Efinbuprofen axetil injection and preparation method thereof

Abstract

The invention provides an Efinprofen axetil injection and a preparation method thereof, the injection is an emulsion prepared from Efinprofen axetil, oil for injection, an emulsifier, an auxiliary emulsifier, an osmotic pressure regulator, a buffer salt, a pH regulator and water for injection, compared with an oral administration route, the Efinprofen axetil injection effectively avoids adverse reaction of gastrointestinal tracts, and has the advantages of simple preparation process and low cost. Compared with the existing flurbiprofen axetil injection or emulsion, the flurbiprofen axetil injection or emulsion has the advantages that the stability is better, the dosage is greatly reduced under the condition that the treatment effect is equivalent, and the generation amount of harmful metabolites acetic acid and acetaldehyde in the body can be effectively reduced, so that the medication safety is improved, and the preparation method in the whole process is simple and suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing elfluprofen ester injection, and the injection prepared by the method. Background Technology

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs), a class of drugs with anti-inflammatory, analgesic, antipyretic, and platelet-reducing effects, are widely used in clinical practice. However, they have numerous gastrointestinal side effects with varying clinical manifestations, ranging from asymptomatic to indigestion, bloating, abdominal pain, ulcers, bleeding, and perforation. In severe cases, they can even be life-threatening. Furthermore, the damage to the gastric mucosa caused by NSAIDs does not change with the dosage form. Therefore, actively preventing ulcers and bleeding-related gastrointestinal mucosal damage caused by NSAIDs is receiving increasing attention in clinical practice.

[0003] Flurbiprofen is a nonsteroidal anti-inflammatory drug (NSAID) that exerts its analgesic effect by inhibiting the activity of cyclooxygenase (COX) in the spinal cord and peripheral nervous system, thereby reducing prostaglandin synthesis. It is widely used for postoperative pain and pain relief in various cancers. Flurbiprofen ester is a prodrug of flurbiprofen, which is rapidly degraded into flurbiprofen in the body to exert its therapeutic effect. In 1992, Nippon Scientific Pharmaceutical Co., Ltd. successfully developed a flurbiprofen ester injection, marketed as Ropion. Each 5ml injection contains 50mg of flurbiprofen ester, primarily used for cancer pain and postoperative pain. Compared to oral medications, it reduces adverse clinical reactions such as gastric mucosal irritation and has a faster onset of action.

[0004] Flurbiprofen ester contains a pair of enantiomers, (S)-flurbiprofen ester and (R)-flurbiprofen ester. (S)-flurbiprofen ester has anti-inflammatory and analgesic effects, while (R)-flurbiprofen ester has no analgesic effect. Under normal circumstances, most adverse drug reactions are related to the dosage. By reducing the clinical dosage, the incidence of drug-related adverse events can be significantly reduced. Effluprofen ester is an enantiomer of flurbiprofen ester, with the common name (S)-flurbiprofen ester and the chemical name S-2-(2-fluoro-4-biphenyl)propionic acid-1-acetoxyethyl ester. After injection into the bloodstream, effluprofen ester is released from liposomes and rapidly hydrolyzed by carboxylesterase to produce (S)-flurbiprofen and 1-hydroxyethyl acetate. 1-hydroxyethyl acetate is further decomposed into acetic acid and acetaldehyde, which have potential safety risks. Compared with flurbiprofen ester injection, elfluprofen ester injection, which has higher pharmacological activity, can achieve the same therapeutic effect with half the dosage. Furthermore, due to the reduced dosage, the amount of its metabolites acetic acid and acetaldehyde will also be halved, which can greatly increase the safety of clinical use.

[0005] Patent CN117982420A discloses an S(+)-flurbiprofen ester injection emulsion and its preparation method. The oil phase of the injection emulsion contains S(+)-flurbiprofen ester as the main component, olive oil and soybean oil as solvents, egg yolk lecithin as an emulsifier, and vitamin E as an antioxidant. The finished product is obtained by filtration sterilization. The addition of vitamin E to the oil phase in this patent helps dissolve egg yolk lecithin in the oil phase and also acts as an antioxidant to prevent oxidation and improve product stability. However, the addition of vitamin E in the formulation prevents the product from being processed using moist heat sterilization, increasing the aseptic risk and production cost during manufacturing, making it difficult to achieve commercial-scale production.

