A pharmaceutical composition for treating diabetic microangiopathy and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition for treating diabetic microangiopathy and a preparation method thereof, the pharmaceutical composition comprising the following raw materials in parts by weight: active drug 5-10 parts, shell copolymer 20 parts, PLGA 35-50 parts, emulsifier 1.5 parts and freeze-drying protective agent 4 parts. The shell copolymer prepared and synthesized from PCL, PEG and a targeting peptide has functions such as drug loading, self-assembly, responsiveness and targeting, the responsiveness of which depends on a disulfide bond connecting the PCL and the PEG, the disulfide bond is broken in an abnormal blood flow environment of a vascular lesion, various drugs in the nanoparticle core are released, and the drug delivery efficiency and the treatment effect are greatly improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a pharmaceutical composition for treating diabetic microvascular complications and its preparation method. Background Technology

[0002] Diabetic microvascular complications are a significant component of chronic diabetic complication, primarily involving structural and functional abnormalities in capillaries and small arteries and veins. They can affect multiple tissues and organs, including the retina, glomeruli, peripheral nerves, and skin, clinically manifesting as diabetic retinopathy, diabetic nephropathy, diabetic peripheral neuropathy, and refractory ulcers. Their development is closely related to multifactorial damage induced by long-term hyperglycemia, including endothelial cell dysfunction, basement membrane thickening, abnormal vascular permeability, persistent inflammatory activation, exacerbated oxidative stress, insufficient microcirculation perfusion, and increased tendency for local microthrombus formation. The pathological process is characterized by multiple stages, multiple pathways, mutual amplification, and continuous progression. Due to the widespread distribution and complex microenvironment of microvascular complications, drugs with a single mechanism of action often cannot cover the entire pathological process, limiting their efficacy. Furthermore, long-term use can lead to increased systemic exposure, insufficient effective concentration in target tissues, and decreased patient compliance. Current clinical treatment strategies typically revolve around blood sugar control, antiplatelet therapy, lipid regulation, and anti-inflammation. However, the coexistence of abnormal hemodynamics, altered vessel wall structure, and high expression of endothelial adhesion molecules in microvascular lesions limits drug retention and penetration efficiency in the lesion area. Furthermore, co-administration of multiple drugs can easily lead to pharmacokinetic mismatch, inconsistent tissue distribution, and unstable combined treatment effects. While existing nanodelivery systems can improve drug solubility and in vivo distribution to some extent, common carrier materials often rely on a single passive targeting mechanism or lack the ability to respond to the characteristic microenvironment of diabetic microvascular lesions.

[0003] Therefore, developing a drug composition and preparation method that can take into account the synergistic effect of multiple drugs, targeted enrichment of lesions and triggered release under abnormal blood flow conditions is of great significance for improving the treatment effect of diabetic microvascular complications and reducing systemic side effects. Summary of the Invention

[0004] In view of the above, the present invention provides a pharmaceutical composition for treating diabetic microvascular complications and a method for preparing the same. The composition is a block polymer with hydrophilic and hydrophobic structures, responsive disulfide bonds and vascular inflammation-targeting peptides. The block polymer is designed to achieve multi-drug co-delivery by relying on its self-assembly capability, thereby improving the drug treatment efficiency and efficacy for diabetic microvascular complications and reducing the side effects of combination drug therapy.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The present invention provides a pharmaceutical composition for treating diabetic microvascular complications, the pharmaceutical composition comprising the following raw materials in parts by weight: 5-10 parts of active pharmaceutical ingredient, 20 parts of shell copolymer, 35-50 parts of PLGA (polylactic acid-glycolic acid copolymer), 1.5 parts of emulsifier, and 4 parts of lyophilization protectant.

[0006] Furthermore, the active drug is selected from two or more of ticagrelor, atorvastatin, pirfenidone, clopidogrel, and ipragliflozin.

[0007] Furthermore, the emulsifier is selected from any one of PVA (polyvinyl alcohol), lecithin, and Tween 80.

