Fat emulsion injection as well as preparation method and application thereof

Abstract

The invention discloses a fat emulsion injection and a preparation method and application thereof.The fat emulsion injection has enhanced stability and antibacterial effect, can be applied to the fields of clinical sedation, anesthesia, analgesia, postoperative nutritional supplement and the like, and meets the requirement for repeated use while improving the stability and safety of the preparation.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a fat emulsion injection, a preparation method and an application thereof. Background Art

[0002] O / W lipid emulsions are oil-in-water (O / W) emulsions with an average particle size of 0.1 to 1 μm, made from an oil phase, an aqueous phase, and an emulsifier. Nutritional lipid emulsions and drug-loaded lipid emulsions, for example, are widely used in clinical practice.

[0003] As a drug delivery system, O / W fat emulsion has certain wound targeting properties, especially high affinity for inflammation and wound sites. It can selectively accumulate at inflammation and wound sites, increase the concentration of drugs in local tissues, avoid direct contact between drugs and body fluids, and reduce irritation at the injection site.

[0004] Because fat emulsions are submicron emulsions, they are thermodynamically unstable and can exhibit instabilities such as aggregation and flocculation. The presence of emulsion particles in the product can affect product yield and content. Furthermore, the presence of emulsion particles can lead to further aggregation, resulting in large emulsions, which can pose a risk of blood vessel occlusion during injection. Furthermore, during the preparation and storage of fat emulsions, the formulation, preparation process, and storage temperature can all affect their stability. Therefore, selecting an appropriate stabilizer can help improve the physical stability of fat emulsions.

[0005] The dosage of lipid substances in fat emulsion prescriptions is high and easily contaminated by microorganisms in the external environment. Therefore, the fat emulsion injections used in clinical practice are mostly single-dose packaging, which cannot meet the needs of multiple use of some drugs and will also cause a certain amount of drug waste. Among the intravenous fat emulsion products that have been launched on the market, Disodium EDTA (US5714520A) has been added, but the antibacterial effect of disodium EDTA is low and it can only delay but not inhibit the growth of microorganisms in the product. It must be used within 12 hours after opening. The use of 2% benzyl alcohol in the prescription of PROPOFOL 28 for pets cannot effectively inhibit mold. US6140373A also discloses further improvements, such as adding other additives on the basis of benzyl alcohol, such as EDTA and sodium benzoate with antibacterial effects. However, it still does not meet the requirements of the pharmacopoeia (the bacterial lg value decreases by 3 in 7 days). At the same time, there is a risk of cardiac and nervous system toxicity when the dosage of benzyl alcohol is too high (Journal of Feline Medicine and Surgery 14(8)516–526; European Medicines Agency 1997 Drug Review Report).

[0006] Therefore, it is necessary to develop a fat emulsion injection with good antibacterial efficacy, higher safety and stability to meet the needs of multiple clinical uses. Summary of the Invention

[0007] To this end, the purpose of the present invention is to provide a fat emulsion injection and its preparation method and application, wherein the fat emulsion injection has enhanced stability and antibacterial effect, can be used in clinical fields such as sedation, anesthesia, analgesia and postoperative nutritional supplementation, while improving the stability and safety of the preparation and meeting the needs of multiple uses.

[0008] The first aspect of the present invention provides a fat emulsion injection, which is an O / W type fat emulsion injection, comprising injection oil, a stabilizer and water for injection.

[0009] In some embodiments of the present invention, the injection oil includes one or more of coconut oil, palm oil, olive oil, fish oil, soybean oil, sunflower oil, rapeseed oil, tea oil, castor oil, cottonseed oil, corn oil, olive oil, and medium-chain triglycerides.

[0010] In some embodiments of the present invention, when the oil for injection comprises a plurality of oil components, the plurality of oil components are mixed in any proportion.

[0011] In some embodiments of the present invention, the content of the injection oil in every 100 mL of the fat emulsion injection is no more than 30 g.

[0012] In some embodiments of the present invention, the stabilizer includes one or more of m-cresol, chlorocresol, and chloroxylenol.

[0013] In the present invention, the stabilizer can significantly increase the stability of emulsion particles in fat emulsion and reduce the aggregation of emulsion particles to form obvious oil droplets; in addition, the stabilizer in the present invention can partially replace the emulsifier to achieve emulsification, thereby reducing the amount of emulsifier used and achieving the effect of increasing the stability of the emulsion.