[0006] Patent CN110200902A discloses a method for preparing an injection of a (S)-flurbiprofen ester pharmaceutical composition. In this method, the oil phase of the injection contains (S)-flurbiprofen ester as the main component, soybean oil and medium-chain triglycerides as solvents, and egg yolk lecithin as an emulsifier. No auxiliary emulsifiers or stabilizers are added. Our research found that during the moist heat sterilization stage, the droplet size of the injection increases significantly, affecting the stability of the emulsion and thus the safety of the medication.

[0007] Therefore, the preparation of an afluprofen ester pharmaceutical composition that is stable and easy to commercialize is of great significance for clinical application. Summary of the Invention

[0008] The purpose of this invention is to provide an efluprofen ester injection solution based on existing technology. This solution is an emulsion made from efluprofen ester, injection oil, emulsifier, auxiliary emulsifier, osmotic pressure regulator, buffer salt, pH adjuster, and water for injection. Compared with oral administration, it effectively avoids gastrointestinal adverse reactions. Compared with existing flurbiprofen ester injection solutions or emulsions, it has better stability. Under conditions of equivalent therapeutic effect, the dosage is significantly reduced, effectively reducing the production of harmful metabolites acetic acid and acetaldehyde in the body, thereby improving the safety of medication.

[0009] The second objective of this invention is to provide a method for preparing the above-mentioned levorprofen ester injection, which is simple and suitable for large-scale industrial production.

[0010] The technical solution of the present invention is as follows:

[0011] An efluprofen ester injection is an emulsion made from efluprofen ester, injection oil, emulsifier, auxiliary emulsifier, osmotic pressure regulator, buffer salt, pH adjuster and water for injection. During the preparation of the emulsion, the pH value is adjusted to 4.5-6.5 using a pH adjuster.

[0012] In this invention, the injectable oil is a solvent that dissolves the active ingredients of the drug, effectively dissolving the drug activity and improving its bioavailability. The injectable oil selected in this invention can be one or more of soybean oil, olive oil, medium-chain triglycerides, castor oil or fish oil, preferably a combination of soybean oil and medium-chain triglycerides.

[0013] In this invention, the emulsifier effectively disperses the injectable oil into microparticles, effectively preserving or adsorbing the active pharmaceutical ingredients. The emulsifier selected in this invention is chosen from lecithin, soybean lecithin, or egg yolk lecithin, preferably egg yolk lecithin. For example, each 5 mL of injection solution contains 30-90 g of egg yolk lecithin, preferably 40-80 g, and more preferably 50-70 g.

[0014] In this invention, the auxiliary emulsifier effectively enhances emulsifier performance, improves antioxidant capacity, and improves emulsion stability. The auxiliary emulsifier selected in this invention is vitamin E polyethylene glycol succinate (TPGS). For example, each 5 mL of injection solution contains 3-22 g of vitamin E polyethylene glycol succinate (TPGS), preferably 4-20 g, and more preferably 5-18 g. Using other similar auxiliary emulsifiers, such as sodium oleate or phosphatidylglycerol, results in a significant decrease in stability.

[0015] In this invention, the main function of the osmotic pressure regulator is to maintain the osmotic pressure balance of the solution, ensure compatibility with biological fluids, and avoid cell damage or irritation. The osmotic pressure regulator selected in this invention can be glucose, glycerol, or sodium chloride, preferably glycerol. For example, each 5 mL injection solution contains 90.5-130.5 g of glycerol, preferably 95.5-125.5 g, and more preferably 100.5-120.5 g.

[0016] In this invention, the buffer salt is mainly used to maintain the pH environment of the drug solution, ensure the stability of the drug, and prevent drug degradation. The buffer salt selected in this invention can be disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, or potassium dihydrogen phosphate, preferably disodium hydrogen phosphate. For example, each 5 mL of injection solution contains 2.5-4.5 g of disodium hydrogen phosphate, preferably 3.0-4.0 g, and more preferably 3.5-3.7 g.