[0008] Furthermore, the freeze-drying protectant is selected from one or more of trehalose, mannitol, sucrose, and sorbitol.

[0009] Further, the shell copolymer comprises the following raw materials: PCL (polycaprolactone), TDE (2,2'-dithiodiethanol), SC-PEG-SC (succinimide carbonate polyethylene glycol), targeting peptide, CDI (carbonyl diimidazole), and DMAP (4-dimethylaminopyridine), wherein the mass ratio of PCL, TDE, SC-PEG-SC, targeting peptide, CDI, and DMAP is 45:8:42:5:4:2.

[0010] Furthermore, the sequence of the targeting peptide is H2N-VHPKQHRGGKGGSKC, as shown in SEQ ID NO.1.

[0011] Furthermore, the preparation method of the shell copolymer is as follows: S1: PCL, CDI, and DMAP were dissolved and stirred together for 1 h. DMAP acted as a nucleophilic catalyst to promote carbonyl transfer. CDI reacted with the terminal hydroxyl group of PCL to generate imidazole carbonate, yielding an intermediate. TDE was slowly added dropwise to the intermediate while stirring. After the addition was complete, stirring was continued for 6 h to introduce a disulfide bond into the PCL molecular chain. The -OH at one end of TDE nucleophilically substituted the carbonyl group of the imidazole carbonate in PCL, causing the imidazole to leave and forming a stable carbonate bond. The -OH at the other end was retained, yielding a reaction solution. The reaction solution was precipitated with cold diethyl ether, purified, and dried to obtain PCL-SS-OH. S2: PCL-SS-OH and SC-PEG-SC are dissolved together and reacted for 2 h. PCL-SS-OH acts as a nucleophile to attack and replace the active carbonate in SC-PEG-SC to generate PCL-SS-PEG-SC, thus obtaining the polymer. S3: Dissolve the target peptide and mix it with the polymer. Adjust the pH to 7.6. Improve the deprotonation efficiency of the amino group under weakly alkaline conditions. Stir the reaction for 4 h. The succinimide activated carbonate at the end of PCL-SS-PEG-SC reacts with the amino group at the N-terminus of the target peptide. The succinimide group leaves and a stable carbamate bond is generated, realizing the covalent connection between the target peptide and the polymer, and obtaining the copolymer (PCL-SS-PEG-pep). The copolymer is purified by dialysis and lyophilized to obtain the shell copolymer.

[0012] This invention also provides a method for preparing a pharmaceutical composition for treating diabetic microvascular complications, the specific steps of which are as follows: Step 1: Dissolve the active pharmaceutical ingredient and PLGA in an organic solvent to obtain the organic phase; dissolve the emulsifier to obtain the emulsion; add the shell copolymer to the emulsion to disperse and dissolve it to obtain the aqueous phase; Step 2: While stirring, the organic phase is slowly added dropwise to the aqueous phase. After the addition is complete, the mixture is ultrasonically emulsified in an ice bath for 5 min to obtain an emulsion. The emulsion is then transferred to a magnetic stirrer and stirred for 6 h to evaporate the organic solvent. PLGA is deposited and solidified in the emulsion droplets to form a drug-loaded core loaded with active drug. The shell copolymer spontaneously assembles on the surface of the drug-loaded core by the hydrophilic-hydrophobic interaction at both ends to form a shell structure with the hydrophobic end facing inward and the hydrophilic end facing outward, thus obtaining a nanoparticle solution. Step 3: The nanoparticle solution is ultrafiltered and centrifuged, the precipitate is collected and washed and resuspended with deionized water to remove free drug, residual emulsifier and residual organic solvent to obtain nanoparticle dispersion. A lyophilization protectant is added to the nanoparticle dispersion, dissolved and lyophilized to obtain a drug composition for treating diabetic microvascular complications.

