, urine samples were collected from mice in metabolic cages, and the albumin content in the urine was detected by enzyme-linked immunosorbent assay (ELISA), and the urine protein / creatinine ratio (UACR) was calculated. The mouse kidneys were dissected in the sagittal plane, and 1 / 4 of the tissue was fixed with 4% paraformaldehyde, dehydrated, transparent, paraffin-embedded, and sectioned. Hematoxylin-eosin (HE) staining was used to observe changes in glomerular morphology and structure, and PAS staining (PAS) was used to detect glomerular glycogen deposition. Another 30 mg of tissue was collected to extract total RNA for the detection of gene transcription levels of inflammatory factors TNF-α, IL-6, and IL-1β. The remaining kidney tissue was homogenized at low temperature, and the malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in the tissue were detected according to the instructions of the MDA and SOD kits.

[0099] S3. Statistical methods

[0100] The quantitative experimental results are expressed as mean ± variance SPSS version 19.0 Statistical Software (Chicago, IL, USA) was used to compare differences among the groups using one-way analysis of variance. Pairwise comparisons between groups were performed using the Turkey post hoc method when P < 0.05, and differences were considered statistically significant.

[0101] 2. Experimental results

[0102] S1. Effects of lipoic acid nanoparticles on blood glucose in experimental diabetic mice

[0103] Blood sugar test results Figure 7 As shown in the results, after treatment with LA monomer, the blood glucose level in the diabetic mice was only stabilized near the initial blood glucose level, with no hypoglycemic effect (p>0.05); whereas the same dose of lipoic acid nanoparticles effectively reduced blood glucose levels by 59.64% (p<0.01). The above results demonstrate the beneficial effects of lipoic acid nanoparticles in improving glucose metabolism in diabetic nephropathy. * P<0.05); significant differences among the lipoic acid monomer group, lipoic acid nanoparticle group and db / db mouse group ( # P<0.05, ## P<0.01); significant difference analysis between lipoic acid nanoparticle group and lipoic acid monomer group ( & P<0.05).

[0104] S2. Effects of lipoic acid nanoparticles on UACR, CRE, and BUN levels and renal tissue lesions in experimental diabetic mice

[0105] The experimental results showed that compared with the model group, the serum CRE in the LA monomer group decreased by 21.05% (p<0.05), the BUN content decreased by 25.45% (p<0.05), and the UACR level decreased by 24.75% (p<0.05), indicating that LA monomer has a certain improvement effect on diabetic renal injury. Compared with the model group, the serum CRE content in the lipoic acid nanoparticle group decreased by 52.63% (p<0.01), the BUN content decreased by 50.91% (p<0.01), and the UACR level decreased by 71.25% (p<0.05) ( Figure 8AC), which were 2.5, 2.0, and 3.3 times that of the same dose of LA monomer, respectively. In addition, the pathological examination results are shown in Figures (8D, E). The glomerular structure of the w / w control group mice was clear, the basement membrane was normal, and a small amount of glycogen deposition was visible in the glomeruli. However, the glomeruli of the db / db model group mice were hypertrophic, the basement membrane was significantly thickened, a large amount of glycogen deposition was observed in the glomeruli, and the foot processes of the podocytes were partially disappeared, indicating that the model group had severe glomerular damage. Compared with the db / db model group, the glomeruli in the LA monomer group were 25.50% smaller (p<0.05), and the basement membrane thickness was reduced by 6.57% ( In the lipoic acid nanoparticle group, the glomerulus shrank by 64.41% (p<0.01), the basement membrane thickness decreased by 18.27% (p<0.01), and the number of foot processes increased by 64.17% (p<0.01). The therapeutic effects were 2.5, 2.8, and 6.3 times that of the same dose of LA monomer, respectively (p<0.05), indicating that lipoic acid nanoparticles have an excellent therapeutic effect on diabetic renal damage. Analysis of significant differences among the control group, lipoic acid monomer group, lipoic acid nanoparticle group, and db / db mouse group ( * P<0.05, # P<0.05, ## P<0.01); significant difference analysis between lipoic acid nanoparticle group and lipoic acid monomer group ( & P<0.05).

