CN100563664C - A kind of liquid preparation and its production and use - Google Patents
A kind of liquid preparation and its production and use Download PDFInfo
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- CN100563664C CN100563664C CNB2006100657682A CN200610065768A CN100563664C CN 100563664 C CN100563664 C CN 100563664C CN B2006100657682 A CNB2006100657682 A CN B2006100657682A CN 200610065768 A CN200610065768 A CN 200610065768A CN 100563664 C CN100563664 C CN 100563664C
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Abstract
The invention belongs to medical technical field, the liquid preparation that relates to a kind of injection, particularly relate to a kind of liquid preparation that contains the injection of nitrous sodium ferricyanide, and the preparation method of this liquid preparation and the application of this liquid preparation in the preparation intravenous drug.Compared with prior art, liquid preparation of the present invention has stable, effective, safe characteristics.
Description
[technical field]
The invention belongs to medical technical field, the liquid preparation that relates to a kind of injection, particularly relate to a kind of liquid preparation that contains the injection of nitrous sodium ferricyanide, and the preparation method of this liquid preparation and the application of this liquid preparation in the preparation intravenous drug.
[background technology]
Nitrous sodium ferricyanide (sodium nitroprusside, sodium nitroprusside, sodium nitroprusside two hydrates, Sodium Nitroprusside, Na
2[Fe (CN)
5NO] 2H
20) is a kind of vasodilator of quick-acting and part-time application.Tremulous pulse and vein smooth muscle all there are direct dilating effect, but do not influence the contraction of uterus, duodenum or cardiac muscle.Vasodilation is lowered peripheral vascular resistance, thereby hypotensive effect is arranged.Vasodilation is all lowered the forward and backward load of heart, and cardiac output improves, so useful to heart failure.Afterload lowers the impedance of aorta and left ventricle when can reduce valvular insufficiency and alleviates and backflow.Clinical hypertensive emergency and the acute heart failure etc. of being widely used in.The crude drug of sodium nitroprusside and injectable powder record version in 2005 " in the Chinese pharmacopoeia.
Because the stability of nitrous sodium ferricyanide existing problems itself, therefore the dosage form of using clinically is more limited, has only lyophilized injectable powder.When the nitrous sodium ferricyanide was made the injection of solution-type, stability problem mainly showed precipitation, decomposes, sees three aspects of phototropic.In clinical practice, injectable powder carries out intravenous drip after diluting as 5% glucose injection with venous transfusion, in the process that instils, often need carry out lucifuge to equipment such as infusion bottle, transfusion catheters and handle.In Japan Patent JP 57146714, disclose a kind of by adding the light inlet attenuator, photolytic method when preventing intravenous drip.In fact, as long as adopt brown ampoule bottle packing, the injection of low capacity is easy to overcome the photodissociation problem, adopts suitable lucifuge method also can easily address this problem when patient's intravenous drip.
People's expectation is changed system into injection with injectable powder, compares with injectable powder, and the advantage of injection mainly contains: (1) uses more convenient: medicinal liquid is extracted directly dilution of back out, needn't dissolve earlier, redilution has alleviated the operation of medical workers burden, has also reduced the probability of microbiological contamination in the dosing process.(2) production cost is lower: lyophilized injectable powder criticizes that the production cycle is long, and energy resource consumption is big, and workshop condition requires high, the packing cost height, and can reduce production costs greatly after making aqueous injection.
The nitrous sodium ferricyanide is made spissated intravenous drip liquid, i.e. injection with small volume, before use, with venous transfusion as the dilution of 5% glucose injection after, carry out infusion to the patient again.But the injection with small volume of nitrous sodium ferricyanide is in the preservation process, and two distinct issues are to produce precipitation, medicine decomposition.For this reason, disclose a kind of avoid muddy and sedimentary method among the Japan Patent JP 7126017, promptly in solution, added organic acid or its sodium salt, sorbitol etc. such as citric acid.The result of this patent disclosure shows, the nitrous sodium ferricyanide solution of making pair is compared with matched group, can not produce muddiness and precipitation under identical experimental condition, and matched group obviously produces precipitation.