[0013] The beneficial effects achieved by this invention are as follows: The pharmaceutical composition for treating diabetic microvascular complications prepared in this invention achieves co-delivery and synergistic release of drugs by co-encapsulating multiple active drugs within a PLGA drug-carrying core. This effectively reduces the risk of fluctuating efficacy due to inconsistent distribution of different drugs in vivo and improves the preventive and therapeutic effects on the multi-stage pathological process of diabetic microvascular complications. The self-designed and constructed triblock polymer PCL-SS-PEG-pep can spontaneously assemble with the drug-carrying core surface through its own hydrophilic-hydrophobic interactions, forming a stable core-shell structure. The targeting peptide is located in the outer layer of the particle, and its amino acid sequence is modified from the polypeptide VHPKQHR, which can specifically recognize and bind to vascular cell adhesion molecule-1 (VCAM-1). Without changing the core recognition sequence VHPKQHR, GGKGGSKC is introduced as a functionalized peptide, where glycine G reduces the distance dependence between VHPKQHR and the carrier surface, making it easier for the core motif to extend and contact the binding site in the hydration layer. Reducing spatial shielding and introducing lysine K and serine S to enhance hydrophilicity and conformation regulation allows the targeting peptide to be more stably extended in an aqueous environment. The sequence-optimized targeting peptide can increase the adhesion and enrichment probability of nanoparticles in the inflammatory-activated microvascular endothelial region. At the same time, the disulfide bond introduced by TDE in PCL-SS-PEG-pep serves as a force-sensitive linker placed on the connection path between the hydrophobic and hydrophilic segments. Under abnormal blood flow shear or local blood flow disturbance, the disulfide bond breaks, which can provide additional responsive triggering factors for the release regulation in the lesion area, making it easier for the drug delivery system to achieve the targeted polymerization process of "enrichment followed by release" at the lesion site.

[0014] The nano-formulation provided by this invention takes into account material structure design, combined drug delivery, and intelligent delivery, and can provide a promising nano-drug delivery system technology solution for the treatment of diabetic microvascular complications. Attached Figure Description

[0015] Figure 1 This is a flowchart illustrating the preparation of a pharmaceutical composition for treating diabetic microvascular complications according to the present invention. Figure 2 The results of lyophilization-reconstitution and microstructure analysis of the pharmaceutical composition for treating diabetic microvascular complications prepared in Example 4; Figure 3 The results of the drug loading and encapsulation efficiency of the pharmaceutical compositions for treating diabetic microvascular complications prepared in Examples 1-5 are presented. Figure 4 The results of the study on the reversal of HMEC-1 cell apoptosis of the pharmaceutical compositions for treating diabetic microvascular complications prepared in the blank group and Comparative Examples 1 and 4 are presented. Detailed Implementation

[0016] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0018] The following embodiments illustrate the preparation process of the pharmaceutical composition for treating diabetic microvascular complications. Figure 1 Unless otherwise specified, all methods are conventional; all quantities are by weight; unless otherwise specified, all materials used in the following examples are new materials purchased from the market; the target peptide sequence used is H2N-VHPKQHRGGKGGSKC, C-terminus is carboxyl-capped, prepared by solid-phase synthesis, purity 96.4%; all active pharmaceutical ingredients used are in raw material form, purity ≥98%, atorvastatin and clopidogrel are their salt forms; the PCL used is hydroxyl-capped polycaprolactone, molecular weight 2000 Da; the SC-PEG-SC used has a molecular weight of 3500 Da, terminal substitution rate ≥90%, purity ≥95%, and dispersity ≤1.10; the PLGA used has a lactic acid:glycolic acid ratio of 50:50, carboxyl-capped, molecular weight 10-20 kDa; the PVA used is PVA1788 type.

