CN107982215B - Clevidipine butyrate emulsion and preparation method and application thereof - Google Patents
Clevidipine butyrate emulsion and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a clevidipine butyrate emulsion and a preparation method and application thereof. The clevidipine butyrate emulsion strictly regulates the contents of the yolk lecithin serving as an emulsifier in Phosphatidylcholine (PC), Phosphatidylethanolamine (PE) and cholesterol (TC), and strictly controls the homogenization pressure in the preparation process, so that the stability of the clevidipine butyrate emulsion in the storage and use processes is improved, and the phenomena of oil production, emulsion breaking, oil-water separation and the like of a sample are still avoided after the clevidipine butyrate emulsion is subjected to three freeze-thaw cycles. The clevidipine butyrate emulsion has strong operability in the preparation process and is easy for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a clevidipine butyrate emulsion as well as a preparation method and application thereof.
Background
Perioperative period refers to the whole process around the operation, starting from the decision of the patient to receive the operation treatment, and going to the basic recovery, including the preoperative period, the intraoperative period and the postoperative period. The Perioperative patients have further raised blood pressure due to pain stimulation caused by mental stress, trauma, pain, operative trauma and disappearance of postoperative anesthesia, and particularly, patients with hypertension in need of surgical operation have higher risk, literature data shows that the Perioperative hypertension is clinically common, the incidence rate reaches 30-60%, and more than 80% of cardiac operation patients and more than 25% of non-cardiac major operation patients can suffer from acute Perioperative hypertension, some hypertension emergencies (hypertensive crisis, hypertensive encephalopathy and acute left heart failure) can occur, the acute hypertension can directly or indirectly cause postoperative complications and death rate increase of the operative patients, so the Perioperative hypertension (Perioperative hypertension) and nursing thereof are important subjects before the nursing work surface of an operative department, and whether the Perioperative treatment is proper or not, In time, it is directly related to the end result of the surgical treatment. Clinical tests show that by reasonable administration, the blood pressure of perioperative patients can be stably reduced, and postoperative complications are reduced, so that the success rate of surgical operations is improved, and the death rate of the operations is reduced.
Clevidipine butyrate reduces mean arterial pressure by selectively relaxing arterial blood vessels and reducing systemic vascular resistance without reducing cardiac filling pressure (preload), and has no influence on myocardial contractility and venous blood vessel capacity. The medicine is also different from the existing intravenous antihypertensive medicine in the metabolic pathway, does not pass through the liver or (and) the kidney, is not affected by the damage of the liver and kidney functions, but undergoes metabolism in blood and tissues, and simultaneously is not accumulated in the body, so the pharmacodynamics and pharmacokinetic advantages are obvious, the systolic pressure of a patient is gradually reduced within 15 minutes after the medicine is taken by the patient in the perioperative period in clinical use, the steady state level is reached after the medicine is taken for 15 minutes, and the change of the heart rate is basically stable within 30 minutes after the medicine is taken.
Clevidipine butyrate belongs to dihydropyridine derivatives, is an ultra-short-acting intravenous calcium channel blocker, has high vascular and myocardial selectivity, and is rapidly metabolized into inactive substances in vivo. It has quick action and rapid elimination of the action, and can increase dosage and accurately control blood pressure. Clevidipine butyrate is almost insoluble in water and is readily soluble in soybean oil, medium chain triglycerides and other fatty oils. Therefore, the emulsion is suitable for preparing O/W liquid emulsion.
Because the emulsion belongs to a thermodynamically unstable system, oil-water separation is easy to occur in the processes of storage and use. Thus, there remains a strong need in the art to provide a formulation that is stable throughout storage and use.
Disclosure of Invention
The invention aims to solve the technical problem of improving the stability of the clevidipine butyrate injection emulsion in the storage and use processes, so that the sample still does not produce the phenomena of oil production, emulsion breaking, oil-water separation and the like after the clevidipine butyrate injection emulsion is subjected to three freeze-thaw cycles. The invention thus provides a clevidipine butyrate emulsion and a preparation method thereof. The clevidipine butyrate emulsion strictly regulates the contents of Phosphatidylcholine (PC), Phosphatidylethanolamine (PE) and cholesterol (TC) in yolk lecithin serving as an emulsifier, and strictly controls the homogenizing pressure in the preparation process. And the clevidipine butyrate emulsion has strong operability in the preparation process and is easy for large-scale production.
The invention adopts the following technical scheme:
the preparation method of the clevidipine butyrate emulsion comprises the following steps:
the content of PC (phosphatidylcholine) in the egg yolk lecithin is 65-90% (w/w, the same applies below), preferably 70-85%, and more preferably 75-80%.