But in the problem that solves solution precipitation and decomposition, but be very difficult.Because the inventor finds, the nitrous sodium ferricyanide is made solution, even make solution, under violent hot conditions of short time,, and be not easy to occur precipitation as 100 ℃ of heating 2 hours by the method for JP 7126017; But regrettably, the nitrous sodium ferricyanide solution of making is in room temperature or long storage time under the high-temperature slightly, placed 2 months as 25 ℃, or 40 ℃ placed after 1 month, and solution can produce tangible precipitation.As pharmaceutical preparation, the medicament of injection particularly, this is infeasible.
The inventor is through great deal of experimental, discovery is made the injection that spissated intravenous drip is used with the nitrous sodium ferricyanide, it is injection with small volume, preparation technology does not have special requirement, the preparation of making not only meets the requirement of clinical application, and have at room temperature (25 ℃) or high temperature (40 ℃) but long preservation and do not produce sedimentary characteristics down, thereby finished the present invention.
[summary of the invention]
Liquid preparation of the present invention is a kind of liquid preparation that wherein contains pharmacological component nitrous sodium ferricyanide.
Pharmacological component in the liquid preparation of the present invention " nitrous sodium ferricyanide " is defined as follows:
" the nitrous sodium ferricyanide " of indication of the present invention, general medicine name is sodium nitroprusside, sodium nitroprusside, sodium nitroprusside dihydrate etc., its English is Sodium Nitroprusside." the nitrous sodium ferricyanide " of indication of the present invention both can be the anhydride of sodium nitroprusside, also can be the dihydrate of the hydrate of sodium nitroprusside, particularly sodium nitroprusside, and the molecular formula of dihydrate is Na
2[Fe (CN)
5NO] 2H
2O.
The invention provides a kind of liquid preparation that contains the injection of nitrous sodium ferricyanide.This liquid preparation is realized by following technical scheme.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention, wherein contain:
(a) in the treatment nitrous sodium ferricyanide of effective dose and
(b) by one or more the medicinal solvent of alcohol of alcohol solvent composition.
Above-mentioned " the medicinal solvent of alcohol " is the main adjuvant as liquid preparation of the present invention, exists as the underlying carrier of preparation, and this is well known in the art.But clearly, liquid preparation of the present invention is not got rid of and can also be contained other situation as the adjuvant of solvent.
Above-mentioned " the medicinal solvent of alcohol " is the pharmaceutically acceptable alcohol solvent composition by one or more.When by more than one alcohol solvent composition " the medicinal solvent of alcohol ", the ratio between these several alcohol solvents is can be arbitrarily.
Forming the alcohol solvent of above-mentioned " the medicinal solvent of alcohol ", is pharmaceutically acceptable pharmaceutic adjuvant with solvent effect, and they are selected from ethanol, 1,2-propylene glycol (so-called propylene glycol), glycerol, polyethylene glycols, isopropyl alcohol etc.
Above-mentioned ethanol is dehydrated alcohol preferably.
Above-mentioned polyethylene glycols preferably molecular weight is 200～600 Polyethylene Glycol.
Further, preferably Polyethylene Glycol-200, Polyethylene Glycol-300, Polyethylene Glycol-400 of above-mentioned Polyethylene Glycol.
The liquid preparation that contains the nitrous sodium ferricyanide of the present invention, the medicinal solvent of alcohol of wherein used alcohol solvent composition by one or more, can adopt single a kind of composition, as independent use ethanol, 1,2-propylene glycol, glycerol, Polyethylene Glycol-200, Polyethylene Glycol-300, Polyethylene Glycol-400.Also can use two or more composition, as the combination of ethanol/propylene glycol, ethanol/glycerol, ethanol/Polyethylene Glycol-200, ethanol/propylene glycol/Polyethylene Glycol-300, Polyethylene Glycol-200/ Polyethylene Glycol-300 etc., the ratio of these combinations is can be arbitrarily.
The present invention it should be explicitly made clear at this point from definition, and above-mentioned " the medicinal solvent of alcohol " when only using single a kind of composition, is consistent with the notion of " alcohol solvent "; When using multiple composition, as using the mixture of ethanol and propylene glycol, this moment " alcohol solvent " refers to ethanol and two kinds of compositions of propylene glycol, and " the medicinal solvent of alcohol " refers to the mixture of two kinds of compositions with arbitrary proportion.To the understanding of " the medicinal solvent of alcohol " and " alcohol solvent " by that analogy.
