A butylphthalide cationic nanoemulsion, its preparation method and application

Abstract

This invention relates to a butylphthalide cationic nanoemulsion, its preparation method, and its application, belonging to the field of pharmaceutical technology. The butylphthalide cationic nanoemulsion comprises an oil phase, an aqueous phase, butylphthalide, an emulsifier, a co-emulsifier, an osmotic pressure regulator, and a cationic surfactant. The butylphthalide content in the nanoemulsion is 0.30%–2.50% by mass. The average particle size of the butylphthalide cationic nanoemulsion is 80–200 nm, the polydispersity index is 0.070–0.200, and the zeta potential is 20–30 mV. This invention solves the problems of poor water solubility and low stability of butylphthalide by preparing it into a nanoemulsion formulation; furthermore, by administering it via nasal administration, it meets the need for rapid neuroprotection in ischemic stroke.

Description

Technical Field

[0001] This invention relates to a butylphthalide cationic nanoemulsion, its preparation method, and its application, belonging to the field of pharmaceutical technology. Background Technology

[0002] Cerebral ischemic stroke, also known as cerebral infarction, is a syndrome caused by local blood supply disorders leading to cerebral ischemia and hypoxia, which in turn causes necrosis and softening of brain tissue. Clinically, it is mainly manifested as sudden focal or diffuse neurological deficits. It is the main type of stroke, accounting for about 80% of all stroke cases. It is characterized by high incidence, high recurrence rate, high disability rate, and high mortality rate. Its prognosis is closely related to the severity of neurological deficits, age, and etiology, which bring a heavy medical burden and economic pressure to patients' families and society.

[0003] Butylphthalide (NBP) is an anti-stroke chemical drug with independent intellectual property rights in my country. It is a synthetic racemic compound with a structure identical to that of natural apigenin A. Pharmacological studies have confirmed that butylphthalide exerts significant neuroprotective effects through multiple mechanisms, including remodeling microcirculation in ischemic areas, protecting mitochondrial function, and inhibiting oxidative stress and neuronal apoptosis. Clinically, it is widely used to improve neurological deficit symptoms in patients with acute ischemic stroke.

[0004] However, butylphthalide is currently mainly available in injection and soft capsule forms, which have significant drawbacks and cannot meet the core needs of rapidly protecting ischemic brain tissue, reducing neurological damage, and lowering the incidence of sequelae. Butylphthalide injection requires intravenous infusion under the supervision of professional medical staff in a hospital, and the preparation and administration process is time-consuming. In the acute phase of ischemic stroke, after brain tissue ischemia and hypoxia, brain cells begin to be damaged and gradually die. Delayed infusion can easily lead to missed opportunities for brain protection, thereby aggravating neurological deficits and increasing the risk of sequelae such as hemiplegia and aphasia. Butylphthalide soft capsules are an oral dosage form, which is often not feasible for patients with acute attacks. Forced administration requires absorption through the gastrointestinal tract and metabolism in the liver, resulting in a slow absorption rate and a long time to reach an effective brain-protective concentration in the blood. This also makes it difficult to quickly penetrate the blood-brain barrier to reach the ischemic lesion and exert its effect, thus failing to achieve the goal of rapid brain protection in the acute phase.

[0005] Nasal administration of drugs has unique physiological advantages. The nasal mucosa is rich in blood vessels and has a direct nasobrain pathway, allowing for rapid absorption and direct transport of the drug to the brain after administration. It bypasses the gastrointestinal tract and liver metabolism, quickly reaching effective neuroprotective concentrations and promptly blocking further damage to ischemic brain tissue. However, the physicochemical properties of butylphthalide significantly limit its nasal application. This drug is oily at room temperature, highly lipid-soluble, and extremely poorly water-soluble. Summary of the Invention

[0006] To address the aforementioned problems in existing technologies, this invention provides a butylphthalide cationic nanoemulsion, its preparation method, and its nasal administration application. Nanoemulsions are thermodynamically stable systems spontaneously generated or prepared through efficient emulsification processes from an oil phase, an aqueous phase, an emulsifier, and a co-emulsifier in appropriate proportions. The dispersed phase droplet size is typically in the nanometer range (e.g., 20-200 nm). Nanoemulsions can significantly improve the solubility of lipid-soluble drugs in aqueous media, increase drug stability, and are expected to promote transmembrane absorption of drugs through various mechanisms. Therefore, this invention solves the problems of poor water solubility and low stability of butylphthalide by preparing it into a nanoemulsion formulation; furthermore, nasal administration allows it to meet the need for rapid neuroprotection in ischemic stroke.