[0106] Effects of S3 and lipoic acid nanoparticles on the levels of MDA, SOD, and gene transcription of inflammatory factors TNF-α, IL-6, and IL-1β in the kidney tissue of experimental diabetic mice

[0107] The improvement effect of diabetic renal oxidative damage was evaluated by measuring the MDA content and SOD activity in the renal tissue. The experimental results showed that compared with the control group mice, the increased MDA and decreased SOD activity levels in the kidneys of diabetic mice indicated that the model mice had oxidative stress damage in the kidneys. In addition, a significant increase in the transcription levels of inflammatory cytokine genes, including TNF-α, IL-1β and IL-6, was observed in the renal tissues of diabetic mice. After 4 weeks of treatment with lipoic acid monomers, the MDA content decreased by 9.8% (p<0.05) and the SOD activity increased by 55% (p<0.05), indicating that it has a certain improvement effect on renal oxidative stress damage. After treatment with lipoic acid nanoparticles, the MDA content in the renal tissue was significantly reduced by 46.34% (p<0.05), and the SOD activity increased by 76.92% (p<0.05) ( Figure 9A, B), which were 4.7 and 1.4 times that of the same dose of LA monomer, respectively (p < 0.05); in terms of inhibiting inflammatory response, the transcription levels of TNF-α, IL-1β and IL-6 in the lipoic acid monomer group were reduced by 22.5%, 18.18% and 23.33%, respectively (p < 0.05), while the transcription levels of the corresponding genes in the lipoic acid nanoparticle group were reduced by 60%, 52.27% and 56.67%, respectively (p < 0.01), which were 2.7, 2.9 and 2.4 times that of the same dose of LA, respectively (p < 0.05) ( Figure 9 CE). The above results show that lipoic acid nanoparticles have an excellent therapeutic effect on oxidative stress and inflammatory damage in the kidneys of diabetic mice. Analysis of significant differences among the control group, lipoic acid monomer group, lipoic acid nanoparticle group and db / db mouse group ( * P<0.05, # P<0.05, ## P<0.01); significant difference analysis between lipoic acid nanoparticle group and lipoic acid monomer group ( & P<0.05).

[0108] Example 7

[0109] Weigh 21.0 mg of irbesartan, a drug for treating diabetic nephropathy, and add it to an aqueous solution of lipoic acid nanovesicles prepared in Example 1 containing 100.0 mg. After thorough mixing under ultrasonic conditions, dialyzate for 48 hours to prepare lipoic acid nanovesicles loaded with irbesartan. With reference to the method described in Example 6, the therapeutic effect of the irbesartan-loaded lipoic acid nanomedicine on diabetic nephropathy described in this embodiment was verified. The results show that after lipoic acid nanoparticles are loaded with irbesartan, the therapeutic effect is better than that of irbesartan monomer or lipoic acid nanoparticles not loaded with irbesartan, and while reducing the dosage of the active ingredient, the therapeutic effect is synergistically enhanced.

[0110] Example 8

[0111] In this example, db / db mice were used as a diabetic peripheral neuropathy model to evaluate the efficacy of the lipoic acid nanoparticles prepared in Example 1 on diabetic peripheral neuropathy (DPN), and the results were compared with those of the clinically used small molecule lipoic acid injection.