The liquid preparation that contains the nitrous sodium ferricyanide of the present invention wherein also contains acceptable accessories, is selected from water for injection, acid-base modifier, light stabilizer, metal chelating agent etc.
Above-mentioned acid-base modifier can be selected from one or more the combination in tartaric acid, citric acid, maleic acid, succinic acid, hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, acetic acid, boric acid, lactic acid, Aspartic Acid, lactobionic acid, gluconic acid, citric acid, maleic acid, succinic acid, tartaric acid, methanesulfonic acid or their salt etc.The preferably combination of one or more in tartaric acid, citric acid, maleic acid or their salt.
Above-mentioned acid-base modifier as the pH value of regulator solution, makes pH value be controlled at 1.0～7.0 scope.
Better, above-mentioned acid-base modifier as the pH value of regulator solution, makes pH value be controlled at 2.0～6.0 scope.
Above-mentioned light stabilizer has and prevents that principal agent nitrous sodium ferricyanide from seeing the effect of phototropic, is selected from one or more the combination in carbazochrome sodium sulfonate (carbazochrome sodium sulfonate), the xanthine dinucleotide disodium salt (flavinadenine dinucleotide disodium) etc.
Above-mentioned metal chelating agent can be selected from one or more the combination among EDTA-2Na, the EDTA-Ca2Na etc.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention wherein can also contain the water for injection that meets the preparation requirement on a small quantity.The consumption of described water for injection is preferably below 40% (v/v) of the cumulative volume of injection liquid medicament of the present invention.
Above-mentioned pharmaceutic adjuvant, the complementary composition as preparation has multiple effect sometimes concurrently, has complexing concurrently as citric acid.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention, by every 1000ml, wherein contain:
(a) nitrous sodium ferricyanide 0.5g～150g
(b) water for injection 0ml～400ml
(c) acid-base modifier 0g～10g
(d) light stabilizer 0g～10g
(d) metal chelating agent 0g～2g
(e) the medicinal solvent of alcohol adds to 1000ml
Preferably, the liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention, by every 1000ml, wherein contain:
(a) nitrous sodium ferricyanide 1g～100g
(b) water for injection 0ml～250ml
(c) acid-base modifier 0g～5g
(d) light stabilizer 0g～5g
(d) metal chelating agent 0g～1g
(e) the medicinal solvent of alcohol adds to 1000ml
Those skilled in the art will readily understand, the medicinal solvent of alcohol of the present invention, finger is except that the principal agent composition, be to exist as the underlying carrier composition of liquid preparation, therefore, the usage ratio of this underlying carrier composition in whole medicament, reasonable definite method is to determine according to the final volume of preparation during preparation.This is the general knowledge of preparation industrial circle.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention, is preferably through dilution and then uses in the mode of intravenous drip during for clinical use in the mode of injection.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention is made the form hyoscine of the injection of solution-type, compares with the injectable powder that uses clinically at present, has remarkable advantages.Its reason is, as long as solution-type injection of the present invention is with after the syringe extraction, can be directly used in drug administration by injection, promptly inject high capacity etc. and ooze solvent for injection (as 0.9% sodium chloride injection 500ml, 5% glucose injection 500ml), the dilution posterior vein instils.But, for injectable powder, it at first needs to dissolve with a spot of solvent for injection (as 5ml water for injection), and then inject high capacity etc. and ooze solvent for injection (as 0.9% sodium chloride injection 500ml, 5% glucose injection 500ml), the dilution posterior vein instils, this intermediary course of dissolution can increase the chance of medicine microbiological contamination, has also increased the operation sequence of clinical practice.
Although the employing the solution of the present invention, the nitrous sodium ferricyanide made injectable liquid preparation after, can obtain above-mentioned clear superiority with respect to injectable powder.Yet JP7126017 is described as patent, and the nitrous sodium ferricyanide is when making solution, and in some cases, after short time placement, solution can produce precipitation, and the inventor also pays close attention to this problem.But unexpected the discovery is, as the result of the test of describing in the embodiment of the invention part, the nitrous sodium ferricyanide that contains of the present invention, its solvent mainly is the medicinal solvent of (or major part is) alcohol, when particularly the amount of water for injection is no more than 40% (v/v), precipitation appears after room temperature (as 25 ℃) or higher temperature (as 40 ℃) following long period (as 6 months) placement, and the solution of making by the method for patent JP7126017 under the same conditions has tangible precipitation to produce, this point but is infusive, because the result shows, adopt the solution of the present invention, can make medicine keep enough stablizing in the long time, thereby the prescription that meets general pharmacy quality requirement, particularly injection.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention, its preparation method is simple, adopts the production technology of conventional solution type injection agent can finish production.
