CN116350579A - Clear propofol injection and preparation method thereof - Google Patents

Clear propofol injection and preparation method thereof Download PDF

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CN116350579A
CN116350579A CN202210852110.5A CN202210852110A CN116350579A CN 116350579 A CN116350579 A CN 116350579A CN 202210852110 A CN202210852110 A CN 202210852110A CN 116350579 A CN116350579 A CN 116350579A
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injection
propofol
cyclodextrin
beta
sodium bicarbonate
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许英挺
井玥
颜青
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Bica Biotechnology Guangzhou Co ltd
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Abstract

The invention relates to a clarified propofol injection and a preparation method thereof, wherein the injection comprises the following components: propofol, cyclodextrin, a stabilizer, a pH regulator and water for injection, wherein the pH value of the injection is 6-9, preferably 7-8.5. The injection can be filtered on line, has few auxiliary materials, low dosage, low concentration of free propofol, convenient storage and good stability.

Description

Clear propofol injection and preparation method thereof
Description of the division
The invention relates to a clarified propofol injection and a preparation method thereof, which are divisional applications of Chinese patent application with the application number of 201811316623.4 and the application date of 2018, 11 and 7.
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to a clarified propofol injection and a preparation method thereof.
Background
The propofol serving as a clinical common intravenous anesthetic is widely applied by the characteristics of quick response, short acting time, quick metabolism and high safety. Commercial propofol emulsions include injectable emulsions, medium-and long-chain fat emulsions and long-chain fat emulsion formulations. The preparation has the defects of complex components, easiness in bacterial contamination, high probability of injection pain, auxiliary materials such as soybean oil and peanut oil Yi Zhimin and the like, and has serious influence on the body of a patient. The propofol injection which does not use emulsion as an auxiliary material can be developed to reduce the medication risk of patients.
The pharmaceutical excipients in the prior art are various in variety and insoluble drugs are also many, but no one excipient can solve the indissolvable defects of all drugs. The techniques of fat emulsion, liposome, lipid microsphere, nanoparticle, albumin, etc. have been used for developing propofol injection.
From 1993 to date, ten or more cyclodextrin-containing agents for clarifying the preparation of propofol injection, such as PCT/GB/00737, WO/2003/06312, W/O/2004/108113, WO/2007/052295, WO/2012/104730 and U.S. Pat. Nos. 7138387, 7034013, 9006215, are disclosed, but these have the disadvantages of high cyclodextrin usage, difficulty in filtration, easiness in bacterial contamination for a long time, too high pH, difficulty in storage, and the like.
A clinical study in 2011 shows (Anesthesia & Analgesia 2011;113:738-41,Crystal B.Wallentine et al.) that sulfobutyl ether-beta-cyclodextrin has an excessively high concentration of free propofol when applied to a propofol injection, and has no obvious effect of reducing pain. Attempts to prepare clear propofol injections by cyclodextrin have been left to stand. So far, no clear propofol injection with low free propofol concentration has been developed successfully.
Disclosure of Invention
In order to prepare clear propofol injection with low free propofol concentration, we have selected the experimental protocol using hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin by screening for alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and their respective derivatives. Through the trial of a large amount of auxiliary materials, finally, we successfully prepare the clarified propofol injection with low free propofol concentration.
An object of the present invention is to provide a clear propofol injection. The injection is characterized in that: clarifying, low dosage of auxiliary materials, low concentration of free propofol, good stability and on-line filtration.
Another object of the present invention is to provide a method for preparing a propofol injection.
The above characteristics of the invention are realized by adopting the following technical scheme.
In one aspect, the invention provides a clear propofol injection, which comprises the following components: propofol, cyclodextrin, a stabilizer, a pH regulator and water for injection, wherein the pH value of the injection is 6-9, preferably 7-8.5.
