High-stability ceftiofur hydrochloride oily injection and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary preparations, and particularly relates to a high-stability ceftiofur hydrochloride oily injection and a preparation method thereof. The injection comprises the following components in percentage by weight: 5%-15% of ceftiofur hydrochloride; 0.5%-1% of hydrogenated castor oil (HCO); 0.5%-2% of span 80; 0.05%-0.3% of an absorption promoter; 0.05%-0.5% of an antioxidant; and the balance of cottonseed oil. Through a ternary auxiliary material synergistic system, a gradient temperature control-high-speed shearing process and an intelligent viscosity regulation and control technology, breakthrough improvement of three core indexes including stability, bioavailability and safety of the oily injection is achieved, meanwhile, the high-concentration ceftiofur hydrochloride long-acting preparation has the remarkable cost advantage, and the industrial blank of a high-concentration ceftiofur hydrochloride long-acting preparation is filled up.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drug preparations, and particularly relates to a high-stability ceftiofur hydrochloride oily injection and a preparation method thereof. Background Art

[0002] Ceftiofur is a third-generation cephalosporin antibiotic specifically for animal use, offering significant clinical advantages: It has a broad antimicrobial spectrum, demonstrating potent antimicrobial activity against common Gram-negative bacteria such as Escherichia coli, Salmonella, Pasteurella multocida (including Pasteurella multocida and Pasteurella multocida), and Actinobacillus pleuropneumoniae. Ceftiofur also exhibits excellent pharmacokinetic properties, with rapid absorption and widespread tissue distribution following intramuscular injection. In clinical practice, it demonstrates sustained efficacy and low toxicity and side effects. Based on these advantages, the drug is widely used in veterinary clinics, primarily for the treatment of respiratory and urinary tract infections in livestock and poultry caused by susceptible bacteria, playing a vital role in safeguarding livestock and poultry health.

[0003] Currently, the main formulations of ceftiofur on the market are powder for injection and injection. Ceftiofur hydrochloride injection is an oil suspension preparation with the characteristics of easy use and long-term sustained release, which is favored by the majority of users. However, there are still many unreasonable aspects in the formulation design of existing ceftiofur hydrochloride injection. Traditional ceftiofur hydrochloride oil injection generally uses a single vegetable oil (such as soybean oil, cottonseed oil) as a solvent, supplemented with a high concentration of thickener (such as aluminum stearate, glyceryl monostearate) to delay drug sedimentation. However, this type of preparation has the following key problems: for example, (1) poor physical stability: due to the lack of an effective thixotropic structure, drug particles are prone to sedimentation during static storage, resulting in stratification; (2) low injection compliance: excessive thickener (usually >3%) is added to inhibit sedimentation, resulting in an injection viscosity exceeding 1000 cP, large injection resistance, and increased animal stress response. Research data show that when the viscosity is >500 cP, the syringe push force must exceed 5N, which is much higher than the ideal range for intramuscular injection (1-3N); (3) Drug degradation risk: The traditional process uses high temperature (>80℃) to dissolve excipients, which leads to the ring-opening degradation of the heat-unstable ceftriaxone β-lactam ring.

[0004] In recent years, researchers have attempted to optimize oily injections through the following approaches, but all have significant shortcomings. For example, it has been proposed that polylactic-co-glycolic acid (PLGA) could be used to encapsulate the drug ceftiofur to improve sustained release. However, PLGA has poor compatibility in the oil phase and requires the addition of large amounts of cosolvents (such as N-methylpyrrolidone), which can cause local tissue irritation. Furthermore, some have used lecithin / poloxamer 188 to prepare nanoemulsions. While this improved bioavailability, the aggregation of nanoparticles in the oil phase resulted in an increase in particle size during storage (D90 increased from an initial 2 μm to 8 μm after 6 months), significantly altering the release behavior. Summary of the Invention

[0005] To overcome the shortcomings and deficiencies of the existing technologies, the present invention provides a novel, highly stable oily ceftiofur hydrochloride injection and its preparation method. By utilizing a ternary excipient synergistic system, a gradient temperature control-high-speed shear process, and intelligent viscosity control technology, this invention achieves breakthrough improvements in the three core indicators of stability, bioavailability, and safety for oily injections. This technology also offers significant cost advantages, filling the industry gap in high-concentration, long-acting ceftiofur hydrochloride formulations.

