Flurbiprofen axetil injection and preparation method thereof

Abstract

The invention provides a flurbiprofen axetil injection and a preparation method thereof, and belongs to the technical field of biological medicines. According to the flurbiprofen axetil injection provided by the invention, oleic acid is used as a pH regulator to control the pH value of an injection preparation, hydrolysis of soybean oil and egg yolk lecithin can be inhibited, and egg yolk phosphatidyl glycerol (EPG) is added as a co-emulsifier, so that the encapsulation efficiency of an emulsion is remarkably improved, the quantity of flurbiprofen axetil free in water is reduced, and the stability of the injection is improved. The later-stage hydrolysis is obviously reduced. Therefore, the content of the flurbiprofen axetil injection provided by the invention is relatively stable, meanwhile, the quantity of the hydrolysate flurbiprofen is small, the relatively stable pH value of the preparation is ensured, the clinical safety and effectiveness of the preparation are ensured, and the validity period is not less than 2 years.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a flurbiprofen axetil injection and a preparation method thereof. Background Art

[0002] Flurbiprofen axetil is the precursor of flurbiprofen, is a kind of non-steroidal anti-inflammatory drug widely used clinically, has antipyretic, anti-inflammatory and analgesic effects. Its mechanism of action is mainly to inhibit the activity of arachidonic acid epoxidase, thereby inhibiting the synthesis of prostaglandins of pain and inflammatory response, and plays an analgesic effect. Its chemical name is (±) 2-(2-fluoro-4-biphenylyl) propionic acid-1-acetoxyethyl ester, and its structural formula is as follows:

[0003]

[0004] Flurbiprofen axetil injection contains 10mg of flurbiprofen axetil per 1mL solution, which is clinically used for postoperative and cancer analgesia. However, since flurbiprofen axetil is insoluble in water, it is difficult to directly prepare an injection. The current method to solve its solubility is mainly to add soybean oil and emulsifiers to prepare flurbiprofen axetil injection emulsion. It is mainly composed of lipid microspheres and the flurbiprofen axetil wrapped therein. Lipomicrospheres are a dispersion system of microsomes with fatty oil as a soft matrix and encapsulated by a phospholipid membrane, with an average diameter of about 200mm, an inner layer of soft matrix oil, and an outer membrane of lecithin, which mainly encapsulates fat-soluble drugs.

[0005] However, the existing flurbiprofen axetil fat emulsion injection still has shortcomings in its prescription and preparation process. First, high-temperature sterilization is required in the preparation process, and there is the problem of flurbiprofen axetil hydrolysis. During the storage process, flurbiprofen axetil is further hydrolyzed, which affects the stability of the preparation and thus the clinical application of the preparation; secondly, during the high-temperature sterilization and storage process, the degradation of the hydrolysis product flurbiprofen and soybean oil and egg yolk lecithin leads to a decrease in the pH value of the emulsion system; thirdly, the currently marketed flurbiprofen axetil fat emulsion is a heterogeneous liquid preparation, which belongs to a thermodynamically and kinetically unstable system. During high-pressure sterilization and long-term storage, the emulsion droplets are easy to merge, resulting in increased particle size and floating oil, which greatly affects the safety and effectiveness of flurbiprofen axetil injection. Therefore, the national drug standard YBH15412004 requires that flurbiprofen axetil injection be stored in a sealed state at 0-20°C to avoid freezing, with a shelf life of 18 months.

[0006] In order to overcome the above-mentioned shortcomings of flurbiprofen axetil injection, researchers have continuously improved the prescription and preparation process. For example, patents CN102988291A, CN1621035A, CN102188393A, CN102552133A, CN102670502A, CN104173279A, CN104188905A, CN104173279B, and CN108712902A all reported related methods for improving flurbiprofen axetil injection. However, as a drug-loaded fat emulsion, the encapsulation rate of the key formulation characteristic indicator of flurbiprofen axetil injection has not been investigated, and it does not meet the requirements of the "Guidelines for Microparticle Preparations" of the Chinese Pharmacopoeia. As a result, the main contradiction leading to the instability of the product still exists, and the product stability and safety have not been substantially improved. Summary of the invention

