Method for improving drug loading capacity of double-drug co-loaded microspheres
Through solubility parameter analysis and molecular dynamics simulation, the drug and polymer formulations were screened, and the emulsification method was used to prepare double-drug microspheres, which solved the problem of low drug loading of double-drug microspheres, and achieved efficient production and long-term release of double-drug microsphere preparations.
Patent Information
- Application Number
- CN202510950559.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-10
- Publication Date
- 2025-08-12
AI Technical Summary
The prior art is difficult to increase the drug loading of double-drug co-loading microspheres without changing the drug or polymer structure, especially in multi-drug treatment strategies, poor miscibility between drugs and polymers leads to low drug loading, and existing methods limit the large-scale production and delivery efficiency of microsphere preparations.
Through solubility parameter analysis and molecular dynamics simulation, the best miscible drug and polymer formula was screened out, and the emulsification method was used to prepare double-drug microspheres to ensure that the drug and polymer are evenly dispersed in the microspheres, avoid crystallization or phase separation, and improve miscibility.
The total drug loading of double-drug microspheres was significantly increased, the proportion of polymers was reduced, potential side effects were reduced, and the long-term controlled release of double-drugs was achieved, reducing the frequency of dosing and the risk of non-compliance.
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Figure CN120459039A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a method for increasing the drug loading capacity of dual-drug co-loaded microspheres. Background Art
[0002] Microspheres are a type of drug formulation that slowly releases loaded drugs, maintaining blood drug concentrations for extended periods and reducing dosing frequency during disease treatment. Microsphere drug loading, which refers to the mass of drug encapsulated within the microspheres, is a key performance parameter of microsphere formulations. While ensuring the stability of the microsphere formulation, the higher the proportion of drug in the microsphere, the lower the proportion of excipients. Increasing the drug loading of microspheres allows for the delivery of more drug at the same dosage while mitigating potential side effects from excipients.
[0003] In the production process of microsphere preparations, the key to increasing the drug loading of microspheres is to improve the miscibility of drugs with the polymer matrix of the microspheres. For example, special functional groups can be modified on the polymer chain to enable stronger intermolecular interactions with the loaded drugs, or the drugs can be pre-designed into nanoparticles to better embed them into the polymer matrix. However, these methods place higher requirements on the matching degree between the polymer synthesis process and the physicochemical properties of the drugs, which limits the large-scale production of microsphere preparations. In particular, when microspheres are used to load multiple drugs for delivery, the applicability of these methods in microsphere formulation design is further limited.
[0004] The pathogenesis of most chronic diseases is complex and often requires intervention with multi-drug treatment strategies represented by fixed-dose combinations. Generally speaking, the vast majority of multi-drug delivery strategies are based on simple mixtures of different drug preparations, or are administered in multiple doses. These delivery strategies present challenges of low delivery efficiency and the risk of missed or overdosed doses. For chronic diseases that require long-term medication, the use of long-acting preparations with high drug loading for drug delivery can reduce the frequency of dosing and avoid the potential risks of non-compliance when patients take their medication on their own.
[0005] However, most of the nearly 20 microsphere products currently on the market are single-drug delivery preparations. The development of dual-drug co-loaded microspheres requires a more complex formulation screening process because it is necessary to consider the miscibility of the two drugs with the microsphere matrix. The miscibility between the drug and the polymer that constitutes the microsphere matrix is one of the key indicators in formulation screening. If the drug and polymer have good miscibility, the drug can be evenly distributed in the polymer matrix, achieving a more stable and uniform distribution, avoiding crystallization or phase separation, thereby preventing drug leakage and reducing the drug loading of the polymer microspheres. By improving the miscibility of the encapsulated drug and the polymer through appropriate drug combination, microsphere preparations with a higher total drug loading can be developed, achieving long-term combined therapeutic effects after a single injection. Summary of the Invention
[0006] The purpose of the present invention is to provide a method for increasing the drug loading capacity of dual-drug co-loaded microspheres, without changing the structure of the drug or polymer or introducing new modifying groups, by rationally designing the formulation and optimizing the intermolecular miscibility, so as to achieve efficient loading of dual drugs in microspheres.
