A method for preparing flurbiprofen ester injection and use thereof

Abstract

The present application relates to a kind of preparation of flurbiprofen injection method and its application, wherein, the method includes the following steps: (1) aqueous phase: in injection water, osmotic pressure regulator and basic pH regulator are added, stirring is mixed uniformly, heating, form aqueous phase;(2) oil phase: injection oil, flurbiprofen, emulsifier are mixed uniformly, heating, stirring is sheared and dissolved, form oil phase;(3) initial milk: after the oil phase and part of the aqueous phase are mixed and sheared on line, the remaining aqueous phase is all added to oil phase tank flushing, flushing water is again sheared on line, after initial milk is prepared, appropriate amount of acidic pH regulator is added, and pH value is adjusted;(4) final milk: control first temperature, initial milk is homogenized under low pressure, control second temperature, then high pressure homogenization is carried out, and final milk is prepared;(5) injection: final milk is cooled, filtered, filled, sterilized, so that flurbiprofen injection is prepared;Optionally, wherein at least one step in steps (1) to (5) is completed under nitrogen protection.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a method for preparing flurbiprofen ester injection and application thereof. BACKGROUND

[0002] Flurbiprofen ester is a prodrug of flurbiprofen. After the drug is distributed to the target site of trauma and tumor in the body, flurbiprofen ester is released from the fat emulsion, and is rapidly hydrolyzed to generate flurbiprofen under the action of carboxyl esterase, so as to play an analgesic effect by inhibiting the synthesis of prostaglandin. At present, flurbiprofen ester is clinically used for treating postoperative pain and pain caused by cancer. The injection form of flurbiprofen ester emulsion has certain targeting and sustained-release properties, can reduce the drug dosage, reduce drug toxicity, and improve drug stability. This preparation can avoid the adverse reactions such as gastric mucosa damage and gastrointestinal disorders caused by oral drugs, and also provides an ideal drug administration route for patients with swallowing difficulties.

[0003] Flurbiprofen ester

[0004] Chemical name: (±)-2-(2-fluoro-4-biphenyl) propionic acid-1-acetoxyethyl ester

[0005] Structural formula:

[0006]

[0007] Flurbiprofen ester is extremely soluble in acetone, methanol, ethanol, acetonitrile, diethyl ether and chloroform, and almost insoluble in water. Therefore, the current clinical application of flurbiprofen ester is mostly in the form of fat emulsion.

[0008] US4613505A discloses flurbiprofen ester intravenous fat emulsion and a preparation method thereof, but does not clearly define the mixing method of oil phase and water phase, and the prepared sample has poor stability.

[0009] The preparation method disclosed by Chinese patent application CN102188393A is to stir and mix the oil phase into the water phase to form a primary emulsion, adjust the pH value by sodium phosphate dibasic and citric acid, and supplement the total amount of water. Then, the primary emulsion is homogenized by a homogenizer, filtered, sealed, sterilized, and the product is obtained. In this patent, the oil phase is added to the water phase, and a primary emulsion is prepared by high-speed stirring. When the batch is enlarged to 300L or more, it is difficult to stir uniformly by high-speed stirring, and the part with a large proportion of oil phase in the mixed phase is difficult to form a stable oil-in-water emulsion, which ultimately affects the emulsification effect. The preparation method disclosed by Chinese patent CN106491533B is to inject the oil phase and the water phase into a high-pressure homogenizer for homogenization and emulsification according to the flow ratio of 1:1-1:2 to form a homogenized liquid. After homogenization is completed, the remaining water phase is added to the homogenized liquid and mixed uniformly. In this patent, a large amount of remaining water phase is added to the homogenized liquid after homogenization, which has the risk of causing the homogenized liquid to separate and demulsify. The examples in this patent are all laboratory scale, which cannot guarantee commercial production. SUMMARY

[0010] The present application provides a preparation method for commercial large-scale production of flurbiprofen injection. The flurbiprofen injection prepared by the present application has good stability and safety, and is easy to operate, especially suitable for commercial production of 300L or more.

[0011] In one aspect, the present application provides a method for preparing flurbiprofen injection, wherein the method comprises the following steps:

[0012] (1) Water phase: adding an osmotic pressure regulator and an alkaline pH regulator in the injection water, supplementing the remaining injection water, stirring and mixing uniformly, heating, and forming a water phase;

[0013] (2) Oil phase: mixing injection oil, flurbiprofen, and emulsifier uniformly, heating, stirring and shearing to dissolve, and forming an oil phase;

[0014] (3) Primary emulsion: after on-line mixing and shearing of the oil phase and part of the water phase, all of the remaining water phase is added for flushing, and the flushing water is sheared on-line to prepare a primary emulsion. Then, an appropriate amount of an acidic pH regulator is added to adjust the pH value;

[0015] (4) Final emulsion: controlling a first temperature, homogenizing the primary emulsion by a low-pressure homogenizer, controlling a second temperature, and then homogenizing by a high-pressure homogenizer to prepare a final emulsion;

[0016] (5) Injection: cooling, filtering, filling, and sterilizing the final emulsion to prepare flurbiprofen injection.