[0014] In some embodiments of the present invention, the content of the stabilizer in every 100 mL of the fat emulsion injection is no more than 1 g.

[0015] In the present invention, the fat emulsion injection comprising injection oil, a stabilizer and injection water can be used for nutritional supplementation after surgery, wherein the injection oil serves as an active ingredient for nutritional supplementation.

[0016] In some embodiments of the present invention, the fat emulsion injection further comprises an active drug.

[0017] In some embodiments of the present invention, the active drug comprises a sedative anesthetic drug selected from one or more of propofol, alfaxalone, and etomidate.

[0018] In some embodiments of the present invention, the active drug comprises a nonsteroidal anti-inflammatory drug selected from one or more of carprofen, meloxicam, flurbiprofen, or pharmaceutically acceptable salts or esters thereof.

[0019] In some embodiments of the present invention, the active drug comprises carprofen methyl ester, carprofen isopropyl ester, meloxicam isopropyl ester, flurbiprofen axetil, flurbiprofen methyl ester (methyl flurbiprofen), flurbiprofen D-glucose alcohol ester.

[0020] In some embodiments of the present invention, the active drug comprises an antiemetic drug selected from one or more of aprepitant, fosaprepitant, and rolapitant.

[0021] In the present invention, active drugs are not limited to the above-mentioned sedative and anesthetic drugs, non-steroidal anti-inflammatory drugs and antiemetic drugs. Compounds that can be used to prepare the O / W type fat emulsion injection of the present invention and have biological activity and pharmacological effects are included in the scope of "active drugs".

[0022] In some embodiments of the present invention, the content of the active drug in every 100 mL of the fat emulsion injection is no more than 2 g.

[0023] In some embodiments of the present invention, the fat emulsion injection further comprises an emulsifier, and the emulsifier comprises one or more of egg yolk lecithin, soybean lecithin, Pluronic F68, poloxamer 188, oleic acid, and sodium oleate.

[0024] In some embodiments of the present invention, the content of the emulsifier in every 100 mL of the fat emulsion injection is no more than 16 g.

[0025] In some embodiments of the present invention, the fat emulsion injection further includes an osmotic pressure regulator, and the osmotic pressure regulator includes one or more of glycerol, glucose, sucrose, and mannitol.

[0026] In some embodiments of the present invention, the content of the osmotic pressure regulator in every 100 mL of the fat emulsion injection is no more than 7 g.

[0027] In some embodiments of the present invention, the fat emulsion injection further includes an antibacterial agent, and the antibacterial agent includes one or more of phenoxyethanol, benzyl alcohol, chlorobutanol, chlorphenesin, ethanol, 1,2-pentanediol, 1,2-hexanediol, and disodium edetate.

[0028] In some embodiments of the present invention, the content of the antibacterial agent in every 100 mL of the fat emulsion injection is no more than 5 g.

[0029] In some embodiments of the present invention, the fat emulsion injection may further include other pharmaceutically acceptable excipients, including but not limited to pH regulators, buffers, and antioxidants.

[0030] In some embodiments of the present invention, the pH adjuster includes hydrochloric acid and sodium hydroxide, which are used to adjust the pH of the injection to 7.0-8.5, close to physiological pH to reduce irritation.

[0031] In some embodiments of the present invention, the buffer comprises a phosphate buffer and a citrate buffer; the phosphate buffer comprises Na2HPO4 / NaH2PO4; and the buffer is used to avoid irritation or drug degradation caused by pH fluctuation.

[0032] In some embodiments of the present invention, the antioxidant includes vitamin E (α-tocopherol) and EDTA (ethylenediaminetetraacetic acid); the vitamin E can prevent fat oxidation; and the EDTA can reduce oxidation reactions as a metal ion chelator.

[0033] The second aspect of the present invention provides a method for preparing a fat emulsion injection, comprising the following steps:

[0034] (1) The active drug and the injection oil are heated and dissolved separately, and then mixed to obtain an oil phase;

[0035] (2) dissolving the osmotic pressure regulator in water for injection and mixing uniformly to obtain an aqueous phase;

[0036] (3) slowly adding the oil phase to the water phase, mixing / stirring / shearing to obtain a primary emulsion;

[0037] (4) The primary emulsion undergoes multiple high-pressure homogenization cycles to obtain an emulsion;

[0038] (5) The emulsion is aseptically filtered or sterilized to obtain a fat emulsion injection;

[0039] The fat emulsion injection comprises an emulsifier, a stabilizer and an antibacterial agent, and the emulsifier, stabilizer and antibacterial agent are dissolved in the oil phase and / or the water phase according to their water solubility and oil solubility.