[0017] In a specific embodiment of the preparation of the injection solution described in this invention, a pH adjuster may be added as needed. The pH adjuster may be citric acid, hydrochloric acid, or acetic acid. The pH value is adjusted to 4.5-6.5 using the pH adjuster; preferably, the pH value is adjusted to 5.0-6.0 using the pH adjuster.

[0018] The levonorgestrel injection provided by this invention contains the following components by weight per 5 mL: levonorgestrel 20-50 g, soybean oil 240-260 g, medium-chain triglycerides 240-260 g, egg yolk lecithin 30-90 g, glycerol 90.5-130.5 g, vitamin E polyethylene glycol succinate 3-22 g, and disodium hydrogen phosphate 2.5-4.5 g.

[0019] The levonorfen ester injection provided by this invention contains the following components by weight per 5 mL: levonorfen ester 20-50 g, soybean oil 245-255 g, medium-chain triglycerides 245-255 g, egg yolk lecithin 40-80 g, glycerin 95.5-125.5 g, vitamin E polyethylene glycol succinate 4-20 g, and disodium hydrogen phosphate 3.0-4.0 g.

[0020] The levonorfen ester injection provided by this invention contains the following components by weight per 5 mL: levonorfen ester 20-50 g, soybean oil 248-252 g, medium-chain triglycerides 248-252 g, egg yolk lecithin 50-70 g, glycerol 100.5-120.5 g, vitamin E polyethylene glycol succinate 5-18 g, and disodium hydrogen phosphate 3.5-3.7 g.

[0021] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 20 g, soybean oil 250 g, medium-chain triglycerides 250 g, egg yolk lecithin 60 g, glycerin 110.5 g, vitamin E polyethylene glycol succinate 10 g, and disodium hydrogen phosphate 3.6 g.

[0022] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 60g, glycerin 110.5g, vitamin E polyethylene glycol succinate 10g, and disodium hydrogen phosphate 3.6g.

[0023] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: 50 g levonorfen ester, 250 g soybean oil, 250 g medium-chain triglycerides, 60 g egg yolk lecithin, 110.5 g glycerin, 10 g vitamin E polyethylene glycol succinate, and 3.6 g disodium hydrogen phosphate.

[0024] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 60g, glycerin 110.5g, vitamin E polyethylene glycol succinate 5g, and disodium hydrogen phosphate 3.6g.

[0025] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 60g, glycerin 110.5g, vitamin E polyethylene glycol succinate 15g and disodium hydrogen phosphate 3.6g.

[0026] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 60g, glycerin 110.5g, vitamin E polyethylene glycol succinate 18g and disodium hydrogen phosphate 3.6g.

[0027] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 50g, glycerol 110.5g, vitamin E polyethylene glycol succinate 10g and disodium hydrogen phosphate 3.6g.

[0028] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 70g, glycerin 110.5g, vitamin E polyethylene glycol succinate 10g, and disodium hydrogen phosphate 3.6g.

[0029] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 60g, glycerin 100.5g, vitamin E polyethylene glycol succinate 10g, and disodium hydrogen phosphate 3.6g.

[0030] For example, the levonorfen ester injection provided by the present invention contains the following components by weight per 5 mL: levonorfen ester 25g, soybean oil 250g, medium-chain triglycerides 250g, egg yolk lecithin 60g, glycerol 120.5g, vitamin E polyethylene glycol succinate 10g and disodium hydrogen phosphate 3.6g.

[0031] The preparation method of levorprofen ester injection provided by the present invention includes the following steps:

[0032] (1) Preparation of oil phase: Heat the oil for injection to 55-75℃, add emulsifier and levonorfen ester, stir and disperse evenly to obtain oil phase;

[0033] (2) Preparation of aqueous phase: Dissolve the osmotic pressure regulator, auxiliary emulsifier and buffer salt in part of the water for injection, heat the resulting mixed solution to 55-75℃, stir and disperse evenly, and then adjust the pH value of the mixed solution to 4.5-6.5 with pH regulator to obtain the aqueous phase;

[0034] (3) Preparation of primary emulsion: The oil phase in step (1) and the aqueous phase in step (2) are mixed, and the resulting mixture is emulsified under high shear to obtain primary emulsion;

[0035] (4) Preparation of final emulsion: Add the colostrum obtained in step (3) to the remaining water for injection, make up to volume, and then homogenize under high pressure to form final emulsion. Filter, fill and sterilize to obtain injection solution.