The content of PE (phosphatidylethanolamine) in the egg yolk lecithin is 5-20%, preferably 10-18%, and more preferably 12-17%.
The TC (cholesterol) content of the egg yolk lecithin is 0.5-2.0%, preferably 1.0-2.0%, and more preferably 1.5-2.0%.
On the basis of the common knowledge in the field, the preferable conditions of the contents of PC, PE and TC in the egg yolk lecithin can be combined with each other to obtain the preferable embodiments of the invention.
The preparation method of the clevidipine butyrate emulsion comprises the following steps:
1) taking a prescribed amount of water, adjusting the pH value to 8-9 by using a pH regulator, adding edetate and glycerol, and stirring to dissolve the edetate and the glycerol uniformly; introducing nitrogen into water to remove oxygen, controlling the water temperature to be 50-90 ℃, adding egg yolk lecithin with the formula amount, and cutting until the egg yolk lecithin is uniformly dispersed; preparing a water phase; the whole process is carried out under the condition of nitrogen protection;
2) heating and dissolving the fatty oil with the prescription amount at 50-90 ℃, adding the clevidipine butyrate and the stabilizer with the prescription amount, uniformly mixing, and charging nitrogen for protection, wherein the system temperature is controlled at 50-90 ℃ to prepare an oil phase;
3) slowly injecting the obtained water phase into the obtained oil phase under the condition of high-speed stirring, and shearing to prepare primary emulsion, wherein the temperature of the emulsion is controlled to be 50-70 ℃;
4) under the protection of nitrogen, homogenizing the obtained primary emulsion twice, wherein the first time is at 40-200bar, the homogenization is performed for 1-6 times, and the second time is at 500-1200bar, and the homogenization is performed for 4-10 times; homogenizing, filtering with 3 μm filter, introducing nitrogen, and bottling; sterilizing; and (4) finishing.
Preferably, the first homogenisation is carried out at a pressure of 80-150bar for 1-6 homogenisation passes, such as 2-3 homogenisation passes, more preferably 6 homogenisation passes.
Preferably, the second homogenization is carried out at a pressure of 600-1000bar, 4-9 times.
In a preferred embodiment of the invention, the colostrum obtained in step 4) is homogenized twice, the first time at a pressure of 80-150bar for 6 times, and the second time at a pressure of 800bar for 7 times.
The sterilization can be carried out by methods conventional in the art, e.g., 121 deg.C, F0And > 12 sterilization.
Further, the fatty oil may be one or more of soybean oil, medium chain triglyceride, peanut oil, olive oil, sesame oil, fish oil, etc., preferably a mixed oil of soybean oil and medium chain triglyceride, more preferably soybean oil.
Further, the egg yolk lecithin is preferably refined egg yolk lecithin, which is commercially available.
Further, the edetate is one or more of sodium calcium edetate, disodium edetate and the like, and is more preferably disodium edetate.
Further, the amount of the edetate is 0.002-0.01% (w/v, the same applies hereinafter), preferably 0.005-0.01%.
Further, the stabilizer may be one or more of capric acid or a salt thereof, lauric acid or a salt thereof, myristic acid or a salt thereof, palmitic acid or a salt thereof, palmitoleic acid or a salt thereof, stearic acid or a salt thereof, linoleic acid or a salt thereof, linolenic acid or a salt thereof, oleic acid or a salt thereof, and the like, and is preferably sodium oleate or oleic acid, and more preferably oleic acid.
Further, the stabilizer is used in an amount of 0.01 to 0.06% (w/v, the same applies hereinafter), preferably 0.03 to 0.06%.
Further, the pH adjusting agent may be selected from phosphates, citrates, acetates, borates, hydrochloric acid, phosphoric acid, sodium hydroxide, etc., preferably sodium hydroxide, such as 2% sodium hydroxide solution.
The raw materials of the invention are all commercially available.
The invention also discloses the clevidipine butyrate emulsion prepared by the method.
