CN112353761B - Dipyridamole self-nanoemulsion preparation and preparation method thereof - Google Patents

Dipyridamole self-nanoemulsion preparation and preparation method thereof Download PDF

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CN112353761B
CN112353761B CN202011331484.XA CN202011331484A CN112353761B CN 112353761 B CN112353761 B CN 112353761B CN 202011331484 A CN202011331484 A CN 202011331484A CN 112353761 B CN112353761 B CN 112353761B
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dipyridamole
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郑春丽
李云
彭桢
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China Pharmaceutical University
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Abstract

The invention discloses a self-nanoemulsion preparation of dipyridamole and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The self-nanoemulsion preparation is prepared from dipyridamole and blank self-nanoemulsion, the blank self-nanoemulsion is prepared from an oil phase, an emulsifier and an auxiliary emulsifier, the dosage of the oil phase is 40-50% of the weight of the blank self-nanoemulsion, and the weight ratio of the emulsifier to the auxiliary emulsifier is 2: 1-4: 1. the preparation method comprises preparing the oil phase, the emulsifier and the co-emulsifier into blank self-nanoemulsion under stirring, adding dipyridamole, and stirring to obtain the drug-loaded self-nanoemulsion. The self-nanoemulsion preparation can be spontaneously emulsified in water to form a nanoemulsion solution with the particle size smaller than 100nm, clear and uniform appearance and good stability, and the nanoemulsion can reduce the precipitation rate of dipyridamole in the stomach and intestine after being orally taken, so that the oral absorption and bioavailability of the medicine are improved.

Description

Dipyridamole self-nanoemulsion preparation and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dipyridamole self-nanoemulsion preparation and a preparation method thereof.
Background
Dipyridamole (DIP), also known as dipyridamole, is a yellow crystalline powder that is not stable to light and therefore needs to be stored in a light-tight, sealed environment. Dipyridamole was developed in 1961 by beliger, germany as a coronary vasodilator for the treatment of angina pectoris; the medicine is found to have the effects of resisting platelets, inhibiting platelet adhesion and aggregation in the 60 s of the 20 th century, and is clinically used for preventing and treating thromboembolic diseases; later, the fact that the dipyridamole has broad-spectrum antiviral effect and immunoregulation effect is discovered successively, and recent researches also discover that the dipyridamole can reverse the multidrug resistance of tumor cells and has synergistic effect when being used with antitumor drugs. With the continuous discovery of new pharmacological effects and clinical applications of dipyridamole, the clinical status of dipyridamole is becoming more and more important, and the development of new dipyridamole preparations is also becoming more and more important.
Dipyridamole is rapidly absorbed after oral administration, is combined with glucuronic acid in the liver and then excreted into the bile, and is absorbed into the blood after entering the small intestine, so that the effect is relatively durable. However, the solubility of the drug has strong pH dependence, i.e., the drug is easily soluble in an acidic medium (the solubility is 36.5mg/mL at pH 1.0 and 37 ℃) and is hardly soluble under weakly alkaline or near-neutral conditions (the solubility is 0.02 mg/mL at pH 7.0 and 37 ℃), which results in poor dissolution and absorption in the gastrointestinal tract after oral administration. In addition, dipyridamole is also a substrate for the action of p-glycoprotein, which further affects its oral absorption. There are studies showing that dipyridamole has an oral bioavailability of only 11% -44% and is subject to large variation.
Dipyridamole preparations on the market at present are dipyridamole tablets, dipyridamole injection and dipyridamole sustained-release capsules recorded in the second department of the 2015 edition of pharmacopoeia of the people's republic of China. Patent CN1698616A discloses an inclusion compound of dipyridamole cyclodextrin and cyclodextrin derivatives, which is prepared by selecting cyclodextrin or its derivatives as inclusion material, and making dipyridamole into cyclodextrin inclusion compound by grinding method or solvent method; although the method can improve the solubility and stability of dipyridamole, an organic solvent with toxic and side effects on a human body is introduced in the preparation process, and cyclodextrin is unstable to acid, can be converted into glucose after being decomposed in vivo, and is not suitable for patients with diabetes. Patent CN104546752A discloses a freeze-dried tablet of dipyridamole composition, which is prepared by adding acidulant to adjust the pH of starch-sucrose solution to acidity, then dissolving the drug, and freeze-drying the obtained mixture in a vacuum freeze-drying oven to obtain the product; the tablet improves the dissolution rate of the dipyridamole in an acidic medium, but does not improve the precipitation problem of the drug in intestinal tracts, and has no remarkable effect on the improvement of the oral absorption and the bioavailability of the drug. Patent CN106692067A discloses a dipyridamole-containing solid dispersion and orally disintegrating tablet, which is prepared from dipyridamole, a carrier and an organic solvent by a spray drying method, wherein the carrier is at least one of hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl methylcellulose succinate; the solid dispersion prepared by the method can improve the solubility of the drug in gastrointestinal fluid, but the degree of inhibiting the crystallization of the drug in the gastrointestinal fluid is limited, and in addition, special spray drying equipment is needed because an organic solvent is introduced in the preparation process, so the production investment cost is higher.
