CN115737548A - Preparation method of famotidine injection - Google Patents
Preparation method of famotidine injection Download PDFInfo
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- CN115737548A CN115737548A CN202211457753.6A CN202211457753A CN115737548A CN 115737548 A CN115737548 A CN 115737548A CN 202211457753 A CN202211457753 A CN 202211457753A CN 115737548 A CN115737548 A CN 115737548A
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- Prior art keywords
- lactic acid
- famotidine
- solution
- water
- injection
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- 229940005526 famotidine injection Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 208
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 116
- 239000004310 lactic acid Substances 0.000 claims abstract description 99
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 99
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 58
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 48
- 239000000243 solution Substances 0.000 claims abstract description 46
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960001596 famotidine Drugs 0.000 claims abstract description 33
- 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 25
- 235000010355 mannitol Nutrition 0.000 claims abstract description 23
- 238000001914 filtration Methods 0.000 claims abstract description 22
- 229930195725 Mannitol Natural products 0.000 claims abstract description 21
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims abstract description 21
- 239000000594 mannitol Substances 0.000 claims abstract description 21
- 229960001855 mannitol Drugs 0.000 claims abstract description 21
- 238000010438 heat treatment Methods 0.000 claims abstract description 19
- 230000001502 supplementing effect Effects 0.000 claims abstract description 3
- 229960000448 lactic acid Drugs 0.000 claims description 100
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- 235000010323 ascorbic acid Nutrition 0.000 claims description 23
- 229960005070 ascorbic acid Drugs 0.000 claims description 23
- 239000011668 ascorbic acid Substances 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002033 PVDF binder Substances 0.000 claims description 6
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 229960003966 nicotinamide Drugs 0.000 claims description 3
- 235000005152 nicotinamide Nutrition 0.000 claims description 3
- 239000011570 nicotinamide Substances 0.000 claims description 3
- 229930182843 D-Lactic acid Natural products 0.000 claims description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229940022769 d- lactic acid Drugs 0.000 claims description 2
- 238000002203 pretreatment Methods 0.000 claims description 2
- 229940083645 famotidine 10 mg/ml Drugs 0.000 claims 1
- 238000003756 stirring Methods 0.000 abstract description 45
- 239000000126 substance Substances 0.000 abstract description 9
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 abstract 1
- 229930003268 Vitamin C Natural products 0.000 abstract 1
- 235000019154 vitamin C Nutrition 0.000 abstract 1
- 239000011718 vitamin C Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 66
- 239000007788 liquid Substances 0.000 description 47
- 238000011049 filling Methods 0.000 description 43
- 239000012153 distilled water Substances 0.000 description 38
- 239000003708 ampul Substances 0.000 description 28
- 229940079593 drug Drugs 0.000 description 25
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- 230000008018 melting Effects 0.000 description 13
- 230000001954 sterilising effect Effects 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 239000000178 monomer Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229940090044 injection Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 101150056637 Hrh2 gene Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
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- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000009210 therapy by ultrasound Methods 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
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- 210000004211 gastric acid Anatomy 0.000 description 1
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Images
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly discloses a preparation method of famotidine injection, which comprises the following steps: 1) Taking lactic acid, adding water to dilute the lactic acid into a solution of 100-300 mg/ml, and heating the solution at the temperature of 80-121 ℃ for 30 min-8 h to obtain a lactic acid solution; 2) Charging nitrogen into water, adding the lactic acid solution obtained in the step 1), nicotinamide, mannitol, famotidine and vitamin C for dissolving, adjusting the pH value to 5.8-6.2, supplementing the balance of water, stirring uniformly and filtering to obtain the product. When the famotidine injection prepared by the invention is stored at normal temperature and under an accelerating condition, the pH value cannot be reduced, the content and related substances are kept stable, the color is kept colorless, and the famotidine injection has practical popularization and application values.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of famotidine injection.