[0007] The object of the present invention is to provide a flurbiprofen axetil injection and a preparation method thereof. The flurbiprofen axetil injection has high quality stability and safety.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a flurbiprofen axetil injection, comprising the following components in percentage by weight:

[0010] Flurbiprofen axetil, soybean oil 5-15%, egg yolk lecithin 0.5-1.5%, egg yolk phosphatidylglycerol 0.005-0.02%, oleic acid 0.1-0.3%, glycerol 2.2-2.25% and water for injection;

[0011] The mass concentration of flurbiprofen axetil in the flurbiprofen axetil injection is 0.5-1.5% 。

[0012] Preferably, the mass concentration of flurbiprofen axetil in the flurbiprofen axetil injection is 1.0%.

[0013] The present invention provides a method for preparing the flurbiprofen axetil injection described in the above technical scheme, comprising the following steps:

[0014] Mixing glycerol with water for injection to obtain an aqueous phase;

[0015] Flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, oleic acid and soybean oil are mixed, and a first shear dispersion is performed to obtain an oil phase after dissolution;

[0016] Performing a second shear dispersion on the water phase and the oil phase to obtain colostrum;

[0017] The colostrum is homogenized and sterilized in sequence to obtain flurbiprofen axetil injection.

[0018] Preferably, the temperature of the aqueous phase is 40-60°C.

[0019] Preferably, the temperature of the oil phase is 60-70°C.

[0020] Preferably, the rotation speed of the first shear dispersion is 15000-25000 rpm, and the time is 10-20 min.

[0021] Preferably, the second shear dispersion has a rotation speed of 15000-25000 rpm, a time of 10-20 min, and a temperature of 40-60°C.

[0022] Preferably, the homogenization pressure is 500-1000 bar, and the number of times is 4-6 times.

[0023] Preferably, the sterilization temperature is 121° C. and the time is 15 min.

[0024] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0025] The invention provides a kind of flurbiprofen axetil injection, the flurbiprofen axetil injection prescription is scientific, soybean oil is used as solvent to dissolve raw materials, egg yolk lecithin is used as emulsifier, glycerol is isotonic regulator, oleic acid is used as pH regulator to control the pH value of injection preparation, the hydrolysis of soybean oil and egg yolk lecithin can be suppressed, and egg yolk phosphatidylglycerol (EPG) is added as co-emulsifier, and the hydrophilic end polyhydroxy molecular structure contained therein makes the encapsulation rate of emulsion significantly improved, so that the number of flurbiprofen axetil free in water is reduced, and late hydrolysis is significantly reduced. Therefore, the content of flurbiprofen axetil in the flurbiprofen axetil injection provided by the present invention is relatively stable, and the number of hydrolyzates flurbiprofen is less at the same time, which ensures that the pH value of the preparation is relatively stable, ensures the safety and effectiveness of the preparation clinically, and the validity period is not less than 2 years.

[0026] The flurbiprofen axetil injection provided by the present invention has stable quality and extremely high encapsulation rate of key preparation characteristic index, so the amount of flurbiprofen axetil hydrolysis under high pressure sterilization and accelerated test is significantly lower, and the pH value has a small downward trend. Under the 40°C accelerated test, the quality can be kept stable for 6 months, the content of flurbiprofen produced by hydrolysis is low, and the downward trend of the pH value of the liquid is lower than that of the commercially available reference preparation Kaifen (Beijing Taide Pharmaceutical Co., Ltd.).

[0027] The flurbiprofen axetil injection provided by the present invention has good appearance and shape, is free of oil floating and stratification, has good physical stability of the preparation, and has higher safety. DETAILED DESCRIPTION

[0028] In the present invention, unless otherwise specified, the raw materials or reagents used are commercially available products well known in the art.

[0029] The present invention provides a flurbiprofen axetil injection, comprising the following components in percentage by weight:

[0030] Flurbiprofen axetil, soybean oil 5-15%, egg yolk lecithin 0.5-1.5%, egg yolk phosphatidylglycerol 0.005-0.02%, oleic acid 0.1-0.3%, glycerol 2.2-2.25% and water for injection;

[0031] The mass concentration of flurbiprofen axetil in the flurbiprofen axetil injection is 0.5-1.5%.

