CN115154421A - Preparation process of flurbiprofen axetil fat emulsion injection - Google Patents
Preparation process of flurbiprofen axetil fat emulsion injection Download PDFInfo
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses a preparation process of flurbiprofen axetil fat emulsion injection, which comprises the following steps: s1, preparing a water phase: dissolving glycerol and disodium hydrogen phosphate in water for injection, adjusting the pH value to 5.5-6.5 by using citric acid, and controlling the temperature to be 61-65 ℃; s2, preparing an oil phase: mixing and dissolving soybean oil, flurbiprofen axetil and egg yolk lecithin, and controlling the temperature to be 66-70 ℃; s3, preparing primary emulsion: adding the oil phase into the water phase to prepare emulsion, wherein the temperature of the emulsion is controlled to be 55-70 ℃; s4, micro-jet homogenization: homogenizing the emulsion by micro-jet, wherein the homogenization temperature is 35-50 ℃; and S5, filtering, filling and sterilizing the liquid medicine to obtain a sample. The flurbiprofen axetil fat emulsion injection prepared by the invention has higher Zeta potential absolute value, stable product quality, particle size and pH value which can meet the requirements of human body, and the process can shorten preparation time, reduce pollution risk and is beneficial to product stability.
Description
Technical Field
The invention relates to the technical field of injection production, in particular to a preparation process of flurbiprofen axetil fat emulsion injection.
Background
Flurbiprofen axetil is a nonsteroidal intravenous targeted analgesic, and is an ester prodrug of flurbiprofen. Compared with flurbiprofen, the flurbiprofen axetil can avoid adverse reactions such as gastric mucosal injury caused by oral administration through intravenous injection, has the advantages of lasting effect, strong selectivity, short acting time, no influence on patient awakening and the like, and is widely applied to treatment of clinical inflammatory pain, cancer pain and postoperative pain.
The fat emulsion injection is a heterogeneous liquid preparation, and belongs to a thermodynamically unstable system. In the preparation process, if the emulsion particles are not uniformly distributed and the Zeta potential absolute value is low, and high-temperature sterilization is added, phenomena of emulsion breaking, layering and the like can occur, and the content of partial main drugs after emulsion breaking can be reduced when the main drugs enter water; the phenomena of particle size increase, emulsion drop agglomeration and the like are easy to occur in the long-term storage process, and the storage is not easy.
The existing preparation process of the flurbiprofen axetil fat emulsion injection comprises the steps of respectively preparing a water phase and an oil phase, then mixing the water phase and the oil phase to prepare a primary emulsion, and then homogenizing the primary emulsion under high pressure to obtain the flurbiprofen axetil fat emulsion injection, wherein the flurbiprofen axetil fat emulsion injection theoretically requires that the smaller the particle size of the flurbiprofen axetil fat emulsion injection is, the better the particle size is (within the range of less than 500 nm), and the pH value is required to meet the human body requirement (weak acidity) as much as possible.
In the prior art, a homogenizer is often adopted for homogenizing colostrum, and although the requirement on equipment is not high, the particle size is easily large, the milk particle distribution is wide, and the absolute value of the Zeta potential is low. In order to meet the requirements of small particle size and uniform distribution of the flurbiprofen axetil fat emulsion injection, micro-jet homogenization is usually adopted during homogenization, the particle size meets the requirements, and the quality of a sample prepared by the method is stable. In addition, in the prior art, the pH is difficult to control to be weak acid in the production process of the flurbiprofen axetil fat emulsion injection, the later adjustment is often needed, impurities and polluted samples are possibly introduced when the pH value is adjusted in the later period, and the safety of the flurbiprofen axetil fat emulsion injection is easily reduced.
Disclosure of Invention
The invention aims to provide a preparation process of a flurbiprofen axetil fat emulsion injection, the Zeta potential absolute value of the flurbiprofen axetil fat emulsion injection prepared by the process is higher, the product quality is stable, the average particle size and the pH value can meet the requirements of human bodies, the preparation time can be shortened by the process, the pollution risk is reduced, and the stability of the product is facilitated.
