CN113797170A - Fluorouracil freeze-dried preparation for injection and preparation method thereof - Google Patents
Fluorouracil freeze-dried preparation for injection and preparation method thereof Download PDFInfo
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Abstract
The invention provides a fluorouracil freeze-dried preparation for injection and a preparation method thereof, belonging to the field of pharmaceutical preparations. The method comprises the following steps: preparing a dosing solution according to a formula, filtering, and filling and semi-tamponading the filtrate according to a preset specification to obtain a filled semi-finished product; and (3) carrying out freeze-drying treatment on the filling semi-finished product, wherein the freeze-drying treatment comprises the following steps: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 1.5-2 hours at a temperature of-45 ℃ to-40 ℃; heating to-15 to-18 ℃ within 0.5 to 1 hour, and keeping for 1 to 2 hours; cooling to-45 ℃ to-40 ℃ within 0.5-1 hour, and keeping for 2.5-3 hours; after vacuumizing, heating to 0-1 ℃ within 1-1.5 hours, and keeping for 35-40 hours; and continuously heating to 33-37 ℃, keeping for 8-10 hours for analysis and drying, and pressing a stopper completely to obtain the freeze-drying agent. The freeze-drying agent has good solubility, clarity and stability, and is beneficial to safe administration in clinic.
Description
Technical Field
The invention relates to a fluorouracil freeze-dried preparation for injection and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Background
Fluorouracil is also called 5-fluorouracil (5-Fu), is a pyrimidine antimetabolite, is a chemotherapy drug commonly used in clinic at present, has the effect on each phase of the proliferation stage, can prevent the formation of thymine, and inhibit the biosynthesis of DNA, thereby inhibiting the growth of cancer cells. It is used clinically in treating digestive tract tumor, such as gastric cancer, intestinal cancer, liver cancer, etc. It is also effective on breast cancer, ovarian cancer, lung cancer, bladder cancer, cervical cancer, pancreatic cancer, etc.
The fluorouracil is not completely absorbed by oral administration and has low bioavailability, plasma can reach a relatively high level after the fluorouracil is injected by a second quick bolus injection, but the plasma is fast in metabolism, the t1/2 of the plasma is about 10-20 min, and the pharmacokinetics of the traditional administration mode is difficult to predict, so that the drug concentration is suddenly increased in the administration process, the drug has potential toxicity and needs to be frequently administered. In order to improve the bioavailability of the medicine, avoid or reduce adverse reactions and improve the clinical curative effect of the medicine to the maximum extent, a plurality of scholars at home and abroad develop the research work of a new dosage form of the medicine.
However, the existing freeze-drying process has the defects of high sublimation speed, short freeze-drying period, easy occurrence of local concentration phenomenon and influence on the crystal form structure of the product, so that the prepared freeze-dried powder has uneven solubility, low clarity and poor stability, and is not beneficial to clinical safe administration.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a fluorouracil freeze-dried preparation for injection, aiming at solving the problems of uneven solubility, low clarity and poor stability of the existing fluorouracil freeze-dried preparation for injection, thereby improving the chemical stability of the medicine and the safety of the medicine.
The invention provides a preparation method of fluorouracil freeze-dried agent for injection, which comprises the following steps:
weighing fluorouracil, edetate disodium, sodium hydroxide, mannitol, water for injection and active carbon according to a formula, and blending according to a preset blending process to obtain a blending liquid;
filtering the mixed solution to remove active carbon in the mixed solution, and filling and semi-plugging the obtained filtrate according to a preset specification to obtain a filled semi-finished product;
freeze-drying the filled semi-finished product to obtain the fluorouracil freeze-dried agent for injection;
the freeze-drying treatment comprises the following steps:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 1.5-2 hours at the temperature of-45 ℃ to-40 ℃;
a primary heating stage: heating to-15 to-18 ℃ within 0.5 to 1 hour, and keeping for 1 to 2 hours;
a primary cooling stage: cooling to-45 ℃ to-40 ℃ within 0.5-1 hour, and keeping for 2.5-3 hours;
a secondary heating stage: after vacuumizing, heating to 0-1 ℃ within 1-1.5 hours, and keeping for 35-40 hours;
and (3) a third temperature rise stage: and continuously heating to 33-37 ℃, keeping for 8-10 hours for analysis and drying, and pressing a stopper to obtain the fluorouracil freeze-dried preparation for injection.