[0040] In some embodiments of the present invention, the emulsifier, stabilizer and antibacterial agent may be both water-soluble and oil-soluble. In this case, the emulsifier, stabilizer and antibacterial agent may be dissolved in both the oil phase and the water phase.

[0041] In some embodiments of the present invention, the method for preparing the fat emulsion injection comprises the following steps:

[0042] (1) The active drug, injection oil, stabilizer, and emulsifier are heated and dissolved separately, and then mixed to obtain an oil phase;

[0043] (2) dissolving the osmotic pressure regulator and the antibacterial agent in water for injection and mixing them uniformly to obtain an aqueous phase;

[0044] (3) slowly adding the oil phase to the water phase, mixing / stirring / shearing to obtain a primary emulsion;

[0045] (4) The primary emulsion undergoes multiple high-pressure homogenization cycles to obtain an emulsion;

[0046] (5) The emulsion is aseptically filtered or sterilized to obtain a fat emulsion injection.

[0047] In some embodiments of the present invention, the heating and dissolving temperature in step (1) is 40-80°C.

[0048] In the present invention, the purpose of heating and dissolving is to dissolve the components in the oil phase. Therefore, the heating and dissolving temperature includes any temperature that can completely dissolve the oil phase components.

[0049] In some embodiments of the present invention, the pressure of the high-pressure homogenization in step (4) is not less than 4000 PSI.

[0050] In some embodiments of the present invention, the number of high-pressure homogenization cycles in step (4) is no less than 2.

[0051] The third aspect of the present invention provides use of the fat emulsion injection according to the first aspect of the present invention in the preparation of a medicament for treating a disease.

[0052] In some embodiments of the present invention, the drugs include sedatives, anesthetics, nonsteroidal anti-inflammatory drugs, antiemetics, and postoperative nutritional supplements.

[0053] In some embodiments of the present invention, a single dose of the fat emulsion injection can be administered to a subject in need thereof in multiple doses.

[0054] The beneficial effects of the present invention are:

[0055] The stabilizer added to the fat emulsion injection of the present invention is intended to increase the stability of the fat emulsion injection. Chlorocresol is typically used only as an antibacterial agent in cosmetics or formulations. However, the present invention unexpectedly discovered that adding chlorocresol to an O / W fat emulsion injection can increase the stability of the emulsion. The resulting formulation is uniform and free of oil droplets, making the emulsion more stable. Therefore, chlorocresol can be used as a stabilizer for O / W emulsions.

[0056] The stabilizer chloromethyl phenol in the present application can partially replace the emulsifier, realize the emulsification, thereby reducing the amount of emulsifier, and realizing the effect of increasing the stability of emulsion.

[0057] Antibacterial agents are usually added to fat emulsion injections to ensure their quality and safety. The stabilizer chloromethyl phenol in the present application itself has certain antibacterial activity, and can enhance the antibacterial efficacy of the preparation product through synergistic effect with other antibacterial agents, especially the antibacterial activity against molds is superior to that reported in the prior art (US6140373A), thereby reducing the probability of contamination by microorganisms in the external environment after opening the preparation. At the same time, the synergistic effect of the stabilizer and the antibacterial agent reduces the amount of the antibacterial agent. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 Zeta potential diagrams of Examples 1-9 and Comparative Examples 1-10;

[0059] Figure 2 Particle size distribution diagrams of Example 1 and Comparative Example 2. DETAILED DESCRIPTION

[0060] The concept and technical effects of the present application will be described below in conjunction with the examples, so as to fully understand the purpose, features and effects of the present application. Obviously, the described examples are only a part of the examples of the present application, but not all the examples. Based on the examples of the present application, other examples obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0061] In addition, in order to better illustrate the present application, numerous specific details are given in the following detailed description. Those skilled in the art should understand that the present application can also be implemented without some specific details. In some examples, the raw materials, methods, means, etc. which are well known to those skilled in the art are not described in detail, so as to highlight the main idea of the present application.