[0007] A butylphthalide cationic nanoemulsion comprises an oil phase, an aqueous phase, butylphthalide, an emulsifier, a co-emulsifier, an osmotic pressure regulator, and a cationic surfactant. The mass percentage of butylphthalide in the nanoemulsion is 0.30% to 2.50%. The average particle size of the butylphthalide cationic nanoemulsion is 80 to 200 nm, the polydispersity index is 0.070 to 0.200, and the zeta potential is 20 to 30 mV.

[0008] The butylphthalide cationic nanoemulsion of this invention has a milky white appearance with a bluish tint and an average particle size of 80-200 nm, more preferably 90-130 nm. The nanoemulsion of this invention exhibits strong loading capacity for the hydrophobic drug butylphthalide, effectively solving the problem of difficult drug administration and improving patient compliance.

[0009] Furthermore, the oil phase is a medium-chain triglyceride (MCT), and the mass percentage of the oil phase in the nanoemulsion is 1.0% to 5.0%.

[0010] Furthermore, the aqueous phase is purified water.

[0011] Furthermore, the emulsifier is one or more of egg yolk lecithin PL-100M, egg yolk lecithin E80, soybean lecithin S100, and soybean lecithin PC80, and the mass percentage of the emulsifier in the nanoemulsion is 0.5% to 2.5%.

[0012] Furthermore, the co-emulsifier is one or more of poloxamer 188, propylene glycol, or isopropanol, and the mass percentage of the co-emulsifier in the nanoemulsion is 0.5% to 2.5%.

[0013] Furthermore, the osmotic pressure regulator is glycerol, and the mass percentage of the osmotic pressure regulator in the nanoemulsion is 1.0% to 3.0%.

[0014] Furthermore, the cationic surfactant is one or more of chitosan, octadecylamine, citrate chloride, and cetrimonium bromide, and the mass percentage of the cationic surfactant in the nanoemulsion is 0.005% to 0.025%.

[0015] Another object of the present invention is to provide a method for preparing the above-mentioned butylphthalide cationic nanoemulsion, comprising the following steps:

[0016] (1) Mix the oil phase with butylphthalide and stir until homogeneous to obtain an oil phase mixture; (2) Place the emulsifier, co-emulsifier, osmotic pressure regulator and cationic surfactant in purified water and stir until completely dispersed to obtain an aqueous mixture; (3) Under high-speed shearing conditions, the oil phase mixture is slowly added dropwise to the aqueous phase mixture to obtain a crude emulsion; (4) The crude emulsion was subjected to high pressure homogenization to obtain butylphthalide cationic nanoemulsion.

[0017] Furthermore, in step (3), the shearing speed is 5000~12000 rpm and the time is 1~9 min.

[0018] Furthermore, in step (4), the homogenization pressure is 300~1500 bar, and the number of times is 3~13.

[0019] This invention employs a high-energy emulsification method, and the small particle size emulsion can significantly improve the dissolution rate and mucosal permeation of butylphthalide, thereby further improving bioavailability and reducing toxic side effects.

[0020] The butylphthalide cationic nanoemulsion prepared by this invention does not contain organic solvents, has higher safety, is simple to prepare, is easy to industrialize, and has better solubility, stability and smaller particle size.

[0021] Another object of the present invention is to provide the application of the above-mentioned butylphthalide cationic nanoemulsion in the preparation of drugs for treating brain diseases.

[0022] Preferably, the brain disease is ischemic stroke.

[0023] Furthermore, the administration method is nasal administration.

[0024] More preferably, the dosage form of the butylphthalide cationic nanoemulsion is a nasal spray.