Preferably, the cyclodextrin is selected from one or more of hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, hydroxypropyl-sulfobutyl ether-beta-cyclodextrin, mannosyl-beta-cyclodextrin and galactosyl-beta-cyclodextrin; preferably hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin.
Preferably, the stabilizer is selected from pharmaceutically acceptable bases or acids including, but not limited to, one or more of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, sodium lactate, sodium hydrogen phosphate, sodium citrate, sodium acetate, ammonium bicarbonate, potassium bicarbonate, phosphoric acid, lactic acid, citric acid, acetic acid, hydrochloric acid, and carbon dioxide, preferably sodium bicarbonate.
Preferably, the pH adjusting agent is selected from pharmaceutically acceptable bases or acids including, but not limited to, sodium bicarbonate, sodium hydroxide, hydrochloric acid, and carbon dioxide.
Preferably, in the injection, the amount of the propofol is 0.5% -2% (w/v), preferably 1% (w/v) in weight percent.
Preferably, the cyclodextrin is present in the injection in an amount of 10% to 30% (w/v), preferably 12% to 25% (w/v) in weight percent.
Preferably, the amount of the stabilizer in the injection is 0.001 to 1.0% (w/v), preferably 0.01 to 1.0% (w/v), more preferably 0.01 to 0.5% (w/v) in terms of weight percent.
In the injection, the amount of the pH adjustor is based on adjusting the injection to an appropriate pH value.
Preferably, the content of free propofol in the injection is not higher than 50. Mu.g/mL, preferably not higher than 35. Mu.g/mL, most preferably not higher than 30. Mu.g/mL.
Preferably, the injection further comprises one or more of a preservative, an antioxidant, a bacteriostatic agent and a permeation regulator. The preservative, antioxidant and bacteriostatic agent, such as EDTA, sodium bisulphite, vitamin C, cysteine and other common reagents, can be correspondingly increased or decreased by preparation personnel according to the process requirements.
In a preferred embodiment, the present invention provides a propofol injection comprising propofol, sulfobutyl ether-beta-cyclodextrin, sodium bicarbonate, a pH regulator other than sodium bicarbonate and water for injection, the pH of the injection being from 6 to 9, preferably from 7 to 8.5;
preferably, in the injection, the amount of the propofol is 1% (w/v) in weight percent;
preferably, in the injection, the sulfobutyl ether-beta-cyclodextrin is present in an amount of 12% -25% (w/v) in weight percent.
Preferably, the sodium bicarbonate is present in the injection in an amount of 0.01-1.0% (w/v) in weight percent.
Preferably, in the injection, the pH regulator other than sodium bicarbonate is sodium hydroxide, hydrochloric acid, or carbon dioxide.
Compared with the existing cyclodextrin preparation, the propofol injection has lower concentration of free propofol. Specifically, cyDex corporation's documents show that the concentration of free propofol in the combination of propofol and cyclodextrin is about 50-80 μg/mL, whereas in the present invention the concentration of free propofol in the aqueous phase is about 30 μg/mL.
In the invention, sodium bicarbonate is used as a stabilizer, and the stabilizer has the following functions: (1) when the cyclodextrin dosage is low, the preparation keeps clear, transparent and oil-free in the storage process; (2) the concentration of free propofol in the aqueous phase is reduced.
The invention is also characterized in that the dosage of sodium bicarbonate is reduced as much as possible, and the pH value and the dosage of sodium bicarbonate are controlled in a safe range suitable for large-capacity transfusion as much as possible.
The invention uses lower sodium bicarbonate (about 0.5 mg/mL) to achieve the effects of reducing pain and safe injection.
The propofol injection is convenient to store and good in stability, is stored at 25 ℃ for 6 months, does not cause precipitation of main medicine to form oil drops, and has the content of the main medicine propofol not lower than 99.5%.