[0019] In the following examples and comparative examples, the shell copolymer comprises the following raw materials in parts by weight: 135 parts PCL, 24 parts TDE, 126 parts SC-PEG-SC, 15 parts targeting peptide, 12 parts CDI, and 6 parts DMAP. The specific preparation method is as follows: S1: Dissolve 135 parts of PCL, 12 parts of CDI, and 6 parts of DMAP in 800 parts of anhydrous dichloromethane and stir for 1 h to obtain an intermediate. Slowly add 24 parts of TDE to the intermediate while stirring. After the addition is complete, continue stirring at 150 rpm for 6 h to obtain a reaction solution. Replace the precipitate with 10 times the volume of cold diethyl ether, centrifuge at 8000 rpm for 5 min, collect the precipitate, resuspend the precipitate in cold diethyl ether, wash, centrifuge and purify, and vacuum dry to obtain PCL-SS-OH. S2: Dissolve 126 parts of PCL-SS-OH and SC-PEG-SC together in 2000 parts of mixed solvent (anhydrous dichloromethane and anhydrous dimethylformamide in a volume ratio of 3:1), stir at 200 rpm for 2 h to generate PCL-SS-PEG-SC, and obtain the polymer; S3: Dissolve 15 parts of the target peptide in 135 parts of deionized water and mix with the polymer. Adjust the pH to 7.6 and stir at 200 rpm for 4 h to obtain a copolymer (PCL-SS-PEG-pep). Dialyze the copolymer using a 3.5 kDa dialysis bag for 24 h and freeze dry to obtain the shell copolymer.

[0020] Example 1: This example provides a pharmaceutical composition for treating diabetic microvascular complications. The pharmaceutical composition comprises the following raw materials in parts by weight: 3 parts ticagrelor, 2 parts clopidogrel, 20 parts shell copolymer, 50 parts PLGA, 1.5 parts PVA, and 4 parts trehalose.

[0021] This embodiment also provides a method for preparing a pharmaceutical composition for treating diabetic microvascular complications, the specific steps of which are as follows: Step 1: Dissolve 3 parts of ticagrelor, 2 parts of clopidogrel and 50 parts of PLGA in 500 parts of ethyl acetate to obtain the organic phase. Dissolve 1.5 parts of PVA in 1500 parts of deionized water to obtain an emulsion. Add 20 parts of shell copolymer to the emulsion to disperse and dissolve, and obtain the aqueous phase. Step 2: While stirring at 200 rpm, slowly add the organic phase dropwise to the aqueous phase. After the addition is complete, sonicate in an ice bath at 100 W for 5 min (on for 2 s, off for 3 s) to obtain an emulsion. Transfer the emulsion to a magnetic stirrer and stir at 400 rpm for 6 h to evaporate the organic solvent and obtain a nanoparticle solution. Step 3: The nanoparticle solution was ultrafiltered and centrifuged. The ultrafiltration tube had a molecular weight cutoff of 50 kDa. The centrifugation speed was 12000 rpm and the centrifugation time was 10 min. The precipitate was collected, washed with deionized water, and resuspended to obtain a nanoparticle dispersion. Four parts of trehalose were added to the nanoparticle dispersion, dissolved, and freeze-dried to obtain a drug composition for treating diabetic microvascular complications.

[0022] Example 2: This example provides a pharmaceutical composition for treating diabetic microvascular complications. The pharmaceutical composition comprises the following raw materials in parts by weight: 4 parts atorvastatin, 4 parts ipalgliflozin, 20 parts shell copolymer, 45 parts PLGA, 1.5 parts lecithin, and 4 parts sucrose.