[0006] Specifically, the present invention is achieved through the following technical solutions:

[0007] In a first aspect, the present invention provides a ceftiofur hydrochloride oily injection, which comprises the following components in weight percentage:

[0008] Ceftiofur hydrochloride 5%-15%;

[0009] Hydrogenated castor oil (HCO) 0.5%-1%;

[0010] Span 80 0.5%-2%;

[0011] Absorption enhancer 0.05%-0.3%;

[0012] Antioxidants 0.05%-0.5%;

[0013] The balance is cottonseed oil.

[0014] As an optional mode, in the above injection, the injection comprises the following components in percentage by weight:

[0015] Ceftiofur hydrochloride 8%-12%;

[0016] HCO 0.6%-0.9%;

[0017] Span 80 0.5%-1%;

[0018] Absorption enhancer 0.08%-0.12%;

[0019] Antioxidants 0.08%-0.2%;

[0020] The balance is cottonseed oil.

[0021] As an optional manner, in the above injection, the absorption promoter is sodium silicate, sodium taurocholate or a combination of the two.

[0022] As an optional manner, in the above injection, the antioxidant is at least one of vitamin E and ascorbyl palmitate.

[0023] As an optional manner, in the above injection, the injection further comprises 0.05%-0.3% oleic acid by weight.

[0024] As an optional mode, in the above injection, the injection comprises the following components in percentage by weight:

[0025] Ceftiofur hydrochloride 8%-12%;

[0026] HCO 0.6%-0.9%;

[0027] Span 80 0.5%-1%;

[0028] Sodium decanoate 0.08%-0.12%;

[0029] Vitamin E 0.1%;

[0030] Ascorbyl Palmitate 0.05%

[0031] The balance is cottonseed oil.

[0032] Preferably, the injection comprises the following components:

[0033] Ceftiofur hydrochloride 10%;

[0034] HCO 0.8%;

[0035] Span 80 0.75%;

[0036] Sodium decanoate 0.1%;

[0037] Vitamin E 0.1%;

[0038] Ascorbyl Palmitate 0.05%

[0039] The balance is cottonseed oil.

[0040] In a second aspect, the present invention provides a method for preparing the injection according to the first aspect, the method comprising the following steps:

[0041] Step 1: Heat 3 / 5 cottonseed oil to 70-80°C, add HCO and stir to dissolve to form a thixotropic glue matrix;

[0042] Step 2: Cool down to 60-65℃, add Span 80 and absorption promoter, and stir at constant temperature for activation;

[0043] Step 3: Gradually cool to 25-30°C, add ceftiofur hydrochloride, and disperse at a low speed for 30-60 minutes;

[0044] Step 4: Add the remaining cottonseed oil, premix at 5000-8000 r / min for 5-10 minutes, and high-speed shear at 10000-15000 r / min for 15-30 minutes, and control the particle size D90 ≤ 5 μm;

[0045] Step 5: Filter, fill, and sterilize.

[0046] As an optional manner, in the above preparation method, in step 1, heating is performed to 75-80°C.

[0047] As an optional manner, in the above preparation method, in step 2, the temperature is lowered to 60-62°C.

[0048] As an optional manner, in the above preparation method, in step 3, the temperature is gradually lowered to 25-28° C., at 300 rpm, and stirred for 30-45 min.

[0049] As an optional manner, in the above preparation method, when the injection solution contains oleic acid, the following steps are further included between step 2 and step 3: gradient cooling to 35-45°C, adding oleic acid to adjust the pH of the oil phase to 7.0±0.2, and stirring for 10-20 minutes.

[0050] As an optional manner, in the above preparation method, in step 4, premixing is performed at 5000-6000 r / min for 5-8 min, and high-speed shearing is performed at 10000-12000 r / min for 15-25 min.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] (1) Thixotropic gel-emulsifier synergistic system: HCO (0.5%-1%) and Span 80 (0.5%-2%) form a dynamic gel network, which makes the viscosity of the preparation >5000 cP when standing (anti-settling) and the viscosity when injected <300 cP (easy to push). There is no delamination in the accelerated test at 40°C for 6 months, and the content retention rate is ≥98.5% (conventional oil preparations ≤95%).