[0112] 1. Experimental Materials and Methods

[0113] S1. Instruments and reagents:

[0114] Blood glucose monitor, Sinocare Biosensing Co., Ltd.;

[0115] Photothermal coccygeal pain meter, Chengdu Taimeng Company;

[0116] RB-200 intelligent hot plate instrument, Chengdu Taimeng Company;

[0117] Malondialdehyde (MDA) assay kit, Nanjing Jiancheng Bioengineering Institute;

[0118] Superoxide dismutase (SOD) test kit, Nanjing Jiancheng Bioengineering Institute;

[0119] Glutathione (GSH) test kit, Nanjing Jiancheng Bioengineering Institute;

[0120] Na + -K + -ATPase (Na+-K+-ATPase) test kit, Nanjing Jiancheng Bioengineering Institute;

[0121] Tumor necrosis factor-α (TNF-α) test kit, Nanjing Jiancheng Bioengineering Institute;

[0122] Interleukin-6 (IL-6) test kit, Nanjing Jiancheng Bioengineering Institute;

[0123] Interleukin-1β (IL-1β) test kit, Nanjing Jiancheng Bioengineering Institute.

[0124] S2. Animal Grouping and Experimental Materials

[0125] Eighteen 16-week-old, SPF-free male C57BL / KsJ db / db mice were provided by the Changzhou Branch of Jiangsu Jicui Yaokang Biotechnology Co., Ltd. and randomly divided into three groups of six mice each based on body weight and blood glucose: the db / db model group, the db / db + lipoic acid nanoparticles group (50 mg / kg), and the db / db + lipoic acid injection group (50 mg / kg). Male w / w mice of the same age and littermate served as the control group. Heat pain thresholds were measured in all mice before treatment to confirm DPN symptoms. Small molecule lipoic acid injection and α-lipoic acid nanoparticles were intraperitoneally injected three times weekly for eight weeks. The control and model groups received an equal volume of normal saline. During the treatment period, blood glucose levels were monitored every three days to confirm the glucose-lowering effects of the drugs. Heat pain thresholds were measured at the end of the eighth week, and the mice were sacrificed for analysis of related factors using assay kits.

[0126] S3. Determination of thermal pain threshold

[0127] A photothermal tail pain meter and an intelligent hot plate instrument were used to monitor pain stimulation and record the latency or threshold for tail flick and paw withdrawal after stimulation. Briefly, the experimental apparatus was set to the appropriate parameters and the mouse was placed in the instrument after the instrument stabilized. When the mouse withdrew its paw, struggled, or swung its tail, the value displayed on the instrument was immediately recorded and the mouse was released. Each mouse was assessed three times with a 20-minute interval between trials, and the average value was used as the threshold.

[0128] S4、Na + -K + -ATPase activity assay

[0129] After 8 weeks of treatment, all mice were sacrificed and their sciatic nerves were isolated. + -K + For ATPase activity, 10 μL of whole blood was collected and added to 240 μL of distilled water to mix, and the Na + -K +- ATPase activity: Mouse sciatic nerve tissue was collected and first minced into fragments (100 mg: 1800 μL) using small scissors in physiological saline and homogenized using a Beed Ruptor 24 Elite. The homogenate was then centrifuged at 3500 rpm for 15 minutes at 4°C, and the supernatant was collected for use.

[0130] S5. Determination of SOD activity, MDA, GSH, TNF-α, IL-6 and IL-1β contents in sciatic nerve

[0131] At the end of the experiment, mice were sacrificed and sciatic nerve cells were isolated. To determine the levels of MDA, GSH, SOD, TNF-α, IL-6, and IL-1β in the sciatic nerve, the sciatic nerve was first minced into fragments (100 mg: 1800 μL) using small scissors in normal saline and homogenized using a Beed Ruptor 24 Elite. The homogenate was then centrifuged at 3500 rpm at 4°C for 15 minutes, and the supernatant was collected for use. SOD activity and the levels of MDA, GSH, TNF-α, IL-6, and IL-1β in the sciatic nerve homogenate were then measured using commercial kits.

[0132] S6. Sciatic nerve morphology analysis

[0133] At the end of the experiment, sacrifice the mouse and dissect the sciatic nerve within 1-3 minutes. Samples of 2 mm x 2 mm in size should be obtained as thinly as possible. Carefully sample the entire sciatic nerve, avoiding mechanical damage such as squeezing with forceps. Use sharp blades to avoid contusion. Immediately fix the tissue in electron microscopy fixative at room temperature for 2 hours, then transfer to 4°C for storage and transport on ice at 4°C. Keep the fixative liquid during storage and transport for subsequent sample preparation and analysis.