[0007] To achieve the above objectives, the present invention provides a method for increasing the drug loading capacity of dual-drug co-loaded microspheres, comprising the following steps: S1. Solubility parameter analysis and miscibility prediction: Calculate the solubility parameters of the drug to be loaded and the polymer material to be selected, use at least one solubility parameter analysis method to evaluate the miscibility of the drug to be loaded and the polymer material to be selected, and predict the degree of miscibility between the drug and the polymer during dual drug loading; S2. Molecular modeling and dual-drug microsphere formulation verification: Through molecular docking and molecular dynamics simulation, the intermolecular interactions and spatial distribution of drugs and polymers during dual-drug encapsulation are verified, and the dual-drug and polymer formulation with the best miscibility is screened; S3. Preparation of dual-drug microspheres by emulsification method: Using the formula screened in S2, an organic phase solution containing dual drugs and polymer and an aqueous solution containing surfactant are prepared, and the polymer microspheres encapsulating the dual drugs are prepared by emulsification method.
[0008] Preferably, in S1, the solubility parameter analysis method includes: Hoftyzer-Van Krevelen method, Yamamoto Molecular Break method, Hansen solubility parameter method, Hildebrand solubility parameter method, Flory-Huggins χ parameter model method, Regular Solution Theory method, UNIFAC / UNIFAC-FV model method, COSMO-RS method, Group Contribution Methods method, Fedors method, Hoy method, Hayes method, Small method, Benedetto method, and Dunkel method.
[0009] Preferably, in S1, the drug to be loaded is selected from a combination of two of the following drugs: tofacitinib, rosiglitazone, chlorthalidone, dasatinib, amitriptyline, bisoprolol, pazopanib, gabapentin, baricitinib, escitalopram, fenofibrate, pregabalin, saxagliptin, metoprolol, gefitinib, lamotrigine, diclofenac, olanzapine, atorvastatin, methylprednisolone, valsartan, ropivacaine, bupivacaine, risperidone, pramipexole, orlistat, clozapine, galantamine, alistat, phenytoin sodium, acarbose, celecoxib, carbidopa, haloperidol, erlotinib, Azathioprine, sertraline, sunitinib, lidocaine, ranolazine, levodopa, ropinirole, hydrochlorothiazide, diltiazem, quetiapine, clomipramine, miglitol, carbamazepine, eplerenone, memantine, pioglitazone, amantidine, chlorpromazine, aripiprazole, benzocaine, nilotinib, topiramate, lapatinib, canagliflozin, fluoxetine, simvastatin, verapamil, venlafaxine, mirtazapine, lovastatin, trifluoperazine, sorafenib, tolvaptan, glyburide, gliquidone, fluvastatin, furosemide, gliclazide, sitagliptin, citalopram, meloxicam, imipramine.
[0010] Preferably, in S1, the selected polymer material is selected from one of the following materials: polypropylene, polycaprolactone, polylactic acid-polyethylene glycol copolymer, polydioxanone, polyhydroxybutyrate, polylactic acid, poly D, L-lactic acid, polyethylene, polycaprolactone, polytrihydroxybutyric acid valerate, acetalized dextran, polylactic acid-glycolic acid copolymer, polyvinyl fluoride, polyamide, polyhydroxyvalerate, polymethyl methacrylate, poly L-lactic acid, polycaprolactone-polyethylene glycol copolymer, polylactide-co-glycolide, hydroxypropyl methylcellulose acetate succinate, and polyurethane.
[0011] Preferably, in S2, the molecular docking method includes one or more of rigid docking, flexible docking, highly flexible docking, semi-flexible docking, rapid flexible docking, covalent docking, multi-stage scoring, and automation; The scoring functions in the molecular docking process include potential energy function, knowledge-driven scoring, and free energy estimation.