[0017] Optionally, at least one of steps (1)-(5) is completed under nitrogen protection.

[0018] The preparation method of this invention improves the mixing method of the oil phase and water phase, abandoning the process of adding the oil phase to the water phase. Instead, it adopts online mixing and shearing of the oil and water phases in a fixed ratio, followed by partial rinsing of the oil phase tank with the water phase and then mixing and shearing again. This can achieve effective emulsification while avoiding the residue of effective components and ensuring the stability of quality. At the same time, the homogenization process is improved, and no water phase is added after mixing, shearing, and homogenization, making the produced product more stable and safe, and suitable for large-scale industrial production.

[0019] In some embodiments, the osmotic pressure regulator is selected from at least one of glycerol, propylene glycol, and PEG400; optionally, the osmotic pressure regulator is glycerol.

[0020] Optionally, the alkaline pH adjuster is selected from at least one of disodium hydrogen phosphate, sodium citrate, sodium acetate, sodium tartrate, sodium bicarbonate, and sodium carbonate; optionally, the alkaline pH adjuster is disodium hydrogen phosphate.

[0021] Optionally, the oil for injection is selected from at least one of soybean oil, medium-chain triglycerides, fish oil, croton oil, olive oil, safflower oil, castor oil, and corn oil; optionally, the oil for injection is soybean oil.

[0022] Optionally, the emulsifier is selected from lecithin; optionally, the lecithin includes at least one of egg yolk lecithin, soybean lecithin, hydrogenated lecithin, and synthetic phospholipids; optionally, the emulsifier is egg yolk lecithin.

[0023] Optionally, the acidic pH adjuster is selected from at least one of acetic acid, tartaric acid, lactic acid, and citric acid; optionally, the acidic pH adjuster is citric acid.

[0024] In some embodiments, the temperature in step (1) is raised to 55°C to 75°C; optionally, the temperature in step (1) is raised to 65°C to 75°C.

[0025] Optionally, in step (2), the temperature is heated to 55℃~75℃; or optionally, in step (2), the temperature is heated to 65~75℃. If the temperature in step (2) is too low, the dissolution time of the emulsifier is too long, which prolongs the process time and is not suitable for industrial or commercial production. If the temperature is too high, the peroxide value is high, the color of the emulsion is darker, and the properties of the emulsion are unstable. Therefore, the inventors found through experiments that when the temperature in step (2) is heated to 65℃~75℃, not only is the dissolution time of the emulsifier shortened, but the peroxide value is also lower, and the appearance of the oil phase formed is light yellow and not easy to change color. Therefore, based on a comprehensive evaluation of the changes in dissolution time, appearance and oxidation index, the preferred oil phase dissolution temperature range in step (2) is 65℃~75℃.

[0026] Optionally, in step (4), the first temperature is controlled to be no lower than the second temperature. The inventors discovered through homogenization temperature experiments that under high pressure, the equipment temperature increases significantly, and excessively high temperatures exceeding the low-pressure temperature lead to a significant increase in PDI. Therefore, to avoid temperature increases under high pressure, it is preferable that the high-pressure temperature be lower than the low-pressure temperature, ensuring that the aqueous and oil phases are emulsified at a uniform temperature regardless of whether homogenization is performed under low or high pressure, thus preventing an increase in PDI.

[0027] Optionally, in step (4), the first temperature is controlled to 55–65°C;

[0028] Optionally, in step (4), the second temperature is controlled to 50-60°C; or, in step (4), the second temperature is controlled to 55-60°C.

[0029] Optionally, the final milk in step (5) is cooled to below 40°C.

[0030] In some embodiments, the oil phase and a portion of the aqueous phase in step (3) are mixed and sheared online in a ratio of 1:(5-7); optionally, the oil phase and a portion of the aqueous phase in step (3) are mixed and sheared in a weight ratio of 1:6. This range of mixing and shearing ensures that the finished emulsion meets quality standards in terms of particle size range D90, average particle size, and PDI, exhibits stable properties, and is not prone to stratification.

[0031] In some embodiments, step (3) adjusts the pH value to 6.3 to 6.8.