In another aspect, the invention provides a preparation method of the propofol injection, which comprises the following steps: adding cyclodextrin (preferably sulfobutyl ether-beta-cyclodextrin) and stabilizer (preferably sodium bicarbonate) into water for injection, dissolving, introducing inert gas, adding propofol, stirring, regulating pH with pH regulator, filtering, and packaging under inert gas protection.
Preferably, the inert gas is nitrogen for reducing the oxygen content.
In the present invention, cyclodextrin is used, for example sulfobutyl ether-beta-cyclodextrin to include propofol which is poorly soluble in water, and after the sulfobutyl ether-beta-cyclodextrin exceeds 22g, the free propofol concentration no longer decreases significantly as the amount of cyclodextrin increases. The addition of sodium bicarbonate reduces the concentration of free propofol and reduces the amount of cyclodextrin used.
The propofol injection of the invention adopts the following method to improve the stability:
1) Loading propofol with a cyclodextrin, such as sulfobutyl ether- β -cyclodextrin, reduces contact of the propofol with an oxidizing agent;
2) Preparing and packaging under sterile nitrogen atmosphere;
3) The propofol is easier to oxidize in a strong alkali environment, and sodium bicarbonate is used as a stabilizer, so that the risk of quality degradation caused by overlarge local alkalinity in the preparation process is reduced;
4) The invention also uses a pH regulator to control the pH between 7 and 8.5 so as to reduce the acid-base balance damage of patients caused by inputting a large amount of high-pH solution.
In a preferred technical scheme, the propofol injection of the invention is prepared as follows:
Figure BDA0003753876060000041
the preparation method comprises the following steps:
at room temperature, 16g of sulfobutyl ether-beta-cyclodextrin, 0.001-0.5 g of sodium bicarbonate and 50mL of water for injection are taken, after stirring and dissolution, nitrogen is introduced into the solution to remove dissolved oxygen, 1000mg of propofol is added under the nitrogen atmosphere, stirring is carried out for 2-6 hours, the pH is regulated to 6-9, water is added to 100mL, filtration and sterilization are carried out after 0.22 mu m, and the mixture is filled into a transparent sterile ampoule bottle, sealed by air-driven sterile nitrogen, and stored at 25 ℃.
In a more preferred embodiment, the propofol injection of the present invention is formulated as follows:
Figure BDA0003753876060000042
the preparation method comprises the following steps: at room temperature, 16.0g of sulfobutyl ether-beta-cyclodextrin, 0.05g of sodium bicarbonate and 50mL of water for injection are taken, after stirring and dissolving, nitrogen is introduced into the solution to remove dissolved oxygen, 1000mg of propofol is added under the nitrogen atmosphere, stirring is carried out for 2-6 hours, the pH value is regulated to 6-9, water is added to 100mL, stirring is uniform, filtration and sterilization are carried out at 0.22 mu m, the solution is filled into a transparent sterile ampoule bottle, air is removed by using sterile nitrogen, and the solution is stored at 25 ℃.
According to the invention, nitrogen is injected into the cyclodextrin solution to drive out dissolved oxygen in the solvent system; the stabilizer is added to reduce the free propofol in the water phase as much as possible, and the probability of oil drop formation caused by precipitation of the main medicine after long-term storage is reduced; the cyclodextrin inclusion rate is improved, the propofol is further included, and the concentration of the free propofol is reduced.
Compared with the prior art, the application has at least the following beneficial technical effects:
the invention combines cyclodextrin, propofol and sodium bicarbonate to obviously reduce the concentration of free propofol, reduce the risk of injection pain of the injection prepared by combining the propofol and the cyclodextrin, and have predictable relieving effect on the occurrence frequency and intensity of the injection pain.
In the existing cyclodextrin patents, the product has the advantages of low auxiliary material consumption, low nephrotoxicity, small hemolysis and the like.
The concentration of sodium bicarbonate in the invention is about 0.5mg/mL, which obviously reduces the possibility of inducing severe alkalosis, hypokalemia and hypocalcemia of normal people and greatly improves the safety.