[0036] In this invention, in step (1), the temperature is raised to 60-70°C.

[0037] In this invention, in step (2), the temperature is raised to 60-70°C.

[0038] In step (2), the amount of water for injection added is 50%-80% of its total amount, preferably 60%-70%, and more preferably 65%.

[0039] In step (2), the pH of the mixed solution is adjusted to 5.0-6.0 with a pH adjuster (e.g., citric acid).

[0040] In this invention, in step (3), the high shearing speed is 10,000 rpm-20,000 rpm, preferably 14,000 rpm-16,000 rpm, more preferably 15,000 rpm; the shearing time is 20 min-40 min, preferably 25 min-35 min, more preferably 30 min.

[0041] In this invention, in step (4), the homogenization pressure is 600 bar to 1000 bar, preferably 750 bar to 850 bar, and more preferably 800 bar; the number of homogenizations is 4 to 10, preferably 5 to 7, and more preferably 6.

[0042] In a preferred embodiment, the preparation method of the levorprofen ester injection provided by the present invention includes the following steps:

[0043] (1) Preparation of oil phase: Mix soybean oil and medium-chain triglycerides, heat the mixture to 60-70℃, add egg yolk lecithin and levorphine ester, stir and disperse evenly to obtain oil phase;

[0044] (2) Preparation of aqueous phase: Dissolve glycerol, vitamin E polyethylene glycol succinate and disodium hydrogen phosphate in 50%-80% (preferably 60%-70%, more preferably 65%) of water for injection. Heat the resulting mixed solution to 60-70°C, stir and disperse evenly. Then use citric acid as a pH adjuster to adjust the pH of the mixed solution to 5.0-6.0 to obtain the aqueous phase.

[0045] (3) Preparation of primary emulsion: The oil phase in step (1) and the aqueous phase in step (2) are mixed, and the resulting mixture is subjected to high-shear emulsification at a speed of 10,000 rpm-20,000 rpm (preferably 14,000 rpm-16,000 rpm, more preferably 15,000 rpm) and a shearing time of 20 min-40 min (preferably 25 min-35 min, more preferably 30 min) to obtain primary emulsion;

[0046] (4) Preparation of final emulsion: Add the pre-emulsion obtained in step (3) to the remaining water for injection, make up to 5 ml, and then perform high-pressure homogenization. The homogenization pressure is 600 bar-1000 bar (preferably 750 bar-850 bar, more preferably 800 bar), and the number of homogenizations is 4-10 times (preferably 5-7 times, more preferably 6 times) to form a final emulsion. The obtained pre-emulsion is filtered through a 0.8 μm filter membrane, and then poured into a 5 ml borosilicate glass ampoule, sealed, and sterilized to obtain the injection solution.

[0047] The advantages of using the technical solution of this invention are as follows:

[0048] The levorprofen ester injection provided by this invention is an emulsion made from levorprofen ester, injection oil, emulsifier, auxiliary emulsifier, osmotic pressure regulator, buffer salt, pH adjuster and water for injection. Compared with oral administration, it effectively avoids gastrointestinal adverse reactions. Compared with existing flurbiprofen ester injections or emulsions, it has better stability. Under the condition of equivalent therapeutic effect, the dosage is greatly reduced, which can effectively reduce the production of harmful metabolites acetic acid and acetaldehyde in the body, thereby improving the safety of medication. The entire preparation method is simple and suitable for large-scale industrial production. Detailed Implementation

[0049] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0050] Examples 1-10

[0051] An afluprofen ester injection is mainly composed of the following components by weight, and the specific components and weights of Examples 1-10 are shown in Table 1.

