CN103768096A - Preparation method of sodium nitroprusside injection - Google Patents
Preparation method of sodium nitroprusside injection Download PDFInfo
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- 229940083618 sodium nitroprusside Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 title claims abstract 8
- 238000002347 injection Methods 0.000 title abstract description 7
- 239000007924 injection Substances 0.000 title abstract description 7
- 229940090044 injection Drugs 0.000 title abstract 2
- 238000004108 freeze drying Methods 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 26
- 239000008215 water for injection Substances 0.000 claims abstract description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012528 membrane Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000005303 weighing Methods 0.000 claims abstract description 6
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 12
- 229940099644 nitropress Drugs 0.000 claims description 8
- 239000003610 charcoal Substances 0.000 claims description 5
- 241001411320 Eriogonum inflatum Species 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 abstract description 5
- 238000010438 heat treatment Methods 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 229930182555 Penicillin Natural products 0.000 abstract 1
- 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 abstract 1
- 239000000654 additive Substances 0.000 abstract 1
- 238000011049 filling Methods 0.000 abstract 1
- 229940049954 penicillin Drugs 0.000 abstract 1
- 230000001502 supplementing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 34
- 230000000052 comparative effect Effects 0.000 description 17
- XRKMNJXYOFSTBE-UHFFFAOYSA-N disodium;iron(4+);nitroxyl anion;pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+4].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] XRKMNJXYOFSTBE-UHFFFAOYSA-N 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 9
- 238000005070 sampling Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000005286 illumination Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000001954 sterilising effect Effects 0.000 description 6
- 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 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000012752 auxiliary agent Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
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- 239000011734 sodium Substances 0.000 description 3
- -1 stirs 15-25min Chemical compound 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 2
- 206010007556 Cardiac failure acute Diseases 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PANJMBIFGCKWBY-UHFFFAOYSA-N iron tricyanide Chemical compound N#C[Fe](C#N)C#N PANJMBIFGCKWBY-UHFFFAOYSA-N 0.000 description 2
- 201000005857 malignant hypertension Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020802 Hypertensive crisis Diseases 0.000 description 1
- 206010058179 Hypertensive emergency Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000001765 aortic valve Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate group Chemical group [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011082 depyrogenation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical class Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004115 mitral valve Anatomy 0.000 description 1
- 239000006259 organic additive Substances 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
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- 229910052709 silver Inorganic materials 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of sodium nitroprusside injection. The preparation method comprises the following steps: (1) accurately weighing sodium nitroprusside according to a mass volume ratio of each 50g of sodium nitroprusside: added water for injection enabling a solution to reach 100mL, adding the water for injection to the sodium nitroprusside so as to dissolve the sodium nitroprusside into a 20%-30% concentrated solution, adding 0.1-0.2% of activated carbon, stirring for 15-25 minutes, and carrying out coarse filtration so as to remove carbon; (2) supplementing the water for injection, and then carrying out refined filtration by using a filtering membrane; and (3) respectively filling the solution subjected to refined filtration into sterile penicillin bottles, partially stoppering, putting in freeze-drying equipment, and carrying out freeze-drying according to a freeze-drying curve. The preparation method has the advantages that proper temperature, pressure and heating rate are adopted in a preparation process, the intense moisture absorption of an inner loose structure of the product is avoided, the product is prevented from absorbing moisture again after being dried, the occurrence of the shrunk product is reduced, and the percent of pass is increased; and additives for improving surface activity do not need to be added, the risk caused by impurity introduction is reduced, and the production efficiency is improved.
Description
Technical field
The invention belongs to field of medicine preparations, be specifically related to a kind of preparation method of lyophilized injection.
Background technology
Sodium nitroprusside (molecular formula: Na
2[Fe (CN)
5nO] 2H
2o, chemical name: sodium nitroprusside two hydrates) be a kind of vasodilator of quick-acting and part-time application, clinically for hypertensive emergency, as the urgent blood pressure lowering of hypertensive crisis, hypertensive encephalopathy, malignant hypertension, pheochromocytoma perioperatively paroxysmal hypertension etc., also can be used for carrying out controlled hypotension during surgical anesthesia.In addition, also can be used for acute heart failure, comprise acute lung edema; Also the acute heart failure during for acute myocardial infarction or valve (Bicuspid valve or aortic valve) incompetence.After quiet, reach immediately blood drug level peak value, its level is determined with dosage.This product is cyanide by erythrocyte metabolism, and in liver, cyanide metabolism is cyanate.After this product administration, almost work immediately and reach effect peak, quiet maintains 1～10 minute after stopping.