[0134] S7. Statistical methods

[0135] The quantitative experimental results are expressed as mean ± variance SPSS version 19.0 Statistical Software (Chicago, IL, USA) was used to compare differences among the groups using one-way analysis of variance. Pairwise comparisons between groups were performed using the Turkey post hoc method when P < 0.05, and differences were considered statistically significant.

[0136] 2. Experimental results

[0137] S1. Effects of lipoic acid nanoparticles on blood glucose in mice with experimental diabetic peripheral neuropathy

[0138] Blood glucose test results showed that after 8 weeks of treatment, the LA monomer group could only stabilize blood glucose near the initial blood glucose value of diabetic mice and had no hypoglycemic effect (p>0.05). However, the lipoic acid nanoparticle group effectively reduced the blood glucose content of diabetic mice, indicating the promoting effect of lipoic acid nanoparticles in improving glucose metabolism in diabetic peripheral neuropathy.

[0139] S2. Changes in thermal pain thresholds of mice in each group

[0140] The results are as follows Figure 10 、 11 The following are the heat plate pain thresholds and photothermal pain thresholds, respectively. Compared with w / w non-diabetic mice, the latency of responses to hot plate and tail flick stimulation in db / db mice was prolonged (p<0.05), indicating significant analgesia in diabetic mice. Compared with db / db mice, the latency to hot plate stimulation in mice treated with small molecule lipoic acid injection was shortened by 13.47% (p<0.05) and the latency to tail flick stimulation was shortened by 14.18% (p<0.05), indicating that LA monomer has a certain improvement effect on the behavior of mice with diabetic peripheral neuropathy. Compared with db / db mice, the latency to hot plate stimulation in mice treated with lipoic acid nanoparticles was shortened by 40.43% (p<0.01) and 31.13% (p<0.01), respectively, which are 3.0 and 2.2 times that of the same dose of small molecule lipoic acid injection (p<0.05). These results demonstrate the excellent therapeutic effect of lipoic acid nanoparticles on the behavior of mice with diabetic peripheral neuropathy. Analysis of significant differences between the control group and db / db mice group ( * P<0.05); significant differences among the lipoic acid monomer group, lipoic acid nanoparticle group and db / db mouse group ( #P <0.05, ## P<0.01); significant difference analysis between lipoic acid nanoparticle group and lipoic acid monomer group ( & P<0.05).

[0141] S3, Na of mice in each group + -K + -Changes in ATPase activity

[0142] Na +- K + -ATPase activity is closely related to microvascular blood supply and peripheral nerve damage. Figure 12 As shown, where a is serum Na + -K + -ATPase activity, b is sciatic nerve Na + -K + -ATPase activity. Compared with non-diabetic mice, Na in erythrocytes and sciatic nerves of db / db mice was higher. + -K +- ATPase activity was reduced. After 8 weeks of treatment, compared with db / db mice, the erythrocyte Na of the low-molecule lipoic acid group was + -K + -ATPase activity increased by 137%, Na in sciatic nerve + -K + -ATPase activity increased by 120%; compared with db / db mice, lipoic acid nanoparticles group had erythrocyte Na + -K + -ATPase activity increased by 234% (p<0.05). + -K + -ATPase activity increased by 206% (p < 0.01), and the activity was increased by 70.80% and 71.67% respectively compared with lipoic acid monomer. The above results show that the Na + -K + -In terms of ATPase activity, lipoic acid nanoparticles have a stronger therapeutic effect than clinical drugs. * P<0.05, ** P<0.01, *** P<0.001); significant differences between the small molecule lipoic acid injection group (50 mg / kg), lipoic acid nanoparticle group (50 mg / kg) and db / db mice group ( # P<0.05, ## P<0.01, ### P<0.001).