[0025] The beneficial effects of this invention are as follows: This invention utilizes a high-speed shearing combined with high-pressure homogenization preparation technique to efficiently load the poorly soluble drug butylphthalide into an oil-phase core, forming a nanoemulsion with uniform particle size and molecular dispersion, thereby significantly improving its apparent solubility in aqueous media. The nanoemulsion uses the oil phase as the drug-carrying core and a composite interfacial film synergistically constructed by specific emulsifiers and co-emulsifiers as a stable outer shell, effectively protecting the drug and maintaining the long-term stability of the formulation. Therefore, this invention provides a butylphthalide cationic nanoemulsion with good stability and low irritation. Nasal administration, through cationic modification, significantly improves the nasal mucosa's permeability. The direct naso-brain pathway allows the drug to rapidly reach the ischemic lesion, overcoming the shortcomings of time-consuming traditional injection administration and slow absorption of oral formulations. This provides a non-invasive and convenient novel local drug delivery strategy for the treatment of stroke. Attached Figure Description

[0026] Figure 1 The TEM image shows the structure of the butylphthalide cationic nanoemulsion obtained in Example 2. Figure 2 This is a section image of nasal mucosa irritation in Example 7; Figure 3 This is a graph showing the neurological function scores of rats in the ischemic stroke model in Example 8; Figure 4 The results of TTC staining and the map of cerebral infarction area in the ischemic stroke model rats in Example 8 are shown. Figure 5 The image shows the H&E staining results of the ischemic stroke model rats in Example 8. Figure 6 The image shows the TUNEL staining results of the ischemic stroke model rats in Example 8. Figure 7 This is a graph showing the results of inflammatory factor content in rats with ischemic stroke in Example 8. Detailed Implementation

[0027] The following non-limiting embodiments are intended to enable those skilled in the art to more fully understand the invention, but do not limit the invention in any way.

[0028] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0029] Unless otherwise specified, the present invention does not have any special limitation on the source of the raw materials, and products prepared by commercially available products or conventional preparation methods known to those skilled in the art are acceptable.

[0030] Example 1 The preparation process of butylphthalide nanoemulsions 1-13 includes the following steps: (1) Weigh 0.60 g butylphthalide and 3.00 g MCT into a beaker and mix them. Stir at room temperature until a homogeneous and transparent oil phase mixture is formed. (2) Place 1.00 g emulsifier, 1.00 g co-emulsifier and 1.00 g glycerol in 90 mL of purified water and stir until completely dispersed to obtain an aqueous mixture; (3) The oil phase mixture was slowly added to the water phase mixture at a speed of 7000~13000 rpm and sheared for 3 min to obtain a crude emulsion; (4) The crude emulsion is homogenized under high pressure at 300~1100 bar for 9 times to obtain nano-emulsion.

[0031] 1. Optimization of emulsifiers in butylphthalide nanoemulsions: In step (2), the emulsifiers were E80, PL-100M, S100, and PC80, and the co-emulsifier was propylene glycol; in step (3), the shear rate was 11000 rpm; in step (4), the homogenization pressure was 900 bar, and nanoemulsions 1, 2, 3, and 4 were prepared. The prepared nanoemulsions were subjected to particle size, PDI, potential, and centrifugal stability tests, and the results are listed in Table 1. As can be seen from Table 1, the nanoemulsions prepared with E80 as the emulsifier had more uniform particle size, better dispersion, and better physical stability.

[0032] Table 1. Particle size, PDI, potential, and centrifugal stability of nanoemulsions

[0033] 2. Optimization of co-emulsifiers in butylphthalide nanoemulsions: In step (2), the emulsifier was E80, and the co-emulsifiers were propylene glycol, isopropanol, and poloxamer 188; in step (3), the shear rate was 11000 rpm; in step (4), the homogenization pressure was 900 bar, and nanoemulsions 1, 5, and 6 were prepared. The particle size, PDI, potential, and centrifugal stability of nanoemulsions 1, 5, and 6 were tested, and the results are listed in Table 2. As can be seen from Table 2, the butylphthalide nanoemulsions prepared with propylene glycol as the co-emulsifier had more uniform particle size, better dispersion, and better physical stability.

[0034] Table 2. Particle size, PDI, potential, and centrifugal stability of nanoemulsions

[0035] 3. Optimization of shear rate in butylphthalide nanoemulsion: In step (2), the emulsifier was E80 and the co-emulsifier was propylene glycol; in step (3), the shear rates were 11000 rpm, 7000 rpm, 9000 rpm, and 13000 rpm; in step (4), the homogenization pressure was 900 bar, and nanoemulsions 1, 7, 8, and 9 were prepared. The particle size, PDI, potential, and centrifugal stability of nanoemulsions 1, 7, 8, and 9 were tested, and the results are listed in Table 3. As can be seen from Table 3, the butylphthalide nanoemulsions prepared at shear rates of 7000~11000 rpm had more uniform particle size, better dispersion, and better physical stability.