Background
Famotidine (Famotidine) is H2 receptor retardant of guazathiazole class, has the characteristic of high affinity to H2 receptor, has obvious inhibition effect on gastric acid secretion, and has inhibition effect on basic secretion and increase of gastric acid and pepsin caused by various stimulations. Famotidine is a basic compound with pKa value of about 7.1, is easy to dissolve under acidic condition, but has poor stability, and is very difficult to dissolve in neutral and alkaline solution (the solubility is below 0.1 w/v%), so in order to develop famotidine injection with high solubility and good stability, auxiliary materials capable of improving the solubility of famotidine need to be selected.
Currently, famotidine injection is mainly available in the following types, in the United states, famotidine injection produced by Merck is mainly taken as a representative, aspartic acid is added into the formula of famotidine injection as a solubilizer, and the product is stableThe product has poor performance and needs to be stored at 2-8 ℃; in Japan, there are 2 kinds, one is a famotidine injection stock preparation produced by LTL company under the trade name of
The solubilizing substance is nicotinamide, and the prescription composition and the preparation mode thereof are disclosed in patent CN 100438871C; the other is famotidine injection solubilized by acetic acid for imitating drugs, and the famotidine injection is filled in a plastic ampoule bottle with a deoxidizer and barrier package; the formulation of famotidine injection in Chinese market is unknown, but it is generally aspartic acid-containing or propylene glycol-containing. On 16 days 4 months in 2020, the national Committee for evaluation of the consistency of the quality and efficacy of pharmaceuticals imitation drugs was examined and determined, and the catalogue of reference preparations for imitation drugs was released (twenty-fifth lot), wherein the famotidine injection produced by LTL ファーマ Kabushiki Kaisha was published in serial number 25-6, and the trade name thereof was named
As a reference formulation; meanwhile, in 14 days 5 months in 2020, the drug evaluation center of the State drug administration issues a notice on the development of the evaluation work of the quality of the imitation drugs of chemical injection and the consistency of the curative effect, which means that the famotidine injection of the domestic manufacturer must be used
The prescription and process must be consistent for the purpose of the study.
Reference is made to marketed in Japan
The specification, its prescription composition contains 10mg of famotidine, 50mg of nicotinamide, 1mg of ascorbic acid, 20mg of D-mannitol, and right amount of lactic acid/pH regulator/water for injection in each 1ml of injection, and the research is carried out according to the preparation process of CN100438871C, and the result shows that the stability of the prepared famotidine injection product is inferior to that of the reference preparation, the sample is placed at 50 ℃,40 ℃ and 25 ℃ for 1 month, the pH of the product is reduced from 6.0 to 5.4-5.6, and the color is changedThe color of the product changes from colorless to light yellow, and the content of the related substances is increased and decreased more than that of the reference preparation.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of famotidine injection, which is prepared from famotidine and auxiliary materials containing lactic acid; the pretreatment method of the lactic acid comprises the following steps: firstly, adding water into lactic acid to dilute the lactic acid into a solution of 100-300 mg/ml, and heating the solution at 80-121 ℃ for 30 min-8 h to obtain the lactic acid solution.
Further, the method specifically comprises the following steps:
1) Taking lactic acid, adding water to dilute the lactic acid into a solution of 100-300 mg/ml, and heating the solution at 80-121 ℃ for 30 min-8 h to obtain a lactic acid solution;
2) Charging nitrogen into water, adding the lactic acid solution obtained in the step 1), nicotinamide, mannitol, famotidine and ascorbic acid for dissolving, adjusting the pH value to be 5.8-6.2, supplementing the balance of water and filtering to obtain the compound preparation;
each 100ml of the famotidine injection comprises 0.5-1.5g of famotidine, 2.5-7.5g of nicotinamide, 1-3g of mannitol, 0.05-0.15g of ascorbic acid and 0.25-0.45g of lactic acid.
Further, adding water into the lactic acid in the step 1) to dilute the lactic acid into a solution of 200-300 mg/ml; preferably, the lactic acid is diluted with water to a solution of 200 mg/ml.
Further, the heating temperature of the lactic acid solution in the step 1) is 80 ℃, and the time is 2-8 h; or the heating temperature of the lactic acid solution is 121 ℃, and the time is 30 min-2 h.
