CN114028346A - Omeprazole sodium for injection and preparation method thereof - Google Patents
Omeprazole sodium for injection and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention provides omeprazole sodium for injection and a preparation method thereof, belonging to the technical field of medicine preparation, wherein the preparation method comprises the steps of dissolving 0.01-0.02 weight part of antioxidant in glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution with the pH value of 10.1-11.1, adding 1 weight part of omeprazole sodium for dissolution, and then carrying out decoloration, sterilization, filtration and freeze-drying to obtain the omeprazole sodium for injection. Aiming at the structural characteristics of omeprazole sodium, the invention effectively inhibits the omeprazole sodium from generating polymerization reaction under the influence of pH value in the preparation, storage and use processes by preparing the glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution with specific pH value, thereby effectively reducing the generation of omeprazole sodium impurities and improving the stability of the omeprazole sodium for injection.
Description
Technical Field
The invention relates to preparation of sterile powder injection, in particular to omeprazole sodium for injection and a preparation method thereof.
Background
Omeprazole sodium is a medicineThe medicine for curing the chemical ulcer is an artificial styrene-acrylic imidazole proton pump inhibitor with the chemical name of 5-methoxy 2- { [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) -methyl]Sulfinyl } -1H-benzimidazole sodium, the parent compound omeprazole, reduces gastric acid secretion through specific action on parietal cell proton pump, and the principle is that omeprazole aggregates in acidic environment in parietal cell and converts to active form, selectively inhibits H+-K+-ATPase activity, thereby reducing gastric acid secretion, for the treatment of duodenal ulcers, Zollinger-Ellison, gastric ulcers and reflux esophagitis, among others.
The chemical structural formula of omeprazole sodium is as follows:
the structural formula of the omeprazole sodium shows that the structural formula of the omeprazole sodium has the chemical structure of sulfonyl benzimidazole, and the sulfonyl benzimidazole is susceptible to various factors such as pH value and heavy metal ions to cause phenomena such as polymerization and color change, so that impurities are easily generated in the preparation, storage and use processes of the omeprazole sodium to cause phenomena such as polymerization and color change, and therefore, how to inhibit the polymerization reaction of sulfonyl benzimidazole in the omeprazole sodium is always a research focus in the preparation process of the omeprazole sodium.
Disclosure of Invention
Aiming at the problems, the invention provides omeprazole sodium for injection and a preparation method thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the raw materials for preparing the active ingredients of the omeprazole sodium for injection comprise: 1 part by weight of omeprazole sodium, 0.01-0.02 part by weight of antioxidant and 45-55 parts by volume of glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution with the pH value of 10.1-11.1;
wherein, the corresponding relation between the parts by weight and the parts by volume is kg: and L.
Further, the glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution is prepared by mixing the following components in a volume ratio of 2.4-5.6: 5: 3.3 to 11.1 of glycine aqueous solution with the concentration of 0.2mol/L, disodium hydrogen phosphate aqueous solution with the concentration of 0.05mol/L and sodium hydroxide aqueous solution with the concentration of 0.1 mol/L.
Further, the antioxidant is disodium ethylene diamine tetraacetate.
A preparation method of omeprazole sodium for injection comprises the steps of dissolving an antioxidant in glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution, adding omeprazole sodium for dissolution, decoloring, sterilizing, filtering and freeze-drying to obtain the omeprazole sodium for injection.
Further, the freeze-drying comprises prefreezing, sublimation drying and resolution drying;
wherein the pre-freezing is performed at-55 to-50 ℃ for 2 to 3 hours;
the sublimation drying comprises the following steps which are carried out in sequence:
heating to-40 to-35 ℃ at a speed of 3.6 to 4.2 ℃/h, and carrying out primary sublimation drying for 3 to 4 h;
heating to-25-20 ℃ at a speed of 3.6-4.2 ℃/h, and carrying out secondary sublimation drying for 4-5 h;
heating to 5-10 ℃ at a speed of 3.6-4.2 ℃/h, and carrying out sublimation drying for the third time for 1-2 h;
the desorption drying comprises the following steps which are carried out in sequence:
heating to 20-25 ℃ at a speed of 3.6-4.2 ℃/h, and carrying out primary desorption drying for 1-2 h;
heating to 30-33 ℃ at a rate of 3.6-4.2 ℃/h, and performing secondary desorption drying for 1-2 h.
