CN117883393A - High-stability cetrorelix freeze-dried powder injection and preparation method thereof - Google Patents
High-stability cetrorelix freeze-dried powder injection and preparation method thereof Download PDFInfo
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- 108700008462 cetrorelix Proteins 0.000 title claims abstract description 46
- 229960003230 cetrorelix Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000002347 injection Methods 0.000 title claims abstract description 14
- 239000007924 injection Substances 0.000 title claims abstract description 14
- 239000000843 powder Substances 0.000 title claims abstract description 7
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 title 1
- KFEFLCOCAHJBEA-ANRVCLKPSA-N cetrorelix acetate Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 KFEFLCOCAHJBEA-ANRVCLKPSA-N 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000001035 drying Methods 0.000 claims abstract description 17
- 229960001865 cetrorelix acetate Drugs 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 15
- 238000007710 freezing Methods 0.000 claims abstract description 13
- 230000008014 freezing Effects 0.000 claims abstract description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 11
- 229930195725 Mannitol Natural products 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 235000010355 mannitol Nutrition 0.000 claims abstract description 11
- 239000000594 mannitol Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000000859 sublimation Methods 0.000 claims abstract description 9
- 230000008022 sublimation Effects 0.000 claims abstract description 9
- 238000004806 packaging method and process Methods 0.000 claims abstract description 7
- 229930182555 Penicillin Natural products 0.000 claims abstract 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract 3
- 229940049954 penicillin Drugs 0.000 claims abstract 3
- 239000007788 liquid Substances 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 238000004321 preservation Methods 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 abstract description 14
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- 239000012535 impurity Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000009477 glass transition Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- 206010068042 Premature ovulation Diseases 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012520 frozen sample Substances 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000002394 ovarian follicle Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000004781 supercooling Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a high-stability cetrorelix freeze-dried powder injection, belonging to the technical field of preparation of medicines. The method comprises the steps of firstly preparing a cetrorelix acetate solution containing mannitol, filtering, and sub-packaging in penicillin bottles; the penicillin is placed in a freeze-drying machine box body, and the freeze-dried pharmaceutical composition is obtained after prefreezing, sublimating and drying. Wherein, the pre-freezing, sublimation and re-drying are equally divided into two stages. The cetrorelix pharmaceutical preparation prepared by the technical scheme of the invention has good stability and can be stored for a long time under the condition of room temperature; in addition, the method is simple to operate, the running time of the freeze-drying process is short, the energy consumption is reduced, and the cost is reduced; more importantly, the product has short redissolution time and low content of related substances, and the quality of the products in and among batches is consistent, thereby being beneficial to commercial and amplified production and clinical use.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to the field of pharmaceutical preparation production, and especially relates to a preparation method of cetrorelix freeze-dried powder injection.
Background
Cetrorelix (Cetrorelix) is a LHRH antagonist developed by ASTAMEDICA in germany, which controls ovarian stimulation and prevents premature ovulation, thus helping conception. Cetrorelix acetate for injection was first marketed in germany by MerckSerono, 8 1999, and FDA approved for sale in the united states in 2000. Clinically, the traditional Chinese medicine is mainly used as auxiliary reproductive medicine, controls the stimulation of ovaries, prevents premature ovarian follicle discharge and helps conception. The aqueous solution of the decapeptides with terminal amide groups, which are acetate salts, of cetrorelix is unstable and cannot be sterilized by terminal sterilization, so that aseptic filtration is adopted for sterilization in production, and the water in the prescription is removed by a freeze drying method to prepare a freeze-dried preparation. The existing cetrorelix acetate domestic commercial product (Sithen Kai) for injection has the preservation condition of 2-8 ℃ and the shelf life of 2 years, and has poor stability in long-term storage and acceleration experiments and greatly increased related substances at high temperature, so that the American FDA (FDA) requires the storage temperature of 2-8 ℃. The improvement scheme disclosed in the prior art is as follows:
CN102423484B discloses a method for preparing cetrorelix composition: (1) Preparing mannitol and cetrorelix acetate solution, and filtering; (2) Subpackaging the solution obtained in the step (1) into containers, and cooling step by step; the first stage, the temperature of the plate layer is reduced to-25 ℃ to 40 ℃ at a cooling rate of not more than 3 ℃/min, and the heat preservation is carried out for not less than 1 hour; the second stage, continuously cooling to less than-40 ℃, and preserving heat for not less than 1 hour; and (3) drying to obtain the freeze-dried pharmaceutical composition. The method increases the number of large ice crystals and reduces the number of small ice crystals when the sample is kept below the freezing temperature for a period of time during pre-freezing; the temperature is reduced again to the desired prefreezing temperature and then sublimated to dryness.