Preferably, the pre-freezing stage specifically comprises: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 2 hours at-45 ℃.
Preferably, the primary temperature raising stage specifically includes: the temperature was raised to-15 ℃ within 0.5 hour and held for 1.5 hours.
Preferably, the primary cooling stage specifically comprises: the temperature is reduced to-45 ℃ within 0.5 hour, and the temperature is kept for 3 hours.
Preferably, the secondary temperature-raising stage specifically includes: after evacuation, the temperature was raised to 0 ℃ over 1 hour and held for 37 hours.
Preferably, the third temperature rise stage specifically includes: and continuously heating to 35 ℃, keeping for 8 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation for injection.
Preferably, the formulation of the fluorouracil freeze-drying agent for injection comprises the following components in parts by weight: 500-510 parts of fluorouracil, 8-9 parts of edetate disodium, 135-138 parts of sodium hydroxide, 400-408 parts of mannitol and 6964-7000 parts of water for injection.
Preferably, the fluorouracil freeze-drying agent for injection further comprises: 80-82 parts of activated carbon.
Preferably, the formulation of the fluorouracil freeze-drying agent for injection comprises the following components in parts by weight: 500 parts of fluorouracil, 0.8 part of edetate disodium, 135 parts of sodium hydroxide, 400 parts of mannitol, 6964 parts of water for injection and 80 parts of activated carbon.
The invention also provides a fluorouracil freeze-dried agent for injection, which is prepared by the preparation method.
The fluorouracil, edetate disodium, sodium hydroxide, mannitol, injection water and active carbon are adopted as raw materials of the fluorouracil freeze-drying agent for injection, wherein fluorouracil is used as an active ingredient of the freeze-drying agent, edetate disodium is used as a stabilizer, sodium hydroxide is used as a pH regulator, mannitol is used as a framework of the freeze-drying agent, injection water is used as a solvent, and the active carbon is used as a heat removal source. The components and the contents have synergistic effect, the quality of the freeze-drying agent is improved together, and the solubility, the clarity and the stability of the freeze-drying agent can be further improved by matching the freeze-drying process provided by the invention, and the safety of the freeze-drying agent in clinical medication 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 with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The terminology used in the embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the examples of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.
The preparation method of the fluorouracil freeze-drying agent for injection provided by the embodiment of the invention takes fluorouracil, edetate disodium, sodium hydroxide, mannitol, water for injection and active carbon as raw materials, all the raw materials have synergistic effect, and can interact with each other to improve the quality of the freeze-drying agent.
The technical solution and the technical effect of the present invention will be further described by specific examples.
Example 1:
weighing the raw materials according to the following formula for later use: 505 parts of fluorouracil, 8.2 parts of edetate disodium, 137 parts of sodium hydroxide, 408 parts of mannitol, 6970 parts of water for injection and 80 parts of activated carbon.
The preparation method of the freeze-drying agent comprises the following steps:
step one, batching: taking sodium hydroxide, preparing 3mol/L sodium hydroxide solution, and cooling to normal temperature for later use. Weighing 70% of injection water in a preparation barrel (55 ℃), adding fluorouracil, slowly adding 3mol/L of prepared sodium hydroxide solution under stirring to completely dissolve the main drug, transferring the liquid medicine to a preparation tank after complete dissolution, starting a stirring paddle, adding mannitol and edetate disodium into the liquid medicine, stirring until complete dissolution, sampling to detect the pH value, and adding the rest of the injection water into the preparation tank when the pH value is within the range of 8.7-9.0; then adding active carbon, stirring and adsorbing for 30 minutes to obtain a mixture.
Step two, filtering and filling: removing active carbon in the mixed solution by a 0.45 mu m filter membrane in the mixed solution, finely filtering by a 0.22 mu m cylinder type filter core, finely filtering and sterilizing by a 0.22 mu m filter membrane for the second time, filling the obtained filtrate according to the specification of 4 g/bottle, and performing half-pressing (namely pressing half height of the bottle cap into the bottle mouth) to obtain a filling semi-finished product.