[0012] Preferably, in S2, the force field for molecular dynamics simulation includes: one or more of GROMOS, OPLS-AA / OPLS3e, AMBER, CHARMM, GAFF, CGenFF, and MARTINI; The result analysis parameters of molecular dynamics simulation include: one or more of the following: root mean square deviation, root mean square fluctuation, mean square displacement, radius of gyration, radial distribution function, number of hydrogen bonds, total system energy, potential energy, kinetic energy, binding free energy, interaction energy, solvent accessible surface area, intermolecular distance, contact frequency, bond length, bond angle, dihedral angle, diffusion coefficient, and charge density.
[0013] Preferably, in S3, the emulsification method includes: a high-pressure homogenization method, a high-shear emulsification method, a microfluidization homogenization method, an ultrasonic emulsification method, a phase transition temperature method, an inverse emulsification method, a microemulsion dilution method, and a microfluidic emulsification method.
[0014] Preferably, in S3, the organic phase solvent includes: isooctane, dioxane, dichloroethane, ethyl acetate, n-heptane, dimethyl sulfoxide, butanone, isopropanol, chloroform, n-butanol, glycerol, acetone, acetic acid, n-hexane, dichloromethane, methyl ethyl ketone, dimethyl carbonate, acetonitrile, N-methylpyrrolidone, ethanol, propylene glycol, methanol, tetrahydrofuran, methyl tert-butyl ether, cyclohexane, dimethylformamide, one or a mixture of several thereof.
[0015] Preferably, in S3, the aqueous phase surfactant includes: sodium lauryl sulfate, polyoxyethylene nonylphenol ether, polyoxyethylene stearate, hydrogenated lecithin, cetrimonium bromide, polysorbate 20, benzalkonium chloride, octyl glucoside, polyoxyethylene lauryl ether, sodium lauryl sulfate, Tween 80, polyoxyethylene hydrogenated castor oil, Tween 20, polysorbate 80, polyoxyethylene added castor oil, poloxamer 407, sodium lauryl sulfonate, polyvinyl alcohol, sodium deoxycholate, polyoxyethylene castor oil derivatives, sodium cholate, lecithin, and soybean lecithin.
[0016] Preferably, the particle size of the dual-drug co-loaded microspheres is 1-1000 μm; and the volume ratio of the organic phase to the aqueous phase is 1:2 to 1:50.
[0017] Therefore, the method of the present invention for increasing the drug loading capacity of dual-drug co-loaded microspheres has the following beneficial effects: (1) Screen the drug to be encapsulated and the candidate polymer material to ensure that they have similar total solubility parameters and solubility parameter items to ensure that the various components in the system are fully miscible when the dual drug and polymer material are mixed for the preparation of microspheres; when the polymer is used to encapsulate the appropriate dual drug, the overall miscibility of the dual drug formulation with the polymer will not be limited by the poorly miscible drug; (2) The dual-drug co-loaded microspheres are prepared by the emulsification method. Since the system miscibility of the dual-drug formulation is better than that of the single-drug formulation, the drug and the polymer can form a stable organic phase when preparing microspheres by the emulsification method. After mixing with the aqueous phase, the drug is emulsified to form uniformly dispersed droplets. Due to the good miscibility of the drug and the polymer in the droplets, the drug is not easy to leak into the external aqueous phase during the solidification process of the droplets to form microspheres, avoiding precipitation to form crystals or particles, and preventing uncontrollable agglomeration and interface aggregation, so that the drug can be fully dispersed in the polymer matrix of the solidified microspheres; (3) The method of the present invention can effectively increase the total drug loading capacity of dual-drug polymer microspheres. Compared with single-drug microspheres, the loaded drug has a higher mass fraction in the microspheres of the same mass. At the same time, the polymer ratio in the dual-drug microspheres is reduced, reducing the potential side effects caused by ingredients other than drugs in the preparation. (4) The method of the present invention improves the drug-polymer miscibility to increase the drug loading capacity of dual-drug microspheres, avoids additional functional group modification of the drug and polymer, and reduces the process cost of formulation development; (5) The dual-drug high-loaded microspheres developed by the method of the present invention are conducive to achieving long-term controlled release of dual drugs after a single administration, which not only achieves combined therapeutic effects but also reduces the frequency of injection administration, avoiding the potential risk of non-compliance when using multiple drugs to treat diseases that require long-term medication.