[0032] In some embodiments, the high pressure in step (4) during high-pressure homogenization is 800-1000 bar, and the homogenization is performed 6-8 times; optionally, the high pressure in step (4) during high-pressure homogenization is 900-1000 bar, and the homogenization is performed 6-8 times.

[0033] Optionally, in step (4), the colostrum is homogenized at a low pressure of 200-400 bar for 1-3 times; or, in step (4), the colostrum is homogenized at a low pressure of 400 bar for 1 time.

[0034] In some embodiments, in step (5), the filter is filtered through a 0.45 to 2 μm filter element; optionally, in step (5), the filter is filtered through a 1 μm filter element.

[0035] Optionally, in step (5), the contents are filled into borosilicate glass ampoules;

[0036] Optionally, in step (5), sterilization is performed at 121°C for 12-15 minutes.

[0037] In some embodiments, the flurbiprofen ester injection solution is prepared from the following components in weight percentage: 0.5-1.5% flurbiprofen ester, 5-20% injection oil, 0.5-2% emulsifier, 1-3% osmotic pressure regulator, 0.001-0.05% alkaline pH regulator, 0.001-0.05% acidic pH regulator, with the balance being water for injection;

[0038] Optionally, the flurbiprofen ester injection solution is prepared from the following components in weight percentage: 1% flurbiprofen ester, 10% oil for injection, 1.2% emulsifier, 2.21% osmotic pressure regulator, 0.032% alkaline pH regulator, 0.01% acidic pH regulator, and the balance being water for injection.

[0039] In some embodiments, the preparation method includes the following steps:

[0040] (1) Under nitrogen protection, add glycerol and disodium hydrogen phosphate to a portion of water for injection, make up the remaining water for injection, stir and mix evenly, and heat to 55℃~75℃ to obtain an aqueous phase; optionally, heat to 65~75℃.

[0041] (2) Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are mixed evenly and heated to 55°C to 75°C. The mixture is stirred and sheared to dissolve the mixture in order to obtain an oil phase. Optionally, the mixture is heated to 65°C to 75°C. Optionally, the stirring and shearing is performed using a high-shear dispersion emulsifier.

[0042] (3) Under nitrogen protection, the oil phase and part of the aqueous phase are mixed and sheared online at a weight ratio of 1:(5-7), and the remaining aqueous phase is added to the rinse. The rinse water is then sheared online to obtain a pre-emulsion. An appropriate amount of citric acid solution is added to adjust the pH value to 6.3-6.8. Optionally, under nitrogen protection, the oil phase and part of the aqueous phase are mixed and sheared online at a weight ratio of 1:6, and the remaining aqueous phase is added to the rinse. The rinse water is then sheared online to obtain a pre-emulsion. An appropriate amount of citric acid solution is added to adjust the pH value to 6.3-6.8.

[0043] (4) Under nitrogen protection, the first temperature is controlled to 55-65°C, the primary emulsion is homogenized at low pressure of 200-400 bar 1-3 times, the second temperature is controlled to 50-60°C, and then homogenized at high pressure of 800-1000 bar 6-8 times to obtain the final emulsion; optionally, the first temperature is not lower than the second temperature; optionally, the primary emulsion is homogenized at low pressure of 400 bar once; optionally, the second temperature is controlled to 55-60°C; optionally, it is homogenized at high pressure of 900-1000 bar 6-8 times.

[0044] (5) Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, filled, and sterilized at 121°C for 15 min to obtain flurbiprofen ester injection.

[0045] In another aspect, the present invention provides a flurbiprofen ester injection solution, wherein the flurbiprofen ester injection solution is prepared by the method described above.

[0046] The flurbiprofen ester injection solution is prepared from the following components in weight percentage: flurbiprofen ester 0.5-1.5%, soybean oil 5-20%, egg yolk lecithin 0.5-2%, glycerol 1-3%, disodium hydrogen phosphate 0.001-0.05%, citric acid 0.001-0.05%, with the balance being water for injection;

[0047] Optionally, the flurbiprofen ester injection is prepared from the following components by weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, 0.01% citric acid, with the balance being water for injection. This flurbiprofen ester injection exhibits good stability and safety.

[0048] In another aspect, the present invention provides a flurbiprofen ester injection solution, wherein the flurbiprofen ester injection solution is prepared from the following components in weight percentage: flurbiprofen ester 0.5-1.5%, soybean oil 5-20%, egg yolk lecithin 0.5-2%, glycerol 1-3%, disodium hydrogen phosphate 0.001-0.05%, citric acid 0.001-0.05%, and the balance being water for injection;

[0049] Optionally, the flurbiprofen ester injection is prepared from the following components in weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, 0.01% citric acid, with the balance being water for injection.