Sodium nitroprusside is the crystallization of red transparent powder powder, soluble in water, and its aqueous solution is unstable, makes the application of injection lyophilized preparation more.Wherein lyophilized injectable powder has and can avoid medicine to go bad, make that product quality is loose, medicine water content is low, be conducive to product Long-term Storage, can recover rapidly the original characteristic of medicinal liquid after adding water because of pyrolytic, and convenient transportation, product dosage accurately, the advantage such as good appearance, therefore, the nipride ampoule lyophilized injectable powder that adopts Freeze Drying Technique to prepare can guarantee the quality of product better than common liquid drugs injection, thereby has been subject to the favor in market.In existing injection preparation process, conventionally add a small amount of auxiliary agent, such as mannitol, glucose, pH value regulator etc. (development of nipride ampoule, preparation and technology, in June, 2010), to obtain the product that meets quality standard.But adding of auxiliary agent also brings the problems such as the risk increasing of process complications, pollution.
Injection class freeze-dried products should be complete block or sponge, has enough intensity, is not broken into powder, the full not atrophy of profile, and color and luster is even one, fully dry, keeps medicine stable, and porous is good, adds water and can recover rapidly state before lyophilizing; The fineness of sterilized powder or crystallization should be suitable, are convenient to subpackage.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, propose a kind of preparation method of Nitropress.
Another object of the present invention is the Nitropress that proposition prepares.
The technical scheme that realizes above-mentioned purpose of the present invention is:
A preparation method for Nitropress, it comprises step:
1) according to every sodium nitroprusside 50g, add to the mass volume ratio of 1000mL with water for injection, accurate weighing sodium nitroprusside, being dissolved in water for injection is 20%～30% concentrated solution, adds 0.1～0.2% quality of activated carbon volume ratio, after stirring, leave standstill 15～25min, coarse filtration takes off charcoal;
2) mend and inject water to 950～980mL, detect pH value to 5.0～7.0, completion amount water for injection, then pass through filter membrane fine straining;
3) fill of the difference of the solution after fine straining, in aseptic cillin bottle, is partly jumped a queue, and is placed in freeze drying equipment, carries out lyophilization by following freeze-drying curve:
Freeze drying equipment temperature is down to-45～-40 ℃, and then constant temperature 1～2 hour is controlled vacuum-20～-5Pa in freeze drying equipment; Extremely-45 ℃～-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-40～-35 ℃ of homoiothermics, constant temperature 2-3 hour, extremely-35～-30 ℃ of homoiothermics, constant temperature 3～4 hours ,-30 ℃～-25 ℃, constant temperature 4～5 hours;-25 ℃～-20 ℃, constant temperature 4～5 hours;-20 ℃～-15 ℃, constant temperature 4～5 hours;-15 ℃～-10 ℃, constant temperature 4～5 hours;-10 ℃～-5 ℃, constant temperature 3～4 hours;-5 ℃～0 ℃, constant temperature 1～2 hour; 0 ℃～10 ℃, constant temperature 0.5～1 hour; 10 ℃～40 ℃, constant temperature 0.5～1 hour; In the time that products temperature is raised to 40 ℃～45 ℃, reduce flaggy temperature to 38～40 ℃ of freeze drying equipment, constant temperature 4～5 o'clock.
Because there being water of crystallization in raw material, therefore through conversion, in prescription, the consumption of sodium nitroprusside should be 43.96g/1000 and props up.
Wherein, described step 2) in, the filter membrane of fine straining is selected from 0.15-0.22 microporous filter membrane.
Wherein, described step 2) in, detect pH value and be 5.0～7.0 and be qualified pH value.Inventor's test of many times is definite, and after adding water by prescription, pH value is 5.0～7.0.