Further, the lactic acid solution in the step 1) is heated at the temperature of 80 ℃ for 8 hours; alternatively, the lactic acid solution is heated at 121 ℃ for 2h.
Further, in the step 2), 80% of the formula amount is dissolved in water, and then the balance of water is replenished; the temperature of the water is 20-30 ℃.
Further, step 2) nitrogen is filled until the dissolved oxygen value is less than 1ppm.
Further, the filtration in the step 2) is firstly carried out by a 0.45 μm +0.22 μm PVDF filter, and then is carried out by a 0.45 μm +0.22 μm PVDF filter.
Further, the solution for adjusting the pH value in the step 2) is a sodium hydroxide solution, and the concentration is 0.1-5 mol/L, preferably 1mol/L.
Furthermore, the famotidine injection comprises 10mg/ml of famotidine, 50mg/ml of nicotinamide, 20mg/ml of mannitol, 1mg/ml of ascorbic acid and 3.5mg/ml of lactic acid.
The mass percentage concentration of the lactic acid is 90% (m/m), and the lactic acid can be selected from DL-lactic acid, L-lactic acid and D-lactic acid under the condition of no special indication; DL-lactic acid is preferred.
The invention is realized by comparing a reference preparation
The prescription analysis of (1) shows that the source of lactic acid influences the solubility and stability of the famotidine injection. According to the following
The famotidine injection with good stability is prepared according to the prescription, and the lactic acid raw material is from a special Japanese supplier, so that the famotidine injection meeting the evaluation standard of the imitation drugs is difficult to be successfully prepared by a production enterprise which cannot obtain the special lactic acid.
According to the preparation method of the famotidine injection provided by the invention, after a lactic acid aqueous solution is heated at a specific temperature for a specific time, the lactic acid aqueous solution, the famotidine, the nicotinamide, the ascorbic acid and the D-mannitol are dissolved in water together under the condition of introducing nitrogen, when the prepared famotidine injection is stored at normal temperature and under an accelerating condition, the pH value cannot be reduced, the color is kept colorless, the contents of related substances and famotidine are not obviously changed, the quality is stable, the pharmaceutical imitation evaluation standard can be met without lactic acid from a specific source, and the preparation method has practical popularization and application values.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Drawings
FIG. 1 is a schematic view of a
Detection pattern of related substance
FIG. 2 spectrum for detecting lactic acid monomer content in comparative example 1
FIG. 3 spectrum for measuring the content of lactic acid monomer in example 1
Detailed Description
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The raw materials, reagents and equipment used in the present invention are all commercially available.
In the present invention, when it is described that "lactic acid is added to distilled water to 200mg/ml", it means that 90% (m/m) of lactic acid is diluted with water to 200mg of 90% lactic acid per 1ml of the solution.
Example 1 Famotidine injection of the invention
Prescription:
the preparation method comprises the following steps:
1) 1mol/L sodium hydroxide preparation: weighing 300g of sodium hydroxide, slowly adding the sodium hydroxide into a 10L stainless steel barrel filled with 7200g of water for injection, and stirring for dissolving;
preparing lactic acid: weighing 1.75kg of lactic acid into a 10L sealable stainless steel pressure container, adding water for injection to 8.75kg to prepare 200mg/ml lactic acid solution, sealing, and heating at 121 ℃ for 2h;
2) Preparing liquid: adding 80% of injection water in batches into the liquid preparation tank, cooling to 20-30 ℃, starting stirring (the rotating speed is set to be 20-50 HZ), and filling nitrogen until the dissolved oxygen value is less than 1ppm;
3) Adding the lactic acid prepared in the step 1), 25kg of nicotinamide and 10kg of mannitol, stirring for 5-10min, and completely dissolving;
4) Adding 5kg of famotidine, and stirring until the famotidine is completely dissolved;
5) Adding 500g of ascorbic acid and stirring until the ascorbic acid is completely dissolved;
6) Regulating the liquid medicine with 1mol/L sodium hydroxide to 5.8-6.2;
7) Adding injection water to 500L, and stirring for no less than 5min;
8) And (3) filtering: filtering the liquid medicine to a receiving tank through a PVDF filter with the diameter of 0.45 mu m and the diameter of 0.22 mu m; filtering the liquid medicine into a buffer tank through a PVDF filter with the diameter of 0.45 mu m and the diameter of 0.22 mu m;
9) Filling: filling the ampoule bottle with 2ml of medicinal liquid, charging nitrogen during filling, and sealing by fusing.