The invention is realized by the following technical scheme:
the preparation process of the flurbiprofen axetil fat emulsion injection comprises the following steps:
s1, dissolving glycerol and disodium hydrogen phosphate in water for injection by stirring, adding water for injection to 60-80% of a preparation amount, adjusting the pH value to 5.5-6.5 by using citric acid, and controlling the temperature to be 63 +/-2 ℃ to serve as a water phase;
s2, mixing, stirring and dissolving the soybean oil, the flurbiprofen axetil and the egg yolk lecithin, and controlling the temperature to be 68 +/-2 ℃ to serve as an oil phase;
s3, adding the oil phase prepared in the step S2 into the water phase prepared in the step S1 under the stirring state to prepare emulsion, weighing to full amount, and uniformly stirring, wherein the temperature of the emulsion is controlled to be 55-70 ℃;
s4, homogenizing and homogenizing the emulsion obtained in the step S3 by adopting high-pressure micro-jet, wherein the homogenizing pressure is 20000psi, the homogenizing is carried out for 3 times, and the homogenizing temperature is 35-50 ℃;
and S5, filtering the homogenized liquid medicine, filling, and sterilizing at 121 ℃ for 15min to obtain a finished product.
The 20000psi in the present invention is equivalent to 1379bar (1 bar ≈ 14.5 psi), where 1bar is one atmosphere.
The water phase does not contain yolk lecithin, namely the yolk lecithin is regulated in the oil phase in the preparation process of the invention, so that the water phase can be filtered by adopting a 0.22 mu m polyethersulfone filter core, bacterial microorganisms and the like are removed, the prepared product is safer, the yolk lecithin is not easy to dissolve in the water phase, and if the yolk lecithin is regulated in the water phase, the water phase cannot be filtered by adopting the 0.22 mu m polyethersulfone filter core.
The pH value of the water phase is controlled to be 5.5-6.5 in the step S1, and the pH value of the sterilized emulsion can be ensured to be 6.0-6.5 by combining the subsequent steps S2, S3 and S4, so that the requirements of a human body are met.
The invention can ensure the stability of the water phase and the oil phase by controlling the temperature of the water phase to be 63 +/-2 ℃ and the temperature of the oil phase to be 68 +/-2 ℃, and the stable colostrum is formed by mixing the oil phase and the water phase according to the proportion of 1:5-1:7 and controlling the temperature of the colostrum to be 55-70 ℃, thereby providing favorable conditions for realizing that the homogenized grain diameter meets the requirement of intravenous injection of a human body. By adopting high-pressure micro-jet homogenization, the grain diameter of the sterilized emulsion is about 200nm, 90 percent of particles are less than or equal to 260nm, the pH value is 6.0-6.5, the Zeta potential is about-50 mv, the product quality is stable, and the emulsion is suitable for intravenous injection of human bodies.
Therefore, the flurbiprofen axetil fat emulsion injection prepared by the process has stable quality such as particle size, zeta potential, pH value and the like, and can meet the requirements of human bodies.
Further, in step S4, after each homogenization, the emulsion is transferred into a transfer tank through a micro-jet, and then the emulsion is transferred into a high-pressure micro-jet after being cooled to 35-50 ℃ for the next homogenization.
Further, in step S4, the emulsion is cooled to 35-50 ℃ before the last homogenization.
Further, in step S4, after the last homogenization, the emulsion is cooled to 30. + -. 5 ℃.
Further, in step S4, after the first homogenization, the emulsion is subjected to dissolved oxygen detection; the objective is to obtain dissolved oxygen data that demonstrates that water for injection and previous oxygen control operations are not problematic, and if dissolved oxygen is detected as unacceptable, nitrogen charging can be used to reduce the dissolved oxygen level.
Further, in step S1, the aqueous phase was filtered using a filter, which was a 0.22 μm polyethersulfone cartridge filter.
Furthermore, the mixing ratio of the oil phase and the water phase is 1:5-1:7.
Preferably, the mixing ratio of oil phase to water phase is 1:6.
Further, nitrogen protection is carried out in the whole preparation process, and dissolved oxygen is controlled to be less than 2mg/L and residual oxygen is controlled to be less than 2%.
Further, in step S4, the homogenization temperature is 35 to 40 ℃.
Further, in step S5, the homogenized liquid medicine is filtered through a 3 μm filter.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. compared with the existing high-pressure homogenization technology, the preparation process disclosed by the invention realizes high-pressure preparation, reduces the homogenization times, reduces the production and preparation time, reduces the pollution risk and is beneficial to product stability.