[0050] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0051] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0052] Figure 1 This is a graph showing the relationship between the number of low-pressure homogenization cycles and the average particle size. Detailed Implementation

[0053] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0054] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0055] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0056] Example 1

[0057] In this embodiment, the flurbiprofen ester injection solution is prepared from the following components in weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, approximately 0.01% citric acid, and the remainder is water for injection.

[0058] Flurbiprofen ester injection, batch size 500L, prescription as follows:

[0059]

[0060]

[0061] The preparation method is as follows:

[0062] 1. Under nitrogen protection, add glycerol and disodium hydrogen phosphate (approximately 0.16 kg) to the prescribed amount of water for injection (approximately 405 kg), stir and mix thoroughly, and heat to 65℃~75℃ to obtain the aqueous phase;

[0063] 2. Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are added to the oil phase tank, heated to 65℃~75℃, and stirred and sheared to dissolve, thus obtaining the oil phase;

[0064] 3. Under nitrogen protection, the oil phase and aqueous phase are mixed online at a weight ratio of 1:6, sheared by an online shearing machine, and finally the remaining aqueous phase is pumped into the oil phase tank for rinsing. The rinsing water is then sheared by an online shearing machine to obtain the primary emulsion. An appropriate amount of 33.3% (w / w) citric acid solution is added to adjust the pH value to 6.3-6.8.

[0065] 4. Under nitrogen protection, control the temperature of the initial emulsion at 55-65℃, homogenize it once at 400 bar low pressure using a homogenizer, control the temperature at 55-60℃, and then homogenize it seven times at 1000 bar to obtain the final emulsion.

[0066] 5. Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, and the filtrate is filled into 5ml borosilicate glass ampoules. The ampoules are then sterilized at 121°C for 15 minutes to obtain the product.

[0067] Example 2

[0068] In this embodiment, the flurbiprofen ester injection solution is prepared from the following components in weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, approximately 0.01% citric acid, and the remainder is water for injection.

[0069] Flurbiprofen ester injection, 300L batch, prescription as follows:

[0070]

[0071] The preparation method is as follows:

[0072] 1. Under nitrogen protection, add glycerol and disodium hydrogen phosphate (approximately 0.096 kg) to the prescribed amount of water for injection (approximately 243 kg), stir and mix thoroughly, and heat to 65℃~75℃ to obtain the aqueous phase;

[0073] 2. Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are added to the oil phase tank, heated to 65℃~75℃, and stirred and sheared to dissolve, thus obtaining the oil phase;

[0074] 3. Under nitrogen protection, the oil phase and aqueous phase are mixed online at a ratio of 1:6, sheared by an online shearing machine, and finally the remaining aqueous phase is pumped into the oil phase tank for rinsing. The rinsing water is then sheared by an online shearing machine to obtain the primary emulsion. An appropriate amount of 33.3% (w / w) citric acid solution is added to adjust the pH value to 6.3-6.8.

[0075] 4. Under nitrogen protection, control the temperature of the initial emulsion at 55-65℃, homogenize it once at 400 bar low pressure using a homogenizer, control the temperature at 55-60℃, and then homogenize it seven times at 1000 bar to obtain the final emulsion.

[0076] 5. Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, and the filtrate is filled into 5ml borosilicate glass ampoules. The ampoules are then sterilized at 121°C for 15 minutes to obtain the product.

[0077] Example 3: Online Shear Ratio Screening Test of Oil Phase and Aqueous Phase

[0078] Flurbiprofen ester injection, 300L batch, prescription as follows:

[0079]

[0080] The preparation method is as follows:

[0081] 1. Under nitrogen protection, add glycerol and disodium hydrogen phosphate (approximately 0.096 kg) to the prescribed amount of water for injection (approximately 243 kg), stir and mix thoroughly, and heat to 65℃~75℃ to obtain the aqueous phase;

[0082] 2. Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are added to the oil phase tank, heated to 65℃~75℃, and stirred and sheared to dissolve, thus obtaining the oil phase;

[0083] 3. Under nitrogen protection, the oil phase and aqueous phase are mixed online in the proportions shown in Table 1, and then sheared by an online shearing machine. Finally, all the remaining aqueous phase is pumped into the oil phase tank for rinsing. The rinsing water is then sheared by an online shearing machine to obtain the primary emulsion. An appropriate amount of 33.3% (w / w) citric acid solution is added to adjust the pH value to 6.3-6.8.

[0084] 4. Under nitrogen protection, control the temperature of the initial emulsion at 55-65℃, homogenize it once at 400 bar low pressure using a homogenizer, control the temperature at 55-60℃, and then homogenize it seven times at 1000 bar to obtain the final emulsion.

[0085] 5. Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, and the filtrate is filled into 5ml borosilicate glass ampoules. The ampoules are then sterilized at 121°C for 15 minutes to obtain the product.