Example 2 Famotidine injection of the present invention
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to 200mg/ml, and heating at 121 ℃ for 30min;
2) Adding 160ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1), the nicotinamide, the mannitol and the famotidine raw material medicines with the prescription amount, and stirring to completely dissolve;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 200ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuously flushing the liquid medicine with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Example 3 Famotidine injection of the invention
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to obtain a lactic acid solution with the concentration of 200mg/ml, and heating at 121 ℃ for 1h;
2) Adding 160ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 200ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Example 4 Famotidine injection of the invention
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to obtain a lactic acid solution with the concentration of 300mg/ml, and heating at 121 ℃ for 30min;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the medicinal liquid with 0.22 μm sterilizing filter head, and charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuously flushing the liquid medicine with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Example 5 Famotidine injection of the invention
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to obtain a lactic acid solution with the concentration of 200mg/ml, and heating at 80 ℃ for 2 hours;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Example 6 Famotidine injection of the invention
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to obtain a lactic acid solution with the concentration of 200mg/ml, and heating at 80 ℃ for 8 hours;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Example 7 Famotidine injection of the invention
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to obtain a lactic acid solution with the concentration of 200mg/ml, and heating at 121 ℃ for 2 hours;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid solution treated in the step 1) and the prescription amounts of the raw materials of nicotinamide, mannitol and famotidine, and stirring to completely dissolve the raw materials;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Comparative example 1
Prescription:
the preparation method comprises the following steps:
1) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding DL-lactic acid according to the prescription amount, continuously adding the nicotinamide, mannitol and famotidine raw material medicines according to the prescription amount, and stirring to completely dissolve;
2) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
3) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
4) Adding distilled water to 100ml, and stirring uniformly;
5) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
6) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Comparative example 2
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to dilute into lactic acid aqueous solution with the concentration of 100 mg/ml;
2) Adding famotidine 1g, nicotinamide 5g and mannitol 2g into 200ml beaker, adding distilled water 75ml, lactic acid aqueous solution 100mg/ml 6.1ml and sodium hydroxide 1 mol/L3 ml, stirring to dissolve
3) After dissolving famotidine, adding 0.1g ascorbic acid into the solution while introducing nitrogen into the solution to dissolve the famotidine;
4) Adjusting the pH value of the liquid medicine to 6.1 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Comparative example 3
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to obtain a lactic acid solution with the concentration of 200mg/ml, and heating at 121 ℃ for 2 hours;
2) Adding 80ml of distilled water into a 200ml beaker, adding the lactic acid treated in the step 1) and the prescription amounts of the raw material medicines of the nicotinamide, the mannitol and the famotidine, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the medicinal liquid with 0.22 μm sterilizing filter head;
7) And filling the liquid medicine (2 ml/bottle) into a 2ml colorless medium borosilicate ampoule bottle, and immediately sealing the ampoule bottle by melting after filling to obtain the prepared famotidine injection without nitrogen filling.