Further, the pressure of sublimation drying is 8-10 Pa; the pressure for the desorption drying is 8-10 Pa.
Further, the sterilization filtration is performed by using a 0.22 μm primary sterilization filter, and then using a 0.22 μm secondary terminal sterilization filtration.
The omeprazole sodium for injection and the preparation method thereof have the beneficial effects that:
aiming at the structural characteristics of omeprazole sodium, the glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution with a specific pH value is prepared, so that the omeprazole sodium is effectively inhibited from being subjected to a polymerization reaction under the influence of the pH value in the preparation, storage and use processes, the generation of omeprazole sodium impurities is effectively reduced, and the stability of the omeprazole sodium for injection is improved;
due to the chemical structural characteristics of omeprazole sodium, the omeprazole sodium is relatively stable when the pH value is 10.1-11.1, so that the preparation is controlled to be always maintained in the pH value range, the stability of the omeprazole sodium can be effectively improved, but the pH value cannot be well controlled by the existing pH buffering agent which can be applied to powder injection at present, so that the specific pH buffering agent which is suitable for the omeprazole sodium is prepared through multiple experimental researches and screening of the reagent which is suitable for the powder injection and can not generate polymerization reaction when coexisting with the omeprazole sodium, and the pH buffering agent is used for controlling the pH value of the omeprazole sodium in the preparation, storage and use processes;
according to the invention, a specific pH buffering agent is selected to prepare a glycine-disodium hydrogen phosphate-sodium hydroxide buffering solution for preparing the omeprazole sodium for injection, so that the stability of the omeprazole sodium for injection is effectively improved;
meanwhile, the glycine in the buffer solution can play a role of an excipient besides maintaining the pH value, so that the plumpness and looseness of the omeprazole sodium for injection are effectively improved, and the omeprazole sodium for injection is prevented from being layered;
furthermore, the disodium hydrogen phosphate in the buffer solution also has the effect of a metal ion chelating agent, so that the pH value can be adjusted, metal ions can be chelated, and the influence of the metal ions on the polymerization phenomenon of the sulfonyl benzimidazole in the omeprazole sodium can be reduced; meanwhile, the dosage of disodium ethylene diamine tetraacetate can be reduced, the disodium ethylene diamine tetraacetate is added in the prior art to play a role in antioxidation, and the influence of metal ions on the omeprazole sodium is reduced by utilizing the metal ion chelation of the disodium ethylene diamine tetraacetate, however, the disodium ethylene diamine tetraacetate has low toxicity and can carry out complexation reaction with calcium ions, so that the dosage of the disodium ethylene diamine tetraacetate is reduced, and the medication safety of the omeprazole sodium for injection can be effectively improved;
according to the invention, by adjusting the technological parameters in the sublimation drying process and the desorption drying process and adopting a slow heating and segmented drying mode, when the omeprazole sodium is under the eutectic point in the drying process, the omeprazole sodium can be fully and uniformly dried, the moisture residue and solute migration in the liquid medicine of the omeprazole sodium in the desorption drying process are prevented, the omeprazole sodium is kept consistent in the upper and lower structures in the desorption process, the upper and lower layering phenomenon in the freeze-drying process is effectively inhibited, and the plumpness and looseness of the omeprazole sodium for injection are ensured; the product prepared by the invention has smooth surface, good appearance and excellent redissolution property;
according to the invention, the eutectic point of omeprazole sodium is researched, the pre-freezing temperature is adjusted, the freeze-drying efficiency is effectively improved, and the total freeze-drying time is reduced;
the omeprazole sodium for injection prepared by the invention has good stability, low impurity content, high safety and excellent re-solubility, and is beneficial to long-term storage.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Example 1 preparation method of omeprazole sodium for injection
The embodiment is a preparation method of omeprazole sodium for injection, and the specific preparation process comprises the following steps in sequence:
boiling water for injection, and cooling;
199.63g of glycine is added into water for injection to prepare 13.3L of glycine aqueous solution, namely 1mol/L of glycine aqueous solution;
144.18g of disodium hydrogen phosphate (dihydrate) is added into water for injection to prepare 16.2L of disodium hydrogen phosphate aqueous solution, namely 0.2mol/L of disodium hydrogen phosphate aqueous solution;
82g of sodium hydroxide is added into water for injection to prepare 20.5L of sodium hydroxide aqueous solution, namely 0.1mol/L of sodium hydroxide aqueous solution.