[0143] S4. Changes in SOD activity and MDA, GSH, TNF-α, IL-6, and IL-1β contents in the sciatic nerve of mice

[0144] The results are as follows Figure 13As shown, compared with w / w non-diabetic mice, db / db mice showed decreased GSH content and SOD activity, while significantly increased MDA content (p < 0.01), indicating significant oxidative stress damage in the sciatic nerves of diabetic mice. After 8 weeks of treatment, the lipoic acid monomer group showed a 30.79% decrease in MDA content (p < 0.05), a 15.76% increase in SOD activity (p < 0.05), and a 10.79% increase in GSH content (p < 0.05). In contrast, the lipoic acid nanoparticle-treated group showed a significant decrease in MDA content (p < 0.01), a 52.94% increase in SOD activity (p < 0.01), and a 17.72% increase in GSH content (p < 0.01), representing 1.7, 3.4, and 1.6 times the levels of the same dose of LA monomer, respectively (p < 0.05). These results demonstrate the excellent therapeutic effect of lipoic acid nanoparticles on oxidative stress in the sciatic nerves of mice with diabetic peripheral neuropathy. Analysis of significant differences between w / w and db / db mouse groups ( * P<0.05, ** P<0.01, *** P<0.001); significant differences between the small molecule lipoic acid injection group (50 mg / kg), lipoic acid nanoparticle group (50 mg / kg) and db / db mice group ( # P<0.05, ## P<0.01, ### P<0.001).

[0145] In terms of suppressing inflammatory response, the results are as follows Figure 14 As shown, compared with w / w non-diabetic mice, the levels of TNF-α, IL-1β and IL-6 cytokines were significantly increased in the sciatic nerve tissue of db / db mice, showing a stronger inflammatory response; compared with db / db mice, the levels of TNF-α, IL-1β and IL-6 cytokines in the lipoic acid monomer group decreased by 34.42%, 27.46% and 38.42%, respectively (p<0.05), while the corresponding cytokine levels in the lipoic acid nanoparticle group decreased by 50.25%, 48.84% and 60.34%, respectively (p<0.01), which were 1.5, 1.8 and 1.6 times that of the same dose of LA (p<0.05), revealing the excellent effect of lipoic acid nanoparticles in the treatment of sciatic nerve inflammation in mice with diabetic peripheral neuropathy. Analysis of significant differences between w / w and db / db mouse groups ( * P<0.05, ** P<0.01, *** P<0.001); significant differences between the small molecule lipoic acid injection group (50 mg / kg), lipoic acid nanoparticle group (50 mg / kg) and db / db mice group ( # P<0.05, ##P<0.01, ### P<0.001).

[0146] S5. Changes in sciatic nerve morphology in mice of each group

[0147] Compared with non-diabetic w / w mice, db / db mice showed obvious axonal demyelination and damage. Compared with db / db mice, the small molecule lipoic acid injection group and the lipoic acid nanoparticle group showed significant myelin regeneration after 8 weeks of treatment, and the lipoic acid nanoparticle group had a significantly better effect than the small molecule lipoic acid injection group. Figure 15 shown.

[0148] exist Figure 15 In the figure, a is non-diabetic mice w / w, b is db / db mice, c is small molecule lipoic acid injection group (50 mg / kg), and d is lipoic acid nanoparticle group (50 mg / kg).

[0149] Example 9

[0150] This embodiment is a lipoic acid nanoparticle tablet drug prepared using lipoic acid nanoparticles, including the following components expressed by mass fraction: 73% lipoic acid nanoparticles (main drug), 10% microcrystalline cellulose (filler), 10% starch slurry (binder), 6% corn starch (disintegrant), 0.2% magnesium stearate (lubricant), and 0.8% talc (lubricant).