CN112807418a discloses a preparation method of cetrorelix preparation, which comprises the steps of freezing mixed solution containing mannitol and cetrorelix acetate in the first-third stage, wherein the conditions in the first stage are as follows: cooling to-20 to-40 ℃, and preserving heat for 0.1 to 2 hours; the conditions of the second stage are: heating to-20 to-5 ℃ and preserving heat for 0.1 to 2 hours; the conditions of the third stage are: cooling to-20 to-40 ℃, and preserving heat for 0.1 to 2 hours. The invention is characterized in that the temperature is firstly reduced to the vicinity of the glass transition temperature of the solution, the solution is kept for a period of time, and then the solution is cooled to be completely frozen after the temperature is raised to a certain temperature. The method employs an annealing process to heat the frozen sample to a temperature above the glass transition temperature and below the melting temperature (eutectic point temperature) during the pre-freezing stage; the product is kept at this temperature for a period of time to allow it to recrystallize (the number of large ice crystals increases and the number of small ice crystals decreases); the temperature is reduced again to the desired prefreezing temperature and then sublimated to dryness.
CN102423484B and CN112807418a protocols provide treatments by different prefreezing modes, such that the number of large ice crystals increases and the number of small ice crystals decreases. The techniques improve the stability of the product to a certain extent, but still have the problems of uneven product quality in the batch, prolonged redissolution time and obvious difference in size between the batches of deamidated cetrorelix impurities. In view of the above, it has practical significance how to prepare and obtain pharmaceutical preparations with good stability, small product difference among batches and uniform quality. Those skilled in the art still desire new methods for preparing cetrorelix acetate compositions, especially freeze-dried compositions, in order to achieve one or more technical effects.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a cetrorelix freeze-dried powder injection with high stability; the cetrorelix pharmaceutical preparation prepared by the technical scheme has good stability and can be stored for a long time under the condition of room temperature; the operation is simple, the running time of the freeze-drying process is short, the energy consumption is reduced, and the cost is reduced.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
The invention provides a preparation method of a stable cetrorelix pharmaceutical composition, which comprises the following steps:
1) Preparing a cetrorelix acetate solution containing mannitol, and filtering; wherein the filtration may be performed using a sterile filter cartridge, such as a 0.2um filter cartridge. The cetrorelix acetate solution containing mannitol is an aqueous solution prepared from mannitol, cetrorelix, acetic acid and water for injection, and is prepared by a conventional preparation method in the field.
2) And (3) pre-freezing, sublimating and drying the solution obtained in the step (1) to obtain the freeze-dried pharmaceutical composition. Wherein the pre-freezing is carried out in two stages:
the first stage: cooling to-10 to-18 ℃, and preserving heat for not less than 0.5 hour;
And a second stage: cooling to-35 to-45 ℃, and preserving heat for not less than 1 hour;
further, according to the preparation method, the first stage in the step 2): cooling to-12 to-16 ℃, and preserving heat for not less than 0.5 hour; the second stage in step 2): cooling to-40 to-45 ℃, and preserving heat for not less than 1 hour;
further, according to the preparation method, the heat preservation time after the first stage of temperature reduction in the step 2) is preferably 0.5 to 3 hours, more preferably 1 to 2 hours;
Further, according to the preparation method, the heat preservation time after the second stage of the step 2) is cooled is preferably 1 to 4 hours, more preferably 2 to 3 hours;
Further, according to the preparation method, the sublimation in the step 2) is performed in two stages, and the vacuum degree is controlled to be 0.15mbar to 0.35mbar. The first stage: heating to-5 ℃ and preserving heat for 6-12 hours; and a second stage: heating to 0 ℃ and preserving heat for 1-4 hours;
Further, according to the preparation method, the re-drying in the step 2) is performed in two stages. In the first stage, the vacuum degree is controlled to be 0.15-0.35 mbar, and the temperature is raised and kept for 1-2 hours; in the second stage, the vacuum degree is controlled to be not more than 0.05mbar, and the temperature is kept for 1 to 4 hours;
Preferably, according to the preparation method, the sublimation in the step 2) is performed in two stages, and the vacuum degree is controlled to be 0.2mbar to 0.3mbar. Wherein the first stage is to heat up to-5 ℃ and keep the temperature for 6-12 hours; and a second stage: heating to 0 ℃ and preserving heat for 1-2 hours;
Preferably, according to the preparation method, the re-drying in step 2) is performed in two stages. The first stage: vacuum degree is controlled between 0.2mbar and 0.3mbar, temperature is raised and heat is preserved for 1 to 2 hours; and in the second stage, the vacuum degree is controlled at the extreme vacuum degree, and the temperature is kept for 2-4 hours. The ultimate vacuum means that the vacuum degree is controlled to be 0.05mbar or less.