And uniformly mixing the glycine aqueous solution, the disodium hydrogen phosphate aqueous solution and the sodium hydroxide aqueous solution to obtain a glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution with the pH value of 10.7.
Adding 0.01kg of disodium ethylene diamine tetraacetate into 50L of glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution at room temperature, fully stirring and dissolving, then adding 1kg of omeprazole sodium, fully stirring and dissolving, adding 20g of medicinal activated carbon, stirring and decoloring for 30min at room temperature, filtering filtrate by a 0.22 mu m primary sterilization filter, and then filtering by a 0.22 mu m secondary terminal sterilization filter to effectively remove bacterial microorganisms 4 to obtain sterile liquid medicine for later use;
subpackaging the sterile liquid medicine according to the required specification (specification 40mg (in terms of omeprazole sodium)), plugging in half, transferring into a freeze dryer for vacuum freeze drying, wherein the vacuum freeze drying comprises prefreezing, sublimation drying and analytical drying;
pre-freezing: firstly, cooling a product in a freeze-drying cabinet to-54 ℃, and pre-freezing for 2 hours at the temperature of-54 ℃;
sublimation drying: vacuumizing to make the pressure in the box be 10Pa, heating to-40 ℃ at the speed of 3.9 ℃/h, and carrying out first sublimation drying for 3.5 h;
keeping the pressure in the box at 10Pa, heating to-20 ℃ at the speed of 3.9 ℃/h, and carrying out secondary sublimation drying for 4.5 h;
keeping the pressure in the box at 10Pa, heating to 5 ℃ at the speed of 3.9 ℃/h, and carrying out sublimation drying for the third time for 1.5 h;
and (3) resolving and drying: keeping the pressure in the box at 10Pa, heating to 20 ℃ at 3.9 ℃/h, and carrying out primary analysis and drying for 1.5 h;
the pressure in the oven was kept at 10Pa, and the temperature was raised to 32 ℃ at 3.9 ℃/h to conduct the second desorption drying for 1.5 h.
The total time of vacuum freeze drying in the preparation process of omeprazole sodium for injection is 36.55 h.
Example 2-6 preparation method of omeprazole sodium for injection
Embodiments 2 to 6 are respectively a method for preparing omeprazole sodium for injection, the steps of which are substantially the same as those of embodiment 1, and the differences are only in the amount of raw materials and process parameters, and the details are shown in table 1:
TABLE 1 summary of the process parameters of examples 2 to 6
The contents of the other portions of examples 2 to 6 are the same as those of example 1.
The omeprazole sodium for injection prepared in the embodiments 2 to 6 has good stability, high content of main drug, less impurities and excellent re-solubility.