[0052] Table 1. Components and Dosage

[0053]

[0054]

[0055] The preparation method of the above-mentioned injection solution includes the following steps:

[0056] (1) Preparation of oil phase: Mix soybean oil and medium-chain triglycerides, heat the mixture to 60-70℃, add egg yolk lecithin and levorphine ester, stir and disperse evenly to obtain oil phase;

[0057] (2) Preparation of aqueous phase: Dissolve glycerol, vitamin E polyethylene glycol succinate and disodium hydrogen phosphate in 65% of total water for injection. Heat the resulting mixed solution to 60-70℃, stir and disperse evenly. Then use citric acid as a pH adjuster to adjust the pH value of the mixed solution to 5.0-6.0 to obtain the aqueous phase.

[0058] (3) Preparation of primary emulsion: The oil phase in step (1) and the aqueous phase in step (2) are mixed, and the resulting mixture is subjected to high-shear emulsification at a speed of 15000 rpm and a shearing time of 30 min to obtain the primary emulsion.

[0059] (4) Preparation of final emulsion: Add the pre-emulsion obtained in step (3) to the remaining water for injection, make up to 5 ml, and then perform high-pressure homogenization at a pressure of 800 bar for 6 times to form a final emulsion. Filter the obtained pre-emulsion through a 0.8 μm filter membrane, pour it into a 5 ml borosilicate glass ampoule, seal it, and sterilize it to obtain the injection solution.

[0060] The difference between Examples 2-10 and Example 1 is that the amounts of levonorfen ester, vitamin E polyethylene glycol succinate, egg yolk lecithin, and glycerin are different.

[0061] Comparative Examples 1-4

[0062] An afluprofen ester injection is mainly composed of the following components by weight, and the specific components and weights of Comparative Examples 1-4 are shown in Table 2.

[0063] Table 2 Components and Dosage

[0064] Formula composition Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Alfluoprofen ester (g) 25 25 25 25 Soybean oil (g) 250 250 250 250 Medium-chain triglycerides (g) 250 250 250 250 Egg yolk lecithin (g) 60 60 60 60 Glycerin (g) 110.5 110.5 110.5 110.5 Vitamin E polyethylene glycol succinate (g) 2 25 / / Sodium oleate (g) / / 10 / Phosphatidylglycerol (g) / / / 10 Disodium hydrogen phosphate (g) 3.6 3.6 3.6 3.6 Adjust the volume with water for injection to the specified level. 5ml 5ml 5ml 5ml

[0065] The difference between Comparative Examples 1-4 and Example 1 is the amount of vitamin E polyethylene glycol succinate used and the replacement of vitamin E polyethylene glycol succinate with sodium oleate and phosphatidylglycerol.

[0066] Comparative Example 5

[0067] The injectable emulsion prepared according to Example 1 in CN117982420A.

[0068] Comparative Example 6

[0069] The injection solution prepared according to Example 1 in CN110200902A.

[0070] Comparative Example 7

[0071] Flurbiprofen ester injection, manufactured by Nippon Scientific Pharmaceutical Co., Ltd., was used as a comparative example 7 of the flurbiprofen ester injection.

[0072] Effect Analysis

[0073] 1. Particle size

[0074] Efluprofen ester injection is a fat emulsion in an oil-in-water system. The active pharmaceutical ingredient, efluprofen ester, is encapsulated within the emulsion droplets. Upon reaching the lesion site, the droplets gradually aggregate and rupture, releasing the drug and significantly improving bioavailability. Maintaining the stability of these droplet particles is crucial for the drug's efficacy. The particle size is fundamental to maintaining this stability. Excessively large droplets can easily cause adverse events such as embolism, and excessively large droplets tend to aggregate, disrupting the oil-water phase balance. With prolonged storage, this can lead to oil droplet precipitation and irreversible changes such as demulsification. Conversely, excessively small droplet sizes cannot effectively encapsulate the active pharmaceutical ingredient, thus hindering the achievement of effective therapeutic results. The average particle size of the injection solution prepared in this invention is preferably less than 400 nm, more preferably 150 nm-250 nm.

[0075] The particle size distribution of the samples prepared in Examples 1-10 and the comparative samples was determined using a Malvern Panalytical nanoparticle size potentiometer (model: Zetasizer Nano ZS90). The results are shown in Table 3.

