Ophthalmic antifungal phospholipid complex solution containing posaconazole and preparation method of ophthalmic antifungal phospholipid complex solution

Abstract

The invention relates to an ophthalmic antifungal phospholipid complex solution containing posaconazole. The ophthalmic antifungal phospholipid complex solution comprises at least one of an anionic phospholipid complex solution, a neutral phospholipid complex solution and a cationic phospholipid complex solution, when the solution is an anionic phospholipid complex solution, the posaconazole, phospholipid, beta-sitosterol, a hydrated buffer solution and an organic solvent are mixed according to a ratio of 10 mg of posaconazole, 20-200 mg of phospholipid, 20-120 mg of beta-sitosterol, 5-20 mL of the hydrated buffer solution and 1-20 mL of the organic solvent; when the solution is a neutral phospholipid complex solution, the posaconazole and phospholipid complex solution is prepared from the following components in proportion: 10 mg of posaconazole, 17.5 to 170 mg of phospholipid, 20 to 120 mg of beta-sitosterol, 2.5 to 30 mg of DSPE-PEG2000, 5 to 20 mL of hydrated buffer solution and 1 to 20 mL of organic solvent; when the solution is a cationic phospholipid complex solution, the following components are proportioned: 10 mg of posaconazole, 17.5 to 170 mg of phospholipid, 20 to 120 mg of beta-sitosterol, 2.5 to 30 mg of DSPE-PEG2000, 20 to 70 mg of a cationic material, 5 to 20 mL of a hydration buffer solution and 1 to 20 mL of an organic solvent. The penetrating power of the phospholipid complex solution in cornea can be remarkably improved, and the effect of treating fungal keratitis is remarkable.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and particularly relates to an ophthalmic antifungal phospholipid complex solution containing posaconazole and a preparation method thereof. Background Art

[0002] Fungal keratitis (FK) is a corneal fungal infection, which is a serious eye disease threatening the vision of patients. In severe cases, it can cause blindness in patients. Corneal fungal infections are caused by more than 100 different species, and more than 95% of them are caused by filamentous fungi Fusarium, Aspergillus and yeasts. In China, Fusarium is the main pathogenic bacterium, followed by Aspergillus and yeasts.

[0003] Polyenes, azoles and pyrimidines are three types of antifungal drugs currently used to treat FK. Polyene antifungal drugs (such as amphotericin B, etc.) irreversibly bind to ergosterol, and by increasing the permeability of the cell membrane, cause the leakage of intracellular substances such as K + , amino acids and nucleotides, disrupt normal cell metabolism, and thus inhibit fungal growth. The mechanism of action of azole drugs (such as fluconazole, itraconazole, posaconazole, etc.) is to inhibit the biosynthesis of ergosterol by inhibiting 14-α demethylation. The N atom on the azole can form a complex with the ferrous ion on the ferrohemoglobin, which is a cofactor of the fungal CYP450 enzyme, inhibit the 14-α methylation process of the CYP450 enzyme, make ergosterol lose its normal shape and physical properties, resulting in leakage due to changes in membrane permeability, and thus cause fungal cell death. The mechanism of action of pyrimidine drugs (such as 5-fluorocytosine) is to interfere with the metabolism of pyrimidines and the synthesis of RNA, DNA and proteins.

[0004] Posaconazole (PCZ) is a second-generation triazole antifungal drug approved by the FDA in 2006 and is a derivative of itraconazole. Chemical name of posaconazole: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolane-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one, and its structural formula is shown as follows: .

[0005] Posaconazole has a broad-spectrum antifungal effect and can be used for the prevention and treatment of invasive fungal infections. Its mechanism of action is to inhibit lanosterol 14α-demethylase (CYP51) on the fungal cell membrane, thereby preventing the biosynthesis of ergosterol in the fungal cell membrane, and then playing a role in inhibiting and killing fungi. Currently, there are 3 dosage forms of posaconazole approved in China, including oral suspension, enteric-coated tablets and injection. Due to its poor solubility, posaconazole (PCZ) is poorly soluble in both water and oil, which limits its clinical application.