Preferably, adopt following more accurate freeze-drying curve:
Solution to be frozen after fine straining is placed in freeze-drier, and device temperature is down to-45 ℃, and then constant temperature 1 hour is controlled vacuum-20～-5Pa in freeze-drier; Extremely-45 ℃～-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-40～-35 ℃ of homoiothermics, constant temperature 2 hours, extremely-35～-30 ℃ of homoiothermics, constant temperature 3 hours ,-30 ℃～-25 ℃, constant temperature 4 hours;-25 ℃～-20 ℃, constant temperature 4 hours;-20 ℃～-15 ℃, constant temperature 4 hours;-15 ℃～-10 ℃, constant temperature 4 hours;-10 ℃～-5 ℃, constant temperature 3 hours;-5 ℃～0 ℃, constant temperature 1 hour; 0 ℃～10 ℃, constant temperature 0.5 hour; 10 ℃～40 ℃, constant temperature 0.5 hour.In the time that solution products temperature is raised to 40 ℃～45 ℃, reduce the flaggy temperature to 40 ℃ of equipment, constant temperature 4 hours.
Wherein, after described step 3), being also included in vacuum is the step that compresses described cillin bottle bottle stopper (aluminium lid) under 2-3Pa condition.
The Nitropress that preparation method of the present invention prepares.
Beneficial effect of the present invention is:
Compared with prior art, because the present invention has adopted suitable and temperature and pressure and heating rate in preparation process, making products made thereby under the condition that there is no organic additive, can realize moisture evenly overflows, stop the strong hygroscopicity of goods internal defect structure, effectively avoid after product dried the moisture absorption again, and then reduce the appearance of atrophy product, significantly improve the qualification rate of product.The preparation method that the present invention proposes does not need to add improves surface-active auxiliary agent, has reduced the risk that impurity is introduced, and has improved production efficiency.
The test result of many batches of products shows, every quality index of sample meets " Chinese Pharmacopoeia " version in 2000 two it " nipride ampoule " every regulation (P838), sample is to high-temperature stable, and stability is better at normal temperatures, and in the process of the test of 36 months, quality does not change.
Accompanying drawing explanation
Fig. 1 is the process chart of Nitropress preparation method of the present invention.
The specific embodiment
Following examples further illustrate content of the present invention, but should not be construed as limitation of the present invention.Without departing from the spirit and substance of the case in the present invention, the modification that the inventive method, step or condition are done or replacement, all belong to scope of the present invention.
If do not specialize, the conventional means that in embodiment, technological means used is well known to those skilled in the art.
In embodiment, sodium nitroprusside crude drug is that Nanjing Jingyu Pharmaceutical Co., Ltd. produces, Na
2[Fe (CN)
5nO] 2H
2o content 97-99%.
Freeze drying equipment is the freeze dryer of German CHRIST, ALPHA1-4.
Embodiment 1
Flow process is as Fig. 1.Aseptic controlling technological measure has: the material that enters fill operation imports into after sterilization; Aseptic clean garment is used after the sterilizing in 121 ℃, 30 minutes of the pure steam of pulse vacuum; For the reception of sterile liquid medicine and fill, moisture-proof equipment, container tool all use through the sterilizing in 121 ℃, 30 minutes of the pure steam of pulse vacuum, and for dry heat resistance, equipment, container tool are all through xeothermic 220 ℃, and sterilizing in 2 hours is used.
1) according to every sodium nitroprusside 50g, add to the mass volume ratio of 1000mL with water for injection, accurate weighing sodium nitroprusside, being dissolved in water for injection is 20%～30% concentrated solution, adds 0.1-0.2% active carbon, stirs 15-25min, kieselguhr coarse filtration takes off charcoal;
2) mend and inject water to 950-980mL, detect pH value, completion amount water for injection.Again through 0.22 μ m microporous filter membrane fine straining.After fine straining, sample detection level, PH, bacterial endotoxin.
3) fill of the difference of the solution after fine straining, in aseptic cillin bottle, is partly jumped a queue, and is placed in freeze drying equipment, carries out lyophilization by freeze-drying curve.
The plug of cillin bottle adopts the sterilizing-drying that the pure steam Fo of pulse vacuum value is 10, and plug outlet is carried out under 100 grades of laminar flow hood; Cillin bottle clean after through 350 ℃ of tunnel ovens, sterilizing in 5 minutes, depyrogenation; Plug oscillator uses water for injection to rinse before production, and 220 ℃, within 2 hours, dry heat sterilization is used, and under fill aseptic hundred grades of 100 grades of laminar flow hood under aseptic ten thousand grades of backgrounds, carries out.