Step three, freeze-drying treatment:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 1.5 hours at the temperature of minus 40 ℃;
a primary heating stage: heating to-15 deg.c within 1 hr and maintaining for 1 hr;
a primary cooling stage: cooling to-45 deg.C within 1 hr, and maintaining for 2.5 hr;
a secondary heating stage: after vacuumizing, the temperature is raised to 1 ℃ within 1.5 hours, and the temperature is kept for 35 hours;
and (3) a third temperature rise stage: and continuously heating to 33 ℃, keeping for 9 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation product for injection.
Example 2:
weighing the raw materials according to the following formula for later use: 510 parts of fluorouracil, 8 parts of edetate disodium, 135 parts of sodium hydroxide, 402 parts of mannitol, 6980 parts of water for injection and 81 parts of activated carbon.
The preparation method of this example is substantially the same as that of example 1, except that:
step three, freeze-drying treatment:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 2 hours at-42 ℃;
a primary heating stage: heating to-18 ℃ within 0.5 hour, and keeping for 2 hours;
a primary cooling stage: cooling to-40 deg.C within 0.5 hr, and maintaining for 3 hr;
a secondary heating stage: after vacuumizing, the temperature is raised to 0 ℃ within 1 hour, and the temperature is kept for 40 hours;
and (3) a third temperature rise stage: and continuously heating to 35 ℃, keeping for 10 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation product for injection.
Example 3:
weighing the raw materials according to the following formula for later use: 502 parts of fluorouracil, 8.5 parts of edetate disodium, 138 parts of sodium hydroxide, 405 parts of mannitol, 7000 parts of water for injection and 82 parts of activated carbon.
The preparation method of this example is substantially the same as that of example 1, except that:
step three, freeze-drying treatment:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 1.5 hours at the temperature of minus 45 ℃;
a primary heating stage: heating to-18 ℃ within 1 hour, and keeping for 1.5 hours;
a primary cooling stage: cooling to-45 deg.C within 1 hr, and maintaining for 2.5 hr;
a secondary heating stage: after vacuumizing, the temperature is raised to 0 ℃ within 1.5 hours, and the temperature is kept for 37 hours;
and (3) a third temperature rise stage: and continuously heating to 37 ℃, keeping for 9 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation product for injection.
Example 4:
weighing the raw materials according to the following formula for later use: 508 parts of fluorouracil, 9 parts of edetate disodium, 136 parts of sodium hydroxide, 400 parts of mannitol, 6960 parts of water for injection and 80 parts of activated carbon.
The preparation method of this example is substantially the same as that of example 1, except that:
step three, freeze-drying treatment:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 2 hours at-40 ℃;
a primary heating stage: heating to-18 ℃ within 0.5 hour, and keeping for 1.5 hours;
a primary cooling stage: cooling to-45 deg.C within 0.5 hr, and maintaining for 2.5 hr;
a secondary heating stage: after vacuumizing, the temperature is raised to 0 ℃ within 1 hour, and the temperature is kept for 36 hours;
and (3) a third temperature rise stage: and continuously heating to 36 ℃, keeping for 10 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation product for injection.
Example 5:
weighing the raw materials according to the following formula for later use: 500 parts of fluorouracil, 8 parts of edetate disodium, 135 parts of sodium hydroxide, 400 parts of mannitol, 6964 parts of water for injection and 80 parts of activated carbon.
The preparation method of this example is substantially the same as that of example 1, except that:
step three, freeze-drying treatment:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 2 hours at-45 ℃;
a primary heating stage: heating to-15 deg.C within 0.5 hr, and maintaining for 1.5 hr;
a primary cooling stage: cooling to-45 deg.C within 0.5 hr, and maintaining for 3 hr;
a secondary heating stage: after vacuumizing, the temperature is raised to 0 ℃ within 1 hour, and the temperature is kept for 37 hours;
and (3) a third temperature rise stage: and continuously heating to 35 ℃, keeping for 8 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation product for injection.
Comparative example 1: this comparative example is essentially the same as example 5 except that: disodium edetate in the raw material is omitted.
Comparative example 2: this comparative example is essentially the same as example 5 except that: the activated carbon in the raw material is omitted.
Comparative example 3: this comparative example is essentially the same as example 5 except that: disodium edetate and active carbon in the raw materials are omitted.
Comparative example 4: this comparative example is essentially the same as example 5 except that: disodium edetate in the raw material is omitted, and the primary heating stage in the freeze-drying treatment step is omitted.