The liquid preparation that contains the nitrous sodium ferricyanide of the present invention can described according to the following steps method be prepared:
(1) get the nitrous sodium ferricyanide, add an amount of (preferred, when accounting for half amount of dosing volume, be relatively more suitable amount; When using the medicinal solvent of alcohol of mixed type, can use the medicinal solvent of alcohol of mix homogeneously, also can use the medicinal solvent of wherein a kind of preferably alcohol of main pharmacological component dissolubility) the medicinal solvent of alcohol, stirring and dissolving,
(2) in case of necessity, add other necessary pharmaceutic adjuvant, stirring and dissolving,
(3) add the full dose of the medicinal solvent of alcohol, stir to the dosing volume,
(4) solution is filtered to clarification, is divided in the medicinal glass bottle again, seal, and sterilization, promptly.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention can be adorned 0.5ml, 1ml, 2ml, 5ml, 10ml, 20ml etc. for every bottle; The amount that contains main constituent nitrous sodium ferricyanide in every bottle can be different specifications such as 0.25mg～3000mg, can be the packing of multiple dose, also can be the packing of single dose, and as the medicament of injection, unit dose package is more suitably.Core of the present invention is to contain the solution of medicine, and is unimportant for the difference on the bale capacity (and/or dosage), because for making injection, single dose is more suitably.
Above-mentioned preparation process should be carried out under the working condition of being correlated with that meets medicine management department regulation, as carrying out under the usually said GMP condition.
Above-mentioned filtering filter, what can list has microporous filter membrane, sintered glass filter, a sand filter etc., but is not limited to that these are several.
For the ease of filtering, in filter process, can adopt positive press filtration, medicinal liquid suitably can also be heated when being heated to 60 ℃ ± 5 ℃ (as), filter again.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention is a sterilization preparation, can adopt sterilizing methods that filtration sterilization method, flowing steam sterilization method, autoclaving etc. are arranged.
The liquid preparation that contains the nitrous sodium ferricyanide of the present invention is to supply clinical practice in the mode of injecting, wherein used crude drug and adjuvant, the related request that should meet injecting drug use, when feeding intake with nitrous sodium ferricyanide dihydrate, should meet the every regulation in 2005 version " Pharmacopoeia of People's Republic of China (two ones) " " sodium nitroprusside " as main composition; The medicinal solvent of various alcohol also should meet the medicinal standard regulation of relevant kind.
The medicinal solvent of various alcohol that the present invention is used all has strict medicinal safety, can be through injecting drug use.The liquid preparation of the injection of making thus that contains the nitrous sodium ferricyanide has the safety of good clinical use.
The liquid preparation that contains the nitrous sodium ferricyanide of the present invention is the sterilization injection, and the mode that can adopt injection is for clinical application.
The liquid preparation that contains the nitrous sodium ferricyanide of the present invention, after room temperature (24 ℃) is placed 24 months down, compare with 0 month goods, the content of main pharmacological component nitrous sodium ferricyanide wherein remains on more than 94.0%, clarity also meets the requirement of injecting drug use, meets the conventional stability requirement of pharmaceutical preparation.The liquid preparation that contains the nitrous sodium ferricyanide of the present invention, after high temperature (40 ℃) is placed 6 months, compare with 0 month goods, the content of main pharmacological component nitrous sodium ferricyanide wherein remains on more than 96.0%, clarity also meets the requirement of injecting drug use, shows that medicine has good stable.On year-on-year basis, the liquid preparation of making by prior art that contains the nitrous sodium ferricyanide is compared with 0 month result after room temperature (24 ℃) is placed 6 months, and remaining rate drops to below 85%; After high temperature (40 ℃) was placed 6 months, to compare with 0 month result, remaining rate drops to below 85%; Each sample precipitation all occurs after 24 ℃ and 40 ℃ are placed 3 months down simultaneously.The product that the liquid preparation that contains the nitrous sodium ferricyanide that explanation prepares by technical scheme of the present invention has than prior art for preparing has better stability.