[0023] This embodiment also provides a method for preparing a pharmaceutical composition for treating diabetic microvascular complications, the specific steps of which are as follows: Step 1: Dissolve 4 parts of atorvastatin, 4 parts of ipragliflozin and 45 parts of PLGA in 500 parts of ethyl acetate to obtain the organic phase. Dissolve 1.5 parts of lecithin in 1500 parts of deionized water to obtain an emulsion. Add 20 parts of shell copolymer to the emulsion to disperse and dissolve, and obtain the aqueous phase. Step 2: While stirring at 200 rpm, slowly add the organic phase dropwise to the aqueous phase. After the addition is complete, use an ice bath to ultrasonically emulsify at 200 W for 5 min (on for 2 s, off for 3 s) to obtain an emulsion. Transfer the emulsion to a magnetic stirrer and stir at 400 rpm for 6 h to evaporate the organic solvent and obtain a nanoparticle solution. Step 3: The nanoparticle solution was ultrafiltered and centrifuged. The ultrafiltration tube had a molecular weight cutoff of 50 kDa. The centrifugation speed was 12000 rpm and the centrifugation time was 10 min. The precipitate was collected, washed with deionized water, and resuspended to obtain a nanoparticle dispersion. Four parts of sucrose were added to the nanoparticle dispersion, dissolved, and freeze-dried to obtain a pharmaceutical composition for treating diabetic microvascular complications.

[0024] Example 3: This example provides a pharmaceutical composition for treating diabetic microvascular complications, the pharmaceutical composition comprising the following raw materials in parts by weight: 4 parts ticagrelor, 4 parts pirfenidone, 3 parts clopidogrel, 20 parts shell copolymer, 35 parts PLGA, 1.5 parts Tween 80, and 4 parts sorbitol.

[0025] This embodiment also provides a method for preparing a pharmaceutical composition for treating diabetic microvascular complications, the specific steps of which are as follows: Step 1: Dissolve 4 parts of ticagrelor, 4 parts of pirfenidone, 3 parts of clopidogrel and 35 parts of PLGA in 500 parts of ethyl acetate to obtain the organic phase. Dissolve 1.5 parts of Tween 80 in 1500 parts of deionized water to obtain an emulsion. Add 20 parts of shell copolymer to the emulsion to disperse and dissolve, and obtain the aqueous phase. Step 2: While stirring at 200 rpm, slowly add the organic phase dropwise to the aqueous phase. After the addition is complete, use an ice bath to ultrasonically emulsify at 300 W for 5 min (on for 2 s, off for 3 s) to obtain an emulsion. Transfer the emulsion to a magnetic stirrer and stir at 400 rpm for 6 h to evaporate the organic solvent and obtain a nanoparticle solution. Step 3: The nanoparticle solution was ultrafiltered and centrifuged. The ultrafiltration tube had a molecular weight cutoff of 50 kDa. The centrifugation speed was 12000 rpm and the centrifugation time was 10 min. The precipitate was collected, washed with deionized water, and resuspended to obtain a nanoparticle dispersion. Four parts of sorbitol were added to the nanoparticle dispersion, dissolved, and freeze-dried to obtain a pharmaceutical composition for treating diabetic microvascular complications.

[0026] Example 4: This example provides a pharmaceutical composition for treating diabetic microvascular complications, the pharmaceutical composition comprising the following raw materials in parts by weight: 3 parts ticagrelor, 3 parts atorvastatin, 3 parts pirfenidone, 20 parts shell copolymer, 46 parts PLGA, 1.5 parts PVA, 4 parts trehalose, and 1 part mannitol.

[0027] This embodiment also provides a method for preparing a pharmaceutical composition for treating diabetic microvascular complications, the specific steps of which are as follows: Step 1: Dissolve 3 parts of ticagrelor, 3 parts of atorvastatin, 3 parts of pirfenidone and 46 parts of PLGA in 500 parts of ethyl acetate to obtain the organic phase. Dissolve 1.5 parts of PVA in 1500 parts of deionized water to obtain an emulsion. Add 20 parts of shell copolymer to the emulsion to disperse and dissolve, and obtain the aqueous phase. Step 2: While stirring at 200 rpm, slowly add the organic phase dropwise to the aqueous phase. After the addition is complete, use an ice bath to ultrasonically emulsify at 200 W for 5 min (on for 2 s, off for 3 s) to obtain an emulsion. Transfer the emulsion to a magnetic stirrer and stir at 400 rpm for 6 h to evaporate the organic solvent and obtain a nanoparticle solution. Step 3: The nanoparticle solution was ultrafiltered and centrifuged. The ultrafiltration tube had a molecular weight cutoff of 50 kDa. The centrifugation speed was 12000 rpm and the centrifugation time was 10 min. The precipitate was collected, washed with deionized water, and resuspended to obtain a nanoparticle dispersion. Four parts of trehalose and one part of mannitol were added to the nanoparticle dispersion, dissolved, and freeze-dried to obtain a pharmaceutical composition for treating diabetic microvascular complications.