[0032] The flurbiprofen axetil injection provided by the present invention comprises flurbiprofen axetil, and the mass concentration of flurbiprofen axetil in the flurbiprofen axetil injection is 0.5-1.5%, preferably 1.0%.

[0033] In the present invention, the mass percentage of the soybean oil is 5-15% (w / v), more preferably 8-12%, and further preferably 10%; the mass percentage of the egg yolk lecithin is 0.5-1.5% (w / v), more preferably 1.0-1.2%; the mass percentage of the egg yolk phosphatidylglycerol is 0.005-0.02% (w / v), more preferably 0.012-0.015%; the mass percentage of the oleic acid is 0.1-0.3% (w / v), more preferably 0.24-0.3%; the mass percentage of the glycerol is 2.2-2.25%, preferably 2.22-2.24%.

[0034] In the present invention, the egg yolk phosphatidylglycerol (EPG) is derived from Avituo (Shanghai) Pharmaceutical Technology Co., Ltd. (for injection).

[0035] The present invention provides a method for preparing the flurbiprofen axetil injection described in the above technical scheme, comprising the following steps:

[0036] Mixing glycerol with water for injection to obtain an aqueous phase;

[0037] Flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, oleic acid and soybean oil are mixed, and a first shear dispersion is performed to obtain an oil phase after dissolution;

[0038] Performing a second shear dispersion on the water phase and the oil phase to obtain colostrum;

[0039] The colostrum is homogenized and sterilized in sequence to obtain flurbiprofen axetil injection.

[0040] In the present invention, the preparation process of the flurbiprofen axetil injection is carried out under nitrogen protection.

[0041] In the present invention, the temperature of the aqueous phase is preferably 40 to 60°C, more preferably 50 to 55°C.

[0042] In the present invention, the temperature of the oil phase is preferably 60-70°C, more preferably 65°C.

[0043] In the present invention, the rotation speed of the first shear dispersion is preferably 15000-25000 rpm, more preferably 20000 rpm, and the time is preferably 10-20 min, more preferably 15 min.

[0044] In the present invention, the rotation speed of the second shear dispersion is preferably 15000-25000 rpm, more preferably 20000 rpm, the time is preferably 10-20 min, more preferably 15 min, and the temperature is preferably 40-60°C, more preferably 50-55°C.

[0045] In the present invention, the homogenization pressure is preferably 500 to 1000 bar, more preferably 800 bar, and the number of times is preferably 4 to 6 times, more preferably 5 times.

[0046] After the homogenization is completed, the present invention preferably filters the obtained emulsion through a 5 μm filter membrane (PES) and then sterilizes it.

[0047] In the present invention, the sterilization temperature is preferably 121° C. and the sterilization time is preferably 15 min.

[0048] In the present invention, the preparation method of the flurbiprofen axetil injection is more preferably:

[0049] Glycerol is added to water for injection, stirred and dissolved to obtain an aqueous phase; flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol and oleic acid are added to soybean oil, dispersed by a first shearing process until completely dissolved to obtain an oil phase; the aqueous phase is added to the oil phase under a second shearing dispersion condition to obtain colostrum; the colostrum is placed in a high-pressure homogenizer for homogenization; the obtained emulsion is filled into an injection bottle, and nitrogen is added into the bottle before and after filling; after filling, the sample is terminally sterilized to obtain a flurbiprofen axetil injection.

[0050] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0051] Example 1

[0052] This embodiment provides 1000 mL of flurbiprofen axetil injection (concentration 1%, w / v), which is prepared from the following ingredients:

[0053] Flurbiprofen axetil 10g

[0054] 100g soybean oil

[0055] Egg yolk lecithin 12g

[0056] Egg yolk phosphatidylglycerol 0.12g

[0057] Oleic acid 2.4g

[0058] Glycerin 22g

[0059] Water for injection 853.48g

[0060] The total amount of all raw materials is 1000 mL.