The present invention provides the application of liquid preparation in the preparation intravenous injection medicine of this injection further.
Particularly, the liquid preparation of injection of the present invention is in the application of preparation in the injectable drug, describedly is applied as the intravenous injection medication.
Further, the application of liquid preparation in the preparation injectable drug that contains the injection of nitrous sodium ferricyanide of the present invention, the liquid preparation of described injection, wherein contain:
(a) in the treatment nitrous sodium ferricyanide of effective dose and
(b) by one or more the medicinal solvent of alcohol of alcohol solvent composition.
Described " the medicinal solvent of alcohol " is pharmaceutically acceptable pharmaceutic adjuvant with solvent effect, and they are selected from ethanol, 1,2-propylene glycol (so-called propylene glycol), glycerol, polyethylene glycols, isopropyl alcohol etc.
The liquid preparation that contains the injection of nitrous sodium ferricyanide of the present invention meets the requirement of injecting drug use, after the intravenous drip liquid dilution that available grade is oozed or height oozes, but makes the medicine of intravenous drip, carries out dropleting medicine-feeding.
Invivo oxyger-supply solution for injection of the present invention can adopt the mode medication of intravenous drip.
For example, before the clinical use liquid preparation of the present invention (containing principal agent 50mg) is taken out, redilution takes suitable lucifuge mode to carry out intravenous drip in 5% glucose injection 250ml～1000ml.When being grown up the time spent, intravenous drip begins per minute by body weight 0.5 μ g/Kg.Increase progressively with per minute 0.5 μ g/Kg according to therapeutic response, adjust dosage gradually, common dose be per minute by body weight 3 μ g/Kg, maximum dose is that per minute is by body weight 10 μ g/Kg.Total amount is for pressing body weight 3.5mg/Kg.When pediatric pharmaceuticals, intravenous drip, per minute is adjusted consumption by body weight 1.4 μ g/Kg gradually by effect.
Like this, the invention provides a kind of stablely, effective, safe, is the liquid preparation of the injection of pharmaceutically-active ingredients with the nitrous sodium ferricyanide.The present invention also provides the preparation method of this liquid preparation simultaneously, and the application of this liquid preparation in the preparation injectable drug.
[specific embodiment]
Illustrate in greater detail the present invention by the following examples, but the present invention is not subjected to the restriction of these embodiment.The nitrous sodium ferricyanide that each following embodiment and reference examples are used is dihydrate, but the present invention is not limited in dihydrate.
Embodiment 1: the liquid preparation that contains the injection of nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 25g
1,2-propylene glycol 400ml
Dehydrated alcohol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, the nitrous sodium ferricyanide of getting recipe quantity adds 400ml propylene glycol and 200ml dehydrated alcohol, and stirring and dissolving adds ethanol again to 1000ml, stirs.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 2ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 100 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 2: the liquid preparation that contains the injection of nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 25g
Dehydrated alcohol 300ml
Polyethylene Glycol-300 adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, aseptic, the pyrogen-free nitrous sodium ferricyanide of getting recipe quantity adds the 300ml dehydrated alcohol, and stirring and dissolving adds Polyethylene Glycol again to 1000ml, stirs.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 2ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 110 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 3: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 25g
Dehydrated alcohol 600ml
Glycerol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, the nitrous sodium ferricyanide of getting recipe quantity adds 600ml dehydrated alcohol and 200ml glycerol, and stirring and dissolving adds active carbon 0.4g, adds glycerol again to 1000ml, stirs.
Clarify to solution with 0.45 μ m filtering with microporous membrane, the filtrate fill is adorned 2ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 110 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 4: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 0.5g
Polyethylene Glycol-200 500ml.
Polyethylene Glycol-300 adds to 1000ml
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, the nitrous sodium ferricyanide of getting recipe quantity adds 500ml Polyethylene Glycol-200, and stirring and dissolving adds Polyethylene Glycol-300 again to 1000ml, stirs.