Freeze-drying curve:
Solution to be frozen after fine straining is placed in freeze-drier, and device temperature is down to-45 ℃, and then constant temperature 1 hour is controlled vacuum-5Pa in freeze-drier; Extremely-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-38 ℃ of homoiothermics, constant temperature 2 hours, extremely-35 ℃ of homoiothermics, constant temperature 3 hours ,-28 ℃, constant temperature 4 hours;-25 ℃, constant temperature 4 hours;-20 ℃, constant temperature 4 hours;-15 ℃, constant temperature 4 hours;-10 ℃, constant temperature 3 hours;-5 ℃, constant temperature 1 hour; 0 ℃, constant temperature 0.5 hour; 30 ℃, constant temperature 0.5 hour.In the time that solution products temperature is raised to 45 ℃, reduce the flaggy temperature to 40 ℃ of equipment, constant temperature 4 hours.
Starting automatic tamponade system is that 2-3Pa condition presses down after bottle stopper in vacuum, and regulating butterfly valve is normal pressure, takes out cillin bottle from freeze drying box, rolls aluminium lid, to obtain final product.
Embodiment 1 technique is total to such an extent that four batches of products are tested.
Embodiment 2
Aseptic controlling technique is with embodiment 1.
1) according to every sodium nitroprusside 50g, add to the mass volume ratio of 1000mL with water for injection, accurate weighing sodium nitroprusside, being dissolved in water for injection is 30% concentrated solution, adds 0.1wt% active carbon, stirs 20min, kieselguhr coarse filtration takes off charcoal;
2) mend and inject water to 980mL, detect pH value, completion amount water for injection.Again through 0.22 μ m microporous filter membrane fine straining.After fine straining, sample detection level, PH, bacterial endotoxin.
3) fill of the difference of the solution after fine straining, in aseptic cillin bottle, is partly jumped a queue, and is placed in freeze drying equipment, carries out lyophilization by freeze-drying curve:
Solution to be frozen after fine straining is placed in freeze-drier, and device temperature is down to-45 ℃, and then constant temperature 1 hour is controlled vacuum-5Pa in freeze-drier; Extremely-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-38 ℃ of homoiothermics, constant temperature 2 hours, extremely-32 ℃ of homoiothermics, constant temperature 3.5 hours ,-25 ℃, constant temperature 4 hours;-20 ℃, constant temperature 4 hours;-17 ℃, constant temperature 4 hours;-15 ℃, constant temperature 4 hours;-10 ℃, constant temperature 3 hours;-5 ℃, constant temperature 1 hour; 5 ℃, constant temperature 0.5 hour; 20 ℃, constant temperature 0.5 hour.In the time that solution products temperature is raised to 45 ℃, reduce the flaggy temperature to 40 ℃ of equipment, constant temperature 4 hours.
Embodiment 2 techniques are total to such an extent that four batches of products are tested.
Comparative example 1
Aseptic controlling technique is with embodiment 1.
1) according to every sodium nitroprusside 50g, add to the mass volume ratio of 1000mL with water for injection, accurate weighing sodium nitroprusside, being dissolved in water for injection is 30% concentrated solution, adds 0.1wt% active carbon, stirs 20min, kieselguhr coarse filtration takes off charcoal;
2) mend and inject water to 980mL, detect pH value, completion amount water for injection.Again through 0.22 μ m microporous filter membrane fine straining.After fine straining, sample detection level, PH, bacterial endotoxin.
3) fill of the difference of the solution after fine straining, in aseptic cillin bottle, is partly jumped a queue, and is placed in freeze drying equipment, carries out lyophilization by freeze-drying curve:
Solution temperature to be frozen after fine straining is down to-40 ± 2 ℃, is then incubated 2.0 hours; Heating rate is 0.2 ℃/min left and right, the shelf of equipment is warming up to-15 ℃, constant temperature 6 hours; Be warming up to-5 ℃, constant temperature 2 hours; Heating rate is 0.3 ℃/min, is warming up to 5 ℃, constant temperature 2 hours; After being warming up to 40 ℃, be incubated 4h.Whole process 24 hours.
Be under 2-3Pa condition, to compress cillin bottle bottle stopper in vacuum.
Comparative example 1 technique is total to such an extent that four batches of products are tested.
Comparative example 2
According to every sodium nitroprusside 50g, mannitol 10g, add to the mass volume ratio of 1000mL with water for injection, accurately take sodium nitroprusside and mannitol, add in the about 800ml of water for injection, constantly stir and make its dissolving, benefit injects water to 1000ml, measure medicinal liquid pH, within the scope of 1mol/L NaOH adjusting pH5.5-6.5, add 0.05% needle-use activated carbon 0.5g, stir and standing 20min, then through 0.8 μ m microporous filter membrane fine straining.After fine straining, sample detection level, PH, bacterial endotoxin.