Comparative example 5: this comparative example is essentially the same as example 5 except that: disodium edetate in the raw material was omitted and the process conditions of the prefreezing stage in the lyophilization process were modified to prefreeze at-50 ℃ for 3 hours.
Comparative example 6: this comparative example is essentially the same as example 5 except that: the active carbon in the raw material is omitted, and the treatment of the primary cooling stage in the freeze-drying process is omitted.
Comparative example 7: this comparative example is essentially the same as example 5 except that: the treatment of the secondary temperature rise stage in the freeze-drying process is omitted.
Comparative example 8: this comparative example is essentially the same as example 5 except that: the active carbon in the raw materials is omitted, and the process conditions of the secondary temperature rise stage in the freeze-drying process are modified into vacuum pumping, and then the temperature is raised to 15 ℃ within 1 hour and kept for 37 hours.
Comparative example 9: this comparative example is essentially the same as example 5 except that: disodium edetate and active carbon in the raw materials are omitted, and the treatment of primary heating and secondary heating stages in the freeze-drying process is omitted.
Comparative example 10: this comparative example is essentially the same as example 5 except that: the raw materials are fluorouracil and water for injection.
Comparative example 11: this comparative example 5 is essentially the same except that: the freeze-drying process comprises the following steps: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 3 hours at-45 ℃; heating to 15 ℃ at the speed of 20 ℃/h, and keeping the temperature for 20 h; and continuously heating to 35 ℃, keeping for 4 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation product for injection.
In order to further explain the technical effects of the present invention, the following experimental examples are further described.
First experiment, physical and chemical indexes
1. Experimental samples: the fluorouracil freeze-drying agent for injection provided by the embodiment 1-5 of the invention.
2. The experimental method comprises the following steps: firstly, foreign matters can be seen in the filtered liquid medicine: see the light inspection method or light scattering method specified in the four parts of the "chinese pharmacopoeia 2015 year edition".
② the content of the liquid medicine: precisely weighing a proper amount of the product, quantitatively diluting the product with a hydrochloric acid solution (9 → 1000) to obtain a solution containing 10 microgram of fluorouracil in each 1ml, and measuring the absorbance at the wavelength of 265nm by an ultraviolet-visible spectrophotometry (general rule 0401) according to the absorption coefficient (E1% 1 cm) of C4H3FN2O2 as 552 to obtain the product.
③ pH value of the liquid medicine: see the method for examining the pH value of fluorouracil injection (general rule 0631) in the "Chinese pharmacopoeia 2015 year edition".
Clarity and color of solution: see clarity test and solution color test methods specified in the chinese pharmacopoeia 2015 year edition.
Fifthly, bacterial endotoxin in the liquid medicine: see the bacterial endotoxin detection method in fluorouracil injection (general rule 1143) in the "chinese pharmacopoeia 2015 year edition".
3. The experimental results are detailed in table 1 below.
TABLE 1
From the experimental results in table 1 above, it can be known that the fluorouracil for injection provided in embodiments 1 to 5 of the present invention meets the standard requirements of the relevant detection items in the chinese pharmacopoeia 2015 edition, and has good safety.
Experiment two, product form and solubility test
The morphology and the solubility at different temperatures of the freeze-drying agents of the embodiments 1 to 5 and the comparative examples 1 to 11 of the invention are tested, and the specific test method comprises the following steps: 1g of the lyophilized powder was added to 50mL of water for injection, and the time for the turbid solution to become a clear solution was recorded, and the experimental results are detailed in Table 2 below.
TABLE 2
From the experimental results in table 2 above, it can be seen that the freeze-drying agents provided in examples 1 to 5 of the present invention are white loose flocculent solids, and the freeze-drying agents provided in comparative examples 1 to 11 are white powdery solids; in addition, by combining the solubilities of the freeze-drying agents of the examples 1 to 5 and the comparative examples 1 to 11 at different temperatures, the dissolution times of the freeze-drying agents of the examples 1 to 5 at the temperatures of 20 ℃, 10 ℃ and 5 ℃ are shorter than those of the freeze-drying agents of the comparative examples 1 to 11, and the experimental results show that the dissolution rates of the freeze-drying agents of the examples 1 to 5 of the invention are obviously improved compared with those of the comparative examples 1 to 11.