The self-nanoemulsion is a system which is composed of an oil phase, an emulsifier and a co-emulsifier, has uniform and clear appearance and stable kinetics and thermodynamics, and can spontaneously form an oil-in-water type nanoemulsion with the particle size of 10-100nm after being diluted by water under mild stirring. The self-nanoemulsion is used as a drug carrier, and has the characteristics of increasing the solubility of insoluble drugs, improving the bioavailability of the drugs, increasing the local and systemic delivery of the drugs, targeting drug release and the like. In recent years, research shows that the nanoemulsion enters blood through a lymphatic route after being orally taken so as to avoid the biotransformation of the medicine in vivo. In addition, the self-nanoemulsion has small and uniform particle size and low surface tension, and the surfactant in the formula has the capacity of activating epithelial cells, so that the medicine can more easily permeate through the gastrointestinal tract mucous membrane and skin, and the oral absorption of the medicine is further promoted.
Based on the above, the invention designs a drug release system prepared from the nanoemulsion to enhance the solubility and dissolution rate of the dipyridamole in the gastrointestinal tract, thereby improving the oral bioavailability of the drug and providing a new idea for developing a dipyridamole preparation suitable for clinical needs.
Disclosure of Invention
The invention aims to provide a self-nanoemulsion preparation of dipyridamole, which can be spontaneously emulsified in water to form a nanoemulsion solution with the particle size of less than 100nm, clear and uniform appearance and good stability.
In order to achieve the purpose, the invention adopts the following technical scheme:
a dipyridamole self-nanoemulsion preparation is prepared from dipyridamole and blank self-nanoemulsion, wherein the dosage ratio of the dipyridamole to the blank self-nanoemulsion is 18 mg: 1g of a compound;
the blank self-nanoemulsion is prepared from an oil phase, an emulsifier and an auxiliary emulsifier, wherein the dosage of the oil phase is 40-50% of the weight of the blank self-nanoemulsion, and the weight ratio of the emulsifier to the auxiliary emulsifier is 2: 1-4: 1.
further, the oil phase is selected from castor oil, caprylic capric acid monoglyceride and propylene glycol monocaprylate, the emulsifier is selected from polyoxyethylene castor oil, caprylic capric acid polyethylene glycol glyceride or lauric acid polyethylene glycol glyceride, and the co-emulsifier is diethylene glycol monoethyl ether or isopropanol.
Further, the oil phase is propylene glycol monocaprylate, the emulsifier is polyoxyethylene castor oil, and the co-emulsifier is diethylene glycol monoethyl ether.
Further, the self-nanoemulsion preparation is prepared from dipyridamole and blank self-nanoemulsion, wherein the dosage ratio of the dipyridamole to the blank self-nanoemulsion is 18 mg: 1g of a compound; the blank self-nanoemulsion is prepared from propylene glycol monocaprylate, polyoxyethylene castor oil and diethylene glycol monoethyl ether, wherein the weight ratio of the propylene glycol monocaprylate to the polyoxyethylene castor oil to the diethylene glycol monoethyl ether is 45: 36.67: 18.33.
the preparation method of the self-nanoemulsion preparation comprises the steps of preparing the oil phase, the emulsifier and the co-emulsifier into blank self-nanoemulsion under the stirring condition, and then adding dipyridamole for stirring to obtain the drug-loaded self-nanoemulsion.