[0061] Preparation method: Each step was carried out under nitrogen protection.

[0062] Add the prescribed amount of glycerol to 853.48 g of water for injection and stir until completely dissolved to obtain an aqueous phase. Keep the temperature at 55°C during the whole process.

[0063] Add the prescribed amount of flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, and oleic acid into soybean oil, and perform shear dispersion at a speed of 20,000 rpm for 15 minutes until completely dissolved to obtain an oil phase, and keep the temperature at 65°C during the whole process;

[0064] The water phase was added to the oil phase under high-speed shearing to prepare colostrum. The shearing speed was 20,000 rpm for 15 minutes, and the temperature was maintained at 55°C throughout the process.

[0065] The colostrum was placed in a high-pressure homogenizer for high-pressure homogenization at a pressure of 800 bar for 5 times;

[0066] The homogenized emulsion was filtered through a 5 μm filter membrane (PES), filled into a vial under nitrogen filling, with a filling volume of 5 mL, and sterilized at 120° C. for 15 min to obtain flurbiprofen axetil injection.

[0067] The flurbiprofen axetil injection is a white milky liquid without oil floating phenomenon, with a pH value of 6.5, 0.38 mg / mL of flurbiprofen and a flurbiprofen axetil content of 100.2%.

[0068] Example 2

[0069] This embodiment provides 1000 mL of flurbiprofen axetil injection (concentration of 0.5%, w / v), which is prepared from the following ingredients:

[0070] Flurbiprofen axetil 5g

[0071] 80g soybean oil

[0072] Egg yolk lecithin 10g

[0073] Egg yolk phosphatidylglycerol 0.08g

[0074] Oleic acid 2.4g

[0075] Glycerin 22g

[0076] Water for injection 880.52g

[0077] The total amount of all raw materials is 1000mL

[0078] Preparation method: Each step was carried out under nitrogen protection.

[0079] Add the prescribed amount of glycerol to 880.52 g of water for injection and stir until completely dissolved to obtain an aqueous phase. Keep the temperature at 55°C during the whole process.

[0080] Add the prescribed amount of flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, and oleic acid into soybean oil, and perform shear dispersion at a speed of 20,000 rpm for 15 minutes until completely dissolved to obtain an oil phase, and keep the temperature at 65°C during the whole process;

[0081] The water phase was added to the oil phase under high-speed shearing to prepare colostrum. The shearing speed was 15000 rpm for 15 min, and the temperature was maintained at 55°C throughout the process.

[0082] The colostrum was placed in a high-pressure homogenizer for high-pressure homogenization at a pressure of 800 bar for 5 times;

[0083] The homogenized emulsion was filtered through a 5 μm filter membrane (PES), filled into a vial under nitrogen filling, with a filling volume of 5 mL, and sterilized at 120° C. for 15 min.

[0084] The flurbiprofen axetil injection is a white milky liquid without oil floating phenomenon, with a pH value of 6.5, 0.28 mg / mL of flurbiprofen, and a flurbiprofen axetil content of 100.0%.

[0085] Example 3

[0086] This embodiment provides 1000 mL of flurbiprofen axetil injection (concentration of 1.5%, w / v), which is prepared from the following ingredients:

[0087] Flurbiprofen axetil 15g

[0088] 100g soybean oil

[0089] Egg yolk lecithin 12g

[0090] Egg yolk phosphatidylglycerol 0.12g

[0091] Oleic acid 2.4g

[0092] Glycerin 22g

[0093] Water for injection 848.48g

[0094] The total amount of all raw materials is 1000mL

[0095] Preparation method: Each step was carried out under nitrogen protection.

[0096] Add the prescribed amount of glycerol to 848.48 g of water for injection and stir until completely dissolved to obtain an aqueous phase. Keep the temperature at 55°C during the whole process.

[0097] Add the prescribed amount of flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, and oleic acid into soybean oil, and perform shear dispersion at a speed of 20,000 rpm for 15 minutes until completely dissolved to obtain an oil phase, and keep the temperature at 65°C during the whole process;

[0098] The water phase was added to the oil phase under high-speed shearing to prepare colostrum. The shearing speed was 20,000 rpm for 15 minutes, and the temperature was maintained at 55°C throughout the process.