[0028] Example 5: This example provides a pharmaceutical composition for treating diabetic microvascular complications, the pharmaceutical composition comprising the following raw materials in parts by weight: 3 parts pirfenidone, 3 parts ipalgliflozin, 20 parts shell copolymer, 40 parts PLGA, 1.5 parts PVA, 3 parts sucrose and 1 part sorbitol.

[0029] This embodiment also provides a method for preparing a pharmaceutical composition for treating diabetic microvascular complications, the specific steps of which are as follows: Step 1: Dissolve 3 parts of pirfenidone, 3 parts of ipragliflozin and 40 parts of PLGA in 500 parts of ethyl acetate to obtain the organic phase. Dissolve 1.5 parts of PVA in 1500 parts of deionized water to obtain an emulsion. Add 20 parts of shell copolymer to the emulsion to disperse and dissolve, and obtain the aqueous phase. Step 2: While stirring at 200 rpm, slowly add the organic phase dropwise to the aqueous phase. After the addition is complete, use an ice bath to ultrasonically emulsify at 200 W for 5 min (on for 2 s, off for 3 s) to obtain an emulsion. Transfer the emulsion to a magnetic stirrer and stir at 400 rpm for 6 h to evaporate the organic solvent and obtain a nanoparticle solution. Step 3: The nanoparticle solution was ultrafiltered and centrifuged. The ultrafiltration tube had a molecular weight cutoff of 50 kDa. The centrifugation speed was 12000 rpm and the centrifugation time was 10 min. The precipitate was collected, washed with deionized water, and resuspended to obtain a nanoparticle dispersion. Three parts of sucrose and one part of sorbitol were added to the nanoparticle dispersion, dissolved, and freeze-dried to obtain a pharmaceutical composition for treating diabetic microvascular complications.

[0030] The difference between Comparative Example 1 and Example 4 is that no shell copolymer was added, and the core-shell nanoparticles were prepared solely by PLGA.

[0031] Morphological characterization: 2 mg of the drug composition prepared in Example 4 was dissolved in a 1 mg / mL solution to examine its lyophilized reconstitution ability. The results were photographed and recorded. See below for details. Figure 2 10 μL of the solution was added to a copper grid, stained with a 2% phosphotungstic acid solution, and its morphology was examined under a TEM (transmission electron microscope). The results are as follows. Figure 2 As shown.

[0032] Encapsulation efficiency and drug loading: 10 mg of each of the drug compositions prepared in Examples 1-5 were dissolved to prepare a 10 mg / mL aqueous solution. The solution was then diluted 10 times with a 1:1 acetonitrile-methanol mixture for demulsification. The content of each active drug was determined by HPLC. The drug loading (%) was calculated as: total mass of active drug / 10 mg × 100%. The results are shown in [Figure number missing]. Figure 3 The nanoparticle dispersions prepared in Examples 1-5 were diluted 10 times with a 1:1 volume ratio of acetonitrile-methanol mixed solvent for demulsification. The concentrations of each active ingredient were determined by HPLC. The encapsulation efficiency (%) was calculated as follows: Total concentration of active ingredient × 10 (dilution factor) × volume of nanoparticle dispersion / total mass of active ingredient × 100%. The results are shown in the figure. Figure 3 .