[0086] Experimental methods: The properties of colostrum and the properties of colostrum after standing for 1 hour, as well as particle size and PDI, were investigated. The results are detailed in Tables 1 and 2.

[0087] Experimental results:

[0088] Table 1 Characteristics of colostrum

[0089] Oil to water ratio Colostrum properties Colostrum properties after 1 h standing 1:1 White, milky liquid, visible creaming Milky liquid separated 1:2 White, milky liquid, visible creaming Milky liquid separated 1:3 White, milky liquid, visible creaming Milky liquid separated 1:4 White, milky liquid, no visible creaming White, milky liquid, no visible creaming 1:5 White, milky liquid, no visible creaming White, milky liquid, no visible creaming 1:6 White, milky liquid, no visible creaming White, milky liquid, no visible creaming 1:7 White, milky liquid, no visible creaming White, milky liquid, no visible creaming

[0090] As shown in Table 1, the pre-emulsions prepared with oil and water phases at ratios of 1:1, 1:2, and 1:3 all exhibited oil floating and stratification after one hour of standing. However, if the pre-emulsion was prepared with an oil and water phase ratio of 1:8, the oil phase tank was rinsed with no remaining water phase, leaving oil phase residue. This residue was then pumped into the pre-emulsion tank, predicting that oil floating would occur in the pre-emulsion. Therefore, the particle size distribution of samples prepared with ratios of 1:4, 1:5, 1:6, and 1:7 will be the primary focus of subsequent investigations.

[0091] Table 2 Results of particle size distribution determination

[0092] Example Oil to water ratio D90 (nm) Average particle size (nm) PDI Example 3(a) 1:4 309.7 237.5 0.211 Example 3(b) 1:5 290.6 210.3 0.071 Example 3(c) 1:6 273.7 196.4 0.052 Example 3(d) 1:7 281.8 212.6 0.062

[0093] Table 2 shows that when the oil-to-water ratio is 1:5, 1:6, and 1:7, the particle size range D90, average particle size, and PDI of the finished product prepared according to the proposed process all meet the quality standards (the PDI of the injection solution prepared by this invention is <0.1). When the oil-to-water ratio is 1:4, although the particle size range D90 and average particle size of the finished product meet the quality standards, the PDI is relatively large. Therefore, the oil-to-water ratio is determined to be 1:(5-7). When the oil-to-water ratio is 1:6, the remaining weight of the water phase used for rinsing is reasonable, the oil phase tank is rinsed more thoroughly to avoid residue, and the remaining small amount of water phase can be uniformly mixed into the oil phase to form a stable oil-in-water emulsion. The preferred oil-to-water ratio is 1:6.

[0094] Example 4 Stability Test

[0095] Example 1 group: Flurbiprofen ester injection prepared in Example 1;

[0096] Example 2 group: Flurbiprofen ester injection prepared in Example 2;

[0097] Comparative example: The reference preparation is Flurbiprofen Axetil Injection manufactured by Nippon Scientific Pharmaceutical Co., Ltd., under the trade name ROPION, with a specification of 5ml: 50mg.

[0098] Test method: Examples 1, 2 and the control were placed at 30℃ and 40℃ for 6 months respectively, and their content, single impurities, flurbiprofen, average particle size and 90% milk particle size were detected. (See Table 3-7 below for details of the results).

[0099] Results: As shown in Tables 3-5, after 6 months of storage at 30℃ and 40℃, the content, individual impurities, and flurbiprofen content of Examples 1 and 2 were superior to those of the control example. For example, after 6 months of storage at 40℃, the flurbiprofen ester content of Examples 1 and 2 decreased by approximately 15.6% and 17.3%, respectively, while that of the control example decreased by approximately 29.2%. Flurbiprofen ester hydrolyzes into flurbiprofen after entering the human body, and then takes effect; however, flurbiprofen has poor solubility, and its concentration in fat emulsion products must be controlled. Excessive flurbiprofen can affect the quality of the finished fat emulsion product, and its poor solubility also poses a risk of precipitation. At 6 months, the amount of flurbiprofen in the control example was significantly higher than that in Examples 1 and 2, nearly twice the amount, indicating that the embodiments of the present invention are more stable than the control example.

[0100] As shown in Tables 6 and 7, after being placed at 40°C for 6 months, Examples 1 and 2 showed little change in average particle size and 90% of the milk particle size, while the control example showed a larger change in average particle size and 90% of the milk particle size, indicating that the examples were safer than the control example.

[0101] Conclusion: The stability and safety of the flurbiprofen ester injection of the present invention are superior to those of the control example (reference preparation).