The injection of the invention is transparent and is convenient for visual inspection before administration. The administration may be performed using an in-line microbial filter.
The invention avoids the use of auxiliary materials such as soybean oil, lecithin and the like with complex technical requirements and high allergy risk, enlarges the applicable population of the propofol injection and reduces the sensitization risk of the auxiliary materials of the propofol injection.
The injection of the invention does not contain lipid which is beneficial to the growth of microorganisms, and can reduce the risk of microorganism infection in long-term administration.
The injection of the present invention does not contain phospholipids. Therefore, the phospholipid blood concentration is not affected by parenteral administration of the composition, and patients allergic to peanut, soybean, etc. can also use the composition.
The injection of the invention does not cause any change in triglyceride removal and lipid metabolism disorder.
Drawings
FIG. 1 is an enlarged view of the hydrogen nuclear magnetic resonance spectrum of a sample prepared according to example 2;
FIG. 2 is an enlarged view of the hydrogen nuclear magnetic resonance spectrum of a sample prepared according to example 9.
Detailed Description
To further illustrate the present invention, the present invention is further described in detail below by way of examples of preparation of novel propofol injection having good stability, convenient storage, and low injection pain.
The preparation propofol content detection method and the free propofol concentration determination method used in the following examples were as follows:
the method for detecting the content of the propofol in the preparation comprises the following steps:
precisely sucking a proper amount of propofol injection, placing in a volumetric flask, adding chromatographic pure methanol to a scale, uniformly mixing, centrifuging, taking supernatant, and measuring the total concentration of propofol in the preparation by using a chromatographic condition HPLC method under a content measuring item;
chromatographic conditions: chromatographic column: c18 4.6X250 mm,5 μm; mobile phase: methanol-water (80:20); detection wavelength: 280nm; flow rate: 1mL/min; column temperature: 25 ℃.
Method for measuring concentration of free propofol:
the prescribed amount of water for injection was replaced with heavy water, and the preparation of the injection was carried out.
Nuclear magnetic resonance hydrogen spectrum conditions: 1H-NMR spectra were obtained at constant temperature (25 ℃) using zg30 pulse sequences. Spectral Width (SWH): 8000Hz, radio frequency center frequency (OIP): hz, sampling points (TD): 32K, sampling time (AQ): 4.09s, relaxation time (D1): 20s, number of Samples (NS): 64.
the calculated content is obtained by comparing the area (A1/n 1) of an absorption peak caused by one proton in the para position of the phenolic hydroxyl group with the area (A2/n 2) of an absorption peak caused by a proton in the same position on the free propofol group, and then calculating the relative percentage content of the sample and the impurity according to the following formula: relative percentage of sample = { (A1/n 1)/(
[ (A1/n 1) + (A2/n 2) ] 100% in the formula, n1, n2 are the number of protons of the specified group.
Examples 1 to 8
At room temperature, taking sulfobutyl ether-beta-cyclodextrin with a prescription amount, adding 50mL of water for injection into the sodium bicarbonate with a corresponding prescription amount, stirring and dissolving, introducing nitrogen into the solution to remove dissolved oxygen, adding 1000mg of propofol under the nitrogen atmosphere, stirring for 2-6 hours, adjusting the pH value to 6-9, adding water to 100mL, stirring uniformly, filtering and sterilizing with 0.22 mu m, filling into a transparent sterile ampoule bottle, sealing with sterile nitrogen and air, and preserving at 25 ℃. The amounts of the raw materials used in each example and the appearance of the obtained injection and the concentration of free propofol are shown in Table 1.
FIG. 1 shows an enlarged view of the hydrogen nuclear magnetic resonance spectrum of a sample prepared according to example 2.
Examples 9 to 10
Examples 9-10 are prepared with reference to Cydex corporation's patent, see in particular examples 1, 2 of US 7034013. FIG. 2 shows an enlarged view of the hydrogen nuclear magnetic resonance spectrum of a sample prepared according to example 9.