Has the advantages that: the self-nanoemulsion preparation can be spontaneously emulsified in water to form a nanoemulsion solution with the particle size of less than 100nm, clear and uniform appearance and good stability. Compared with oral solid preparation, the nanoemulsion has the advantages of low production cost, simple process and the like, and can reduce the precipitation rate of dipyridamole in stomach and intestine after oral administration, thereby improving the oral absorption and bioavailability of the drug.
Drawings
Figure 1 is a pseudo-ternary phase diagram of a blank self-nanoemulsion.
Figure 2 is the particle size and PDI results of the oil phase screening.
FIG. 3 shows particle size and PDI results from the emulsifier to co-emulsifier ratio screen.
FIG. 4 shows the particle size and PDI results of the drug dosing screening.
Fig. 5 is the appearance results of blank self-nanoemulsion and drug-loaded self-nanoemulsion.
Fig. 6 is a particle size distribution plot of a blank self-nanoemulsion.
Fig. 7 is a particle size distribution diagram of the drug loaded nanoemulsion.
Figure 8 is the in vitro dissolution results for a commercial formulation and from a nanoemulsion.
Detailed Description
The invention is described in further detail below with reference to the figures and the specific examples, which should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
Example 1
1. Preliminary screening of oil phase, emulsifier and co-emulsifier
Respectively weighing excessive Dipyridamole (DIP) in 2g common oil phase (oleic acid, ethyl oleate, castor oil, glyceryl monooleate, medium chain triglyceride, glyceryl monolinoleate, caprylic capric acid monoglyceride, propylene glycol monocaprylate, oleic acid macrogol glyceride), emulsifier (Tween 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, caprylic capric acid macrogol glyceride, lauric acid macrogol glyceride) and auxiliary emulsifier (diethylene glycol monoethyl ether, polyethylene glycol 400, isopropanol, 1, 2-propylene glycol), ultrasonic dissolving, vortex mixing uniformly, placing in constant temperature shaking table 37 deg.C (measuring lauric acid glyceride at 50 deg.C) to shake at 100rpm for 48h, centrifuging (8000rpm, 20min), diluting 100 μ L supernatant with ethanol to a certain volume, measuring absorbance at 293nm, and calculating the equilibrium solubility of DIP in different oily auxiliary materials.
The results are as follows:
auxiliary materials Equilibrium solubility (mg/g)
Oleic acid 4.56
Oleic acid ethyl ester 1.71
Castor oil 5.93
Glyceryl monooleate 3.17
Medium chain triglycerides 0.21
Monolinolic acid glyceride 4.72
Caprylic capric acid monoglyceride and diglyceride 14.34
Propylene glycol monocaprylate 13.93
Oleic acid polyethylene glycol glyceride 1.84
Tween 80 7.62
Polyoxyethylene hydrogenated castor oil 9.10
Polyoxyethylene Castor oil 9.30
Caprylic capric acid polyethylene glycol glyceride 10.47
Lauric acid polyglycol glyceride 14.34
Diethylene glycol monoethyl ether 38.09
Polyethylene glycol 400 17.50
Isopropanol (I-propanol) 54.62
1, 2-propanediol 32.42
As can be seen from the above table, DIP has a high solubility in castor oil, caprylic/capric acid monoglyceride, propylene glycol monocaprylate, polyoxyethylene castor oil, caprylic/capric acid macrogol glyceride, lauric macrogol glyceride, diethylene glycol monoethyl ether, and isopropyl alcohol.
2. Compatibility test of auxiliary Material
According to the equilibrium solubility measurement results of DIP in different oil phases, an oil phase, an emulsifier and a co-emulsifier which are good in DIP dissolution are respectively selected for an auxiliary material compatibility experiment. Mixing the selected oil phase, emulsifier and co-emulsifier according to the weight ratio of 2:2:1, and performing vortex and shaking uniformly to form transparent and uniform blank self-nanoemulsion. Draw 200. mu.L of blank from nanoemulsion slowly drop-add to 40mL of deionized water, gently stir at 100rpm at 37 ℃, after it self-emulsifies completely, observe whether clear or translucent microemulsion with light blue opalescence can be formed. And (3) inspecting the self-emulsifying effect by adopting a visual inspection method, and measuring the self-emulsifying time to select an oil phase, an emulsifier and an auxiliary emulsifier with better auxiliary material compatibility.