[0099] The colostrum was placed in a high-pressure homogenizer for high-pressure homogenization at a pressure of 1000 bar for 5 times;

[0100] The homogenized emulsion was filtered through a 5 μm filter membrane (PES), filled into a vial under nitrogen filling, with a filling volume of 5 mL, and sterilized at 120° C. for 15 min.

[0101] The flurbiprofen axetil injection is a white milky liquid without oil floating phenomenon, with a pH value of 6.3, 0.42 mg / mL of flurbiprofen and a flurbiprofen axetil content of 99.2%.

[0102] Example 4

[0103] This embodiment provides 1000 mL of flurbiprofen axetil injection (concentration 1%, w / v), which is prepared from the following ingredients:

[0104] Flurbiprofen axetil 10g

[0105] 120g soybean oil

[0106] Egg yolk lecithin 12g

[0107] Egg yolk phosphatidylglycerol 0.12g

[0108] Oleic acid 2.4g

[0109] Glycerin 22g

[0110] Water for injection 833.48g

[0111] The total amount of all raw materials is 1000mL

[0112] Preparation method: Each step was carried out under nitrogen protection.

[0113] Add the prescribed amount of glycerol to 833.48 g of water for injection and stir until completely dissolved to obtain an aqueous phase. Keep the temperature at 55°C during the whole process.

[0114] Add the prescribed amount of flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, and oleic acid into soybean oil, and perform shear dispersion at a speed of 20,000 rpm for 15 minutes until completely dissolved to obtain an oil phase, and keep the temperature at 65°C during the whole process;

[0115] The water phase was added to the oil phase under high-speed shearing to prepare colostrum. The shearing speed was 20,000 rpm for 15 minutes, and the temperature was maintained at 55°C throughout the process.

[0116] The colostrum was placed in a high-pressure homogenizer for high-pressure homogenization at a pressure of 1000 bar for 5 times;

[0117] The homogenized emulsion was filtered through a 5 μm filter membrane (PES), filled into a vial under nitrogen filling, with a filling volume of 5 mL, and sterilized at 120° C. for 15 min.

[0118] The flurbiprofen axetil injection is a white milky liquid without oil floating phenomenon, with a pH value of 6.4, 0.36 mg / mL of flurbiprofen and a flurbiprofen axetil content of 99.5%.

[0119] Test Example 1

[0120] 5 mL of each of the commercially available product Kaifen (flurbiprofen axetil injection, without the addition of egg yolk phosphatidylglycerol (EPG)), flurbiprofen axetil injection prepared in Example 1, Example 2, Example 3, and Example 4 were put into an ultrafiltration tube, and an ultrafiltration membrane with a molecular weight cutoff of 3 kDa was used. The mixture was centrifuged at a speed of 5000 r / min for 15 min, and the ultrafiltration dialysate was collected and directly sampled and analyzed. The content of flurbiprofen axetil in the aqueous phase was calculated, and the encapsulation efficiency of the preparation was calculated. The results are shown in Table 1.

[0121] The encapsulation efficiency calculation formula is as follows:

[0122]

[0123] Table 1 Test results of flurbiprofen axetil drug content and encapsulation efficiency of different flurbiprofen axetil injections

[0124] sample Total drug content in the preparation (mg / mL) Drug amount in aqueous phase (mg / mL) Encapsulation rate (%) Example 1 10.02 0.29 97.1 Example 2 5.00 0.18 96.4 Example 3 14.88 0.60 96.0 Example 4 9.95 0.20 98.0 Commercially available product: Kaifen 9.62 0.84 91.2

[0125] The results in Table 1 show that the encapsulation rates of the flurbiprofen axetil injection samples in the embodiments of the present invention all reach above 96%, which is in compliance with the provisions of the "Guidelines for Microparticle Preparations" of Part IV of the Chinese Pharmacopoeia, and has obvious advantages compared with the commercially available product Kaifen.