Experimental example 1 measurement of Properties of omeprazole sodium for injection
Comparative example 1 is a comparative experiment of the preparation process of omeprazole sodium for injection in example 3 [ specification 40mg (in terms of omeprazole sodium) ], except that a disodium hydrogen phosphate-sodium hydroxide buffer solution having a pH of 11.1 is used, and the obtained preparation has a poor form and is agglomerated;
comparative example 2 is a comparative experiment of the preparation process of omeprazole sodium for injection in example 3 [ specification 40mg (in terms of omeprazole sodium) ] except that a disodium hydrogen phosphate-sodium hydroxide buffer solution having a pH of 11.1 is used and other excipients are used instead of glycine (here, mannitol);
comparative example 3 is a comparative experiment of the preparation process of omeprazole sodium for injection in example 5 [ specification 40mg (in terms of omeprazole sodium) ], except that glycine-sodium hydroxide buffer solution with pH 10.6 is used, the obtained preparation has bad form and has caking;
comparative example 4 is a comparative experiment of the preparation process of omeprazole sodium for injection [ specification 40mg (in terms of omeprazole sodium) ] of example 5, except that glycine-sodium hydroxide buffer solution having pH of 10.6 is used, and other excipients are used instead of glycine (here, mannitol is used);
the procedure for the preparation of comparative example 5 was: adding 0.03kg of disodium ethylene diamine tetraacetate into 50L of water for injection at room temperature, fully stirring and dissolving, then adding 10 wt% of sodium hydroxide aqueous solution to adjust the pH value to 11.0, then adding 1kg of omeprazole sodium, fully stirring and dissolving, adjusting the pH value of a small amount of 10 wt% of sodium hydroxide aqueous solution to 11.0 again, adding 20g of medicinal activated carbon, stirring and decoloring for 30min at room temperature, filtering the filtrate through a 0.22 mu m primary sterilization filter, and then performing 0.22 mu m secondary terminal sterilization filtration to effectively remove bacterial microorganisms, transferring the obtained sterile liquid medicine into a precooled freeze dryer for vacuum freeze drying, wherein the vacuum freeze drying procedure is the same as that in example 1.
Because the pH value of omeprazole sodium for injection is 10.1-11.1 specified in pharmacopoeia, a comparative example with the pH value of less than 10.1 or more than 11.1 is not added.
a1) Accelerated test
Omeprazole sodium for injection prepared in the embodiments 1 to 6 and the comparative examples 1 to 5 is respectively placed under the conditions of 40 +/-2 ℃ and RH75 +/-5% for 24 months, samples are respectively taken at 1 st, 3 rd, 6 th, 12 th and 24 th months in the period, detection is carried out according to detection items and methods specified in Chinese pharmacopoeia (2020 edition second part), and compared with day 0, the specific detection result is shown in the following table:
TABLE 2 summary of test results of accelerated test
As can be seen from Table 2, the stability of the omeprazole sodium for injection prepared in the embodiments 1 to 6 of the invention is superior to that of the omeprazole sodium for injection prepared in the comparative examples 1 to 5, and the content of related substances in the omeprazole sodium for injection prepared in the embodiments 1 to 6 is lower, which indicates that the process parameters of the invention are more beneficial to the preparation and storage of the omeprazole sodium for injection.
a2) Compatibility stability detection
Considering the safety of clinical compatibility application, the omeprazole sodium for injection prepared in examples 1 to 6 and comparative examples 1 to 5 is respectively combined with 100mL of 5% glucose or 100mL of 0.9% sodium chloride infusion, the solution stability is investigated, samples are taken and tested for 0, 2, 4, 8 and 12 hours, the test method is determined according to the color, pH value, insoluble particles and content specified in Chinese pharmacopoeia (2020 edition second part), and the specific test results are shown in the following table:
TABLE 3 summary of the testing results of compatibility stability test
As can be seen from Table 3, the stability of the clinical compatibility of the omeprazole sodium for injection prepared in the embodiments 1 to 6 of the invention is superior to that of the comparative examples 1 to 5, and the omeprazole sodium for injection prepared in the invention has no obvious change in quality within 12 hours of the compatibility with infusion solution, and can ensure the stability and effectiveness in clinical use.
a3) Resolubility detection
Taking the omeprazole sodium for injection prepared in the embodiments 1-6 and the comparative examples 1-5, respectively adding 10mL of a special solvent of the omeprazole sodium for injection for dissolution, and observing the dissolution speed, wherein the specific test results are shown in the following table:
TABLE 4 summary of the results of the redissolution test
As can be seen from Table 4, the omeprazole sodium for injection prepared in the embodiments 1 to 6 of the invention has good re-solubility.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (7)
1. The omeprazole sodium for injection is characterized in that raw materials for preparing active ingredients of the omeprazole sodium for injection comprise: 1 part by weight of omeprazole sodium, 0.01-0.02 part by weight of antioxidant and 45-55 parts by volume of glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution with the pH value of 10.1-11.1;
wherein, the corresponding relation between the parts by weight and the parts by volume is kg: and L.