The results are as follows:
prescription Time of emulsification Traits Whether or not to self-emulsify
Castor oil: polyoxyethylene castor oil: diethylene glycol monoethyl ether <1min C Whether or not
Castor oil: caprylic capric acid polyethylene glycol glyceride: diethylene glycol monoethyl ether >2min E Whether or not
Castor oil: lauric acid macrogolglycerides: diethyl (diethylene)Glycol monoethyl ether >2min E Whether or not
Castor oil: polyoxyethylene castor oil: isopropanol (I-propanol) <1min C Whether or not
Castor oil: caprylic capric acid polyethylene glycol glyceride: isopropanol (I-propanol) >2min E Whether or not
Castor oil: lauric acid macrogolglycerides: isopropanol (I-propanol) >2min E Whether or not
Caprylic capric acid monoglyceride: polyoxyethylene castor oil: diethylene glycol monoethyl ether <2min B Is that
Caprylic capric acid monoglyceride: caprylic capric acid polyethylene glycol glyceride: diethylene glycol monoethyl ether >2min D Whether or not
Caprylic capric acid monoglyceride: lauric acid macrogolglycerides: diethylene glycol monoethyl ether >2min C Whether or not
Caprylic capric acid monoglyceride: polyoxyethylene castor oil: isopropanol (I-propanol) <1min B Is that
Caprylic capric acid monoglyceride: caprylic capric acid polyethylene glycol glyceride: isopropanol (I-propanol) >2min E Whether or not
Caprylic capric acid monoglyceride: lauric acid macrogolglycerides: isopropanol (I-propanol) <1min C Whether or not
Propylene glycol monocaprylate: polyoxyethylene castor oil: diethylene glycol monoethyl ether <1min A Is that
Propylene glycol monocaprylate: caprylic capric acid polyethylene glycol glyceride: diethylene glycol monoethyl ether >2min E Whether or not
Propylene glycol monocaprylate: lauric acid macrogolglycerides: diethylene glycol monoethyl etherAlkyl ethers >2min C Whether or not
Propylene glycol monocaprylate: polyoxyethylene castor oil: isopropanol (I-propanol) <1min A Is that
Propylene glycol monocaprylate: caprylic capric acid polyethylene glycol glyceride: isopropanol (I-propanol) >2min E Whether or not
Propylene glycol monocaprylate: lauric acid macrogolglycerides: isopropanol (I-propanol) >2min C Whether or not
The characteristics are as follows:
a: the appearance is clear with light blue opalescence
B: the appearance is semi-transparent with light blue opalescence
C: the appearance is milky white
D: milky white and oily appearance
E: difficult to emulsify and has a large amount of oil drops
Based on the above results, four prescriptions were selected: a: caprylic capric acid monoglyceride: polyoxyethylene castor oil: diethylene glycol monoethyl ether; b: caprylic capric acid monoglyceride: polyoxyethylene castor oil: isopropyl alcohol; c: propylene glycol monocaprylate: polyoxyethylene castor oil: diethylene glycol monoethyl ether; d: propylene glycol monocaprylate: polyoxyethylene castor oil: and (3) isopropanol.
3. Drawing of pseudo ternary phase diagram
In the self-emulsifying drug delivery system formulation, the oil phase and the emulsifier are generally 25-70% (w/w), and the co-emulsifier is generally 0-25% (w/w). Based on the experimental result of the compatibility of the auxiliary materials, the proportion of the emulsifier, the co-emulsifier and the oil phase is changed within the mass ratio variation range, the components with different proportions are weighed and mixed in a vortex mode to form the uniform and transparent blank self-nanoemulsion. Sucking 150 mu L of blank from the nano-emulsion, adding the blank into 30mL of deionized water, stirring the mixture at 100rpm at 37 ℃, observing the appearance of the solution after the self-emulsification is completed, placing a prescription point of the emulsion which forms transparent or semitransparent emulsion with light blue opalescence in a pseudo-ternary phase diagram, and selecting a system with a larger area as an optimal self-emulsification drug delivery system.
As shown in FIG. 1, the emulsion region of formula C (propylene glycol monocaprylate: polyoxyethylene castor oil: diethylene glycol monoethyl ether) is largest from the nanoemulsion, and thus the oil phase, emulsifier and co-emulsifier used in the formula are defined as propylene glycol monocaprylate, polyoxyethylene castor oil and diethylene glycol monoethyl ether, respectively.