[0053] (2) Antioxidant synergy: Vitamin E (0.05%-0.5%) is combined with ascorbyl palmitate (0.01%-0.05%) to enhance antioxidant capacity and improve formulation stability.

[0054] (3) Sustained release and long-term effect: Particle size control (D90 ≤ 5 μm) and thixotropic structure work synergistically, and the cumulative release in vitro for 72 hours is ≥ 90% (traditional preparations reach 90% in 48 hours).

[0055] (4) Synergistic optimization of drug absorption kinetics: The combination of sodium decanoate and HCO increased the drug dissolution rate by 82.4% under physiological pH conditions, exceeding the physicochemical theoretical value by 22.0%.

[0056] (5) Gradient temperature control technology: dissolve HCO at 75°C → activate emulsifier at 60°C → disperse drug at 25°C to avoid degradation of heat-sensitive components, and the process yield is ≥97%.

[0057] (6) Step shearing (premixing + high-speed homogenization) makes the D90 difference between batches ≤0.5μm (RSD<5%). DETAILED DESCRIPTION

[0058] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0059] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0060] The present invention will be further described below in conjunction with the embodiments:

[0061] Preparation Example:

[0062] Example 1:

[0063] Formula composition, in weight percentage:

[0064] Ceftiofur hydrochloride: 5%

[0065] HCO: 0.5%

[0066] Span 80: 0.5%

[0067] Sodium caprate: 0.05%

[0068] Vitamin E: 0.05%

[0069] Cottonseed oil: 93.9%

[0070] Preparation method:

[0071] Step 1: Heat 3 / 5 of the total amount of cottonseed oil (56.34 kg) to 75°C, add HCO (0.5 kg), and stir for 40 minutes to dissolve;

[0072] Step 2: Cool to 60°C, add Span 80 (0.5 kg) and sodium caprate (0.05 kg), and stir at constant temperature for 20 minutes;

[0073] Step 3: Gradual cooling to 25°C, adding ceftiofur hydrochloride (5 kg), and stirring at low speed (300 rpm) for 30 min;

[0074] Step 4: Add cottonseed oil to a total weight of 100 kg and proceed in sequence:

[0075] 5000r / min premixing for 5min;

[0076] 10000r / min high speed shearing for 15min;

[0077] Step 5: 0.45μm filtration and nitrogen filling.

[0078] Example 2:

[0079] Formula composition, in weight percentage:

[0080] Ceftiofur hydrochloride: 10%

[0081] HCO: 0.8%

[0082] Span 80: 0.75%

[0083] Sodium caprate: 0.1%

[0084] Vitamin E: 0.1%

[0085] Ascorbyl palmitate: 0.05%

[0086] Cottonseed oil: 88.2%

[0087] Preparation method:

[0088] Step 1: Heat 3 / 5 of the total amount of cottonseed oil (60 kg) to 78°C, add HCO (0.8 kg), and stir for 45 minutes;

[0089] Step 3: Cool to 62°C, add Span 80 (0.75 kg), sodium caprate (0.1 kg), vitamin E (0.2 kg) and ascorbyl palmitate (0.05 kg), and stir for 25 minutes;

[0090] Step 3: Cool to 28°C at 1°C / min, add ceftiofur hydrochloride (10 kg), and stir at 300 rpm for 40 min;

[0091] Step 4: Add cottonseed oil to a total weight of 100 kg, and perform step shearing: premixing at 6000 rpm for 8 minutes, and high-speed shearing at 12000 rpm for 22 minutes;

[0092] Step 5: Sterile filter through 0.22 μm and aliquot with nitrogen filling.