[0102] Table 3 Results of Stability Content Determination

[0103]

[0104] Table 4 Results of Stability Measurement for Single Impurities

[0105]

[0106]

[0107] Table 5 Results of Flurbiprofen Stability Determination

[0108]

[0109] Table 6 Results of Stability Average Particle Size Measurement

[0110]

[0111] Table 7 Results of particle size determination at 90% stability

[0112]

[0113]

[0114] Example 5: Homogenization Process Optimization

[0115] In this embodiment, the flurbiprofen ester injection solution is prepared from the following components in weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, approximately 0.01% citric acid, and the remainder is water for injection.

[0116] Flurbiprofen ester injection, 300L batch, prescription as follows:

[0117]

[0118] The preparation method is as follows:

[0119] 1. Under nitrogen protection, add glycerol and disodium hydrogen phosphate (approximately 0.096 kg) to the prescribed amount of water for injection (approximately 243 kg), stir and mix thoroughly, and heat to 65℃~75℃ to obtain the aqueous phase;

[0120] 2. Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are added to the oil phase tank, heated to 65℃~75℃, and stirred and sheared to dissolve, thus obtaining the oil phase;

[0121] 3. Under nitrogen protection, the oil phase and aqueous phase are mixed online at a ratio of 1:6, sheared by an online shearing machine, and finally the remaining aqueous phase is pumped into the oil phase tank for rinsing. The rinsing water is then sheared by an online shearing machine to obtain the primary emulsion. An appropriate amount of citric acid solution is added to adjust the pH value to 6.3-6.8.

[0122] 4. Under nitrogen protection, control the temperature of the initial emulsion at 55-65℃, homogenize it 1-3 times at 400 bar using a homogenizer, controlling the temperature at 55-60℃, and then homogenize it 1-8 times at 800, 900 and 1000 bar respectively to obtain the final emulsion.

[0123] 5. Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, and the filtrate is filled into 5ml borosilicate glass ampoules. The ampoules are then sterilized at 121°C for 15 minutes to obtain the product.

[0124] Experimental methods and results: see Tables 8 and 9.

[0125] Table 8 Results of Low-Pressure Homogeneous Pressure Investigation

[0126]

[0127]

[0128] As shown in Table 8, after high-shear mixing of the oil and aqueous phases, the average particle size of the primary emulsion was >1 μm. After one pass of low-pressure homogenization, the particle size of the primary emulsion significantly decreased. The average particle size decreased with increasing pressure; therefore, 400 bar was the preferred low-pressure homogenization pressure. Homogenization was performed five times each at 200 bar and 400 bar, with samples taken after each homogenization to measure the average particle size. The results are shown below. Figure 1 .

[0129] The results showed that after one homogenization, further low-pressure homogenization did not significantly reduce the average particle size. Therefore, 400 bar was selected as the preferred low-pressure homogenization pressure for one homogenization.

[0130] Table 9 Results of particle size distribution determination

[0131]

[0132]

[0133] As shown in Table 9, the prepared fat emulsions prepared under homogenization pressures of 900 bar and 1000 bar meet the quality standards for particle size range (D90), average particle size, and PDI (average particle size should be 100–350 nm, and the cumulative particle size of 90% of the emulsion particles should not exceed 600 nm (D90); PDI is generally required to be less than or equal to 0.2). Therefore, a high-pressure homogenization pressure of 900–1000 bar for 6–8 cycles is selected. At a homogenization pressure of 800 bar, the particle size range D90 is approximately 330 nm, which meets the quality standard requirements, but is significantly higher than the particle size range under homogenization pressures of 900 bar and 1000 bar. Therefore, high-pressure homogenization for 6–8 cycles at 800–1000 bar is determined, with 6–8 cycles at 900–1000 bar being preferred.

[0134] Example 6: Screening of Temperature in High-Pressure Homogenization Process

[0135] Theoretically, the emulsification temperature of fat emulsions only needs to be higher than the phase transition temperature of phospholipids. Provided the stability of the raw materials and excipients is ensured, increasing the temperature (e.g., above 50°C) is beneficial for improving the emulsification effect. However, above 65°C, the PDI (particulate index) of the resulting formulation tends to increase significantly.

[0136] Based on the dosage of the formulation under the colostrum preparation process selection section, egg yolk lecithin and flurbiprofen ester were dissolved in soybean oil to prepare the oil phase. Glycerin and disodium hydrogen phosphate were dissolved in water for injection to prepare the aqueous phase. After the oil and aqueous phases were mixed under high shear to prepare the colostrum, the pH of the colostrum was adjusted to approximately 6.5 with citric acid. Then, it was homogenized once at 400 bar and seven times at 1000 bar using a high-pressure homogenizer. The homogenization temperatures were set at 50℃, 55℃, and 60℃, respectively, to investigate the effect of homogenization temperature on the fat emulsion particle size.