The amounts of the raw materials used in each example and the appearance of the obtained injection and the concentration of free propofol are shown in Table 1.
TABLE 1
Figure BDA0003753876060000071
As can be seen from examples 1 to 10, when the sodium bicarbonate content was higher than 1% (w/v), the preparation was slightly yellowish, and the stability was poor, and the sodium bicarbonate content was lower than 0.01% (w/v), and the preparation was opalescent. Comparing example 9 with example 10, increasing the concentration of sulfobutyl ether- β -cyclodextrin did not significantly reduce the concentration of free propofol.
In examples 8-10 without sodium bicarbonate, when sulfobutyl ether-beta-cyclodextrin was 16g, there were oil droplets floating on the liquid surface after standing, indicating that the cyclodextrin did not effectively include propofol, and when sulfobutyl ether-beta-cyclodextrin was 22g, the solution was clear, indicating that at least 22g of sulfobutyl ether-beta-cyclodextrin was required to effectively include propofol. The solution was clear at 30g of sulfobutyl ether- β -cyclodextrin, but the free propofol concentration was not significantly reduced. In comparison, in the formulation using an appropriate amount of sodium bicarbonate, the content of free propofol was significantly reduced, as were the amounts of sulfobutyl ether- β -cyclodextrin and sodium bicarbonate.
Example 11
At room temperature, 18.0g of sulfobutyl ether-beta-cyclodextrin, 100mg of sodium citrate and 50mL of water for injection are taken, nitrogen is introduced into the solution after stirring and dissolution, dissolved oxygen is removed, 1000mg of propofol is added under the nitrogen atmosphere, stirring is carried out for 2-6 hours, the pH value is regulated to 6-9, water is added to 100mL, stirring is uniform, filtration and sterilization are carried out at 0.22 mu m, the solution is filled into a transparent sterile ampoule bottle, air-packing is carried out by using sterile nitrogen, the solution is preserved at 25 ℃, and the concentration of free propofol is measured to be 37.3 mu g/mL.
Example 12
At room temperature, 18.0g of sulfobutyl ether-beta-cyclodextrin, 100mg of meglumine and 50mL of water for injection are taken, nitrogen is introduced into the solution after stirring and dissolution, dissolved oxygen is removed, 1000mg of propofol is added under the nitrogen atmosphere, stirring is carried out for 2-6 hours, the pH value is regulated to 6-9, water is added to 100mL, stirring is uniform, filtration and sterilization are carried out at 0.22 mu m, the solution is filled into a transparent sterile ampoule bottle, the sterile nitrogen is used for driving out air for encapsulation, the solution is preserved at 25 ℃, and the concentration of free propofol is measured to be 36.6 mu g/mL.
Example 13
At room temperature, 18.0g of sulfobutyl ether-beta-cyclodextrin, 100mg of ammonium bicarbonate and 50mL of water for injection are taken, nitrogen is introduced into the solution after stirring and dissolution, dissolved oxygen is removed, 1000mg of propofol is added under the nitrogen atmosphere, stirring is carried out for 2-6 hours, the pH value is regulated to 6-9, water is added to 100mL, stirring is uniform, filtration and sterilization are carried out at 0.22 mu m, the solution is filled into a transparent sterile ampoule bottle, air-packing is carried out by using sterile nitrogen, the solution is preserved at 25 ℃, and the concentration of free propofol is measured to be 35.2 mu g/mL.
Example 14
At room temperature, taking 20.0g of sulfobutyl ether-beta-cyclodextrin, 100mg of ammonium acetate, adding 50mL of water for injection, stirring and dissolving, introducing nitrogen into the solution to remove dissolved oxygen, adding 1000mg of propofol under nitrogen atmosphere, stirring for 2-6 hours, adjusting the pH value to 6-9, adding water to 100mL, stirring uniformly, filtering and sterilizing at 0.22 mu m, filling into a transparent sterile ampoule bottle, sealing with sterile nitrogen and air, preserving at 25 ℃, and measuring the concentration of free propofol to be 38.7 mu g/mL.