Comparative example 4
Prescription:
the preparation method comprises the following steps:
1) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding 0.35g of L-lactic acid, continuously adding the nicotinamide, mannitol and famotidine raw material medicines according to the prescription amount, and stirring to completely dissolve;
2) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
3) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
4) Adding distilled water to 100ml, and stirring uniformly;
5) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
6) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Comparative example 5
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, and adding distilled water to make the lactic acid reach 200mg/ml;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid diluted in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the medicinal liquid with 0.22 μm sterilizing filter head, and charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Comparative example 6
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to 200mg/ml, and heating at 40 ℃ for 4h;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the medicinal liquid with 0.22 μm sterilizing filter head, and charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
Comparative example 7
Prescription:
the preparation method comprises the following steps:
1) Taking lactic acid with the prescription amount, adding distilled water to 200mg/ml, and heating at 60 ℃ for 2h;
2) Adding 80ml of distilled water into a 200ml beaker, filling nitrogen until the dissolved oxygen value is less than 1ppm, adding the lactic acid treated in the step 1) and the prescription amounts of the nicotinamide, the mannitol and the famotidine raw material medicines, and stirring to completely dissolve the raw material medicines;
3) Adding the ascorbic acid with the prescription amount, and stirring to completely dissolve;
4) Adjusting the pH value of the liquid medicine to 5.8-6.2 by using 1mol/L sodium hydroxide;
5) Adding distilled water to 100ml, and stirring uniformly;
6) Filtering the liquid medicine with a 0.22 μm sterilizing filter head, and continuously charging nitrogen;
7) Flushing a 2ml colorless medium borosilicate ampoule bottle with nitrogen, filling the liquid medicine (2 ml/bottle), continuing flushing with nitrogen after filling, and immediately sealing the ampoule bottle by melting to obtain the famotidine injection.
The advantageous effects of the present invention are further illustrated by the following test examples
Test example 1 quality test of famotidine injection
1. Method for producing a composite material
Three batches of the commercial product were taken
Carrying out quality detection;
the famotidine injection prepared in the examples 1-6 and the comparative examples 1-7 are stored in the environment with different temperatures for 1 month, and then the appearance of the injection is observed by sampling, and the content of lactic acid monomer, the content of famotidine and related substances thereof are detected. The specific quality detection method comprises the following steps:
1) Method for detecting content of lactic acid monomer
Flow rate: lml/min
Column temperature: 40 deg.C
Detection wavelength: 210nm
Sample introduction amount: 10 μ l
A chromatographic column: YMC-Pack ODS-AQ 4.6 mm. Times.250mm, 5 μm
Mobile phase A: 4.950g tetramethylammonium hydroxide in 400ml H 2 And in O, adjusting the pH value to 2.01 by using phosphoric acid, diluting to 450ml by using water, performing suction filtration, adding 50ml of acetonitrile, uniformly mixing, and performing ultrasonic treatment to obtain the product.
Mobile phase B: 4.958g tetramethylammonium hydroxide in 150ml H 2 And in O, adjusting the pH value to 1.97 by using phosphoric acid, diluting to 200ml by using water, carrying out suction filtration, adding 300ml of acetonitrile, uniformly mixing, and carrying out ultrasonic treatment to obtain the final product.
Diluent (b): weighing 450ml of water, adjusting the pH value to 3.51 by using glacial acetic acid, adding 50ml of acetonitrile, and uniformly mixing.
The gradient program is as follows:
| T(min) | A | B％ | |
| 0 | 90 | 10 | |
| 24 | 30 | 70 | |
| 29 | 30 | 70 | |
| 30 | 90 | 10 | |
| 35 | 90 | 10 |
2) Method for detecting content of famotidine injection
A chromatographic column: kromasil C18,4.6 mm. Times.250mm, 5 μm
Flow rate: 1.5ml/min
Column temperature: 35 deg.C
Sample introduction amount: 20 μ l
Detection wavelength: 270nm
Mobile phase: acetate buffer (taking 13.6g of sodium acetate, putting into 900ml of water, adjusting pH value to 6.0 +/-0.2 with glacial acetic acid, adding water to 1000 ml)
3) Method for detecting related substances of famotidine injection
A chromatographic column: kromasil C18,4.6 mm. Times.250mm, 5 μm
Flow rate: 1.5ml/min
Column temperature: 35 deg.C
Sample introduction amount: 20 μ l
Detection wavelength: 270nm
Mobile phase A: acetate buffer (taking 13.6g of sodium acetate, putting into 900ml of water, adjusting pH value to 6.0 +/-0.2 with glacial acetic acid, adding water to 1000 ml)
And (3) mobile phase B: acetonitrile
The gradient elution was as follows:
2. results
Commercially available product
The detection results are shown in table 1 and fig. 1; the detection results of famotidine injection prepared by different preparation methods are shown in tables 1-4 and figures 2-3.