[0137] Table 10 High Pressure Homogenization Temperature Screening

[0138]

[0139] The above results indicate that the temperature during high-pressure homogenization is one of the process parameters affecting the quality of fat emulsions. As the high-pressure homogenization temperature increases, the particle size tends to decrease. When the high-pressure homogenization temperature is 55℃–60℃, the average particle size of the product before sterilization is approximately 200–210 nm, and the PDI values ​​are relatively small and stable. The PDI changes little at 55℃ and 60℃. Therefore, a high-pressure homogenization temperature of 55–60℃ is preferred.

[0140] Example 7: Investigation of pH Adjuster Addition Method

[0141] Based on the above prescription dosage, egg yolk lecithin and flurbiprofen ester were dissolved in soybean oil to prepare the oil phase.

[0142] Method 1: Dissolve glycerol and disodium hydrogen phosphate in water for injection to prepare an aqueous phase. Mix and shear the oil and aqueous phases to prepare a colostrum. Adjust the pH of the colostrum to about 6.5 with citric acid. Homogenize the colostrum once at low pressure (400 bar) and seven times at high pressure (1000 bar) to obtain the finished product.

[0143] Method 2: Dissolve glycerol, disodium hydrogen phosphate and an equal amount of citric acid from Method 1 in water for injection to prepare an aqueous phase. Mix the oil phase and aqueous phase and shear to prepare a pre-emulsion. The pre-emulsion is homogenized once at low pressure (400 bar) and seven times at high pressure (1000 bar) to obtain the finished product.

[0144] The pH value, properties, methoxyaniline value, flurbiprofen, related substances, zeta potential and free fatty acids of both were tested. At the same time, both were placed at a high temperature of 60°C for 12 days, and samples were taken for testing on the 5th and 12th days. The test results are shown in Table 11.

[0145] Table 11 Results of the investigation on pH adjuster addition methods

[0146]

[0147] The test results show that the Zeta potential value of the product prepared by Method 2 is significantly lower than that of Method 1, which may lead to instability in the milk particles. The contents of related substances and flurbiprofen in the Product 2 are significantly higher than those in Method 1. This indicates that adding the pH adjuster via Method 1 effectively reduces the formation of related substances and flurbiprofen, resulting in a more stable product. Considering the ease of pH adjustment, Method 1 with the added pH adjuster was chosen.

[0148] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0149] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing flurbiprofen ester injection, wherein, The preparation method includes the following steps: (1) Aqueous phase: Add osmotic pressure regulator and alkaline pH regulator to water for injection, stir and mix evenly, and heat to 55℃~75℃ to form an aqueous phase; (2) Oil phase: Mix the injection oil, flurbiprofen ester and emulsifier evenly, heat to 55℃~75℃, stir and shear to dissolve, and form the oil phase; (3) Colostrum: The oil phase and part of the aqueous phase are mixed and sheared online at a weight ratio of 1: (5~7). The remaining aqueous phase is added to the oil phase tank for rinsing. The rinsing water is then sheared online to obtain the colostrum. An appropriate amount of acidic pH adjuster is added to adjust the pH value to 6.3~6.

8. (4) Final emulsion: The first temperature is controlled to be no lower than the second temperature. The first temperature is controlled to 55~65℃. The primary emulsion is homogenized under low pressure at 200~400 bar for 1~3 times. The second temperature is controlled to 50~60℃. Then it is homogenized under high pressure at 800~1000 bar for 6~8 times to obtain the final emulsion. (5) Injection solution: The final emulsion is cooled to below 40°C, filtered, filled, and sterilized to prepare flurbiprofen ester injection solution; Steps (1) to (5) are performed under nitrogen protection; The flurbiprofen ester injection solution is prepared from the following components in weight percentage: flurbiprofen ester 0.5~1.5%, injection oil 5~20%, emulsifier 0.5~2%, osmotic pressure regulator 1~3%, alkaline pH regulator 0.001~0.05%, acidic pH regulator 0.001~0.05%, and the balance being water for injection; The osmotic pressure regulator is glycerol; the alkaline pH regulator is disodium hydrogen phosphate; the injection oil is soybean oil; the emulsifier is egg yolk lecithin; and the acidic pH regulator is citric acid.

2. The method according to claim 1, wherein, The oil phase and part of the aqueous phase in step (3) are mixed and sheared at a weight ratio of 1:

6.

3. The method according to claim 1, wherein, In step (4), the high pressure for homogenization is 900~1000 bar, and the homogenization is performed 6~8 times; And / or, in step (4), the low pressure of colostrum homogenization is 400 bar, and homogenization is performed once.