Example 15
At room temperature, 10.0g of sulfobutyl ether-beta-cyclodextrin, 50mg of sodium hydrophosphate and 50mL of water for injection are taken, nitrogen is introduced into the solution after stirring and dissolution, dissolved oxygen is removed, 500mg of propofol is added under the nitrogen atmosphere, stirring is carried out for 2-6 hours, the pH value is regulated to 6-9, water is added to 100mL, stirring is uniform, filtration and sterilization are carried out at 0.22 mu m, the solution is filled into a transparent sterile ampoule bottle, the sterile nitrogen is used for driving out air for encapsulation, the solution is preserved at 25 ℃, and the concentration of free propofol is measured to be 33.7 mu g/mL.
Example 16
At room temperature, taking 20.0g of sulfobutyl ether-beta-cyclodextrin, 100mg of sodium lactate, adding 50mL of water for injection, stirring and dissolving, introducing nitrogen into the solution to remove dissolved oxygen, adding 1000mg of propofol under nitrogen atmosphere, stirring for 2-6 hours, adjusting the pH value to 6-9, adding water to 100mL, stirring uniformly, filtering and sterilizing at 0.22 mu m, filling into a transparent sterile ampoule bottle, sealing with sterile nitrogen and air, preserving at 25 ℃, and measuring the concentration of free propofol to be 36.1 mu g/mL.
Comparative example 1
Taking the propofol commercial injection to obtain Li Ma mL, adding 1mL of 5% sodium bicarbonate, filling into a transparent sterile ampoule bottle, sealing by using sterile nitrogen to remove air, preserving at 25 ℃, and calculating to obtain the final concentration of the sodium bicarbonate of 0.25%.
Comparative example 2
Taking the propofol commercial injection to obtain Li Ma mL, adding 5mL of 5% sodium bicarbonate injection, filling into a transparent sterile ampoule bottle, driving out air by sterile nitrogen, packaging, preserving at 25 ℃, and calculating the final concentration of sodium bicarbonate to be 1.25%.
Example 17Stability investigation of Propofol injection
Samples were prepared according to the formulations of examples 1-3 and comparative examples 1-2, examined, placed in a light-shielding environment at 40 ℃ and measured for various stability-related data at various time points as shown in table 2. As can be seen from Table 2, the propofol injection of the present invention has good stability.
TABLE 2
Figure BDA0003753876060000101
For further investigation of stability, samples were prepared with the recipe of example 2, and the stability-related data were measured at different time points in a light-protected environment at 25℃as shown in Table 3.
TABLE 3 Table 3
Figure BDA0003753876060000102
The instruction book of sodium bicarbonate injection shows that the application concentration for clinically treating metabolic acidosis is 1.4-8%. It is shown in US8546453 that sodium bicarbonate at a final concentration of approximately 1.4% reduces injection pain and that low concentrations of sodium bicarbonate (0.25%) do not reduce injection pain. However, the long-time infusion of the emulsion can greatly increase the concentration of bicarbonate in human body, and the acid-base balance of patients is likely to be broken, so that the discomfort of the patients is caused. The invention greatly reduces the final concentration of sodium bicarbonate and has better safety.

Claims (11)

1. A clarified propofol injection, comprising the following components: propofol, cyclodextrin, a stabilizer, a pH regulator and water for injection, wherein the pH value of the injection is 6-9, preferably 7-8.5.
2. The propofol injection according to claim 1, which consists of propofol, cyclodextrin, a stabilizer, a pH adjuster and water for injection; or comprises propofol, cyclodextrin, stabilizer, pH regulator, auxiliary components and water for injection, wherein the auxiliary components are selected from one or more of antioxidant, bacteriostatic agent and osmotic regulator; the pH of the injection is 6-9, preferably 7-8.5.