[0062] The shearing device is a shearing machine B25 series of Shanghai Bierter Fluid Equipment Co., Ltd.; the homogenizing device is a homogenizing machine AH-BASIC 30 of ATS An Tu Si Nanometer Technology (Suzhou) Co., Ltd. Each commercially available raw material can be obtained conventionally.

[0063] EXAMPLES

[0064] The fat emulsion injection with chloromethyl phenol as the stabilizer and benzyl alcohol as the antibacterial agent was prepared according to Examples 1-9 in Table 1 below.

[0065]

[0066] The preparation method of Example 1 includes the following steps:

[0067] (1) Under nitrogen protection, sterile, pyrogen-free propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin, sodium oleate, and chlorocresol were heated and dissolved at 50°C and mixed uniformly to obtain an oil phase;

[0068] (2) Under nitrogen protection, glycerol, benzyl alcohol, and water for injection were mixed uniformly, sterilized and filtered through a 0.22 μm filter membrane, and the remaining water for injection was added and mixed uniformly to obtain an aqueous phase;

[0069] (3) Under nitrogen protection, the oil phase was slowly added to the water phase and sheared at 8000 RPM to obtain a primary emulsion;

[0070] (4) Under nitrogen protection, the primary emulsion was subjected to high-pressure homogenization at 6000 PSI for 5 cycles to obtain an emulsion;

[0071] (5) The emulsion obtained in step (4) is filtered through a 5 μm filter membrane, filled with nitrogen, and sterilized to obtain a fat emulsion injection.

[0072] The preparation method of Example 2 is the same as that of Example 1.

[0073] The preparation method of Example 3 is substantially the same as that of Example 1, except that the oil phase consists of propofol, soybean oil, castor oil, egg yolk lecithin, and chlorocresol, and the aqueous phase consists of sucrose, benzyl alcohol, and water for injection.

[0074] The preparation method of Example 4 is substantially the same as that of Example 1, except that the oil phase consists of flurbiprofen axetil, soybean oil, egg yolk lecithin, sodium oleate and chlorocresol, and the aqueous phase consists of glycerol, benzyl alcohol and water for injection.

[0075] The preparation method of Example 5 is substantially the same as that of Example 1, except that the oil phase consists of aprepitant, soybean oil, castor oil, egg yolk lecithin, sodium oleate and chlorocresol, and the aqueous phase consists of sucrose, benzyl alcohol and water for injection.

[0076] The preparation method of Example 6 is substantially the same as that of Example 1, except that the oil phase consists of soybean oil, medium-chain triglycerides, egg yolk lecithin, sodium oleate, and chlorocresol, and the aqueous phase consists of glycerol, benzyl alcohol, and water for injection.

[0077] The preparation method of Example 7 is substantially the same as that of Example 1, except that the oil phase consists of propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin, and chlorocresol, and the aqueous phase consists of glycerol, benzyl alcohol, and water for injection.

[0078] The preparation method of Example 8 comprises the following steps:

[0079] (1) Under nitrogen protection, sterile, pyrogen-free propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin, sodium oleate, and chlorocresol were heated and dissolved at 50°C and mixed uniformly to obtain an oil phase;

[0080] (2) Under nitrogen protection, glycerol, benzyl alcohol, and water for injection were mixed uniformly, sterilized and filtered through a 0.22 μm filter membrane, and the remaining water for injection was added and mixed uniformly to obtain an aqueous phase;

[0081] (3) Under nitrogen protection, the oil phase was slowly added to the water phase and sheared at 9000 RPM to obtain a primary emulsion;

[0082] (4) Under nitrogen protection, the primary emulsion was homogenized at 5000 PSI for 8 cycles to obtain an emulsion;

[0083] (5) The emulsion obtained in step (4) is filtered through a 5 μm filter membrane, filled with nitrogen, and sterilized to obtain a fat emulsion injection.

[0084] The preparation method of Example 9 comprises the following steps:

[0085] (1) Under nitrogen protection, sterile, pyrogen-free propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin, sodium oleate, and chlorocresol were heated and dissolved at 50°C and mixed uniformly to obtain an oil phase;

[0086] (2) Under nitrogen protection, glycerol, benzyl alcohol, and water for injection were mixed uniformly, sterilized and filtered through a 0.22 μm filter membrane, and the remaining water for injection was added and mixed uniformly to obtain an aqueous phase;

[0087] (3) Under nitrogen protection, the oil phase was slowly added to the water phase and sheared at 10000 RPM to obtain a primary emulsion;

[0088] (4) Under nitrogen protection, the primary emulsion was subjected to high-pressure homogenization at 8000 PSI for 4 cycles to obtain an emulsion;

[0089] (5) The emulsion obtained in step (4) is filtered through a 5 μm filter membrane, filled with nitrogen, and sterilized to obtain a fat emulsion injection.