[0151] The preparation method of the lipoic acid nanoparticle tablet medicine is as follows:

[0152] S1. Separately pass 73% lipoic acid nanoparticles (main drug), 10% microcrystalline cellulose (filler), and 6% corn starch (disintegrant) through a 100-mesh sieve, then premix the above materials and pass through a 20-mesh sieve.

[0153] S2. Add 10% starch slurry (binder) to prepare a soft material, and pass the soft material through a 20-mesh sieve to prepare wet granules;

[0154] S3, drying the wet granules in a drying oven at 40°C for 60 min, and passing the dried granules through a 20-mesh sieve for granulation;

[0155] S4. Add 0.2% magnesium stearate (lubricant) and 0.8% talc (lubricant) and mix well.

[0156] S5. Use a punch die to perform tableting.

[0157] The db / db type 2 diabetic mice were used as a model of diabetic peripheral neuropathy to evaluate the efficacy of tablet drugs prepared using lipoic acid nanoparticles and compare them with the currently available small molecule lipoic acid tablets.

[0158] Eighteen 16-week-old male C57BL / KsJ db / db mice, SPF grade, were selected and provided by the Changzhou branch of Jiangsu Jicui Yaokang Biotechnology Co., Ltd. They were randomly divided into three groups according to body weight and blood sugar, with 6 mice in each group, namely db / db model group, db / db+lipoic acid nanoparticle tablet group (50 mg / kg) and db / db+small molecule lipoic acid tablet group (50 mg / kg). W / w male mice of the same litter of the same age and size were selected as the control group. The heat pain threshold of all mice was measured before administration to determine the symptoms of DPN. Small molecule lipoic acid tablets and lipoic acid nanoparticle tablets were orally administered three times a week, two tablets each time, for a total of 8 weeks. During the treatment period, the blood sugar changes of the mice were tested every 3 days to clarify the hypoglycemic effect of the nanomedicine. At the end of the 8th week, the heat pain threshold was tested; the mice were sacrificed and other related factors were tested using a detection kit. The results showed that after 8 weeks of treatment with lipoic acid nanoparticle tablets, blood sugar and heat pain threshold were reduced, and Na + -K + -ATPase activity, improvement of tissue lesions and relief of inflammation were significantly better than those of small molecule lipoic acid tablets, indicating that the lipoic acid nanoparticle tablets prepared in this example have excellent therapeutic effects on diabetic peripheral neuropathy.

[0159] The present invention systematically sorts out the problems existing in the use of existing small molecule lipoic acid in the treatment of diabetes and its complications. The study found that the existing small molecule lipoic acid mainly has the following prominent problems:

[0160] 1. After small molecule lipoic acid is injected intravenously into the human body, it will be metabolized by the kidneys during blood circulation. 80-90% of small molecule lipoic acid enters the renal tubules through the glomeruli and is excreted with urine. It cannot reach some nerve tissues, has a short retention time, a short action time, and a poor therapeutic effect.

[0161] 2. During the storage of small molecule lipoic acid, due to the instability of the disulfide bond in the structure, when exposed to heat or light, the disulfide bond in the dithiol ring will break, forming unstable free radicals, resulting in the inactivation of lipoic acid; in a low pH and high humidity environment, the thiol groups formed by the broken disulfide bond will aggregate together in a disorderly manner to form some obvious light yellow colloidal substances. These colloidal substances are degradation products of lipoic acid polymers, which are difficult to dissolve and absorb. Therefore, the existing small molecule lipoic acid has a short shelf life and requires harsh storage conditions.

[0162] 3. Due to the low solubility of lipoic acid in aqueous solutions, existing methods for preparing small-molecule lipoic acid injections increase the solubility of small-molecule lipoic acid in water by adding alkaline cosolvents such as meglumine, ethylenediamine, and tromethamine. This not only reduces the lipoic acid content per unit mole of the injection, but the complex composition also increases the risk of adverse effects. Furthermore, alkaline cosolvents increase the likelihood of degradation of small-molecule lipoic acid.