[0033] Apoptosis assay: Human microvascular endothelial cells (HMEC-1) were cultured and treated with 25 mM glucose for 48 h during their logarithmic growth phase, followed by TNF-α (10 ng / mL) treatment for 6 h to induce a diabetic microangiopathy cell model. 100 μg of the drug compositions prepared in Comparative Example 1 and Example 4 were added to each cell, and after incubation for 24 h, endothelial cell apoptosis was assessed by flow cytometry. The control group consisted of normal cells without added drugs. Results are shown below. Figure 4 .

[0034] Figure 2 The results showed that the drug composition prepared in Example 4 had good lyophilized reconstitution properties, and its morphology was a spherical nanoparticle structure with a particle size of about 50-100 nm, which was relatively uniform.

[0035] Figure 3The results showed that the drug composition prepared in Example 4 had the highest encapsulation efficiency and less drug loss, while the drug composition prepared in Example 3 had the highest drug loading, indicating that the core-shell copolymer had good drug loading efficiency.

[0036] Figure 4 The results showed that the drug composition prepared in Example 4 had a good ability to reverse microvascular endothelial cell apoptosis. Compared with the drug composition of Comparative Example 1 which was not responsive and targeted modified, human microvascular endothelial cells HMEC-1 had a high drug utilization rate of the nanoparticles prepared in Example 4, showing good potential for treating diabetic microvascular complications.

[0037] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0038] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for treating diabetic microvascular complications, characterized in that, The pharmaceutical composition comprises the following raw materials in parts by weight: 5-10 parts of active pharmaceutical ingredient, 20 parts of shell copolymer, 35-50 parts of PLGA, 1.5 parts of emulsifier, and 4 parts of lyophilization protectant; The shell copolymer comprises the following raw materials: PCL, TDE, SC-PEG-SC, targeting peptide, CDI, and DMAP; The amino acid sequence of the target peptide is H2N-VHPKQHRGGKGGSKC, as shown in SEQ ID NO.1; The preparation method of the shell copolymer is as follows: S1: Dissolve PCL, CDI, and DMAP together to obtain an intermediate. Add TDE dropwise to the intermediate to react and obtain a reaction solution. Precipitate the reaction solution with cold diethyl ether, purify it, and dry it to obtain PCL-SS-OH. S2: React PCL-SS-OH and SC-PEG-SC to obtain a polymer; S3: Dissolve the target peptide and mix it with the polymer. Adjust the pH to obtain a copolymer. Purify the copolymer by dialysis and freeze-dry it to obtain a shell copolymer.

2. The pharmaceutical composition for treating diabetic microvascular complications according to claim 1, characterized in that, The mass ratio of PCL, TDE, SC-PEG-SC, targeting peptide, CDI, and DMAP is 45:8:42:5:4:

2.

3. The pharmaceutical composition for treating diabetic microvascular complications according to claim 2, characterized in that, The active drug is selected from two or more of ticagrelor, atorvastatin, pirfenidone, clopidogrel, and ipalgliflozin.

4. The pharmaceutical composition for treating diabetic microvascular complications according to claim 2, characterized in that, The emulsifier is selected from any one of PVA, lecithin, and Tween 80.

5. The pharmaceutical composition for treating diabetic microvascular complications according to claim 2, characterized in that, The freeze-drying protectant is selected from one or more of trehalose, mannitol, sucrose, and sorbitol.

6. A method for preparing a pharmaceutical composition for treating diabetic microvascular complications according to any one of claims 1-5, characterized in that, The specific steps are as follows: Step 1: Dissolve the active pharmaceutical ingredient and PLGA to obtain the organic phase; dissolve the emulsifier to obtain the emulsion; add the shell copolymer to the emulsion to disperse and dissolve, thus obtaining the aqueous phase; Step 2: Add the organic phase dropwise to the aqueous phase, emulsify, stir and evaporate to obtain a nanoparticle solution; Step 3: The nanoparticle solution is ultrafiltered and centrifuged, the precipitate is collected, washed and resuspended to obtain a nanoparticle dispersion, a freeze-drying protectant is added to it and freeze-dried to obtain a pharmaceutical composition for treating diabetic microvascular complications.

Images