From the comparison results of example 5 and comparative examples 1 to 3, it can be found that the addition of edetate disodium and/or activated carbon in the preparation of the lyophilized preparation can significantly shorten the dissolution time of the lyophilized preparation, that is, the edetate disodium, activated carbon and other components have synergistic effects, which can significantly shorten the dissolution time of the lyophilized preparation, and at the same time, the clarity of the solution is better, and a good product form can be obtained, which is beneficial to safe clinical medication.
From the comparison result of the example 5 and the comparative example 4, it can be found that the addition of edetate disodium can increase the stability of the freeze-drying agent product, and meanwhile, by adopting the freeze-drying treatment process of pre-freezing (cooling), heating, cooling, heating and heating, the product can form a good crystal structure in the freeze-drying stage, the occurrence of local concentration is reduced, so that the freeze-drying agent with stable performance is obtained, the dissolving time of the freeze-drying agent is obviously shortened, and the safety of clinical medication is facilitated.
From the comparison result of example 5 and comparative example 5, it can be concluded that adding edetate disodium and controlling the temperature condition of the prefreezing stage of the lyophilization treatment at-45 ℃ for 2h is more beneficial to forming a good crystal structure, maintaining the stability of the product, shortening the dissolution time of the lyophilizer, and enabling the lyophilizer solution to have good clarity and be beneficial to the safety of clinical administration.
From the comparison result of the example 5 and the comparative example 6, it can be shown that the heat generated during the mixing reaction of the materials during the compounding period can be better absorbed by adding the activated carbon, the property of the materials is favorably maintained, and the sublimation time of the mixed materials can be delayed by performing one-time cooling treatment after the treatment of the temperature rising stage in sequence, so that the crystal form with stable structure is favorably formed, the moisture in the materials can be removed better and faster, the solid with loose structure can be obtained, the dissolving time of the freeze-drying agent can be shortened on the whole, and the clear solution is obtained, thereby being favorable for the safety of clinical administration.
From the comparison result of the example 5 and the comparative example 7, it can be seen that, in the freeze-drying treatment, after the secondary temperature rise stage is vacuum pumping, the temperature rises to 0 ℃ within 1 hour, the temperature is kept for 37 hours, the freeze-drying period and the temperature are reasonably controlled, the solubility of the obtained product is better, the product has uniform properties, and the safety of clinical medication is facilitated.
From the comparison of example 5 and comparative example 8, it can be seen that the addition of activated carbon and the control of the treatment conditions in the secondary temperature raising stage to 0 ℃ within 1 hour after vacuum pumping and the maintenance for 37 hours can obtain better product solubility and clarity than the temperature raising to 15 ℃ within 1 hour and the maintenance for 37 hours.
From the comparison results of example 5 and comparative example 9, it can be seen that the addition of activated carbon and edetate disodium, and the lyophilization process of prefreezing (cooling), raising temperature, lowering temperature, raising temperature, and raising temperature, can effectively shorten the dissolution time of the lyophilizer and achieve better clarity. The experimental result shows that the active carbon and the edetate disodium are added, and the freeze-drying process provided by the invention can obviously improve the solubility and clarity of the product, and is beneficial to the safety of clinical administration.
From the comparison results of example 5 and comparative example 10, it can be seen that the fluorouracil lyophilized preparation for injection prepared by using fluorouracil and water for injection alone has a solubility and clarity inferior to those of the lyophilized preparation prepared by using fluorouracil, edetate disodium, sodium hydroxide, mannitol, water for injection and activated carbon. The experimental result shows that the edetate disodium, the sodium hydroxide, the mannitol, the activated carbon and the fluorouracil have a synergistic effect, and the solubility and the clarity of the product can be improved.
From the comparison result of the embodiment 5 and the comparative example 11, the fluorouracil freeze-drying agent for injection prepared by the freeze-drying process provided by the invention has the advantages that compared with the freeze-drying agent prepared by the freeze-drying process of placing the qualified product for filling in a freeze-drying box, pre-freezing at-45 ℃ for 3 hours, vacuumizing, setting the temperature rise speed of a shelf of a freeze-dryer to be 20 ℃/h, raising the temperature to 15 ℃ for 20 hours, continuing raising the temperature to 35 ℃ for 4 hours for analysis and drying, completely plugging, and completing freeze-drying, the solubility and the clarity of the freeze-drying agent are obviously improved, and the safety of clinical administration is more facilitated.