[0126] Test Example 2

[0127] Stability test of flurbiprofen axetil injection

[0128] The accelerated test method was used to investigate the drug stability of different flurbiprofen axetil injections (using samples of Example 1 and the commercially available Kaifen product). The prepared flurbiprofen axetil injections were placed in a stability test chamber at a temperature of 40°C ± 2°C, and samples were taken once at 0th month, 1st month, 2nd month, 3rd month and 6th month, respectively. The properties, visible foreign matter, pH value, flurbiprofen axetil and content of the test samples were checked regularly. The results are shown in Tables 2 and 3.

[0129] Table 2 Accelerated stability test results of samples in Example 1

[0130]

[0131]

[0132] The results in Table 2 show that the flurbiprofen axetil injection of the present invention was subjected to an accelerated stability test at a temperature of 40°C ± 2°C. The 6-month sample had good external properties, no oil floating phenomenon, and the pH value and content determination results were relatively stable, meeting the quality control requirements.

[0133] Table 3 Accelerated stability test results of commercially available Kaifen samples

[0134] time Characteristics Visible foreign matter pH Flurbiprofen Flurbiprofen Axetil Content 0 month White milky liquid No floating oil phenomenon 5.9 2.48mg / mL 96.2％ January White milky liquid There is oil floating phenomenon 5.6 3.88mg / mL 95.8％ February White milky liquid There is oil floating phenomenon 5.4 4.42mg / mL 95.0％ March White milky liquid There is oil floating phenomenon 5.2 4.80mg / mL 94.7％ June White milky liquid There is oil floating phenomenon 4.8 6.38mg / mL 91.3％

[0135] The results in Table 3 show that the commercially available Kaifen Flurbiprofen Axetil Injection (trade name: Kaifen) was subjected to an accelerated stability test at a temperature of 40°C ± 2°C. Although the quality met the quality standard requirements, the 6-month sample had oil floating phenomenon, the pH value and content determination results decreased significantly, and the amount of hydrolysis product Flurbiprofen was large.

[0136] The flurbiprofen axetil injection of the present invention has good stability, can be stored at room temperature, and has a shelf life of not less than 2 years.

[0137] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A flurbiprofen axetil injection, characterized in that: Includes the following components in percentage by mass: Flurbiprofen axetil, soybean oil 5-15%, egg yolk lecithin 0.5-1.5%, egg yolk phosphatidylglycerol 0.005-0.02%, oleic acid 0.1-0.3%, glycerol 2.2-2.25% and water for injection; The mass concentration of flurbiprofen axetil in the flurbiprofen axetil injection is 0.5-1.5%.

2. The flurbiprofen axetil injection according to claim 1, characterized in that The mass concentration of flurbiprofen axetil in the flurbiprofen axetil injection is 1.0%.

3. The method for preparing the flurbiprofen axetil injection according to claim 1 or 2, characterized in that: The following steps are involved: Mixing glycerol with water for injection to obtain an aqueous phase; Flurbiprofen axetil, egg yolk lecithin, egg yolk phosphatidylglycerol, oleic acid and soybean oil are mixed, and a first shear dispersion is performed to obtain an oil phase after dissolution; Performing a second shear dispersion on the water phase and the oil phase to obtain colostrum; The colostrum is homogenized and sterilized in sequence to obtain flurbiprofen axetil injection.

4. The preparation method according to claim 3, characterized in that: The temperature of the water phase is 40-60°C.

5. The preparation method according to claim 3, characterized in that: The temperature of the oil phase is 60-70°C.

6. The preparation method according to claim 3, characterized in that: The first shearing dispersion has a rotation speed of 15000-25000 rpm and a time of 10-20 min.

7. The preparation method according to claim 3, characterized in that: The second shearing dispersion has a rotation speed of 15000-25000 rpm, a time of 10-20 min, and a temperature of 40-60°C.

8. The preparation method according to claim 3, characterized in that: The homogenization pressure is 500-1000 bar, and the number of times is 4-6 times.

9. The preparation method according to claim 3, characterized in that: The sterilization temperature is 121° C. and the time is 15 min.

Images