[0018] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments of the present invention. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.
[0020] Figure 1 Schematic diagram comparing the miscibility of dual-drug microsphere formulations versus single-drug microsphere formulations; Figure 2 is the Flory-Huggins χ parameter for methylprednisolone, lidocaine, and PLGA; Figure 3 This is a comparison diagram of the distance between drug and polymer molecules from the molecular dynamics simulation in Example 1; Figure 4 This is an optical microscope photograph of poly(lactic-co-glycolic acid)-encapsulated methylprednisolone and lidocaine dual-drug microspheres prepared in Example 1; Figure 5 This is a comparison of the drug loading of dual-drug microspheres and single-drug microspheres in Example 1; Figure 6 This is an optical microscope photograph of the poly(lactic-co-glycolic acid)-encapsulated simvastatin and fenofibrate dual-drug microspheres prepared in Example 2; Figure 7 This is a comparison of the drug loading of dual-drug microspheres and single-drug microspheres in Example 2; Figure 8 This is an optical microscope photograph of the polylactic acid-encapsulated atorvastatin and celecoxib dual-drug microspheres prepared in Example 3; Figure 9 This is a comparison chart of the drug loading of dual-drug microspheres and single-drug microspheres in Example 3. DETAILED DESCRIPTION
[0021] The technical solution of the present invention is further described below with reference to the accompanying drawings and embodiments.
[0022] In order to make the purpose, technical solutions and advantages of the present application clearer, more thorough and more complete, the technical solutions of the present invention are clearly and completely described below through the accompanying drawings and Examples. The following detailed description is an explanation of the embodiments and is intended to provide further details of the present invention. Unless otherwise specified, all technical terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the application belongs.
[0023] The instruments, equipment, reagents and materials used in the examples were obtained from commercial sources.
[0024] Example 1 A method for preparing poly(lactic-co-glycolic acid) (PLGA)-encapsulated methylprednisolone and lidocaine dual-drug microspheres comprises the following steps: S1. Use the Group Contribution Methods method to calculate the solubility parameters and Flory-Huggins χ parameters of methylprednisolone, lidocaine, and PLGA, respectively, to confirm that the drug and polymer in the dual-drug microsphere system have good miscibility compared with the single-drug microsphere system, such as Figure 1 Based on the solubility parameters of the drug molecules and polymers, the Flory-Huggins χ parameter of methylprednisolone and PLGA was calculated to be 1.45, and the Flory-Huggins χ parameter of lidocaine and PLGA was 0.88, as shown in Figure 2. Figure 2 As shown in the figure, the smaller the Flory-Huggins χ parameter between the drug and polymer, the better the miscibility between the two. Due to the addition of lidocaine, which has better miscibility with PLGA, the distribution of methylprednisolone in the microspheres is improved, resulting in better miscibility between the drug and polymer in the dual-drug microsphere system compared to the single-drug microspheres.
[0025] S2. Analyze the number of hydrogen bonds and intermolecular distances through molecular docking and molecular dynamics simulation under the GROMOS force field (50-100 ns).
[0026] The distance between drug and polymer molecules in molecular dynamics simulation is as follows Figure 3As shown in the figure, A represents single-drug methylprednisolone microspheres, and B represents dual-drug methylprednisolone and lidocaine microspheres. Molecular dynamics simulation results show that the intermolecular distances between all drug molecules and the polymer in the dual-drug microsphere system are smaller than those in the single-drug microsphere system. This is attributed to the improved miscibility and thorough mixing of the drug and polymer in the dual-drug system, resulting in a more compact overall distribution of the drug molecules and polymer.