2. The average particle size of the flurbiprofen axetil fat emulsion injection prepared by the preparation process is about 200nm, 90 percent of particles are less than or equal to 260nm, the Zeta potential is-50mv, the higher the absolute value of the Zeta potential is, the more stable the system is, namely the dissolution or dispersion can resist aggregation. The pH value of the whole process flow is between 6.0 and 6.5, and the pH value does not need to be additionally adjusted, so that the safety is improved.
3. According to the invention, the yolk lecithin is added into the oil phase, the yolk lecithin is slightly lipophilic as a surfactant, the yolk lecithin is more stable when being added into the oil phase, and the water phase can be filtered by adopting a 0.22 mu m polyether sulfone filter core, so that bacterial microorganisms and the like can be removed, and the prepared product is safer.
4. The invention improves the encapsulation rate of the flurbiprofen axetil by controlling the proportion range of the oil phase and the water phase, so that the degradation of the flurbiprofen axetil is reduced, and the safety of the product is improved.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limitations of the present invention.
Example 1:
the preparation process of the flurbiprofen axetil fat emulsion injection comprises the following steps:
s1, dissolving glycerol and disodium hydrogen phosphate in injection water by stirring, adding the injection water to 70% of a preparation amount, adjusting the pH value to 5.5-6.5 by using citric acid, and controlling the temperature to 63 +/-2 ℃ to be used as a water phase;
specifically, the method comprises the following steps:
1 ten thousand ml of water for injection is added into the preparation tank 1, 1100g of glycerol (for injection), appropriate amount of disodium hydrogen phosphate (Na 2HPO 4) and citric acid are added under the condition of filling nitrogen, stirring is started, the stirring frequency is 10-20 HZ, and the stirring is carried out for 5-10 min. Closing the feeding port, vacuumizing to below-0.06 MPa, charging nitrogen, repeating the steps for more than 3 times, and finally keeping positive pressure by using nitrogen. And (2) starting nitrogen, filtering the solution in the preparation tank 1 to the preparation tank 2 through a barrel filter (polyether sulfone filter element, 0.22 mu m), after the aqueous phase solution is transferred, rinsing the preparation tank 1 with injection water, transferring the washing solution to the preparation tank 2, adding the injection water to a constant volume of 3.5 ten thousand ml, controlling the temperature to be 61-65 ℃, adding citric acid to adjust the pH value to 5.5-6.5 when necessary, and keeping the aqueous phase for later use.
S2, mixing soybean oil, flurbiprofen axetil and egg yolk lecithin to prepare an oil phase, and heating the oil phase to 66-70 ℃;
specifically, the method comprises the following steps:
under the protection of nitrogen, 5000g of soybean oil, 500g of flurbiprofen axetil and 600g of egg yolk lecithin are added into an oil tank, a feeding port is closed, the oil tank is vacuumized to be below-0.06 MPa, nitrogen is charged into the oil tank, the steps are repeated for more than 3 times, and finally positive pressure is maintained by using the nitrogen. Starting stirring (the frequency of the stirrer is 10-30 HZ), heating to 66-70 ℃, stirring for 10-20 minutes, and keeping the oil phase for later use.
S3, preparing primary emulsion: under the stirring state, adding the oil phase prepared in the step S2 into the water phase prepared in the step S1 to prepare emulsion, wherein the mixing ratio of the oil phase to the water phase is 1:6, and the temperature of the emulsion is controlled to be 55-65 ℃;
specifically, the method comprises the following steps:
starting the preparation tank 2 to stir (the stirrer frequency is 10-30 HZ), pressing the oil phase into the preparation tank 2 by using nitrogen, leaching the oil tank by using about 2000ml of water for injection after the transfer is finished, pressing the leaching water into the preparation tank 2 by using nitrogen, continuously stirring for 5-10 min to prepare primary emulsion, adding the water for injection to 5 thousands ml, and stirring for 1-2 min to uniformly mix. Controlling the temperature at 55-65 ℃ to homogenize by microjet.
S4, micro-jet homogenization: homogenizing the emulsion obtained in the step S3 by using micro-jet, wherein the homogenizing pressure is 20000Psi, and the homogenizing is carried out for 3 times, and the temperature is 35-40 ℃.