The invention also provides a stable cetrorelix pharmaceutical composition, which is prepared by the preparation method.
Compared with the prior art, the invention has the following beneficial effects:
1. The cetrorelix pharmaceutical preparation prepared by the method has good stability and can be stored for a long time under the condition of room temperature.
2. The invention has simple operation, short running time of the freeze-drying process, reduced energy consumption and reduced cost.
3. The product prepared by the method has short redissolution time, low content of related substances and consistent quality of the product among batches, and is beneficial to commercial and amplified production and clinical use.
4. The method of the invention freezes the cetrorelix medicine liquid to-2 ℃ to-10 ℃ below zero (eutectic point-7.94 ℃) and keeps the temperature, so that the medicine liquid in each bottle is not frozen at the temperature due to the effects of heat conduction and supercooling temperature after the temperature of the medicine liquid is uniform. After the heat preservation is finished, the temperature is quickly reduced, so that the liquid medicine is quickly frozen, separation and migration of the solvent and the solute are reduced, and the medicines in each bottle are uniformly distributed. Cooling to lower temperature, and maintaining for a period of time to ensure that each bottle of liquid medicine is frozen completely. Vacuumizing, heating to a higher temperature to sublimate most of water, heating to 0 ℃ and removing a small amount of water ice crystals; and 2 steps of re-drying, wherein the temperature is increased to the final temperature and a certain vacuum degree is maintained to enhance heat conduction and make the heat treatment among the samples uniform, and the drying temperature is maintained and the vacuum degree is reduced to the limit (such as 0.05mbar and below) to control the final moisture. Through the combined control of prefreezing, sublimating and re-drying, the product which meets the requirements, has consistent homogeneous quantity and good stability is finally prepared.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below, but the present invention is not limited thereto. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The cetrorelix acetate solution containing mannitol is prepared by the following method:
Precisely weighing cetrorelix acetate, dissolving cetrorelix with acetic acid, adding injectable water, and mixing. And adding mannitol to dissolve and mix uniformly, and continuously adding water for injection to the total volume to obtain a cetrorelix acetate solution (hereinafter referred to as 'liquid medicine') containing mannitol. Filtering the medicinal liquid with 0.2 μm filter core, sterilizing, and packaging into container with 1 ml/branch.
Example 1 prescription (1000):
Filtering and sub-packaging the liquid medicine prepared according to the prescription amount of raw auxiliary materials, and freeze-drying the liquid medicine, wherein the specific steps are as follows:
A pre-freezing stage, wherein the temperature is kept for 60min after the temperature is reduced from room temperature to-12 ℃ for 20min, and the temperature is kept for 60min after the temperature is reduced to-45 ℃ for 20min; in the sublimation stage, vacuum is started, the vacuum degree is controlled at 0.2mbar, the temperature is raised to-5 ℃ for 10min, then the temperature is kept for 480min, and the temperature is kept for 120min after the temperature is raised to 0 ℃ for 10 min; a re-drying stage, wherein the vacuum degree is controlled at 0.2mbar, the temperature is increased to 25 ℃ for 10min, the temperature is kept for 120min, and the temperature is kept at 25 ℃ for 240min under the extreme vacuum degree; cetrorelix acetate for injection is obtained. The total lyophilization run time was 19.2h.