[0090] Comparative Example

[0091] Comparative fat emulsion injections not containing chlorocresol were prepared according to the prescriptions of Comparative Examples 1-11 in Table 2 below.

[0092]

[0093] Note: " / " indicates that the component is not contained. The preparation method of Comparative Examples 1-10 comprises the following steps:

[0094] (1) Under nitrogen protection, sterile, pyrogen-free propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin, and sodium oleate were heated and dissolved at 50°C and mixed uniformly to obtain an oil phase;

[0095] (2) Under nitrogen protection, glycerol, benzyl alcohol, and water for injection were mixed uniformly, sterilized and filtered through a 0.22 μm filter membrane, and the remaining water for injection was added and mixed uniformly to obtain an aqueous phase;

[0096] (3) Under nitrogen protection, the oil phase was slowly added to the water phase and sheared at 8000 RPM to obtain a primary emulsion;

[0097] (4) Under nitrogen protection, the primary emulsion was subjected to high-pressure homogenization at 6000 PSI for 5 cycles to obtain an emulsion;

[0098] (5) The emulsion obtained in step (4) is filtered through a 5 μm filter membrane, filled with nitrogen, and sterilized to obtain a fat emulsion injection.

[0099] The preparation method of Comparative Example 2 is roughly the same as that of Comparative Example 1, except that the oil phase consists of propofol, soybean oil, medium-chain triglycerides, and egg yolk lecithin, and the aqueous phase consists of glycerol, methylparaben, propylparaben, and water for injection.

[0100] The preparation method of Comparative Example 3 is substantially the same as that of Comparative Example 1, except that the oil phase consists of propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin and sodium oleate, and the aqueous phase consists of glycerol, anhydrous ethanol and water for injection.

[0101] The preparation method of Comparative Example 4 is substantially the same as that of Comparative Example 1, except that the oil phase consists of propofol, soybean oil, medium-chain triglycerides, egg yolk lecithin, and sodium oleate, and the aqueous phase consists of sucrose, benzyl alcohol, and water for injection.

[0102] The preparation method of Comparative Example 5 is roughly the same as that of Comparative Example 1, except that the oil phase consists of flurbiprofen axetil, soybean oil, castor oil, egg yolk fat and sodium oleate, and the aqueous phase consists of glycerol, methylparaben, propylparaben and water for injection.

[0103] The preparation method of Comparative Example 6 is roughly the same as that of Comparative Example 1, except that the oil phase consists of flurbiprofen axetil, soybean oil, medium-chain triglycerides, egg yolk lecithin and sodium oleate, and the aqueous phase consists of sucrose, propylparaben, anhydrous ethanol and water for injection.

[0104] The preparation method of Comparative Example 7 is substantially the same as that of Comparative Example 1, except that the oil phase consists of flurbiprofen axetil, soybean oil egg yolk lecithin and sodium oleate, and the aqueous phase consists of glycerol, benzyl alcohol and water for injection.

[0105] The preparation method of Comparative Example 8 is substantially the same as that of Comparative Example 1, except that the oil phase consists of aprepitant, soybean oil, castor oil, egg yolk lipids and sodium oleate, and the aqueous phase consists of sucrose, benzyl alcohol and water for injection.

[0106] The preparation method of Comparative Example 9 is substantially the same as that of Comparative Example 1, except that the oil phase consists of soybean oil, medium-chain triglycerides, egg yolk lecithin, and sodium oleate, and the aqueous phase consists of glycerol, benzyl alcohol, and water for injection.

[0107] The preparation method of Comparative Example 10 is substantially the same as that of Comparative Example 1, except that the oil phase consists of soybean oil, castor oil, egg yolk lecithin and sodium oleate, and the aqueous phase consists of glycerol, propylparaben, anhydrous ethanol and water for injection.