In this example, to further control the quality of the emulsion after homogenization:
in step S4, homogenizing for 3 times at 20000Psi, transferring the emulsion from high-pressure microjet to a transfer tank after each homogenization, cooling the emulsion to 35-40 ℃, and transferring to high-pressure microjet for next homogenization.
In step S4, after the homogenization for the 1 st time, the emulsion is subjected to dissolved oxygen detection to ensure that the dissolved oxygen is less than 2mg/L.
In step S4, after the last homogenization, the emulsion is cooled to 30. + -. 5 ℃ by means of a heat exchanger.
And S5, filtering the liquid medicine through a filter element with the size of 3 mu m, filling, and sterilizing at the temperature of 121 ℃ for 15min to obtain a finished product.
The dissolved oxygen is controlled to be less than 2mg/L and the residual oxygen is controlled to be less than 2 percent in the whole preparation process.
Specifically, the method comprises the following steps:
residual oxygen treatment of pipelines and containers for preparation: the whole system of the preparation system (the oil tank, the preparation tank 1 and the preparation tank 2), the homogenizing system (the turnover tank) and the filling system (the standing tank) carries out residual oxygen treatment on the pipeline and the container after cleaning, and finally, nitrogen is used for keeping positive pressure for standby.
Example 2:
this example is based on example 1, and differs from example 1 in that:
the temperature of the emulsion in step S3 is controlled to be 65-70 ℃, the homogenization temperature of the emulsion in step S4 is 40-50 ℃, and the rest is the same as that of the emulsion in the embodiment 1.
Comparative example 1:
this comparative example is based on example 1 and differs from example 1 in that:
the temperature of the water phase in the step S1 is controlled to be 50-60 ℃, the temperature of the oil phase in the step S2 is controlled to be 50-60 ℃, the temperature of the emulsion in the step S3 is controlled to be 65-70 ℃, the homogenization temperature of the emulsion in the step S4 is 25-35 ℃, and the rest is consistent with the embodiment 1.
Comparative example 2:
this comparative example is based on example 1 and differs from example 1 in that:
and step S4, continuously homogenizing the emulsion obtained in the step S3 at high pressure by using a high-pressure homogenizer, wherein the homogenization is performed for 5 times under the condition that the homogenization pressure is 750/75bar and for 2 times under the condition that the homogenization pressure is 150/75 bar.
The key indexes of the flurbiprofen axetil fat emulsion injection obtained in the above examples 1 to 2 and comparative examples 1 to 2 are detected, and the results are shown in table 1:
TABLE 1
As can be seen from Table 1:
1) Particle size, zeta potential and pH value of the flurbiprofen axetil fat emulsion injection prepared in the embodiment 1 and the embodiment 2 are detected, and the detection result is as follows: the average grain diameter is 180-210nm, 90% of grains are less than or equal to 260nm, the Zeta potential is-45-60mV, and the pH value is 6.0-6.5. The water phase temperature is controlled to be 61-65 ℃, the oil phase temperature is controlled to be 66-70 ℃, the temperature of the primary emulsion liquid is controlled to be 55-70 ℃, and the homogenization temperature of S4 is 35-50 ℃, so that the particle size and the distribution of the prepared sample and the Zeta potential have no obvious difference. On the premise of the temperature control range of the invention, the Zeta potential, the average grain diameter and the distribution of the emulsion are not obviously influenced by the temperature change, and the product quality is stable.
2) And detecting the particle size, the Zeta potential and the pH value of the flurbiprofen axetil fat emulsion injection prepared in the comparative example 1, wherein the detection result is as follows: the average grain diameter is 200-240nm, 90 percent of grains are less than or equal to 360nm, the pH value is 6.0-6.5, and the Zeta potential is-20-40 mV. Comparing the data of comparative example 1 with those of examples 1 and 2, it can be seen that the water phase temperature, oil phase temperature, colostrum and micro-jet homogenization temperature are out of the range of the present invention, the average particle size of the product is larger, the emulsion particle distribution is wider, and the stability is slightly poor.