The invention also comprises the application of the clevidipine butyrate emulsion in the preparation of antihypertensive drugs.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
Example 1
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 77%, the content of PE in refined egg yolk lecithin is 18%, and the content of TC in refined egg yolk lecithin is 1.1%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Example 2
A clevidipine butyrate emulsion is prepared by the following steps:
the PC content, PE content and TC content of the refined egg yolk lecithin are respectively 80%, 13% and 1.8%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Example 3
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 70%, the content of PE in refined egg yolk lecithin is 20%, and the content of TC in refined egg yolk lecithin is 0.8%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800barAnd 7 times in quality. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Example 4
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 90%, the content of PE in refined egg yolk lecithin is 6%, and the content of TC in refined egg yolk lecithin is 2%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Example 5
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 68%, the content of PE in refined egg yolk lecithin is 19%, and the content of TC in refined egg yolk lecithin is 1.5%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Example 6
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 77%, the content of PE in refined egg yolk lecithin is 18%, and the content of TC in refined egg yolk lecithin is 1.1%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Comparative example 1
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the PC content of the refined egg yolk lecithin is 92 percent, the PE content is 4.7 percent and the TC content is 2.0 percent.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Comparative example 2
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 64%, the content of PE in refined egg yolk lecithin is 20%, and the content of TC in refined egg yolk lecithin is 0.2%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 80-150bar for 6 times and 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Comparative example 3
A clevidipine butyrate emulsion is prepared by the following steps:
wherein the content of PC in refined egg yolk lecithin is 77%, the content of PE in refined egg yolk lecithin is 18%, and the content of TC in refined egg yolk lecithin is 1.1%.
The preparation method comprises the following steps:
1. taking a prescription amount of fresh water for injection, adding 2% sodium hydroxide to adjust the pH value to 9.0, adding sodium ethylene diamine tetracetate and glycerol, stirring to dissolve the water uniformly, introducing nitrogen into the water to remove oxygen, controlling the water temperature to be 75 ℃, adding a prescription amount of refined egg yolk lecithin, and shearing until the refined egg yolk lecithin is uniformly dispersed, wherein the whole process is finished in the nitrogen protection to be used as a water phase.
2. Taking clevidipine butyrate with the prescription amount, heating fatty oil at 75 ℃ to dissolve, adding soybean oil with the prescription amount and stability, uniformly mixing, filling nitrogen for protection, and controlling the oil temperature at 75 ℃ to be used as an oil phase.
3. The water phase is sheared at high speed while the oil phase is injected slowly, and is sheared into primary emulsion, and the temperature of the emulsion is controlled at 60 ℃.
4. Homogenizing the primary emulsion under nitrogen protection at 800bar for 7 times. Filtering with a 3 μm filter, introducing nitrogen, and packaging. 121 ℃ and F0And > 12 sterilization.
Examples of the experiments
The results of The experiments conducted on examples 1 to 6, comparative examples 1 to 3 and The former drug (supplied by The medicinal Company, lot number: 16FE032101) were shown in Table 1 below.
As can be seen from the experimental results shown in Table 1, the clevidipine butyrate emulsion of the invention has the purified egg yolk lecithin PC content of 65-90% and the PE content of 5-20%, preferably 10-18% and more preferably 12-17% in the prescription; the TC content is in the range of 0.5-2.0%, 40-200bar is adopted in the homogenizing process, and after 5-6 times of homogenizing, 500-1200bar is adopted for homogenizing for 4-10 times. A more stable sample can be produced.
The specific experimental method is as follows:
the method for measuring the particle size of the emulsion particles comprises the following steps: taking the product, examining according to the particle size and particle size distribution determination method (I XE third method in appendix of the four parts of Chinese pharmacopoeia 2015 edition), by the method, adopting Mastersizer2000, absorption rate of 0.001, refractive index of 1.365, shading degree of 5-10%. The particles with the particle size of more than 5 microns are measured by a light resistance method based on a single particle optical sensing technology, and the calculation method is that the weighted total volume of the emulsion particles with the particle size of more than 5 microns accounts for the volume of the oil phase.
Related substance determination method: chromatographic conditions, octadecylsilane chemically bonded silica (Kromasil 100-5C 18150X 4.6mm) as filler; adjusting pH to 6.0 with triethylamine in methanol-0.02% phosphoric acid water solution (73: 27) as mobile phase; the detection wavelength was 240 nm. And (4) avoiding light. Precisely measuring 2ml of the product, placing the product in a 5ml measuring flask, adding acetonitrile to dilute to a scale, strongly shaking, and immediately filtering to obtain a test solution; precisely measuring 1ml of the test solution into a 100ml measuring flask, diluting to scale with the mobile phase, and shaking up to obtain a control solution. And (3) injecting 20 mu l of the reference solution into a liquid chromatograph, adjusting the detection sensitivity to enable the peak height of the clevidipine butyrate chromatographic peak to be about 20% of the full scale, precisely measuring 20 mu l of each of the test solution and the reference solution, respectively injecting into the liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times. If an impurity peak exists in a chromatogram of the test solution, the maximum single impurity and total impurity content is calculated.