[0036] Table 3. Particle size, PDI, potential, and centrifugal stability of nanoemulsions

[0037] 4. Optimization of homogenization pressure in butylphthalide nanoemulsions: In step (2), the emulsifier was E80 and the co-emulsifier was propylene glycol; in step (3), the shear rate was 11000 rpm; in step (4), the homogenization pressures were 900 bar, 300 bar, 500 bar, 700 bar, and 1100 bar, respectively, to prepare nanoemulsions 1, 10, 11, 12, and 13. The particle size, PDI, potential, and centrifugal stability of nanoemulsions 1, 10, 11, 12, and 13 were tested, and the results are listed in Table 4. According to the homogenization pressure screening results shown in Table 4, the average particle size and PDI of the formulation gradually decreased with the increase of homogenization pressure. Considering the particle size, PDI, and production cost, this invention determined 900 bar as the optimal homogenization pressure.

[0038] Table 4. Particle size, PDI, potential, and centrifugal stability of nanoemulsions

[0039] Example 2 A method for preparing a butylphthalide cationic nanoemulsion includes the following steps: (1) Weigh 0.60 g butylphthalide and 3.00 g MCT into a beaker and mix them. Stir at room temperature until a homogeneous and transparent oil phase mixture is formed. (2) Place 1.00 g E80, 1.00 g propylene glycol, 1.00 g glycerol and 0.015 g citrate in 90 mL of purified water and stir until completely dispersed to obtain an aqueous mixture; (3) The oil phase mixture was slowly added to the water phase mixture at 11,000 rpm and sheared for 3 min to obtain a crude emulsion; (4) The crude emulsion is homogenized under high pressure at 900 bar for 9 times to obtain butylphthalide cationic nanoemulsion.

[0040] Example 3 Replace the citrate in step (2) of Example 2 with chitosan, and keep all other parameters the same as in Example 2.

[0041] Example 4 Replace citrate chloride in step (2) of Example 2 with octadecylamine, and keep all other parameters the same as in Example 2.

[0042] Example 5 Replace cetirizine chloride in step (2) of Example 2 with cetrimonium bromide, and keep all other parameters the same as in Example 2.

[0043] The butylphthalide cationic nanoemulsions prepared in Examples 2-5 were tested for particle size, PDI, potential, and centrifugal stability. They were then tested again after being placed at 40°C for 7 days. The results are listed in Table 5. Table 5 shows that the butylphthalide cationic nanoemulsions prepared using citalopram chloride and cetrimonium bromide have more uniform particle size, better dispersion, and better physical stability. Considering both the stability and safe concentration of the nanoemulsions, this invention determines citalopram chloride as the optimal cationic surfactant.

[0044] Table 5 shows the particle size, PDI, and potential of the butylphthalide cationic nanoemulsions prepared in Examples 2-5, as well as the particle size, PDI, potential, and centrifugal stability of the butylphthalide nanoemulsions after being placed at 40°C for 7 days.

[0045] Example 6 In vitro permeation experiment of butylphthalide cationic nanoemulsion 1. Experimental Materials and Conditions Experimental formulations: Butylphthalide cationic nanoemulsion, butylphthalide anionic nanoemulsion (nanoemulsion 1 prepared according to the preparation method in Example 1, wherein in step (2) the emulsifier is E80 and the co-emulsifier is propylene glycol; in step (3) the shear rate is 11000 rpm; in step (4) the homogenization pressure is 900 bar) and butylphthalide raw material in Example 2 of this invention.

[0046] Experimental materials: Fresh sheep nasal mucosa 2. Experimental Methods Fresh sheep nasal mucosa was fixed between the supply and receiving pools. Simulated nasal fluid containing 2.5% SDS at 37°C was added to both pools. After the system equilibrated for 15 minutes, the diffusion medium in the supply pool was removed and replaced with butylphthalide cationic nanoemulsion, butylphthalide anionic nanoemulsion, and butylphthalide active pharmaceutical ingredient, respectively. The apparatus was placed in a 37°C constant-temperature magnetic stirrer and stirred at 300 rpm, with the supply and receiving pools clamped together. Samples were taken at fixed points to determine the butylphthalide content and calculate the cumulative permeation Q. n .