The invention uses fluorouracil, edetate disodium, sodium hydroxide, mannitol, water for injection and active carbon for compounding, and adopts a freeze-drying process of repeated pre-freezing and sublimation temperature reduction, thereby providing reasonable freeze-drying temperature and time range, wherein the repeated pre-freezing is helpful for improving the crystal form of the product, and the ice crystals are well cut and distributed uniformly. A uniform ice crystal structure is beneficial to maintain structural stability of the product during the sublimation stage. Reduce sublimation temperature, make sublimation rate slow down, can reduce the condition that local concentration appears to through the time of extension sublimation drying in order to guarantee that moisture obtains abundant sublimation, can be effective and solve the poor problem of solubility.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention. The sample obtained by the patented method has better stability.
Claims (10)
1. The preparation method of the fluorouracil freeze-dried preparation for injection is characterized by comprising the following steps:
a. weighing fluorouracil, edetate disodium, sodium hydroxide, mannitol, water for injection and active carbon according to a formula, and blending according to a preset blending process to obtain a blending liquid;
b. filtering the mixed solution to remove active carbon in the mixed solution, and filling and semi-plugging the obtained filtrate according to a preset specification to obtain a filled semi-finished product;
c. freeze-drying the filled semi-finished product to obtain the fluorouracil freeze-dried agent for injection; the freeze-drying treatment comprises the following steps:
a pre-freezing stage: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 1.5-2 hours at the temperature of-45 ℃ to-40 ℃;
a primary heating stage: heating to-15 to-18 ℃ within 0.5 to 1 hour, and keeping for 1 to 2 hours;
a primary cooling stage: cooling to-45 ℃ to-40 ℃ within 0.5-1 hour, and keeping for 2.5-3 hours;
a secondary heating stage: after vacuumizing, heating to 0-1 ℃ within 1-1.5 hours, and keeping for 35-40 hours;
and (3) a third temperature rise stage: and continuously heating to 33-37 ℃, keeping for 8-10 hours for analysis and drying, and pressing a stopper to obtain the fluorouracil freeze-dried preparation for injection.
2. The method for preparing fluorouracil lyophilized formulation for injection as claimed in claim 1, wherein the prefreezing stage in step c is specifically: placing the filled semi-finished product in a freeze-drying device, and pre-freezing for 2 hours at-45 ℃.
3. The method for preparing fluorouracil lyophilized formulation for injection as claimed in claim 2, wherein the one-time warming stage in step c is specifically: the temperature was raised to-15 ℃ within 0.5 hour and held for 1.5 hours.
4. The method for preparing fluorouracil lyophilized formulation for injection as claimed in claim 3, wherein the one-time cooling stage in step c is specifically: the temperature is reduced to-45 ℃ within 0.5 hour, and the temperature is kept for 3 hours.
5. The method for preparing fluorouracil lyophilized formulation for injection as claimed in claim 4, wherein the secondary temperature raising stage in step c is specifically: after evacuation, the temperature was raised to 0 ℃ over 1 hour and held for 37 hours.
6. The method for preparing fluorouracil lyophilized formulation for injection as claimed in claim 5, wherein the three warming stages in step c are specifically: and continuously heating to 35 ℃, keeping for 8 hours for analysis and drying, and pressing a full plug to obtain the fluorouracil freeze-dried preparation for injection.
7. The preparation method of fluorouracil lyophilized preparation for injection as claimed in claim 1, wherein the formulation of fluorouracil lyophilized preparation for injection comprises the following components in parts by weight: 500-510 parts of fluorouracil, 8-9 parts of edetate disodium, 135-138 parts of sodium hydroxide, 400-408 parts of mannitol and 6964-7000 parts of water for injection.
8. The method of preparing fluorouracil lyophilizate for injection as claimed in claim 7, wherein said fluorouracil lyophilizate for injection further comprises: 80-82 parts of activated carbon.
9. The preparation method of fluorouracil lyophilized preparation for injection as claimed in claim 8, wherein the formulation of fluorouracil lyophilized preparation for injection comprises the following components in parts by weight: 500 parts of fluorouracil, 0.8 part of edetate disodium, 135 parts of sodium hydroxide, 400 parts of mannitol, 6964 parts of water for injection and 80 parts of activated carbon.
10. A fluorouracil lyophilized preparation for injection, which is characterized by being prepared by the preparation method according to any one of claims 1 to 9.
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