For formulations that are prone to phase separation, viscosity reduction, precipitation or aggregation, low temperature or freeze-thaw tests should be considered. The low-temperature test and the freeze-thaw test both comprise three cycles, each cycle of the low-temperature test is firstly placed at 2-8 ℃ for 2 days, then placed at 40 ℃ for 2 days, and sampled and detected. Each cycle of the freeze-thaw test is to place the mixture at minus 20 to minus 10 ℃ for 2 days and then at 40 ℃ for 2 days, and then sampling and detecting.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (17)
1. The preparation method of the clevidipine butyrate emulsion is characterized in that the clevidipine butyrate emulsion is prepared according to the following formula:
the content of PC in the egg yolk lecithin is 65-90%, the content of PE is 5-20%, and the content of TC is 0.5-2.0%;
the preparation method of the clevidipine butyrate emulsion comprises the following steps:
1) taking a prescribed amount of water, adjusting the pH value to 8-9 by using a pH regulator, adding edetate and glycerol, and stirring to dissolve the edetate and the glycerol uniformly; introducing nitrogen into water to remove oxygen, controlling the water temperature to be 50-90 ℃, adding egg yolk lecithin with the formula amount, and shearing until the egg yolk lecithin is uniformly dispersed; preparing a water phase; the whole process is carried out under the condition of nitrogen protection;
2) heating and dissolving the fatty oil with the prescription amount at 50-90 ℃, adding the clevidipine butyrate and the stabilizer with the prescription amount, uniformly mixing, and charging nitrogen for protection, wherein the system temperature is controlled at 50-90 ℃ to prepare an oil phase;
3) slowly injecting the obtained water phase into the obtained oil phase under the condition of high-speed stirring, and shearing to prepare primary emulsion, wherein the temperature of the emulsion is controlled to be 50-70 ℃;
4) under the protection of nitrogen, homogenizing the obtained primary emulsion twice, wherein the first time is at 40-200bar, the homogenization is performed for 1-6 times, and the second time is at 500-1200bar, and the homogenization is performed for 4-10 times; homogenizing, filtering with 3 μm filter, introducing nitrogen, and bottling; sterilizing; and (4) finishing.
2. The method according to claim 1, wherein the first homogenization in step 4) is performed at a pressure of 80-150bar for 1-6 times; the second homogenization is carried out at the pressure of 600-1000bar for 4-9 times.
3. The method according to claim 1, wherein the first homogenization in step 4) is performed at a pressure of 80-150bar for 6 times, and the second homogenization is performed at a pressure of 800bar for 7 times.
4. The method according to any one of claims 1 to 3, wherein the egg yolk lecithin has a PC content of 70 to 85%, a PE content of 10 to 18%, and a TC content of 1.0 to 2.0%.
5. The method according to claim 4, wherein the yolk lecithin contains 75-80% PC, 12-17% PE and 1.5-2.0% TC.
6. The preparation method according to any one of claims 1 to 3, wherein the fatty oil is one or more of soybean oil, medium-chain triglyceride, peanut oil, olive oil, sesame oil and fish oil; and/or the presence of a gas in the gas,
the pH regulator is selected from phosphate, citrate, acetate, borate, hydrochloric acid, phosphoric acid and sodium hydroxide.
7. The method according to claim 6, wherein the fatty oil is a mixed oil of soybean oil and medium-chain triglyceride.
8. The preparation method according to any one of claims 1 to 3, 5 and 7, wherein the edetate is one or more of calcium sodium edetate and disodium edetate.
9. The method according to any one of claims 1 to 3, 5 and 7, wherein the amount of edetate is 0.002 to 0.01%.
10. The method of claim 9, wherein the amount of edetate is 0.005-0.01%.
11. The preparation method according to any one of claims 1 to 3, 5, 7 and 10, wherein the stabilizer is one or more of capric acid or a salt thereof, lauric acid or a salt thereof, myristic acid or a salt thereof, palmitic acid or a salt thereof, palmitoleic acid or a salt thereof, stearic acid or a salt thereof, linoleic acid or a salt thereof, linolenic acid or a salt thereof and oleic acid or a salt thereof.
12. The method of claim 11, wherein the stabilizer is sodium oleate or oleic acid.
13. The method of claim 12, wherein the stabilizer is oleic acid.
14. The method according to any one of claims 1 to 3, 5, 7, 10 and 12, wherein the stabilizer is used in an amount of 0.01 to 0.06%.
15. The method of claim 14, wherein the stabilizer is used in an amount of 0.03 to 0.06%.
16. Clevidipine butyrate emulsion prepared according to the method of any one of claims 1-15.
17. Use of clevidipine butyrate emulsion according to claim 16 for the preparation of an antihypertensive drug.
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