4. Screening of oil phase in proportion to total system
And determining the proportion of the oil phase in the self-nanoemulsion formula according to the result of pseudo-ternary phase diagram experimental screening. The emulsifier and co-emulsifier were mixed as follows 2: ratio of 1 (K)m) The mixture is obtained by uniformly mixing, and the influence of the oil phase ratio of 25, 30, 35, 40, 45, 50, 55, 60 and 65 percent on the particle size and PDI of the nano-emulsion is examined. The results are as follows:
oil phase proportion/%) Particle size/nm PDI
25 205.37±3.45 0.314±0.023
30 164.79±3.11 0.323±0.017
35 143.60±1.50 0.290±0.010
40 81.77±1.98 0.251±0.032
45 53.97±1.59 0.231±0.008
50 86.06±1.73 0.223±0.036
55 111.26±9.33 0.197±0.033
60 123.43±3.11 0.221±0.006
65 142.42±2.84 0.237±0.029
As can be seen from the above table and FIG. 2, when the oil phase ratio is > 35%, the PDI is less than 0.3; when the proportion of the oil phase is 40-50%, the particle size is below 100nm, which shows that the particle size of the self-nano emulsion is small and uniform.
5. Ratio of emulsifier to co-emulsifier (K)m) Screening of (2)
The ratio of emulsifier to co-emulsifier (K) was examined based on the results of the oil phase, emulsifier and co-emulsifier screensm) 1:2, 1:1, 2:1, 3:1, 4:1, 6:1, 8:1, respectively, on the nanoemulsion particle size and PDI. The results are as follows:
Km particle size/nm PDI
1:2 352.63±8.86 0.320±0.02
1:1 127.82±4.12 0.299±0.010
2:1 49.18±5.65 0.261±0.008
3:1 68.08±2.77 0.231±0.012
4:1 93.77±11.52 0.262±0.023
6:1 118.80±2.14 0.294±0.010
8:1 127.05±7.96 0.323±0.010
As can be seen from the above table and FIG. 3, when the emulsifier to co-emulsifier ratio K ismThe particle size is relatively uniform when the particle size is 1:1 to 6:1, and the PDI is less than 0.3; when K ismWhen the particle diameter is 2:1, 3:1 and 4:1, the particle diameter is less than 100 nm.
6. Determination of dosage
Accurately weighing 1g of blank self-nanoemulsion under the optimal formula (45% of propylene glycol monocaprylate, 36.67% of polyoxyethylene castor oil, 18.33% of diethylene glycol monoethyl ether and w/w) in a penicillin bottle, respectively adding 20mg, 18mg, 16 mg and 15mg of DIP into the system A, and uniformly stirring to obtain self-nanoemulsion preparations with different drug contents. The self-nanoemulsion preparation is placed at room temperature for a week to observe whether a drug precipitates or not. About 150. mu.L of the self-emulsion was additionally sucked and added to 30mL of deionized water, gently stirred at 37 ℃ at 100rpm, after its self-emulsification was completed, the particle size and PDI of the solution were measured, and the emulsified self-nanoemulsion was centrifuged (4000r/min, 20min) to observe the presence or absence of separation.
Figure BDA0002795956920000071
As is clear from the above table and FIG. 4, when the amount of the drug to be added was 20mg, the drug was precipitated after leaving for one week, but when the amount of the drug to be added was 18mg or less, the drug was not precipitated. The medicine adding amount has no great influence on the particle size and PDI of the medicine-carrying self-nano emulsion, and the medicine-carrying self-nano emulsion is not layered after centrifugation, which shows that the centrifugal stability is better.
7. The preparation process comprises the following steps: taking oily auxiliary materials (45% of propylene glycol monocaprylate, 36.67% of polyoxyethylene castor oil, 18.33% of diethylene glycol monoethyl ether and w/w) under an optimal formula, forming uniform, clear and transparent blank self-nanoemulsion under magnetic stirring, and adding a formula amount of medicine (18mg/g) into the blank self-nanoemulsion to stir to obtain bright yellow, uniform and clear medicine-carrying self-nanoemulsion. The drug-loaded nanoemulsion was added dropwise to deionized water with gentle stirring (37 ℃, 100rpm) to obtain an emulsified dipyridamole self-nanoemulsion.