2. The omeprazole sodium for injection according to claim 1, wherein the glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution is a mixture of glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution and sodium hydroxide in a volume ratio of 2.4-5.6: 5: 3.3 to 11.1 of glycine aqueous solution with the concentration of 0.2mol/L, disodium hydrogen phosphate aqueous solution with the concentration of 0.05mol/L and sodium hydroxide aqueous solution with the concentration of 0.1 mol/L.
3. Omeprazole sodium for injection according to claim 1 or 2, wherein the antioxidant is disodium edetate.
4. A preparation method of omeprazole sodium for injection according to any of claims 1 to 3, characterized in that the preparation method comprises the steps of dissolving an antioxidant in glycine-disodium hydrogen phosphate-sodium hydroxide buffer solution, adding omeprazole sodium for dissolution, decoloring, sterilizing, filtering and freeze-drying to obtain the omeprazole sodium for injection.
5. The process for preparing omeprazole sodium for injection according to claim 4, wherein the lyophilization comprises prefreezing, sublimation drying and resolution drying;
wherein the pre-freezing is performed at-55 to-50 ℃ for 2 to 3 hours;
the sublimation drying comprises the following steps which are carried out in sequence:
heating to-40 to-35 ℃ at a speed of 3.6 to 4.2 ℃/h, and carrying out primary sublimation drying for 3 to 4 h;
heating to-25-20 ℃ at a speed of 3.6-4.2 ℃/h, and carrying out secondary sublimation drying for 4-5 h;
heating to 5-10 ℃ at a speed of 3.6-4.2 ℃/h, and carrying out sublimation drying for the third time for 1-2 h;
the desorption drying comprises the following steps which are carried out in sequence:
heating to 20-25 ℃ at a speed of 3.6-4.2 ℃/h, and carrying out primary desorption drying for 1-2 h;
heating to 30-33 ℃ at a rate of 3.6-4.2 ℃/h, and performing secondary desorption drying for 1-2 h.
6. The preparation method of omeprazole sodium for injection according to claim 5, wherein the pressure of sublimation drying is 8-10 Pa; the pressure for the desorption drying is 8-10 Pa.
7. The process for preparing omeprazole sodium for injection according to any of claims 4 to 6, wherein the sterile filtration is performed by using a 0.22 μm primary sterile filter and then using a 0.22 μm secondary terminal sterile filtration.
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| CN115227656A (en) * | 2022-08-29 | 2022-10-25 | 海南锦瑞制药有限公司 | Preparation method of omeprazole sodium for injection |
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| CN104043101A (en) * | 2014-05-23 | 2014-09-17 | 杭州诺泰制药技术有限公司 | Icatibant composition for injection and preparation method and preparation thereof |
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| CN1843356A (en) * | 2006-02-21 | 2006-10-11 | 成都欣捷高新技术开发有限公司 | Powder injection of dolasetron and its pharmaceutically acceptable salt, and its preparation method |
| CN101703483A (en) * | 2009-11-19 | 2010-05-12 | 海南利能康泰制药有限公司 | Omeprazole sodium freeze-dried powder injection and preparation method thereof |
| CN104043101A (en) * | 2014-05-23 | 2014-09-17 | 杭州诺泰制药技术有限公司 | Icatibant composition for injection and preparation method and preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115227656A (en) * | 2022-08-29 | 2022-10-25 | 海南锦瑞制药有限公司 | Preparation method of omeprazole sodium for injection |
| CN115227656B (en) * | 2022-08-29 | 2023-07-25 | 海南锦瑞制药有限公司 | Preparation method of omeprazole sodium for injection |
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