[0006] Phospholipid complexes are formed by encapsulating single or multiple layers of lipid bilayers in the form of concentric circles, similar to microspheres of cell membranes, and their main components are phospholipids and sterols. As a drug carrier, phospholipid complexes can endow drugs with advantages such as targeting, prolonged drug efficacy, reduced drug toxicity, improved therapeutic effect, avoidance of tolerance, and alteration of the administration route, thus being widely concerned in the medical field. Phospholipid complexes have hydrophilic and hydrophobic microdomains, which enables them to transport water-soluble and water-insoluble drugs. At the same time, phospholipid complexes have a bilayer membrane structure and good compatibility with biological membranes, making them an ideal carrier for ocular drug delivery. Compared with other nanocarriers, liposomes have advantages such as better stability, biodegradability, biocompatibility and non-immunogenicity. Therefore, phospholipid complexes are more suitable for the treatment of fungal keratitis, and there is currently no report on the treatment of fungal keratitis with posaconazole phospholipid complexes. Based on this, this application was developed. Summary of the Invention

[0007] The purpose of the present invention is to provide an ophthalmic antifungal phospholipid complex solution containing posaconazole to solve the deficiencies of the prior art. Compared with traditional ophthalmic dosage forms, the product of the present invention has stable physicochemical properties, can significantly improve the penetration of posaconazole phospholipid complex in the cornea, and has good corneal permeability, so its therapeutic effect on fungal keratitis is remarkable.

[0008] The present invention also provides a preparation method of the above-mentioned ophthalmic antifungal phospholipid complex solution containing posaconazole.

[0009] To achieve the above purpose, the present invention adopts the following technical solutions: An ophthalmic antifungal phospholipid complex solution containing posaconazole, which comprises at least one of anionic, neutral and cationic phospholipid complex solutions; When it is an anionic phospholipid complex solution, it is prepared from raw materials with the following ratios: Posaconazole 10 mg, phospholipid 20 - 200 mg, β-sitosterol 20 - 120 mg, hydration buffer solution 5 - 20 mL, organic solvent 1 - 20 mL; When it is a neutral phospholipid complex solution, it is prepared from raw materials with the following ratios: Posaconazole 10 mg, phospholipid 17.5 - 170 mg, β-sitosterol 20 - 120 mg, DSPE-PEG 2000 2.5 - 30 mg, hydration buffer solution 5 - 20 mL, organic solvent 1 - 20 mL; When it is a cationic phospholipid complex solution, it is prepared from raw materials with the following ratios: Posaconazole 10 mg, phospholipid 17.5 - 170 mg, β-sitosterol 20 - 120 mg, DSPE-PEG 2000 2.5 - 30 mg, cationic material 20 - 70 mg, hydration buffer solution 5 - 20 mL, organic solvent 1 - 20 mL.

[0010] Specifically, the phospholipid can be at least one of soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, etc.

[0011] Specifically, the hydration buffer solution can be phosphate buffer solution with a pH value of 5 - 8.

[0012] Specifically, the organic solvent can be at least one of methanol, ethanol, dichloromethane, chloroform, acetone, DMF (N,N-dimethylformamide), etc.

[0013] Furthermore, the cationic material can be at least one of lipophilic compounds such as octadecylamine, octadecanamide, trimethyl-2,3-dioleyloxypropylammonium bromide, etc., and water-soluble compounds such as quaternary ammonium salt chitosan.

[0014] As a preference, for the ophthalmic antifungal phospholipid complex solution containing posaconazole, when it is an anionic phospholipid complex solution, it is prepared from raw materials with the following ratios: posaconazole 10 mg, phospholipid 20 - 120 mg, β-sitosterol 20 - 80 mg, the dosage of hydration buffer solution is 5 - 15 mL, and the dosage of organic solvent is 1 - 10 mL.

[0015] The present invention provides a preparation method of the above-mentioned ophthalmic antifungal phospholipid complex solution containing posaconazole, which includes the following steps: 1) Weigh each component according to the formula ratio, and add posaconazole, phospholipid, β-sitosterol and DSPE-PEG 2000 into a round-bottomed flask. 2) Add the organic solvent into the round-bottomed flask, and ultrasonicate and stir to fully dissolve each solid component; 3) Rotavapor to remove the organic solvent and form a light yellow film on the inner wall of the round-bottomed flask; 4) Add the hydration buffer solution into the round-bottomed flask, stir and ultrasonicate to obtain the ophthalmic antifungal phospholipid complex solution containing posaconazole; When the cationic material is a fat-soluble compound, it is added to the eggplant-shaped flask in step 1); when the cationic material is a water-soluble compound, it is added to the eggplant-shaped flask in step 4).

[0016] Specifically, in step 3), the organic solvent is removed by the thin-film hydration method, and the rotary evaporation temperature is 30-45 °C.