3. The propofol injection of claim 2, wherein the cyclodextrin is selected from one or more of hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, hydroxypropyl-sulfobutyl ether-beta-cyclodextrin, mannosyl-beta-cyclodextrin, and galactosyl-beta-cyclodextrin; preferably hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin.
4. A propofol injection as claimed in any one of claims 1-3 wherein, the stabilizer is selected from pharmaceutically acceptable bases or acids, including, but not limited to, one or more of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, sodium lactate, sodium hydrogen phosphate, sodium citrate, sodium acetate, ammonium bicarbonate, potassium bicarbonate, phosphoric acid, lactic acid, citric acid, acetic acid, hydrochloric acid, and carbon dioxide; sodium bicarbonate is preferred;
preferably, the pH adjusting agent is selected from pharmaceutically acceptable bases or acids including, but not limited to, sodium bicarbonate, sodium hydroxide, hydrochloric acid, and carbon dioxide.
5. A propofol injection as claimed in any one of claims 1-3 wherein, in the injection, the amount of propofol is 0.5-2% (w/v), preferably 1% (w/v) by weight;
preferably, the cyclodextrin is present in the injection in an amount of 10% to 30% (w/v), preferably 12% to 25% (w/v) in weight percent.
6. Propofol injection according to any one of claims 1 to 5, wherein the amount of stabilizer in the injection is 0.001-1.0% (w/v), preferably 0.01-1.0% (w/v), more preferably 0.01-0.5% (w/v) in weight percent.
7. Propofol injection according to any of claims 1 to 6, wherein the content of free propofol in the injection is not higher than 50 μg/mL, preferably not higher than 35 μg/mL, most preferably not higher than 30 μg/mL.
8. The propofol injection of any one of claims 1 to 7, wherein the antioxidant is sodium bisulphite and the bacteriostatic agent is vitamin C.
9. The clear propofol injection consists of propofol, sulfobutyl ether-beta-cyclodextrin, sodium bicarbonate, a pH regulator except sodium bicarbonate and water for injection, wherein the pH value of the injection is 6-9, preferably 7-8.5;
preferably, in the injection, the amount of the propofol is 0.5% -2% (w/v), preferably 1% (w/v) in weight percent;
preferably, the sulfobutyl ether-beta-cyclodextrin is present in the injection in an amount of 10% to 30% (w/v), preferably 12% to 25% (w/v), in weight percent.
Preferably, the amount of sodium bicarbonate other than sodium bicarbonate in the injection is 0.001-1.0% (w/v), preferably 0.01-1.0% (w/v), more preferably 0.01-0.5% (w/v);
preferably, the pH adjusting agent other than sodium bicarbonate is selected from pharmaceutically acceptable bases or acids including, but not limited to, sodium bicarbonate, sodium hydroxide, hydrochloric acid, carbon dioxide.
10. The clarified propofol injection according to claim 9, which consists of propofol, sulfobutyl ether-beta-cyclodextrin, sodium bicarbonate, a pH adjuster other than sodium bicarbonate and water for injection.
11. A process for the preparation of the propofol injection as claimed in any one of claims 1 to 9 comprising the steps of:
adding cyclodextrin and stabilizer into water for injection, dissolving, introducing inert gas, adding propofol, stirring, adjusting pH with pH regulator, and filtering;
preferably, the inert gas is nitrogen;
more preferably, the preparation method comprises the steps of adding sodium bicarbonate and sulfobutyl ether-beta-cyclodextrin into water for injection, dissolving, introducing inert gas such as nitrogen, adding propofol, stirring until suspended propofol oil drops disappear, continuing stirring for 2-6 hours at the moment, regulating the pH value by a pH regulator, filtering, and charging nitrogen.
CN202210852110.5A 2018-11-07 2018-11-07 Clear propofol injection and preparation method thereof Pending CN116350579A (en)

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