(1) And (3) characterization: observing the appearance of the blank and the drug-loaded self-nanoemulsion; measuring the emulsification time from the nanoemulsion; the particle size and PDI of blank and drug-loaded self-nano emulsion are determined by utilizing a dynamic light scattering principle. The results are as follows:
preparation group Self-emulsifying time/s Particle size/nm PDI
Blank self-nanoemulsion 17.41±1.02 45.59±1.55 0.231±0.004
Drug-loaded self-nanoemulsion 16.30±1.16 51.03±0.94 0.251±0.011
As shown in fig. 5, the blank is clear, uniform, and transparent from the nanoemulsion appearance. The emulsion is emulsified by deionized water to form a uniform, semitransparent self-nanoemulsion solution with light blue opalescence. The drug-loaded self-nanoemulsion is clear and uniform in appearance and has bright yellow fluorescence. The deionized water is emulsified to form a uniform, semitransparent and opalescent self-nanoemulsion solution.
As shown in fig. 6 and 7, the drug loading was slightly larger than the blank self-nanoemulsion in terms of particle size and PDI, probably because DIP was encapsulated in the nanoemulsion droplets.
(2) In vitro dissolution: 3 batches of DIP self-nanoemulsion were prepared according to the optimal prescription (propylene glycol monocaprylate 45%, polyoxyethylene castor oil 36.67%, diethylene glycol monoethyl ether 18.33%, w/w, drug loading 18mg/g), measured according to XC dissolution test method, supplement of pharmacopoeia of the people's republic of China (2010 version), using 75mL0.1M HCl solution as medium, temperature (37 + -0.5) DEG C, rotation speed 100rpm, sampling 2mL at 5, 15, 30, 60, 120min respectively, and supplementing medium with the same volume and temperature. After 2h, the pH of the medium was adjusted to 6.8 immediately with 25mL of 0.2moL/L sodium phosphate solution, and 2mL was sampled at 130, 150, 180, 240, 300min and replenished. Filtering the sample with 0.45 μm filter membrane, demulsifying the filtrate with ethanol, diluting with hydrochloric acid to appropriate times, measuring absorbance at 284nm, and calculating the dissolution rate of DIP at each time point.
The dissolution of the drug from simulated gastrointestinal fluids for the commercial formulation of DIP and the self-nanoemulsion of DIP is shown in FIG. 8. As can be seen, both formulations were almost completely dissolved within the first 2 h; however, when the medium was switched to simulated intestinal fluid at pH 6.8, the dissolution of the commercial formulation was significantly reduced, with only about 3% of the drug being dissolved, while the self-emulsifying formulation was still able to dissolve more than 90% of the drug. This is because DIP has a good solubility in an acidic medium, and thus the drug may be rapidly released from a commercially available preparation without precipitation, but when the medium is converted into a simulated intestinal fluid, free drug leaked out in an acidic medium precipitates due to a rapid decrease in the solubility of DIP, resulting in a decrease in the dissolution rate of the drug. On one hand, the medicine in the self-emulsifying preparation is encapsulated in emulsion drops in an acidic medium, so that the leakage of the medicine is reduced, and on the other hand, when part of the leaked medicine is transferred to simulated intestinal fluid, the medicine is solubilized by the self-nano emulsion, so that the dissolution rate of the DIP is improved. Therefore, the prepared DIP self-nanoemulsion can improve the dissolution rate of the medicament in the gastrointestinal tract, and lays a foundation for further improving the bioavailability of DIP.

Claims (2)

1. A self-nanoemulsion formulation of dipyridamole, characterized by: the self-nanoemulsion preparation is prepared from dipyridamole and blank self-nanoemulsion, wherein the dosage ratio of the dipyridamole to the blank self-nanoemulsion is 1-18 mg: 1g of a compound;
the blank self-nanoemulsion is prepared from oil-phase propylene glycol monocaprylate, an emulsifier polyoxyethylene castor oil and a co-emulsifier diethylene glycol monoethyl ether, wherein the weight ratio of the propylene glycol monocaprylate to the polyoxyethylene castor oil to the diethylene glycol monoethyl ether is 45: 36.67: 18.33.
2. the method of preparing a self-nanoemulsion formulation of claim 1, characterized in that: preparing the oil phase, the emulsifier and the co-emulsifier into blank self-nanoemulsion under the stirring condition, and then adding dipyridamole for stirring to obtain the drug-loaded self-nanoemulsion.
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