[0076] Table 3. Particle size distribution results

[0077]

[0078] As shown in Table 3, auxiliary emulsifiers were added in Examples 1-10 and Comparative Examples 2-4, resulting in good stability of the droplets during sterilization and minimal change in droplet size before and after sterilization. Comparative Example 1 only added a small amount of auxiliary emulsifier, so its effect was not significant. Comparative Examples 5 and 6 did not add auxiliary emulsifiers, resulting in larger changes in droplet size before and after sterilization. Excessively large droplets can affect product stability and medication safety.

[0079] 2. Release curve

[0080] Referring to the sixth method (flow cell method) of General Chapter 0931 in Part IV of the Chinese Pharmacopoeia, the release curves of each formulation sample in pH 7.4 phosphate buffer + 0.1% Tween 80 medium were detected using a flow cell dissolution meter (model: DS-7CP) from Huarong Analytical Instruments Co., Ltd. The results are shown in Tables 4 and 5.

[0081] Table 4 Release Curve Results

[0082]

[0083] Table 5 Release Curve Results

[0084]

[0085] As shown in Tables 4 and 5, in Comparative Example 1, the amount of auxiliary emulsifier added was too small, and the phospholipid layer was easily broken, resulting in a faster release rate of the main component in the first 5 minutes. In contrast, in Comparative Example 2, the amount of auxiliary emulsifier added was too large, and the phospholipid layer was too tightly bound, resulting in a slower release of the main component in the first 5 minutes. In Comparative Examples 5 and 6, no auxiliary emulsifier was added, so the release rate of the main component in the first 5 minutes was relatively fast. Since this patent is an improvement on Comparative Example 7, in order to ensure the effectiveness of the product, a formulation with a release curve close to that of Comparative Example 7 is preferred.

[0086] 3. Stability

[0087] The samples in the examples and comparative examples were subjected to accelerated testing for 1 month, 3 months and 6 months under the conditions of 40℃±2℃ and 75%±5% humidity. The results are shown in Table 6.

[0088] Table 6 Results of Accelerated Tests

[0089]

[0090]

[0091] As shown in Table 6, sufficient auxiliary emulsifiers were added in Examples 1-10 and Comparative Example 2, resulting in stable properties of the samples under accelerated conditions. The samples accelerated for 6 months showed no significant change compared to the samples at day 0. However, in Comparative Example 1, the amount of auxiliary emulsifier added was too small, failing to improve emulsion stability and causing demulsification, thus affecting product quality. Comparative Examples 3 and 4 used different auxiliary emulsifiers, sodium oleate and phosphatidylglycerol, respectively, which improved emulsion stability during sterilization, resulting in minimal change in droplet size before and after the emulsion process. However, demulsification still occurred under accelerated conditions, affecting product quality. Comparative Examples 5 and 6, lacking auxiliary emulsifiers, showed droplet rupture within 1-3 months of accelerated processing, indicating poor stability and impacting product quality. Comparative Example 7 is a marketed control product, which this patent improved upon. Accelerated testing showed that the sample prepared by this patent exhibited significantly better stability than Comparative Example 7.

[0092] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An eloxim ester injection, characterized in that, The injection solution is an emulsion made from levoroprine ester, injection oil, emulsifier, co-emulsifier, osmotic pressure regulator, buffer salt, pH adjuster, and water for injection. During the emulsion preparation process, the pH value is adjusted to 4.5-6.5 using a pH adjuster. The injection oil is one or more of soybean oil, medium-chain triglycerides, olive oil, castor oil, or fish oil. The emulsifier is lecithin, soybean lecithin, or egg yolk lecithin. The co-emulsifier is vitamin E polyethylene glycol succinate. The osmotic pressure regulator is glycerol, glucose, or sodium chloride. The buffer salt is disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, or potassium dihydrogen phosphate. The pH adjuster is citric acid, hydrochloric acid, or acetic acid.

2. The levorprofen ester injection according to claim 1, characterized in that, The oil for injection is soybean oil and medium-chain triglycerides; the emulsifier is egg yolk lecithin; the osmotic pressure regulator is glycerol; the buffer salt is disodium hydrogen phosphate; the pH regulator is citric acid; during the preparation of the emulsion, the pH value is adjusted to 5.0-6.0 using a pH regulator.