Solution after fine straining respectively fill, in aseptic cillin bottle, is partly jumped a queue, and is placed in freeze drying equipment, carries out lyophilization by following freeze-drying curve:
Solution to be frozen after fine straining is placed in freeze-drier, and device temperature is down to-45 ℃, and then constant temperature 1 hour is controlled vacuum-5Pa in freeze-drier; Extremely-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-38 ℃ of homoiothermics, constant temperature 2 hours, extremely-32 ℃ of homoiothermics, constant temperature 3.5 hours ,-25 ℃, constant temperature 4 hours;-20 ℃, constant temperature 4 hours;-17 ℃, constant temperature 4 hours;-15 ℃, constant temperature 4 hours;-10 ℃, constant temperature 3 hours;-5 ℃, constant temperature 1 hour; 5 ℃, constant temperature 0.5 hour; 20 ℃, constant temperature 0.5 hour.In the time that solution products temperature is raised to 45 ℃, reduce the flaggy temperature to 40 ℃ of equipment, constant temperature 4 hours.
Experimental example 1 conventional physico-chemical properties detects
According to " Chinese Pharmacopoeia " version in 2000 two " nipride ampoules " (P838), utilize ascorbic acid to react aobvious blue with sodium nitroprusside and sodium hydroxide, product is checked.Through the inspection to embodiment 1, embodiment 2, each four batch samples of comparative example, result is all positive reaction.Meet the regulation of " Chinese Pharmacopoeia " version in 2000 two " nipride ampoules ".
Regulation according to " Chinese Pharmacopoeia " version in 2000 two " nipride ampoules ": sample thief, add water and make the solution containing 10mg sodium nitroprusside in every 1ml, spectrophotography (two appendix IV A of Chinese Pharmacopoeia version in 2000) is measured, and embodiment 1, embodiment 2, each four batch samples of comparative example 1,2 have absorption maximum at the wavelength place of 394nm
Assay:
Potentiometric titration (two appendix VII A of Chinese Pharmacopoeia version in 2000), take the saturated calomel electrode with potassium nitrate salt bridge as reference electrode, silver electrode is indicating electrode, with silver nitrate titration liquid (0.1mol/L) titration.Every 1ml silver nitrate titration liquid (0.1mol/L) is equivalent to the Na of 14.90mg
2fe (CN)
5nO2H
2o.Four batches of " nipride ampoule " samples of three experimental examples are measured to (constant-current titration figure is shown in accompanying drawing), and result is as table 1.
Table 1: assay result
| Embodiment 1 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Content (%) | 104.44 | 104.71 | 105.94 | 104.51 |
| Embodiment 2 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Content (%) | 103.47 | 102.55 | 103.20 | 104.31 |
| Comparative example 1 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Content (%) | 99.44 | 103.36 | 105.91 | 101.31 |
| Comparative example 2 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Content (%) | 103.66 | 103.25 | 105.90 | 101.39 |
Outward appearance and other conventional sense the results are shown in Table 2.
Table 2 conventional physico-chemical properties testing result
Loss on drying: sample thief, be dried to constant weight at 120 ℃, less loss weight must not be crossed 12.6% (two appendix VIII L of Chinese Pharmacopoeia version in 2000).Through each four batch samples of embodiment 1, embodiment 2 are checked, result all meets pharmacopeia regulation (in table 3).Product physicochemical property after comparative example 1 lyophilizing is poor; Comparative example 2 products adopt and the same freeze-drying curve of embodiment 2, are added with mannitol, and the conventional physico-chemical properties of product is obviously difference not, and example 2 continues to investigate by experiment.
Table 3: Weight loss on drying detection
| Embodiment 1 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Less loss weight (%) | 6.39 | 6.05 | 6.45 | 6.65 |
| Embodiment 2 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Less loss weight (%) | 6.05 | 6.45 | 6.61 | 6.39 |
| Comparative example 1 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Less loss weight (%) | 6.80 | 7.45 | 6.73 | 7.39 |
| Comparative example 2 | The 1st batch | The 2nd batch | The 3rd batch | The 4th batch |
| Less loss weight (%) | 6.80 | 6.75 | 6.73 | 6.10 |
Experimental example 2: study on the stability
Investigation project comprises: 1. appearance luster, 2. pH value, 3. clarity, 4. cyanide, the 5. iron cyanide, 6. ferrocyanide, 7. loss on drying, 8. content.