[0093] Example 3:

[0094] Formula composition, in weight percentage:

[0095] Ceftiofur hydrochloride: 15%

[0096] HCO: 1%

[0097] Span 80: 1.8%

[0098] Sodium taurocholate: 0.15%

[0099] Ascorbyl palmitate: 0.1%

[0100] Oleic acid: 0.1%

[0101] Cottonseed oil: 81.85%

[0102] Preparation method:

[0103] Step 1: Take 3 / 5 of the total amount of cottonseed oil (60 kg), heat it to 80°C, add HCO (1 kg), and stir for 50 minutes;

[0104] Step 2: Cool to 62°C, add Span 80 (1.8 kg), sodium taurocholate (0.15 kg), and ascorbyl palmitate (0.1 kg), and stir for 30 min;

[0105] Step 3: Cool to 40°C at 1.5°C / min, add oleic acid (0.1 kg) to adjust the pH of the oil phase to 7.0 ± 0.2, and stir for 15 min;

[0106] Step 4: Continue to cool to 25-28°C, add ceftiofur hydrochloride (15 kg), and stir at 300 rpm for 45 minutes;

[0107] Step 5: Add cottonseed oil to a total weight of 100 kg, and perform step shearing: premixing at 6000 rpm for 8 min, and high-speed shearing at 12000 rpm for 25 min (control the particle size D90 ≤ 4 μm);

[0108] Step 6: Sterile filter through 0.22 μm and aliquot with nitrogen filling.

[0109] Effect embodiment:

[0110] Effect Example 1: Thixotropic gel-emulsifier synergistic system HCO (0.5%-1%) and Span 80 (0.5%-2%) form a dynamic gel network, synergistic verification (based on 10% ceftiofur hydrochloride injection) 1. Experimental group:

[0111] The test formulation (Example 2) includes, by weight percentage, ceftiofur hydrochloride: 10%, HCO: 0.8%, Span 80: 0.75%, sodium caprate: 0.1%, vitamin E: 0.1%, ascorbyl palmitate: 0.05%, and cottonseed oil: 88.2%.

[0112] Key process: Dissolve HCO at 78℃ → Add Span 80 at 62℃

[0113] Comparative Example 1: HCO 0.8% (without Span 80), other components and amounts are the same as in Example 2, cottonseed oil is added to make the total amount 100%, and the key processes are the same as above.

[0114] Comparative Example 2: Span 80 0.75% (without HCO), other components and amounts are the same as in Example 2, cottonseed oil is added to make the total amount 100%, and the key process is to directly dissolve Span 80 at 60°C.

[0115] Comparative Example 3: HCO 0.8% + Tween 80 0.75% (instead of Span 80), other components and amounts are the same as in Example 2, cottonseed oil is added to make the total amount 100%, and the key process is the same as above.

[0116] 2. Verification indicators:

[0117] (1) Physical stability: Accelerated sedimentation volume ratio at 40℃ for 3 months.

[0118] (2) Rheological properties: Thixotropic recovery rate (viscosity recovery rate after standing at 25°C for 1 hour).

[0119] (3) Injection force: 18G needle injection force (N).

[0120] 3. Test results:

[0121] The comparison of the results of each group is shown in Table 1. The experimental results show that in the preferred test formula of the present invention, HCO provides a thixotropic skeleton and Span 80 reduces the interfacial tension, and the two play an optimal synergistic role in forming a "gel-sol" intelligent conversion system.

[0122] Table 1: Comparison of results of each group

[0123]

[0124] Effect Example 2: Sodium decanoate (0.05%-0.3%) and HCO synergistically promote drug absorption 1. Experimental grouping and medium design

[0125] Table 2: Experimental groups

[0126]

[0127]

[0128] Note: Normal basic formula: by weight percentage, ceftiofur hydrochloride: 10%, Span 80: 0.75%, vitamin E: 0.1%, ascorbyl palmitate: 0.05%, cottonseed oil is added to the total amount of 100%.

[0129] Media switching operation:

[0130] (1) 0-4h: pH 6.8 PBS + 0.5% SDS (simulated muscle environment)

[0131] (2) After 4 hours, the medium was quickly drained and pH 7.4 PBS preheated to 37°C was immediately added (to simulate drug entry into the blood).

[0132] Key Operations (Pulping)

[0133] Paddle speed: 50 rpm, temperature: 37 ± 0.5 °C, sampling points: 0.5, 1, 2, 4 (switching medium), 4.5, 5, 6, 8, 12 h

[0134] Table 3: Medium formulation

[0135]

[0136] Note: SDS: simulates muscle tissue surface activity to prevent drug adsorption. BSA: simulates blood protein binding to reflect the real absorption environment.