[0017] Specifically, in step 2), it is stirred at 1200-1800 r / min for 1-2 h under a magnetic stirrer. Furthermore, in step 4), it is ultrasonically treated in an ultrasonic crusher for 5-30 min.

[0018] In the present invention, the fat-soluble drug posaconazole, phospholipids, β-sitosterol, etc. are dissolved in an organic solvent, and then the organic solvent is removed by a rotary evaporator and a hydration buffer solution is added to prepare a phospholipid complex solution containing posaconazole. Finally, an ultrasonic crusher can be used for treatment to reduce the particle size of the phospholipid complex. PEG-modified phospholipids and / or positively charged phospholipid-modified phospholipid complexes can also be added. Compared with traditional ophthalmic dosage forms, the ophthalmic antifungal phospholipid complex solution containing posaconazole in the present invention has stable physicochemical properties, can significantly improve the penetration of the posaconazole phospholipid complex in the cornea, and has good corneal permeability, so its therapeutic effect on fungal keratitis is remarkable. The preparation method of the antifungal phospholipid complex solution containing posaconazole in the present invention is simple, has good reproducibility, and is applicable to industrial production.

[0019] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: The ophthalmic antifungal phospholipid complex solution containing posaconazole provided by the present invention is prepared by dissolving fat-soluble materials such as posaconazole, phospholipids, β-sitosterol, etc. in an organic solvent, dissolving water-soluble materials in a phosphate buffer solution, forming a thin film by a rotary evaporator, then hydrating with the phosphate buffer solution, and finally performing ultrasonic size reduction on the whole particles through an ultrasonic crusher to form a posaconazole phospholipid complex. The average particle size of the posaconazole phospholipid complex is less than 200 nm, and its physicochemical properties are stable, which can significantly enhance the absorption of the posaconazole phospholipid complex in the cornea and make its antifungal effect better. Description of the Drawings

[0020] Figure 1 、 3 、5 are the particle size distribution diagrams of three kinds of antifungal phospholipid complex solutions prepared in Examples 2, 3, and 4 of the present invention; Figure 2 、 4 、6 are the Zeta potential distribution diagrams of three kinds of antifungal phospholipid complex solutions prepared in Examples 2, 3, and 4 of the present invention; Figure 7Inhibitory zone results of three anti-fungal phospholipid complex solutions against Aspergillus flavus and Fusarium in Example 5; the left figure shows Aspergillus; the right figure shows Fusarium; in the figures, a: Saline, b: anionic phospholipid complex solution, c: cationic phospholipid complex solution, d: neutral phospholipid complex solution; Figure 8 In Example 6, the corneal penetration behavior of the drug was observed after dropping the C6-labeled carrier solution on the ocular surface; Figure 9 Slit lamp photographs of anti-fungal keratitis models in different groups; white light photograph (a), fluorescein sodium staining photograph (b). Detailed implementation manners

[0021] The technical solutions of the present invention will be further introduced in detail below in conjunction with examples, but the protection scope of the present invention is not limited thereto.

[0022] In the following examples, unless otherwise specified, the raw materials used are all ordinary commercially available products that can be directly purchased, or can be prepared by conventional techniques in the art.

[0023] Example 1 An ophthalmic anti-fungal anionic phospholipid complex solution containing posaconazole is composed of raw materials in the following proportions: 10 mg of posaconazole, 80 mg of soybean lecithin, 30 mg of β-sitosterol, 15 mL of a hydration buffer solution (phosphate buffer solution, pH value 5 - 8), and 5 mL of dichloromethane.

[0024] The optimal preparation method of the above-mentioned ophthalmic anti-fungal phospholipid complex solution containing posaconazole is as follows: 1) Weigh each component according to the formula amount, and add posaconazole, phospholipid, and β-sitosterol to an eggplant-shaped flask; 2) Add the organic solvent to the eggplant-shaped flask and dissolve each component raw material under ultrasonic treatment; 3) Place the eggplant-shaped flask on a magnetic stirrer and stir at 1500 r / min for 1.5 h to fully dissolve it; 4) Place the fully dissolved component raw materials on a rotary evaporator to evaporate the organic solvent, and form a light yellow film evenly distributed in the eggplant-shaped flask; 5) Add the phosphate buffer solution to the eggplant-shaped flask containing the above-prepared light yellow film, and stir for 2 h to form a stable, uniform, and light-transmitting phospholipid complex solution; 6) Ultrasonic the above-prepared phospholipid complex solution in an ultrasonic disintegrator for 15 min to obtain an ophthalmic anti-fungal anionic phospholipid complex solution containing posaconazole.