A. exposure experiments to light: get the 1st batch sample of embodiment 1, the 1st batch sample of comparative example 2, putting illumination is the light cupboard internal radiation of 4500 ± 500lx, respectively at the 5th, 10 days sampling, by stability high spot reviews item detect, and with 0 day comparison, the results are shown in Table 4.
Table 4: strong illumination test (4500lx ± 500lx illumination)
Result of the test: this product was placed after 10 days under strong illumination condition, and its content declines to some extent.Show that this product has certain sensitivity to light, in the time of storage and use, answer lucifuge.Comparative example 2 products are added with mannitol, but do not affect for the performance under product illumination condition.After two duplicate samples illumination, outward appearance is still pink crystallization.
B. hot test: get the 1st batch sample of embodiment 1, lucifuge is positioned in temperature 60 C thermostatic drying chamber, respectively at the 5th, 10 days sampling, by stability high spot reviews item detect, and with 0 day comparison, the results are shown in Table 5.
Table 5: hot test (60 ℃)
Result of the test: this product is placed 10 days under 60 ℃ of conditions of high temperature, the content of surveying and 0 day relatively, difference is less, shows that sample is more stable to high temperature.Comparative example 2 samples are poor to high-temperature stability.It is still pink crystallization that two duplicate samples are placed rear outward appearance.
C. high wet test
The 1st batch sample of getting embodiment 1, comparative example 2 is placed under 25 ℃, relative humidity 90% scholar's 5% condition and investigates 10 days, respectively at sampling in the 5th, 10 days, detect by stability high spot reviews item, and with comparison in 0 day, the results are shown in Table 6.
Table 6: high humidity result of the test
Accelerated test and long term test: investigate according to " Chinese Pharmacopoeia " 2000 two appendix XIX C of version " medicine stability test guideline ".
Three batch samples (commercially available back, the i.e. additional small paper box of sample) after embodiment 1, under the condition of 40 ℃ ± 2 ℃ of temperature, RH75% ± 5%, are placed in to electrothermostat and place 6 months.In the time of the 1st, 2,3 and 6 the end of month, sampling detects respectively.Investigation the results are shown in Table 7.
Table 7: accelerated test (40 ℃ ± 2 ℃, RH75% ± 5%)
Accelerated test result: three batch samples (commercially available back) are placed after 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, RH75% ± 5%, every investigation indexs such as its appearance luster, pH value, clarity, cyanide, the iron cyanide, ferrocyanide, loss on drying and content have no significant change, and show that this product is stable to high temperature.
Long term test:
Embodiment 1 three batch samples, comparative example 2 one batch samples (commercially available back) are placed in to electrothermostat and place 12 months under the condition of 25 ℃ ± 2 ℃ of temperature, RH60% ± 10%.Sampling in every 3 months once, respectively at 3 months, 6 months, 9 months and sampling in 12 months, detects by this product investigation project.After 12 months, continued to investigate respectively at 18 months, 24 months, 36 months, sampling detects.To investigate result and data comparison (in table 8) in 0 month.