Example 2 prescription (10000 counts):
Filtering and sub-packaging the liquid medicine prepared according to the prescription amount of raw auxiliary materials, and freeze-drying the liquid medicine, wherein the specific steps are as follows:
A pre-freezing stage, wherein the temperature is kept for 30min after the temperature is reduced from room temperature to-14 ℃ for 30min, and then the temperature is kept for 120min after the temperature is reduced to-40 ℃ for 40min; in the sublimation stage, vacuum is started, the vacuum degree is controlled at 0.3mbar, the temperature is raised to-5 ℃ for 30min, then the temperature is kept for 600min, and the temperature is raised to 0 ℃ for 30min, then the temperature is kept for 120min; a re-drying stage, wherein the vacuum degree is controlled at 0.3mbar, the temperature is increased to 25 ℃ for 30min, the temperature is kept for 120min, and the temperature is kept at 25 ℃ for 240min under the extreme vacuum degree; cetrorelix acetate for injection is obtained. The total lyophilization run time was 23.2h.
Example 3 prescription (1000):
Filtering and sub-packaging the liquid medicine prepared according to the prescription amount of raw auxiliary materials, and freeze-drying the liquid medicine, wherein the specific steps are as follows:
A pre-freezing stage, wherein the temperature is kept for 60min after the temperature is reduced from room temperature to minus 16 ℃ for 40min, and the temperature is kept for 180min after the temperature is reduced to minus 40 ℃ for 30 min; in the sublimation stage, vacuum is started, the vacuum degree is controlled at 0.2mbar, the temperature is raised to-5 ℃ for 120min, then the temperature is kept for 600min, and the temperature is raised to 0 ℃ for 10min, then the temperature is kept for 60min; the drying stage is carried out, the vacuum degree is controlled at 0.2mbar, the temperature is increased to 20 ℃ for 60min, the heat is preserved for 240min, and the temperature is increased to 25 ℃ for 120min under the limit vacuum degree of 0.05 mbar; cetrorelix acetate for injection is obtained. The total lyophilization run time was 25.3h.
Comparative example 1 prescription (1000):
Filtering and sub-packaging the liquid medicine prepared according to the prescription amount of raw auxiliary materials, and freeze-drying the liquid medicine, wherein the specific steps are as follows:
In the pre-freezing stage, the temperature of the plate is reduced to minus 25 ℃ at 0.5 ℃/min, the temperature is kept for 120min, and then the temperature is reduced to minus 40 ℃ at 0.5 ℃/min, and the temperature is kept for 180min; in the primary sublimation stage, the vacuum degree is controlled at 0.3mbar, the temperature is raised to-5 ℃ for 120min, then the temperature is kept for 600min, and then the temperature is raised to 0 ℃ for 10min, and then the temperature is kept for 60min; the drying stage is carried out, the vacuum degree is controlled at 0.3mbar, the temperature is kept for 240min after the temperature is increased to 20 ℃ for 60min, and the drying is carried out for 120min after the temperature is increased to 25 ℃ under the vacuum degree of the polar root; cetrorelix acetate for injection is obtained. The total lyophilization run time was 27.2h.
Experimental example 1: accelerated stability test (high temperature 40 ℃) and product quality test results are shown in table 1
Table 1 product quality inspection and detection results
* And (3) injection: the degradation speed of the deamidated cetrorelix in the sample reserving inspection is inconsistent due to the non-uniform quality of the sample, so that the detection result has obvious fluctuation.
The total impurities of the existing varieties on the market are increased to 3.74% after accelerating for 6 months, the deaminated cetrorelix impurities are increased to 2.79%, and the total impurities exceed the set limit value. In addition, the detected content of degraded deaminated cetrorelix impurities showed significant fluctuations during the investigation.