3) And detecting the particle size, the Zeta potential and the pH value of the flurbiprofen axetil fat emulsion injection prepared in the comparative example 2, wherein the detection result is as follows: the average grain diameter is 200-240nm, 90 percent of grains are less than or equal to 330nm, the pH value is 6.0-6.5, and the Zeta potential is-20-40 mV. From the comparison of the data of comparative example 2 with those of examples 1 and 2, it can be seen that: the emulsion prepared by the comparative example has larger grain diameter, wider distribution and worse stability than the emulsion prepared by the embodiment, namely when high-pressure micro-jet is adopted for homogenizing treatment, the consistency of emulsion grains is obviously improved, the average grain diameter of the emulsion is reduced, the absolute value of potential is also increased, the system stability is increased, and the product quality is more stable.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The preparation process of the flurbiprofen axetil fat emulsion injection is characterized by comprising the following steps of:
s1, dissolving glycerol and disodium hydrogen phosphate by stirring with injection water, adding the injection water to 60-80% of the preparation amount, adjusting the pH value to 5.5-6.5 by using citric acid, and controlling the temperature to be 63 +/-2 ℃ to serve as a water phase;
s2, mixing, stirring and dissolving the soybean oil, the flurbiprofen axetil and the egg yolk lecithin, and controlling the temperature to be 68 +/-2 ℃ to serve as an oil phase;
s3, adding the oil phase prepared in the step S2 into the water phase prepared in the step S1 under the stirring state to prepare emulsion, weighing to full amount, and uniformly stirring, wherein the temperature of the emulsion is controlled to be 55-70 ℃;
s4, homogenizing and homogenizing the emulsion obtained in the step S3 by adopting high-pressure micro-jet, wherein the homogenizing pressure is 20000psi, the homogenizing is carried out for 3 times, and the homogenizing temperature is 35-50 ℃;
and S5, filtering, filling and sterilizing the homogenized liquid medicine to obtain a finished product.
2. The process for preparing a flurbiprofen axetil fat emulsion injection according to claim 1, wherein in step S4, the emulsion is transferred from the microfluidics into a transfer tank after each homogenization, and then the emulsion is transferred into the high pressure microfluidics for the next homogenization after cooling the emulsion to a temperature of 35-50 ℃.
3. The process for preparing flurbiprofen axetil fat emulsion injection as claimed in claim 2, wherein in step S4, before the last homogenization, the emulsion is cooled to 35-50 ℃.
4. The process for preparing a flurbiprofen axetil fat emulsion injection according to claim 3, wherein in step S4, after the last homogenization, the emulsion is cooled to 30 ± 5 ℃.
5. The process for preparing flurbiprofen axetil fat emulsion injection according to claim 1, wherein in step S4, after the first homogenization, the emulsion is subjected to dissolved oxygen detection.
6. The process for preparing flurbiprofen axetil fat emulsion injection according to claim 1, wherein in step S1, the aqueous phase is filtered by a filter, wherein the filter is a 0.22 μm polyethersulfone cartridge filter.
7. The process for preparing flurbiprofen axetil fat emulsion injection according to claim 1, wherein the mixing ratio of the oil phase and the water phase is 1:5-1:7.
8. The process for preparing flurbiprofen axetil fat emulsion injection according to claim 1, wherein the nitrogen protection is performed during the whole preparation process, and the dissolved oxygen is controlled to be less than 2mg/L and the residual oxygen is controlled to be less than 2%.
9. The process for preparing flurbiprofen axetil fat emulsion injection according to claim 1, wherein the homogenization temperature in step S4 is 35-40 ℃.
10. The process for preparing flurbiprofen axetil fat emulsion injection according to any one of claims 1 to 9, wherein the homogenized liquid medicine is filtered through a 3 μm filter in step S5.
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| CN202111005130.0A CN113559061A (en) | 2021-08-30 | 2021-08-30 | Process for preparing flurbiprofen axetil fat emulsion injection |
| CN2021110051300 | 2021-08-30 |
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| CN102988291A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Flurbiprofen axetil fat emulsion injection composition and preparation method thereof |
| CN108186565A (en) * | 2018-03-16 | 2018-06-22 | 宁波宁融生物医药有限公司 | A kind of method that phosphatide dissolution in low temperature-micro jetting technology prepares compound grease nano-emulsion |
| CN113559061A (en) * | 2021-08-30 | 2021-10-29 | 四川科伦药业股份有限公司 | Process for preparing flurbiprofen axetil fat emulsion injection |
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2021
- 2021-08-30 CN CN202111005130.0A patent/CN113559061A/en not_active Withdrawn
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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