[0108] The preparation method of Comparative Example 11 is substantially the same as that of Comparative Example 1, except that the oil phase consists of soybean oil, medium-chain triglycerides, egg yolk lecithin, and sodium oleate, and the aqueous phase consists of glycerol, benzyl alcohol, and water for injection.

[0109] Test Example 1: Stability Test

[0110] This test example compares the stability of the fat emulsion injections of Examples 1-9 and Comparative Examples 1-11.

[0111] All samples were sterilized, cooled to room temperature, and placed at room temperature for 1-3 hours before testing.

[0112] The stability results of fat emulsion injection are shown in Table 3 below.

[0113] Table 3

[0114] sample Oil droplets Average particle size (nm) Zeta potential (mV) Example 1 — 165 -42.4 Example 2 — 171 -41.2 Example 3 — 170 -40.8 Example 4 — 175 -42.5 Example 5 — 173 -39.8 Example 6 — 180 -40.7 Example 7 — 175 -48.1 Example 8 — 153 -40.2 Example 9 — 154 -39.6 Comparative Example 1 ++ 179 -15.2 Comparative Example 2 ++ 192 -13.5 Comparative Example 3 + 186 -20.1 Comparative Example 4 + 171 -19.2 Comparative Example 5 + 183 -18.3 Comparative Example 6 + 180 -19.3 Comparative Example 7 + 193 -22.5 Comparative Example 8 + 201 -17.6 Comparative Example 9 ++ 189 -11.8 Comparative Example 10 + 182 -17.8 Comparative Example 11 ++ NA NA

[0115] Note: Oil droplets can be observed visually under illumination. "—" indicates no oil droplets were observed, "+" indicates a small amount of oil droplets were observed, and "++" indicates significant oil droplets were observed. The emulsion particle size distribution was determined using a Malvern MS3000 particle size analyzer.

[0116] The above test results show that: (1) No obvious oil droplets were observed in Examples 1-9, and the absolute value of their Zeta potential was significantly greater than that of Comparative Examples 1-10 (see the results in Figure 1 , significant difference: p = 1.82 × 10 -12), indicating that the addition of chlorocresol can significantly increase the stability of the emulsion particles in the fat emulsion; (2) In Examples 2 and 3, the amount of chlorocresol is increased and the amount of sodium oleate is reduced, and the emulsification effect of Example 1 can also be achieved, proving that chlorocresol can partially replace the emulsifier sodium oleate and has the effect of increasing the stability of the emulsion; (3) Examples 1, 8, and 9 show that under the preparation method of the present invention, the same prescription can obtain a stable emulsion without oil droplets; (4) Comparative Examples 1-10 do not add chlorocresol, and their emulsification effects are inferior to those of Examples 1-9, with clearly visible oil droplets; (5) The particle size distribution of Example 1 and Comparative Example 2 is as follows Figure 2 As shown, it can be seen that the fat emulsion obtained in Example 1 has a uniform particle size distribution, while the fat emulsion obtained in Comparative Example 2 has an uneven particle size distribution. The above experimental results show that chlorocresol as a stabilizer can significantly increase the stability of fat emulsion injection. (6) Comparative Example 11 uses more than 5% of antibacterial agent, and the emulsion emulsification effect is very poor, with a large number of oil droplets.

[0117] Test Example 2: Antibacterial efficacy test

[0118] The antibacterial efficacy of the fat emulsion injections of Examples 1-6 and Comparative Examples 1-10 was tested according to Section 1121 of Part IV of the Chinese Pharmacopoeia (2020 Edition). The steps of culture medium preparation, bacterial solution preparation, suitability test, test sample inoculation, antibacterial efficacy determination, and surviving bacterial count determination were described in Section 1121 of Part IV of the Chinese Pharmacopoeia (2020 Edition).

[0119] The criteria for determining antibacterial efficacy are shown in Table 4 below, where "A" represents the desired antibacterial efficacy standard. In exceptional cases, if the antibacterial agent may increase the risk of adverse reactions, the antibacterial efficacy standard "B" should be met. For example, if the antibacterial agent may increase the risk of adverse reactions, the antibacterial efficacy standard should be at least 3% of the lg value within 7 days.

[0120] Table 4

[0121] Criteria for judging the antibacterial efficacy of injections, ophthalmic preparations, and preparations for uterus and breast

[0122]

[0123] Note: NR test bacteria did not recover growth.

[0124] NI did not increase, which means that the amount of test bacteria increased by no more than 0.51g compared with the previous measurement time.