[0137] 2. Preparation and feeding of test samples for each experimental group

[0138] The test sample in each test group was heated in a water bath until fully fluid (HCO needed to be completely dissolved), kept constant at 40°C, and vacuum degassed for 10 min to eliminate bubbles. The sample was then filled into capsules (hard gelatin capsules, size 0) at a filling volume of 1.00±0.01 g / capsule (containing 100 mg of ceftiofur). The capsules were fixed with a stainless steel sinker, with the inner distance of the sinker being 25±2 mm from the cup.

[0139] 3. Judgment basis

[0140] Table 4: Criteria for judging synergy

[0141]

[0142] 4. Dissolution data

[0143] 4.1 Dissolution rate data at time points

[0144] Table 5: Dissolution rate data at time points

[0145]

[0146]

[0147] Note: * indicates that the result of comparative example 2 was significantly higher than that of the other three groups when compared with the other three groups.

[0148] Results: The dissolution rate of comparative example 2 (using sodium caprate alone) at pH 6.8 was significantly higher than that of the other groups (P<0.01), demonstrating a burst release effect.

[0149] 4.2 Calculation of key kinetic parameters

[0150] 4.2.1 4h cumulative dissolution rate (Q 4h ) Statistical comparison

[0151] Table 6: 4h cumulative dissolution rate (Q 4h ) Statistical comparison

[0152]

[0153] Results: There was no significant difference between the experimental group and comparative examples 1 and 3 (P>0.05), indicating that sodium decanoate did not affect the sustained-release properties of HCO.

[0154] 4.2.2 4-8h dissolution rate (K 4-8h ,% / h)

[0155] Table 7: 4-8h dissolution rate (K 4-8h ,% / h)

[0156]

[0157]

[0158] Results: The K value of the experimental group (15.5) was greater than the theoretical superposition value (12.7). Compared with the comparative example 1, the experimental group increased by 82.4% (P<0.001).

[0159] 4.2.3 Relative Dissolution Rate (RDR)

[0160] RDR=Ktest group / Kcomparative ratio 1=15.5 / 8.5=1.82>1.5.

[0161] 4.3 Mechanism-related data

[0162] 4.3.1 Specificity comparison

[0163] Table 8: Specificity comparison results

[0164]

[0165] Results: Oleic acid could not replace sodium decanoate, suggesting that the penetration-enhancing effect was molecule-specific.

[0166] Conclusion: The combination of sodium decanoate and HCO increased the drug dissolution rate by 82.4% at physiological pH and exceeded the theoretical value by 22.0%, demonstrating that the two synergistically optimized drug absorption kinetics.

[0167] Effect Example 3: Efficacy Test

[0168] 1. Experimental Design

[0169] Test group: injection of the present invention (10% concentration, formulation of Example 2);

[0170] Control group: Yisuida;

[0171] Blank group: normal saline;

[0172] Trial location: Three porcine pleuropneumonia outbreak farms in Liaoning, Henan, and Sichuan;

[0173] Sample size: n = 600 (experimental group / control group / blank group = 300 / 240 / 60);

[0174] Evaluation period: 0-14 days.

[0175] 2. Subject screening criteria

[0176] Table 9: Screening criteria for subjects

[0177]

[0178] Table 10: Scoring criteria for respiratory symptoms

[0179]

[0180] 3. Dosage regimen and grouping

[0181] Table 11: Dosage regimen and grouping

[0182]

[0183]

[0184] 4. Evaluation indicators and detection methods

[0185] Table 12: Evaluation preparation and detection methods

[0186]

[0187] Lung lesion scoring standard (0-4 points)

[0188] 0 points: no lesion;

[0189] 1 point: <10% consolidation in a single lobe;

[0190] 2 points: 10-30% consolidation in a single leaf;

[0191] 3 points: consolidation of one lobe >30% or two lobes <20%;

[0192] 4 points: diffuse consolidation or pleural adhesions.