[0025] The average particle size of the ophthalmic antifungal anionic phospholipid complex solution containing posaconazole prepared with the above raw material ratio is 150 nm. The drug content of the posaconazole ophthalmic antifungal phospholipid complex solution was determined by microcolumn centrifugation and ultraviolet spectrophotometry (UV), and the encapsulation efficiency of the drug in the posaconazole phospholipid complex was 93.24%.

[0026] Example 2 An ophthalmic antifungal anionic phospholipid complex solution containing posaconazole is composed of the following raw materials in the following proportions: 10 mg of posaconazole, 80 mg of soybean lecithin, 30 mg of β-sitosterol, 10 mL of a hydration buffer solution (phosphate buffer solution, pH value 5-8), and 5 mL of dichloromethane.

[0027] The preparation method of the above anionic antifungal phospholipid complex solution is as follows: 1) Weigh each component according to the formula amount, and add posaconazole, phospholipid, and β-sitosterol to a round-bottomed flask; 2) Add the organic solvent to the round-bottomed flask and dissolve each component raw material under ultrasonic waves; 3) Place the round-bottomed flask under a magnetic stirrer and stir at 1500 r / min for 1.5 h to fully dissolve it; 4) Place the fully dissolved component raw materials on a rotary evaporator to evaporate the organic solvent, and form a light yellow film evenly distributed in the round-bottomed flask; 5) Add the phosphate buffer solution to the round-bottomed flask containing the light yellow film prepared above, and stir for 2 h to form a stable, uniform, and light-transmitting phospholipid complex solution; 6) Ultrasonic the prepared phospholipid complex solution in an ultrasonic disintegrator for 15 min to obtain an ophthalmic antifungal anionic phospholipid complex solution containing posaconazole.

[0028] Example 3 An ophthalmic antifungal neutral phospholipid complex solution containing posaconazole is composed of the following raw materials in the following proportions: 10 mg of posaconazole, 70 mg of soybean lecithin, 30 mg of β-sitosterol, 10 mg of DSPE-PEG 2000 10 mL of a hydration buffer solution (phosphate buffer solution, pH value 5-8), and 5 mL of dichloromethane.

[0029] The preparation method refers to Example 2.

[0030] Example 4 An ophthalmic antifungal cationic phospholipid complex solution containing posaconazole is composed of the following raw materials in the following proportions: Posaconazole 10 mg, soybean lecithin 70 mg, β-sitosterol 30 mg, DSPE-PEG 2000 10 mg, cationic material quaternary ammonium chitosan 30 mg, hydration buffer solution (phosphate buffer solution, pH value 5 - 8) with a dosage of 10 mL, dichloromethane 5 mL.

[0031] The preparation method of the above cationic antifungal phospholipid complex solution is as follows: 1) Weigh each component according to the formula amount, and put posaconazole, phospholipid, β-sitosterol and DSPE-PEG 2000 , into an eggplant-shaped flask; 2) Add the organic solvent into the eggplant-shaped flask and dissolve each component raw material under ultrasonic; 3) Place the eggplant-shaped flask under a magnetic stirrer and stir at 1500 r / min for 1.5 h to fully dissolve it; 4) Place the fully dissolved component raw materials on a rotary evaporator to evaporate the organic solvent, and make a light yellow film evenly distributed in the eggplant-shaped flask; 5) Add the cationic material and phosphate buffer solution into the eggplant-shaped flask containing the light yellow film prepared above, and stir for 2 h to make a stable, uniform and transparent phospholipid complex solution; 6) Ultrasonic the prepared phospholipid complex solution in an ultrasonic crusher for 15 min to obtain an ophthalmic antifungal cationic phospholipid complex solution containing posaconazole.

[0032] The particle size and potential distribution of the three different-charge antifungal phospholipid complex solutions prepared in Examples 2, 3, and 4 above are as shown in Figure 1 , 2 , 3, 4, 5, 6. It can be seen from the figure that: the particle sizes of the three different-charge nano-formulations are all below 200 nm, and the PDI is all less than 0.3. The particle sizes are small and the distribution is relatively uniform. The potentials are -24.0 mV, -3.81 mV, and 21.7 mV respectively, and the absolute values of their potentials are relatively large. Therefore, it is speculated that the three different-charge antifungal phospholipid complex solutions have good stability.