[0163] The lipoic acid nanoparticles in the drug for lowering blood sugar and / or ameliorating diabetic complications described herein have a particle size of 10-300 nm, far larger than the critical particle size of the glomerular filtration system. Therefore, the lipoic acid nanoparticles can circulate with the blood and reach nerve tissue throughout the body, significantly increasing their in vivo retention time and enabling efficient absorption of lipoic acid by peripheral nerve tissue, thereby enhancing the therapeutic effect. The disulfide bonds between the monomers are cross-linked and polymerized, encapsulating the more active disulfide bonds within the nanoparticles, thereby enhancing their stability and extending their shelf life.

[0164] The hydrophilic groups in lipoic acid nanoparticles are located on the outside of the nanoparticles, while the hydrophobic groups are located inside. This allows them to dissolve in water without any solvents, resulting in a solubility far higher than that of lipoic acid monomers. Furthermore, this increased solubility eliminates the need for solvents, reducing costs and injection risks.

[0165] Example 10

[0166] 25.0 mg of the lipoic acid nanoaggregates prepared in Example 3 were added to an aqueous solution containing 100 mg of poly(lactic-co-glycolic acid) (PLGA). The mixture was thoroughly mixed under ultrasonic conditions and dialyzed to produce lipoic acid nanoparticles loaded on PLGA micelles. Similarly, 25.0 mg of the lipoic acid nanoaggregates prepared in Example 3 were added to an aqueous solution containing 100 mg of poly(lactic-co-glycolic acid) (PDLLA). The mixture was thoroughly mixed under ultrasonic conditions and dialyzed to produce lipoic acid nanoparticles loaded on PDLLA micelles. The hypoglycemic effects of the two carrier-loaded lipoic acid nanoparticles obtained in this example were verified using the method described in Example 4. The results showed that the clearance time of the lipoic acid nanoparticles was prolonged and the drug's efficacy was prolonged after loading with different carriers, resulting in superior therapeutic effects.

[0167] Example 11

[0168] Lipoic acid nanoparticles were prepared using the method described in Example 1. Polyethylene glycol (PEG-1000) was then grafted onto the lipoic acid nanoparticles using 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine esterification. Compared to ungrafted nanoparticles, the PEG-1000-modified nanoparticles effectively reduced protein adsorption, delayed nanoparticle clearance, and prolonged drug efficacy, resulting in superior therapeutic efficacy.

[0169] The above description is only a preferred embodiment of the present invention, which is merely illustrative and not restrictive of the present invention. A person skilled in the art will understand that many changes, modifications, and even equivalent changes may be made thereto within the spirit and scope defined by the claims of the present invention, but all of these changes will fall within the scope of protection of the present invention.

Claims

1. An application of lipoic acid nanoparticles, characterized in that, The method is used to prepare a drug for lowering blood sugar and / or improving diabetic complications, wherein the diabetic complications include at least one of diabetic nephropathy and diabetic peripheral neuropathy. The lipoic acid nanoparticles are formed by cross-linking polymerization of lipoic acid and / or lipoic acid salt through disulfide bonds.

2. The use according to claim 1, characterized in that The lipoic acid nanoparticles are formed by cross-linking polymerization of lipoic acid and / or lipoic acid salt through disulfide bonds and then being modified with polyethylene glycol.

3. The use according to claim 1, characterized in that The lipoic acid nanoparticles are formed by cross-linking polymerization of lipoic acid and / or lipoic acid salt through disulfide bonds and then being loaded by liposomes and polymers.

4. The use according to claim 1, characterized in that The drug for improving diabetic complications can improve diabetic complications through the dual effects of lowering blood sugar and inhibiting oxidative stress.

5. The use according to claim 1, characterized in that Combining lipoic acid nanoparticles with other active ingredients.

6. The use according to claim 1, characterized in that The particle size of the lipoic acid nanoparticles is 10-300 nm.

7. The use according to claim 1, characterized in that The lipoic acid nanoparticles are prepared into injections, capsules, tablets, pills or oral solutions.

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