[0047] 3. Experimental Results The permeability of the nasal mucosa was measured by liquid chromatography, and the results of the permeability parameters for each group are shown in Table 6.

[0048] Table 6. Cumulative infiltration of nasal mucosa in each group

[0049] The results showed that after butylphthalide was prepared into nanoemulsions, the cumulative drug permeation through the nasal mucosa was 0.74 mg and 0.51 mg, respectively, which was higher than that of the butylphthalide raw material group (0.27 mg), and approximately 2.74 and 1.89 times that of the raw material group. This indicates that preparing the drug into nanoemulsions can effectively improve its penetration into the nasal mucosa. The cumulative drug permeation through the nasal mucosa of the cationic nanoemulsion group was 1.45 times that of the anionic nanoemulsion group, indicating that the cationic modified nanoemulsion can improve the permeation through the nasal mucosa by electrostatic adsorption with the nasal mucosa, and has a greater advantage in drug permeation through the nasal mucosa.

[0050] Example 7 Butylphthalide nanoparticle nasal mucosa irritation test 1. Experimental Materials and Conditions Experimental formulation: Butylphthalide cationic nanoemulsion obtained in Example 2 of this invention. The dosage per administration was 4.8 mg / kg.

[0051] Experimental animals: 12 SPF-grade male SD rats, weighing 180-220 g (purchased from the animal facility of Shenyang Pharmaceutical University).

[0052] Animal housing environment: room temperature: 20~25℃; humidity: 40~60%; lighting: artificial light, 12 hours of daylight, 12 hours of darkness.

[0053] 2. Experimental Methods Experimental animals were divided into two groups: one group received physiological saline as a control (Normal), and the other group received the experimental formulation (butylphthalide cationic nanoemulsion obtained in Example 2, Nanoemulsion). The drugs were administered twice daily for 7 consecutive days. Animals were sacrificed 24 hours after the last administration, and nasal mucosa tissue was collected for pathological examination. The results are shown below. Figure 2 .

[0054] 3. Experimental Results Figure 2 The results showed that the nasal mucosa morphology was normal after 7 days of continuous use of butylphthalide cationic nanoemulsion, indicating that butylphthalide cationic nanoemulsion has no obvious irritation and can be applied in clinical practice.

[0055] Example 8 Pharmacodynamic study of butylphthalide cationic nanoemulsion in ischemic stroke 1. Experimental Materials and Conditions Experimental formulation: The butylphthalide cationic nanoemulsion obtained in Example 2 of this invention was used as a control with butylphthalide sodium chloride injection.

[0056] Experimental animals: 24 SPF-grade SD rats, weighing 240-280 g (purchased from the animal facility of Shenyang Pharmaceutical University).

[0057] 2. Experimental Methods (1) Establishment of a rat model of cerebral ischemia-reperfusion (MCAO): SD rats were anesthetized and fixed, and the common carotid artery, internal carotid artery and external carotid artery were separated. An incision was made at the common carotid artery, and a suture thrombus was passed through the internal carotid artery to the middle cerebral artery. Postoperative treatment was performed, and reperfusion was performed 1 hour later.

[0058] (2) Grouping: The experimental animals were randomly divided into 4 groups, with 6 animals in each group: sham operation group, model group, butylphthalide sodium chloride injection group, and butylphthalide cationic nanoemulsion group. The butylphthalide sodium chloride injection group was administered via tail vein bolus injection (7 mg / kg), while the other groups were administered via nasal injection (4.8 mg / kg), twice daily for 7 days.

[0059] 3. Detection indicators (1) Evaluation of neurological function; (2) TTC staining and infarct volume; (3) H&E staining; (4) TUNEL staining; (5) Inflammatory factors: the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the brain.

[0060] 4. Experimental Results (1) Neurological function evaluation results as follows Figure 3 As shown, 7 days after MCAO modeling, the neurological deficit scores of the model group rats were significantly increased, indicating severe neurological dysfunction. The neurological deficit symptoms in the rats were greatly improved after treatment with butylphthalide sodium chloride injection and butylphthalide cationic nanoemulsion.