[0033] Example 5 For the three antifungal phospholipid complex solutions with different charges prepared by the methods of the above Examples 2, 3, and 4, the diameter of the inhibition zone was measured by an improved filter paper method, specifically as follows: The fungi (Aspergillus flavus strain, Fusarium solani strain) were picked into a 1.5 mL EP tube containing 400 μL of normal saline. After grinding the fungi evenly in the normal saline with a sterile grinding rod, 100 μL was pipetted and added to a 5 mL EP tube containing 4 mL of normal saline and mixed evenly, and then poured into a conical flask containing 400 mL of Sabouraud dextrose agar medium and shaken evenly. About 25 mL of Sabouraud dextrose medium (SDA, preparation: 6.5 g of Sabouraud dextrose agar medium was added to 100 mL of deionized water, and after preparation, it was sterilized) was added to each petri dish. After standing for 5 min, holes were punched with a 6 mm borer. About 50 μL of normal saline, phospholipid complex solution, and PCZ suspension (PCZ suspension preparation: 0.1 g of CMC-Na was added to 10 ml of deionized water and swollen at room temperature for 6 h, and then 10 mg of posaconazole was added and magnetically stirred at room temperature for 2 h, the same below) were taken and placed in the holes. After culturing in a water bath incubator at 24 °C for 48 h, the diameter of the inhibition zone was measured and recorded with a vernier caliper. Each group was repeated three times in parallel.

[0034] The results of the inhibition zone experiment showed (see details in Figure 7 ): The inhibition diameter of the anionic phospholipid complex against Aspergillus flavus was 21.3 ± 0.6 mm; the inhibition diameter of the neutral phospholipid complex against Aspergillus flavus was 17.0 ± 1.0 mm; the inhibition diameter of the cationic phospholipid complex against Aspergillus flavus was 27.7 ± 0.6 mm. The inhibition diameter of the anionic phospholipid complex against Fusarium was 21.3 ± 0.6 mm; the inhibition diameter of the neutral phospholipid complex against Fusarium was 16.7 ± 0.6 mm; the inhibition diameter of the cationic phospholipid complex against Fusarium was 25.0 ± 1.0 mm. Therefore, the bacteriostatic effect of the cationic phospholipid complex was the strongest, followed by the anionic phospholipid complex, and the weakest was the neutral phospholipid complex.

[0035] Example 6 The three antifungal phospholipid complex solutions with different charges prepared by the methods of the above Examples 2, 3, and 4 were used to study the drug penetration behavior of the three antifungal phospholipid complex solutions in the corneas of New Zealand white rabbits by a two-photon laser confocal microscope. Specifically: Twenty-four normal and disease-free New Zealand white rabbits were randomly divided into 4 groups, namely the PCZ suspension, the anionic phospholipid complex solution, the neutral phospholipid complex solution, and the cationic phospholipid complex solution. Each group was respectively given 100 μL of a nano-preparation containing coumarin 6 (C6) (the C6 content was equivalent to the amount of PCZ, and the preparation method was the same as that of the antifungal phospholipid complex solution containing PCZ). The rabbit eyeballs were removed at 30, 60, and 120 min after administration and placed on a foam fixing plate with the cornea facing up, and then placed on a two-photon laser confocal microscope for collection and photography. The results are shown in Figure 8 .

[0036] As Figure 8 shown, with the prolongation of the action time, C6 gradually diffused and penetrated into the corneal stroma, but most of the drug models were still retained in the corneal epithelial cell layer. The fluorescence intensity of C6 also decreased with the prolongation of the action time among different preparation groups. There was no fluorescence in the PCZ suspension group at 2 h. There was weak fluorescence in the corneal epithelial cell layer in the anionic phospholipid complex group and the neutral phospholipid complex group at 2 h. The fluorescence intensity in the cationic phospholipid complex group was stronger than that in the anionic phospholipid complex group and the neutral phospholipid complex group at 2 h. Based on this, it can be shown that: the cationic phospholipid complex group can not only prolong the retention time on the ocular surface, but also enhance the penetration ability of the drug in the corneal epithelium, so as to deliver the drug to the corneal stroma to exert its efficacy.