4. The method according to claim 1, wherein, In step (5), the filter is filtered through a 0.45-2μm filter element; And / or, in step (5), it is filled into a borosilicate glass ampoule; And / or, in step (5), sterilization is performed at 121°C for 12~15 min.

5. The method according to claim 4, wherein, In step (5), the filter is filtered through a 1μm filter element.

6. The method according to claim 1, wherein, The flurbiprofen ester injection solution is prepared from the following components in weight percentage: 1% flurbiprofen ester, 10% injection oil, 1.2% emulsifier, 2.21% osmotic pressure regulator, 0.032% alkaline pH regulator, 0.01% acidic pH regulator, and the balance being water for injection.

7. The method according to any one of claims 1-6, wherein, The method includes the following steps: (1) Under nitrogen protection, add glycerol and disodium hydrogen phosphate to the prescribed amount of water for injection, stir and mix evenly, and heat to 55℃~75℃ to form an aqueous phase; (2) Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are mixed evenly, heated to 55℃~75℃, and stirred and sheared to dissolve, forming an oil phase; the stirring and shearing are carried out using a high-shear dispersion emulsifier. (3) Under nitrogen protection, the oil phase and part of the aqueous phase are mixed and sheared online at a weight ratio of 1: (5~7). The remaining aqueous phase is added to the oil phase tank for rinsing. The rinsing water is then sheared online to obtain the initial emulsion. An appropriate amount of citric acid solution is added to adjust the pH value to 6.3~6.

8. (4) Under nitrogen protection, the first temperature is controlled to 55~65℃, the primary emulsion is homogenized at low pressure of 200~400 bar 1~3 times, the second temperature is controlled to 50~60℃, and then homogenized at high pressure of 800~1000 bar 6~8 times to obtain the final emulsion. The first temperature is not lower than the second temperature. (5) Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, filled, and sterilized at 121°C for 15 min to obtain flurbiprofen ester injection. The flurbiprofen ester injection is prepared from the following components in weight percentage: flurbiprofen ester 0.5-1.5%, soybean oil 5-20%, egg yolk lecithin 0.5-2%, glycerol 1-3%, disodium hydrogen phosphate 0.001-0.05%, citric acid 0.001-0.05%, and the balance being water for injection.

8. The method according to any one of claims 1-6, wherein, The method includes the following steps: (1) Under nitrogen protection, add glycerol and disodium hydrogen phosphate to the prescribed amount of water for injection, stir and mix evenly, and heat to 65~75℃ to form an aqueous phase; (2) Under nitrogen protection, soybean oil, flurbiprofen ester, and egg yolk lecithin are mixed evenly, heated to 65~75℃, and stirred and sheared to dissolve, forming an oil phase; the stirring and shearing are carried out using a high-shear dispersion emulsifier; (3) Under nitrogen protection, the oil phase and part of the aqueous phase are mixed and sheared online at a weight ratio of 1:

6. The remaining aqueous phase is then added to the rinse water, which is then sheared online to obtain the initial emulsion. An appropriate amount of citric acid solution is added to adjust the pH value to 6.3~6.

8. (4) Under nitrogen protection, the first temperature is controlled to 55~65℃, the primary emulsion is homogenized once at a low pressure of 400 bar, the second temperature is controlled to 55~60℃, and then homogenized 6~8 times at a high pressure of 900~1000 bar to obtain the final emulsion. The first temperature is not lower than the second temperature. (5) Under nitrogen protection, the final emulsion is cooled to below 40°C, filtered through a 1μm filter, filled, and sterilized at 121°C for 15 min to obtain flurbiprofen ester injection. The flurbiprofen ester injection is prepared from the following components by weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, 0.01% citric acid, and the balance being water for injection.

9. A flurbiprofen ester injection, wherein, The flurbiprofen ester injection solution is prepared by the method described in any one of claims 1-5. The flurbiprofen ester injection is prepared from the following components in weight percentage: flurbiprofen ester 0.5-1.5%, soybean oil 5-20%, egg yolk lecithin 0.5-2%, glycerol 1-3%, disodium hydrogen phosphate 0.001-0.05%, citric acid 0.001-0.05%, and the balance being water for injection.

10. A flurbiprofen ester injection, wherein, The flurbiprofen ester injection is prepared by the method described in any one of claims 1-8. The flurbiprofen ester injection is prepared from the following components by weight percentage: 1% flurbiprofen ester, 10% soybean oil, 1.2% egg yolk lecithin, 2.21% glycerol, 0.032% disodium hydrogen phosphate, 0.01% citric acid, and the balance being water for injection.

Images