[0027] S3. Preparation of dual-drug microspheres: Dissolve 10 mg of methylprednisolone, 10 mg of lidocaine, and 20 mg of PLGA in 1 mL of a mixture of ethyl acetate and dimethyl sulfoxide. Once fully dissolved, this serves as the organic phase for preparing microspheres using the emulsion method. A 1% w / v aqueous solution of polyoxyethylene-polyoxypropylene ether block copolymer is prepared as the aqueous phase for preparing microspheres using the emulsion method.
[0028] The volume ratio of the organic phase to the aqueous phase was 1:15. Microspheres were prepared by microfluidic emulsification. A syringe pump was used to control the flow rate of the two phases flowing into the capillary microfluidic device. The emulsion droplets were collected at the outlet of the capillary microfluidic device and added to a 1% w / v aqueous solution of polyoxyethylene polyoxypropylene ether block copolymer. The microspheres formed after the emulsion droplets solidified were then washed with pure water and freeze-dried to prepare methylprednisolone and lidocaine dual-drug microspheres. The optical microscope image is shown below. Figure 4 As shown, the average particle size of the dual-drug microspheres is 30 μm.
[0029] Comparison of drug loading of poly(lactic acid-co-glycolic acid)-encapsulated methylprednisolone and lidocaine dual-drug microspheres and poly(lactic acid-co-glycolic acid)-encapsulated methylprednisolone single-drug microspheres Figure 5 The total drug loading of the prepared methylprednisolone and lidocaine dual-drug microspheres was 22.87%, which was 80.80% higher than that of the methylprednisolone single-drug microspheres.
[0030] Example 2 A method for preparing poly(lactic-co-glycolic acid) (PLGA)-encapsulated simvastatin and fenofibrate dual-drug microspheres comprises the following steps: S1. The solubility parameters and Flory-Huggins χ parameters of simvastatin, fenofibrate, and PLGA were calculated using the Hansen solubility parameter method to predict the miscibility of drugs and polymers in microspheres during dual drug encapsulation.
[0031] S2. The number of hydrogen bonds and the distance between drug and polymer molecules within 50-100 ns were further evaluated by molecular docking and molecular dynamics simulation under the AMBER force field to determine the formula with the best miscibility.
[0032] S3. Preparation of dual-drug microspheres: 10 mg of simvastatin, 10 mg of fenofibrate, and 20 mg of PLGA were dissolved in 1 mL of ethyl acetate. After fully dissolved, the organic phase was used as the emulsion method to prepare microspheres. A 1% w / v aqueous solution of polyoxyethylene polyoxypropylene ether block copolymer was prepared as the aqueous phase for preparing microspheres by emulsification. The volume ratio of the organic phase to the aqueous phase was 1:30. Microspheres were prepared by microfluidic emulsification. A syringe pump was used to control the flow rate of the two phases flowing into the capillary microfluidic device. The emulsion droplets were collected at the outlet of the capillary microfluidic device and added to a 1% w / v aqueous solution of polyoxyethylene polyoxypropylene ether block copolymer. The microspheres formed after the emulsion solidified were washed with pure water and freeze-dried to prepare simvastatin and fenofibrate dual-drug microspheres, the optical microscope image of which is shown in Figure 2. Figure 6 As shown, the average particle size is 20 μm.
[0033] Comparison of drug loading of poly(lactic-co-glycolic acid)-encapsulated simvastatin and fenofibrate dual-drug microspheres and poly(lactic-co-glycolic acid)-encapsulated simvastatin single-drug microspheres Figure 7 The total drug loading of the prepared simvastatin and fenofibrate dual-drug microspheres was 64.80%, which was 17.78% higher than that of the simvastatin single-drug microspheres.