[0061] (2) TTC staining results are as follows Figure 4 As shown, the brain tissue in the sham surgery group was stained red and there was no infarct area; the model group showed a large area of ​​white infarct area, indicating that the model was successfully established; after administration of butylphthalide sodium chloride injection and butylphthalide cationic nanoemulsion, the infarct area decreased significantly, improving the degree of brain injury.

[0062] (3) H&E staining results are as follows Figure 5As shown, brain cells in the sham-operated group were normal in size and shape, tightly packed, and intact. In the model group, numerous vacuoles appeared between cells, cell arrangement was disordered, and nuclei were condensed. The degree of damage significantly decreased after administration of butylphthalide sodium chloride injection and butylphthalide cationic nanoemulsion.

[0063] (4) TUNEL staining results are as follows Figure 6 As shown, a small number of green apoptotic cells were occasionally observed in the sham surgery group, while a large number of green apoptotic cells appeared in the model group. The number of green apoptotic cells was significantly reduced after administration of butylphthalide sodium chloride injection and butylphthalide cationic nanoemulsion.

[0064] (5) Results of inflammatory factor levels as follows Figure 7 As shown, butylphthalide sodium chloride injection and butylphthalide cationic nanoemulsion treatment can reduce MDA content and increase SOD and GSH-Px content, significantly improving the level of oxidative stress in the brain.

[0065] 5. Experimental Conclusions All the above results demonstrate that butylphthalide cationic nanoemulsion has a significant therapeutic effect on ischemic stroke when administered via nasal cavity.

Claims

1. A butylphthalide cationic nanoemulsion, characterized in that: The butylphthalide cationic nanoemulsion comprises an oil phase, an aqueous phase, butylphthalide, an emulsifier, a co-emulsifier, an osmotic pressure regulator, and a cationic surfactant. The butylphthalide content in the nanoemulsion is 0.30% to 2.50% by mass. The average particle size of the butylphthalide cationic nanoemulsion is 80 to 200 nm, the polydispersity index is 0.070 to 0.200, and the zeta potential is 20 to 30 mV.

2. The butylphthalide cationic nanoemulsion according to claim 1, characterized in that: The oil phase is a medium-chain triglyceride, and the mass percentage of the oil phase in the nanoemulsion is 1.0% to 5.0%; the aqueous phase is purified water.

3. The butylphthalide cationic nanoemulsion according to claim 1, characterized in that: The emulsifier is one or more of PL-100M, E80, S100, and PC80, and the mass percentage of the emulsifier in the nanoemulsion is 0.50% to 2.50%.

4. The butylphthalide cationic nanoemulsion according to claim 1, characterized in that: The co-emulsifier is one or more of poloxamer 188, propylene glycol, or isopropanol, and the mass percentage of the co-emulsifier in the nanoemulsion is 0.50% to 2.50%.

5. The butylphthalide cationic nanoemulsion according to claim 1, characterized in that: The osmotic pressure regulator is glycerol, and the mass percentage of the osmotic pressure regulator in the nanoemulsion is 1.0% to 3.0%.

6. The butylphthalide cationic nanoemulsion according to claim 1, characterized in that: The cationic surfactant is one or more of chitosan, octadecylamine, citrate chloride or citrate bromide, and the mass percentage of the cationic surfactant in the nanoemulsion is 0.005% to 0.025%.

7. The method for preparing butylphthalide cationic nanoemulsion according to any one of claims 1 to 6, characterized in that: Includes the following steps: (1) Mix the oil phase with butylphthalide and stir until homogeneous to obtain an oil phase mixture; (2) Dissolve the emulsifier, co-emulsifier, osmotic pressure regulator and cationic surfactant in purified water and stir until completely dispersed to obtain an aqueous mixture; (3) Under high-speed shearing conditions, the oil phase mixture is slowly added dropwise to the aqueous phase mixture to obtain a crude emulsion; (4) The crude emulsion was subjected to high pressure homogenization to obtain butylphthalide cationic nanoemulsion.

8. The preparation method according to claim 7, characterized in that: In step (3), the shearing speed is 5000~12000 rpm and the time is 1~9 min; in step (4), the homogenization pressure is 300~1500 bar and the number of times is 3~13.

9. The use of the butylphthalide cationic nanoemulsion according to claim 1 in the preparation of drugs for treating brain diseases.

10. The application according to claim 9, characterized in that: The brain disease described is ischemic stroke, and the administration method is nasal administration.

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