3. The levorprofen ester injection according to claim 2, characterized in that, Each 5mL injection solution contains the following components by weight: 20-50g of levorbutol ester, 240-260g of soybean oil, 240-260g of medium-chain triglycerides, 30-90g of egg yolk lecithin, 90.5-130.5g of glycerol, 3-22g of vitamin E polyethylene glycol succinate, and 2.5-4.5g of disodium hydrogen phosphate.

4. The levorprofen ester injection according to claim 3, characterized in that, Each 5mL injection solution contains the following components by weight: 20-50g of levoropyram ester, 245-255g of soybean oil, 245-255g of medium-chain triglycerides, 40-80g of egg yolk lecithin, 95.5-125.5g of glycerol, 4-20g of vitamin E polyethylene glycol succinate, and 3.0-4.0g of disodium hydrogen phosphate.

5. The levorprofen ester injection according to claim 4, characterized in that, Each 5mL injection solution contains the following components by weight: 20-50g of levoropyram ester, 248-252g of soybean oil, 248-252g of medium-chain triglycerides, 50-70g of egg yolk lecithin, 100.5-120.5g of glycerin, 5-18g of vitamin E polyethylene glycol succinate, and 3.5-3.7g of disodium hydrogen phosphate.

6. The levorprofen ester injection according to claim 5, characterized in that, Each 5 mL of injection solution contains the following components by weight: 20g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 110.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 110.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 50g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 110.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 110.5g of glycerin, 5g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 110.5g of glycerin, 15g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 110.5g of glycerin, 18g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 50g of egg yolk lecithin, 110.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 70g of egg yolk lecithin, 110.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 100.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate; 25g of levonorfen ester, 250g of soybean oil, 250g of medium-chain triglycerides, 60g of egg yolk lecithin, 120.5g of glycerin, 10g of vitamin E polyethylene glycol succinate, and 3.6g of disodium hydrogen phosphate.

7. The preparation method of the levorprofen ester injection according to claim 1, characterized in that, Includes the following steps: (1) Preparation of oil phase: Heat the injection oil to 55-75℃, add emulsifier and levonorfen ester, stir and disperse evenly to obtain oil phase; (2) Preparation of aqueous phase: Dissolve the osmotic pressure regulator, auxiliary emulsifier and buffer salt in part of the water for injection, heat the resulting mixed solution to 55-75℃, stir and disperse evenly, and then adjust the pH value of the mixed solution to 4.5-6.5 with pH regulator to obtain the aqueous phase; (3) Preparation of primary emulsion: The oil phase in step (1) and the aqueous phase in step (2) are mixed, and the resulting mixture is emulsified under high shear to obtain primary emulsion; (4) Preparation of final emulsion: Add the colostrum obtained in step (3) to the remaining water for injection, make up to volume, and then homogenize under high pressure to form final emulsion. Filter, fill and sterilize to obtain injection solution.

8. The method for preparing levorprofen ester injection according to claim 7, characterized in that, The oil for injection is soybean oil and medium-chain triglycerides; the emulsifier is egg yolk lecithin; the osmotic pressure regulator is glycerol; the buffer salt is disodium hydrogen phosphate; and the pH regulator is citric acid.

9. The method for preparing levorprofen ester injection according to claim 8, characterized in that, In step (1), the temperature is raised to 60-70°C; in step (2), the temperature is raised to 60-70°C; the amount of water for injection added is 50%-80% of its total amount, preferably 60%-70%, more preferably 65%; and the pH value of the mixed solution is adjusted to 5.0-6.0 with a pH adjuster.

10. The method for preparing levorbutin ester injection according to claim 8, characterized in that, In step (3), the high shear speed is 10,000 rpm-20,000 rpm, preferably 14,000 rpm-16,000 rpm, more preferably 15,000 rpm; the shearing time is 20 min-40 min, preferably 25 min-35 min, more preferably 30 min; in step (4), the homogenization pressure is 600 bar-1000 bar, preferably 750 bar-850 bar, more preferably 800 bar; the number of homogenizations is 4-10 times, preferably 5-7 times, more preferably 6 times.

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