[0034] Example 3 A method for preparing polylactic acid-encapsulated atorvastatin and celecoxib dual-drug microspheres comprises the following steps: S1. The solubility parameters and Flory-Huggins χ parameters of atorvastatin, celecoxib, and polylactic acid were calculated using the Fedors method to predict the miscibility of drugs and polymers in microspheres during dual drug loading. S2. Through molecular docking combined with molecular dynamics simulation under the GAFF force field, the radial distribution function and binding free energy of the system within 50-100 ns were further evaluated to determine the formula with the best miscibility.
[0035] S3. Preparation of dual-drug microspheres: Take 20 mg of atorvastatin, 20 mg of celecoxib, and 30 mg of polylactic acid and dissolve them in 1 mL of dichloromethane. After they are fully dissolved, they are used as the organic phase for preparing microspheres by emulsification. A 2% w / v aqueous solution of polyvinyl alcohol is prepared as the aqueous phase for preparing microspheres by emulsification. The volume ratio of the organic phase to the aqueous phase is 1:10. Microspheres are prepared by ultrasonic emulsification, and the microspheres formed after the droplets formed by ultrasonic emulsification solidify are collected by centrifugation, then washed with pure water and freeze-dried to prepare atorvastatin and celecoxib dual-drug microspheres. The optical microscope image is shown as follows: Figure 8 As shown, the average particle size is 100 μm.
[0036] Comparison of drug loading of poly(lactic-co-glycolic acid)-encapsulated atorvastatin and celecoxib dual-drug microspheres and poly(lactic-co-glycolic acid)-encapsulated atorvastatin single-drug microspheres Figure 9 The total drug loading of the prepared atorvastatin and celecoxib dual-drug microspheres was 76.65%, which was 54.22% higher than that of the atorvastatin single-drug microspheres.
[0037] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the same. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solutions of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.
Claims
1. A method for increasing the drug loading of dual-drug co-loaded microspheres, characterized in that: The steps include: S1. Solubility parameter analysis and miscibility prediction: Calculate the solubility parameters of the drug to be loaded and the polymer material to be selected, use at least one solubility parameter analysis method to evaluate the miscibility of the drug to be loaded and the polymer material to be selected, and predict the degree of miscibility between the drug and the polymer during dual drug loading; S2. Molecular modeling and dual-drug microsphere formulation verification: Through molecular docking and molecular dynamics simulation, the intermolecular interactions and spatial distribution of drugs and polymers during dual-drug encapsulation are verified, and the dual-drug and polymer formulation with the best miscibility is screened; S3. Preparation of dual-drug microspheres by emulsification method: Using the formula screened in S2, an organic phase solution containing dual drugs and polymer and an aqueous solution containing surfactant are prepared, and the polymer microspheres encapsulating the dual drugs are prepared by emulsification method.
2. A method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S1, the solubility parameter analysis methods include: Hoftyzer-Van Krevelen method, Yamamoto Molecular Break method, Hansen solubility parameter method, Hildebrand solubility parameter method, Flory-Huggins χ parameter model method, Regular Solution Theory method, UNIFAC / UNIFAC-FV model method, COSMO-RS method, Group Contribution Methods method, Fedors method, Hoy method, Hayes method, Small method, Benedetto method, and Dunkel method.
3. A method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S1, the drugs to be loaded are selected from two combinations of the following drugs: tofacitinib, rosiglitazone, chlorthalidone, dasatinib, amitriptyline, bisoprolol, pazopanib, gabapentin, baricitinib, escitalopram, fenofibrate, pregabalin, saxagliptin, metoprolol, gefitinib, lamotrigine, diclofenac, olanzapine, atorvastatin, methylprednisolone, valsartan, ropivacaine, bupivacaine, risperidone, pramipexole, orlistat, clozapine, galantamine, alistat, phenytoin sodium, acarbose, celecoxib, carbidopa, haloperidol, erlotinib, Sertraline, sunitinib, lidocaine, ranolazine, levodopa, ropinirole, hydrochlorothiazide, diltiazem, quetiapine, clomipramine, miglitol, carbamazepine, eplerenone, memantine, pioglitazone, amantidine, chlorpromazine, aripiprazole, benzocaine, nilotinib, topiramate, lapatinib, canagliflozin, fluoxetine, simvastatin, verapamil, venlafaxine, mirtazapine, lovastatin, trifluoperazine, sorafenib, tolvaptan, glyburide, gliclazide, fluvastatin, furosemide, gliclazide, sitagliptin, citalopram, meloxicam, imipramine.