Table 8: long term test (25 ℃ ± 2 ℃, RH60% ± 10%)
Long-term experiment result shows: the product that preparation method of the present invention obtains has excellent long-time stability.After the product placement that comparative example 2 obtains exceedes 12 months, quality obviously declines.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, do not departing under the prerequisite of the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a preparation method for Nitropress, is characterized in that, comprises step:
1) according to every sodium nitroprusside 50g, add to the mass volume ratio of 1000mL with water for injection, accurate weighing sodium nitroprusside, being dissolved in water for injection is 20%～30% concentrated solution, adds 0.1～0.2% quality of activated carbon volume ratio, after stirring, leave standstill 15～25min, coarse filtration takes off charcoal;
2) mend and inject water to 950～980mL, detect pH value to 5.0～7.0, completion amount water for injection, then pass through filter membrane fine straining;
3) fill of the difference of the solution after fine straining, in aseptic cillin bottle, is partly jumped a queue, and is placed in freeze drying equipment, carries out lyophilization by following freeze-drying curve:
Freeze drying equipment temperature is down to-45～-40 ℃, and then constant temperature 1～2 hour is controlled vacuum-20～-5Pa in freeze drying equipment; Extremely-45 ℃～-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-40～-35 ℃ of homoiothermics, constant temperature 2-3 hour, extremely-35～-30 ℃ of homoiothermics, constant temperature 3～4 hours ,-30 ℃～-25 ℃, constant temperature 4～5 hours;-25 ℃～-20 ℃, constant temperature 4～5 hours;-20 ℃～-15 ℃, constant temperature 4～5 hours;-15 ℃～-10 ℃, constant temperature 4～5 hours;-10 ℃～-5 ℃, constant temperature 3～4 hours;-5 ℃～0 ℃, constant temperature 1～2 hour; 0 ℃～10 ℃, constant temperature 0.5～1 hour; 10 ℃～40 ℃, constant temperature 0.5～1 hour; In the time that products temperature is raised to 40 ℃～45 ℃, reduce flaggy temperature to 38～40 ℃ of freeze drying equipment, constant temperature 4～5 o'clock.
2. preparation method as claimed in claim 1, is characterized in that, described step 2) in, the filter membrane of fine straining is selected from 0.15～0.22 microporous filter membrane.
3. preparation method as claimed in claim 1, is characterized in that, described step 2) in, detecting pH value is 5.0～7.0 to be qualified pH value.
4. preparation method as claimed in claim 1, is characterized in that, in described step 3), adopts following freeze-drying curve:
Solution to be frozen after fine straining is placed in freeze-drier, and device temperature is down to-45, and then constant temperature 1 hour is controlled vacuum-20～-5Pa in freeze-drier; Extremely-45 ℃～-40 ℃ of homoiothermics, constant temperature 1 hour, extremely-40～-35 ℃ of homoiothermics, constant temperature 2 hours, extremely-35～-30 ℃ of homoiothermics, constant temperature 3 hours ,-30 ℃～-25 ℃, constant temperature 4 hours;-25 ℃～-20 ℃, constant temperature 4 hours;-20 ℃～-15 ℃, constant temperature 4 hours;-15 ℃～-10 ℃, constant temperature 4 hours;-10 ℃～-5 ℃, constant temperature 3 hours;-5 ℃～0 ℃, constant temperature 1 hour; 0 ℃～10 ℃, constant temperature 0.5 hour; 10 ℃～40 ℃, constant temperature 0.5 hour.In the time that solution products temperature is raised to 40 ℃～45 ℃, reduce the flaggy temperature to 40 ℃ of equipment, constant temperature 4 hours.
5. preparation method as claimed in claim 1, is characterized in that, after described step 3), being also included in vacuum is the step that compresses described cillin bottle bottle stopper under 2～3Pa condition.
6. the Nitropress that the arbitrary described preparation method of claim 1～5 prepares.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107412259A (en) * | 2017-08-08 | 2017-12-01 | 湖南科伦制药有限公司 | A kind of preparation method of sodium nitroprussiate freeze drying powder injection |
| CN110615448A (en) * | 2018-06-20 | 2019-12-27 | 四川科瑞德凯华制药有限公司 | Method for preparing sodium nitroprusside |
| CN115350140A (en) * | 2022-09-06 | 2022-11-18 | 广东宏远集团药业有限公司 | Sodium nitroprusside composition for injection and preparation method thereof |
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| Title |
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| 徐芳辉等: "注射用硝普钠的研制", 《中国医药导报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107412259A (en) * | 2017-08-08 | 2017-12-01 | 湖南科伦制药有限公司 | A kind of preparation method of sodium nitroprussiate freeze drying powder injection |
| CN107412259B (en) * | 2017-08-08 | 2020-08-11 | 湖南科伦制药有限公司 | Preparation method of sodium nitroprusside freeze-dried powder injection |
| CN110615448A (en) * | 2018-06-20 | 2019-12-27 | 四川科瑞德凯华制药有限公司 | Method for preparing sodium nitroprusside |
| CN115350140A (en) * | 2022-09-06 | 2022-11-18 | 广东宏远集团药业有限公司 | Sodium nitroprusside composition for injection and preparation method thereof |
| CN115350140B (en) * | 2022-09-06 | 2024-09-06 | 广东宏远集团药业有限公司 | Sodium nitroprusside composition for injection and preparation method thereof |
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