The total impurities of the product prepared in the comparative example 1 are increased to 1.19% after accelerating for 6 months, and the deamidated cetrorelix impurities are increased to 0.28%, so that the product is more stable than the products on the market. However, the maximum value of the detected content of the degraded deamidated cetrorelix impurity during the investigation appears at the time point of 3 months and is 0.38%, and the detected content is up to 0.25% when the detection speed is increased by 1 month. Comparative example 1 had the longest redissolution time and the greatest turbidity value at 3 months of acceleration.
The cetrorelix preparation prepared according to the freeze-drying process of the invention has short overall operation time, and the accelerated test results show that the total related substances increase little, the degradation deamidation cetirix Qu Rui g preparation has little intra-batch variation, the quality can be kept stable and consistent in the amplification experiment, the commercial amplification production is facilitated, and in addition, the re-dissolution time of the cetrorelix preparation prepared by the invention is quick, and the clinical application is facilitated. The scheme of the invention can ensure the stable quality of the single preparation product in the period of validity during transportation and storage, and can provide the preparation with consistent quality for patients.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A preparation method of a high-stability cetrorelix freeze-dried powder injection is characterized in that,
The cetrorelix pharmaceutical composition comprises cetrorelix, mannitol, organic solvent acetic acid and water for injection; preparation
The method comprises the following steps:
(1) Preparing a cetrorelix acetate solution containing mannitol, filtering, and sub-packaging the liquid medicine in a penicillin bottle;
(2) Pre-freezing, sublimating and drying the solution in the step (1) to obtain a freeze-dried pharmaceutical composition;
wherein the pre-freezing is carried out in two stages:
the first stage: cooling to-10 to-18 ℃, and preserving heat for not less than 0.5 hour;
and a second stage: cooling to-35 to-45 ℃, and preserving heat for not less than 1 hour.
2. The method of manufacturing according to claim 1, characterized in that:
A first stage in step (2): cooling to-12 to-16 ℃, and preserving heat for not less than 0.5 hour;
A second stage in the step (2): cooling to-40 to-45 ℃, and preserving heat for not less than 1 hour.
3. The preparation method according to claim 1 or 2, characterized in that:
the heat preservation time is 0.5 to 3 hours, preferably 1 to 2 hours after the temperature is reduced in the first stage in the step (2);
the temperature is kept for 1 to 4 hours, preferably 2 to 3 hours after the temperature is reduced in the second stage in the step (2).
4. The method of manufacturing according to claim 1, characterized in that:
the sublimation in the step (2) is carried out in two stages, and the vacuum degree is controlled to be 0.15 mbar-0.35 mbar;
the first stage: heating to-5 ℃ and preserving heat for 6-12 hours;
And a second stage: heating to 0 ℃ and preserving heat for 1-4 hours.
5. The method according to claim 1 or 4, wherein:
the sublimation vacuum degree in the step (2) is controlled to be 0.2 mbar-0.3 mbar;
the first stage: heating to-5 ℃ and preserving heat for 6-12 hours;
And a second stage: heating to 0 ℃ and preserving heat, and preferably preserving heat for 1-2 hours.
6. The method of manufacturing according to claim 1, characterized in that:
the re-drying in the step (2) is carried out in two stages;
The first stage: vacuum degree is controlled to be 0.15 mbar-0.35 mbar, heating is carried out, and heat is preserved for 1-2 hours;
And a second stage: vacuum degree is controlled to be not more than 0.05 mbar, and heat preservation is carried out for 1-4 hours.
7. The method of manufacturing according to claim 6, wherein:
In the re-drying in the step (2):
The first stage: preferably, the vacuum degree is controlled to be 0.2 mbar-0.3 mbar, and the temperature is raised and kept for 1-2 hours;
and a second stage: preferably, the vacuum degree is controlled under the extreme vacuum of the freeze dryer, and the temperature is kept for 2-4 hours.
8. The method of manufacturing according to claim 1, characterized in that: the organic solvent is acetic acid with the concentration of 36.6 percent.
9. A high stability cetrorelix pharmaceutical composition, characterized in that: the cetrorelix pharmaceutical composition prepared by the preparation method of the cetrorelix pharmaceutical composition according to any one of claims 1-8 is a freeze-dried powder injection.
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| CN202311826583.9A CN117883393A (en) | 2023-12-28 | 2023-12-28 | High-stability cetrorelix freeze-dried powder injection and preparation method thereof |
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