[0037] Example 7 The three antifungal phospholipid complex solutions with different charges prepared by the methods of the above Examples 2, 3, and 4 were used to establish a fungal keratitis mouse model by the "cross-scratch method". Twelve hours after successful modeling of the mice, the mice without significant conjunctival symptoms and other abnormalities were randomly divided into 5 groups, with 8 mice in each group. This experiment was set up with 5 experimental groups: an anionic control group (normal saline, Saline group), a cationic control group (natamycin eye drops, natamycin group), an anionic phospholipid complex solution group, a neutral phospholipid complex solution group, and a cationic phospholipid complex solution group. Eye drops were administered, and 5 μL was given using a 10 μL pipette. During the administration period, from 8:00 to 20:00 every day, the drug was administered once every 4 hours. The treatment effects of fungal keratitis in each group of mice were observed by slit lamp photography and fluorescein staining photography on the 1st, 3rd, 5th, and 7th days during the administration period. The results are shown in Figure 9 .

[0038] Figure 9The results showed that compared with the normal saline group, the antifungal effects of the three phospholipid complex solutions were significant. However, compared with the cationic control group, the effects of the anionic and neutral phospholipid complex solutions on fungal keratitis were relatively weak, and the cationic phospholipid complex solution had the strongest effect on fungal keratitis. This may be attributed to the addition of quaternary ammonium chitosan, which makes the surface of its nanoparticles carry positive charges, enhances the adhesion to the corneal mucin layer, and thus enhances the effect on fungal keratitis.

Claims

1. An ophthalmic antifungal phospholipid complex solution containing posaconazole, characterized in that: including at least one of anionic, neutral and cationic phospholipid complex solutions; When it is an anionic phospholipid complex solution, it is prepared from the following raw materials: Posaconazole 10 mg, phospholipids 20-200 mg, β-sitosterol 20-120 mg, hydration buffer solution 5-20 mL, organic solvent 1-20 mL; When it is a neutral phospholipid complex solution, it is prepared from the following raw materials: Posaconazole 10 mg, phospholipids 17.5-170 mg, β-sitosterol 20-120 mg, DSPE-PEG 2000 2.5-30 mg, 5-20 mL hydration buffer solution, 1-20 mL organic solvent; When it is a cationic phospholipid complex solution, it is prepared from the following raw materials: Posaconazole 10 mg, phospholipids 17.5-170 mg, β-sitosterol 20-120 mg, DSPE-PEG 2000 2.5-30 mg, cationic material 20-70 mg, hydration buffer solution 5-20 mL, organic solvent 1-20 mL.

2. The ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 1, characterized in that: The phospholipid is at least one of soybean lecithin, hydrogenated soybean lecithin and egg yolk lecithin.

3. The ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 1, characterized in that: The hydration buffer solution is a phosphate buffer solution with a pH value of 5-8.

4. The ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 1, characterized in that: The organic solvent is at least one of methanol, ethanol, dichloromethane, chloroform, acetone and DMF.

5. The ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 1, characterized in that: The cationic material is at least one of octadecylamine, octadecylamide, trimethyl-2,3-dioleyloxypropylamine bromide and quaternary ammonium salt chitosan.

6. The method for preparing the ophthalmic antifungal phospholipid complex solution containing posaconazole according to any one of claims 1 to 5, characterized in that: The following steps are involved: 1) Weigh each component according to the formula ratio, and mix posaconazole, phospholipids, β-sitosterol and DSPE-PEG 2000 Add to eggplant-shaped bottle; 2) Add the organic solvent into the eggplant-shaped bottle, and fully dissolve the solid components by ultrasonication and stirring; 3) The organic solvent is removed by rotary evaporation, and a light yellow film is formed on the inner wall of the eggplant-shaped bottle; 4) Adding hydration buffer solution into the eggplant-shaped bottle, stirring and ultrasonicating, thereby obtaining an ophthalmic antifungal phospholipid complex solution containing posaconazole; Wherein, when the cationic material is a fat-soluble compound, it is added into the eggplant-shaped bottle in step 1); when the cationic material is a water-soluble compound, it is added into the eggplant-shaped bottle in step 4).

7. The method for preparing the ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 6, characterized in that: In the step 3), the organic solvent is removed by thin film hydration method, and the rotary evaporation temperature is 30-45°C.

8. The method for preparing the ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 6, characterized in that: In the step 2), the mixture is stirred at 1200-1800 r / min under a magnetic stirrer for 1-2 h.

9. The method for preparing the ophthalmic antifungal phospholipid complex solution containing posaconazole according to claim 6, characterized in that: In the step 4), ultrasonic treatment is performed in an ultrasonic pulverizer for 5 to 30 minutes.

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