[0193] 5. Results

[0194] 5.1 Primary Endpoint Data (Day 7)

[0195] Table 13: Primary endpoint data (Day 7)

[0196]

[0197] 5.2 Secondary Endpoint Data

[0198] Table 14: Secondary endpoint data

[0199] index experimental group control group difference P-value Body temperature recovery time (h) 28.5±6.3 58.2±10.1 ↓51.0％ <0.001 ADG(g / d) 687±58 432±49 ↑59.0％ <0.001 Relapse rate (14 days) 3 / 289(1.0％) 38 / 206(18.4％) ↓94.6％ <0.001 Lung lesion score (dead pigs) 1.2±0.3(n＝5) 3.5±0.6(n＝18) ↓65.7％ <0.001

[0200] 5.3 Changes in Inflammatory Factors (Day 7)

[0201] Table 15: Changes in inflammatory factors (Day 7)

[0202]

[0203] Result analysis: The cure rate of the injection of the present invention on day 7 was 96.3% (95% CI: 93.7-98.2), which was 12.3% higher than that of the commercially available Yisuda (85.8%) (P < 0.001, χ 2 =21.3), the average daily weight gain of the experimental group was 687 g / d, which was 59.0% higher than that of the control group (432 g / d) (P<0.001), and the serum IL-6 level decreased by 57.3% (P<0.001), confirming that sodium decanoate reduced local irritation and the recurrence rate was reduced by 94.6%. This shows that the high-stability ceftiofur hydrochloride oily injection developed by the present invention has good effect, high cure rate, low recurrence rate, and can also reduce drug costs for the aquaculture industry.

[0204] The above are only preferred embodiments of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A ceftiofur hydrochloride oily injection, characterized in that: The injection solution comprises the following components in percentage by weight: Ceftiofur hydrochloride 5%-15%; Hydrogenated castor oil (HCO) 0.5%-1%; Span 80 0.5%-2%; Absorption enhancer 0.05%-0.3%; Antioxidants 0.05%-0.5%; The balance is cottonseed oil.

2. The injection according to claim 1, characterized in that: The injection solution comprises the following components in weight percentage: Ceftiofur hydrochloride 8%-12%; HCO 0.6%-0.9%; Span 80 0.5%-1%; Absorption enhancer 0.08%-0.12%; Antioxidants 0.08%-0.2%; The balance is cottonseed oil.

3. The injection according to claim 1, characterized in that: The absorption promoter is sodium silicate, sodium taurocholate or a combination thereof, and / or the antioxidant is at least one of vitamin E and ascorbyl palmitate.

4. The injection according to claim 1, characterized in that: Calculated by weight percentage, the injection further contains 0.05%-0.3% oleic acid.

5. The injection according to any one of claims 1 to 4, characterized in that: The injection solution comprises the following components in weight percentage: Ceftiofur hydrochloride 8%-12%; HCO 0.6%-0.9%; Span 80 0.5%-1%; Sodium decanoate 0.08%-0.12%; Vitamin E 0.1%; Ascorbyl Palmitate 0.05% The balance is cottonseed oil.

6. The method for preparing the injection according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: Step 1: Heat 3 / 5 cottonseed oil to 70-80°C, add HCO and stir to dissolve to form a thixotropic glue matrix; Step 2: Cool down to 60-65℃, add Span 80 and absorption promoter, and stir at constant temperature for activation; Step 3: Gradually cool to 25-30°C, add ceftiofur hydrochloride, and disperse at a low speed for 30-60 minutes; Step 4: Add the remaining cottonseed oil, premix at 5000-8000 r / min for 5-10 minutes, and high-speed shear at 10000-15000 r / min for 15-30 minutes, and control the particle size D90 ≤ 5 μm; Step 5: Filter, fill, and sterilize.

7. The preparation method according to claim 6, characterized in that: In step 1, heat to 75-80°C, and in step 2, cool to 60-62°C.

8. The preparation method according to claim 6, characterized in that: In step 3, the temperature was gradually lowered to 25-28°C, and the mixture was stirred at 300 rpm for 30-45 min.

9. The preparation method according to claim 6, characterized in that: When the injection solution contains oleic acid, the following steps are further included between step 2 and step 3: gradually cooling to 35-45° C., adding oleic acid to adjust the pH of the oil phase to 7.0±0.2, and stirring for 10-20 minutes.

10. The preparation method according to claim 6, characterized in that: In step 4, premixing is performed at 5000-6000 r / min for 5-8 min, and high-speed shearing is performed at 10000-12000 r / min for 15-25 min.

Images