4. A method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S1, the polymer material to be selected is selected from one of the following materials: polypropylene, polycaprolactone, polylactic acid-polyethylene glycol copolymer, polydioxanone, polyhydroxybutyrate, polylactic acid, poly D, L-lactic acid, polyethylene, polycaprolactone, polytrihydroxybutyrate valerate, acetalized dextran, polylactic acid-glycolic acid copolymer, polyvinyl fluoride, polyamide, polyhydroxyvalerate, polymethyl methacrylate, poly L-lactic acid, polycaprolactone-polyethylene glycol copolymer, polylactide-co-glycolide, hydroxypropyl methylcellulose acetate succinate or polyurethane.
5. The method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S2, molecular docking methods include one or more of the following: rigid docking, flexible docking, highly flexible docking, semi-flexible docking, rapid flexible docking, covalent docking, multi-stage scoring, and automation; The scoring functions in the molecular docking process include potential energy function, knowledge-driven scoring, and free energy estimation.
6. A method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S2, the force fields for molecular dynamics simulations include one or more of GROMOS, OPLS-AA / OPLS3e, AMBER, CHARMM, GAFF, CGenFF, and MARTINI; The result analysis parameters of molecular dynamics simulation include: one or more of the following: root mean square deviation, root mean square fluctuation, mean square displacement, radius of gyration, radial distribution function, number of hydrogen bonds, total system energy, potential energy, kinetic energy, binding free energy, interaction energy, solvent accessible surface area, intermolecular distance, contact frequency, bond length, bond angle, dihedral angle, diffusion coefficient, and charge density.
7. A method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S3, the emulsification method includes: a high-pressure homogenization method, a high-shear emulsification method, a microfluidization homogenization method, an ultrasonic emulsification method, a phase transition temperature method, an inverse emulsification method, a microemulsion dilution method, and a microfluidic emulsification method.
8. The method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S3, the organic phase solvent includes: one or a mixture of isooctane, dioxane, dichloroethane, ethyl acetate, n-heptane, dimethyl sulfoxide, butanone, isopropanol, chloroform, n-butanol, glycerol, acetone, acetic acid, n-hexane, dichloromethane, methyl ethyl ketone, dimethyl carbonate, acetonitrile, N-methylpyrrolidone, ethanol, propylene glycol, methanol, tetrahydrofuran, methyl tert-butyl ether, cyclohexane, and dimethylformamide.
9. The method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: In S3, the aqueous phase surfactant includes: sodium lauryl sulfate, polyoxyethylene nonylphenol ether, polyoxyethylene stearate, hydrogenated lecithin, cetrimonium bromide, polysorbate 20, benzalkonium chloride, octyl glucoside, polyoxyethylene lauryl ether, sodium lauryl sulfate, Tween 80, polyoxyethylene hydrogenated castor oil, Tween 20, polysorbate 80, polyoxyethylene added castor oil, poloxamer 407, sodium lauryl sulfate, polyvinyl alcohol, sodium deoxycholate, polyoxyethylene castor oil derivatives, sodium cholate, lecithin, and one of soybean lecithin.
10. The method for increasing the drug loading of dual-drug co-loaded microspheres according to claim 1, characterized in that: The particle size of the dual-drug co-loaded microspheres is 1-1000 μm; the volume ratio of the organic phase to the aqueous phase is 1:2 to 1:50.