Wherein, the content of the lactic acid monomer refers to the mass percentage of the lactic acid monomer in the lactic acid.
TABLE 1 detection results of famotidine injection for 0 day
TABLE 2 stability results of famotidine injection at 50 deg.C for 1 month
TABLE 3 stability results of famotidine injection at 40 deg.C for 1 month
TABLE 4 results of famotidine injection at 25 deg.C for 1 month
From the above results it can be seen that: (1) when the famotidine injection is prepared, the lactic acid is diluted to a certain concentration and is heated, and the content of the lactic acid monomer is higher than that of the lactic acid which is not heated; during the storage period of stability, the pH value of the famotidine injection prepared by diluting and heating lactic acid has no obvious trend of reduction, the change trend of related substances and contents is smaller, and the quality is more stable.
(2) The famotidine injection prepared without lactic acid treatment has obvious pH lowering trend, relevant matter increasing trend and relevant matter content lowering trend during stable storage.
(3) The famotidine injection is prepared without filling nitrogen after the lactic acid is heated, the pH value does not decrease during the stable storage period, but the color of the solution changes obviously.
Claims (10)
1. A preparation method of famotidine injection is characterized in that the famotidine injection is prepared from famotidine and auxiliary materials containing lactic acid; the pretreatment method of the lactic acid comprises the following steps: firstly, adding water into lactic acid to dilute the lactic acid into a solution of 100-300 mg/ml, and heating the solution at 80-121 ℃ for 30 min-8 h to obtain the lactic acid solution.
2. The method of claim 1, wherein: the method specifically comprises the following steps:
1) Taking lactic acid, adding water to dilute the lactic acid into a solution of 100-300 mg/ml, and heating the solution at 80-121 ℃ for 30 min-8 h to obtain a lactic acid solution;
2) Charging nitrogen into water, adding the lactic acid solution obtained in the step 1), nicotinamide, mannitol, famotidine and ascorbic acid for dissolving, adjusting the pH value to be 5.8-6.2, supplementing the balance of water and filtering to obtain the compound preparation;
every 100ml of the famotidine injection comprises 0.5-1.5g of famotidine, 2.5-7.5g of nicotinamide, 1-3g of mannitol, 0.05-0.15g of ascorbic acid and 0.25-0.45g of lactic acid.
3. The method according to claim 2, wherein the lactic acid is diluted with water to a solution of 200 to 300mg/ml in step 1); preferably, the lactic acid is diluted with water to a solution of 200 mg/ml.
4. The preparation method according to claim 2, wherein the lactic acid solution in step 1) is heated at 80 ℃ for 2-8 h; or the heating temperature of the lactic acid solution is 121 ℃, and the time is 30 min-2 h.
5. The method according to claim 4, wherein the lactic acid solution in step 1) is heated at 80 ℃ for 8h; alternatively, the lactic acid solution is heated at 121 ℃ for 2h.
6. The preparation method of claim 2, wherein in the step 2), 80% of the formula amount is dissolved in water, and then the balance of water is made up; the temperature of the water is 20-30 ℃.
7. The method of claim 2, wherein step 2) comprises charging nitrogen to a dissolved oxygen value of < 1ppm.
8. The method of claim 2, wherein the filtering of step 2) is performed by filtering through a 0.45 μm +0.22 μm PVDF filter and then through a 0.45 μm +0.22 μm PVDF filter; the solution for adjusting the pH value is a sodium hydroxide solution, and the concentration is 0.1-5 mol/L, preferably 1mol/L.
9. The method of claim 2, wherein the famotidine injection comprises famotidine 10mg/ml, nicotinamide 50mg/ml, mannitol 20mg/ml, ascorbic acid 1mg/ml and lactic acid 3.5mg/ml.
10. The production method according to any one of claims 2 to 9, wherein the lactic acid is selected from the group consisting of DL-lactic acid, L-lactic acid and D-lactic acid; DL-lactic acid is preferred.
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