[0125] The results of the comparison of the antibacterial efficacy of Examples 1-3 and Comparative Examples 1, 2, 4, and 10 are shown in Table 5 below.

[0126] Table 5

[0127]

[0128]

[0129] Note: NI stands for no increase, meaning the number of test bacteria increased by no more than 0.5 log relative to the previous measurement time. " / " indicates that the number of colonies is too large to be counted.

[0130] The antibacterial test data show that the antibacterial effects of Examples 1-3 on Aspergillus niger, Staphylococcus aureus, and Pseudomonas aeruginosa (7 days, 14 days, and 28 days) are all better than those of Comparative Examples 1, 2, 4, and 10. This indicates that the synergistic antibacterial effect of chlorocresol and benzyl alcohol is better than that of Comparative Example 1 (single antibacterial agent, benzyl alcohol), better than that of Comparative Example 2 (synergistic antibacterial agents, methylparaben and propylparaben), and better than that of Comparative Example 4 (synergistic antibacterial agents, ethanol and benzyl alcohol), and Comparative Example 10 (synergistic antibacterial agents, ethanol and propylparaben) is optimized.

[0131] While the embodiments of the present invention have been described in detail above with reference to the accompanying drawings, the present invention is not limited to the embodiments described above. Various modifications may be made within the scope of knowledge possessed by a person skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof may be combined with one another unless there is a conflict.

Claims

1. A fat emulsion injection, characterized in that: The fat emulsion injection is an O / W type fat emulsion injection, which includes injection oil, a stabilizer and water for injection.

2. The fat emulsion injection according to claim 1, characterized in that The injection oil includes one or more of coconut oil, palm oil, olive oil, fish oil, soybean oil, sunflower oil, rapeseed oil, tea oil, castor oil, cottonseed oil, corn oil, olive oil, and medium-chain triglycerides.

3. The fat emulsion injection according to claim 1, characterized in that The stabilizer includes one or more of m-cresol, chlorocresol, and chloroxylenol.

4. The fat emulsion injection according to claim 1, characterized in that The fat emulsion injection further comprises active drugs, which include sedative and anesthetic drugs, nonsteroidal anti-inflammatory drugs and antiemetic drugs.

5. The fat emulsion injection according to claim 1, characterized in that The fat emulsion injection further comprises an antibacterial agent, which comprises one or more of phenoxyethanol, benzyl alcohol, chlorobutanol, chlorphenesin, ethanol, 1,2-pentanediol, 1,2-hexanediol, and disodium edetate.

6. The fat emulsion injection according to claim 1, characterized in that The fat emulsion injection further comprises an emulsifier, and the emulsifier comprises one or more of egg yolk lecithin, soybean lecithin, Pluronic F68, poloxamer 188, oleic acid, and sodium oleate.

7. The fat emulsion injection according to claim 1, characterized in that The fat emulsion injection further comprises an osmotic pressure regulator, and the osmotic pressure regulator comprises one or more of glycerol, glucose, sucrose, and mannitol.

8. The method for preparing the fat emulsion injection according to any one of claims 1 to 7, comprising the following steps: (1) The active drug and the injection oil are heated and dissolved separately, and then mixed to obtain an oil phase; (2) dissolving the osmotic pressure regulator in water for injection and mixing uniformly to obtain an aqueous phase; (3) slowly adding the oil phase to the water phase, mixing / stirring / shearing to obtain a primary emulsion; (4) The primary emulsion undergoes multiple high-pressure homogenization cycles to obtain an emulsion; (5) The emulsion is aseptically filtered or sterilized to obtain a fat emulsion injection; The fat emulsion injection comprises an emulsifier, a stabilizer and an antibacterial agent, and the emulsifier, stabilizer and antibacterial agent are dissolved in the oil phase and / or the water phase according to their water solubility and oil solubility.

9. The preparation method according to claim 8, characterized in that The pressure of the high-pressure homogenization in step (4) is not less than 4000 PSI; the number of multiple high-pressure homogenization cycles in step (4) is not less than 2 times.

10. Use of the fat emulsion injection according to any one of claims 1 to 7 in preparing medicines for treating diseases.

11. The use according to claim 10, characterized in that The drugs include sedatives, anesthetics, nonsteroidal anti-inflammatory drugs, antiemetics and postoperative nutritional supplements.

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