Be filtered to the solution clarification with G6 incipient fusion filter, the filtrate fill is adorned 0.5ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 110 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 5: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 150g
Water for injection 400ml
Citric acid monohydrate 10g
1, the 2-propylene glycol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, aseptic, the pyrogen-free nitrous sodium ferricyanide of getting recipe quantity adds citric acid and 400ml water for injection, and stirring and dissolving adds propylene glycol again to 1000ml, stirs.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 20ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 110 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 6: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 100g
Water for injection 250ml
Tartaric acid 1g
EDTA-2Na 2g
Dehydrated alcohol 200ml
1, the 2-propylene glycol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, aseptic, the pyrogen-free nitrous sodium ferricyanide of getting recipe quantity adds tartaric acid and 250ml water for injection, stirring and dissolving, add EDTA-2Na 2g and dehydrated alcohol 200ml, add propylene glycol again, stir to 1000ml.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 1ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 100 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 7: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 25g
Carbazochrome sodium sulfonate 0.2
Water for injection 50ml
Glycerol 100ml
Ethanol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, get the nitrous sodium ferricyanide and the carbazochrome sodium sulfonate of recipe quantity, add injection water and glycerol, stirring and dissolving adds ethanol again to 1000ml, stirs.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 1ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 100 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 8: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 1g
Polyethylene Glycol-200 300ml
Polyethylene Glycol-300 200ml
Dehydrated alcohol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, the nitrous sodium ferricyanide of getting recipe quantity adds Polyethylene Glycol-200 and Polyethylene Glycol-300, and stirring and dissolving adds dehydrated alcohol to 1000ml, stirs.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 20ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 100 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 9: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 10g
1, the 2-propylene glycol adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, the nitrous sodium ferricyanide of getting recipe quantity adds the 500ml propylene glycol, and stirring and dissolving adds 1 again, and the 2-propylene glycol stirs to 1000ml.
Clarify to solution with 0.22 μ m filtering with microporous membrane, the filtrate fill is adorned 10ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 110 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Embodiment 10: the liquid preparation that contains the nitrous sodium ferricyanide
Prescription (by 1000ml):
Nitrous sodium ferricyanide 25g
Glacial acetic acid 3ml
EDTA-2Na 0.2g
Polyethylene Glycol-200/ Polyethylene Glycol-300 (2: 1) adds to 1000ml.
Preparation method:
Under the condition that meets medicine manufacturing GMP requirement, get nitrous sodium ferricyanide, the EDTA-2Na of recipe quantity, the volume ratio that adds Polyethylene Glycol-200 and Polyethylene Glycol-300 is the about 500ml of mixture of 2: 1 ratio, stirring and dissolving, the volume ratio that adds Polyethylene Glycol-200 and Polyethylene Glycol-300 again is that 2: 1 the mixture of ratio is to about 950ml, ice acetic acid 3ml, the volume ratio that adds Polyethylene Glycol-200 and Polyethylene Glycol-300 be 2: 1 the mixture of ratio to 1000ml, stir.
Clarify to solution with 0.45 μ m filtering with microporous membrane, the filtrate fill is adorned 2ml for every in brown ampoule bottle, and inflated with nitrogen seals, and 110 ℃ of sterilization 15min make the injection that contains the nitrous sodium ferricyanide.
Reference examples 1: embodiment 1 preparation contains the liquid preparation of nitrous sodium ferricyanide among the referenced patent JP7126017
Prescription (by 1000ml):
Nitrous sodium ferricyanide 3g
Sodium citrate 6g
Water for injection adds to 1000ml.
Preparation method: undertaken by patented method, bottled with the brown ampoule of 2ml, and inflated with nitrogen, 110 ℃ of pressure sterilizing 10min.
Embodiment 2 preparations contain the liquid preparation of nitrous sodium ferricyanide among reference examples 2: the referenced patent JP 7126017
Prescription (by 1000ml):
Nitrous sodium ferricyanide 3g
Sorbitol 2g
Water for injection adds to 1000ml.
Preparation method: undertaken by patented method, bottled with the brown ampoule of 2ml, and inflated with nitrogen, 110 ℃ of pressure sterilizing 10min.
Reference examples 3: embodiment 3 preparations contain the liquid preparation of nitrous sodium ferricyanide among the referenced patent JP7126017
Prescription (by 1000ml):
Nitrous sodium ferricyanide 3g
Tartaric acid 0.05g
Disodium hydrogen phosphate,anhydrous 0.1g
Water for injection adds to 1000ml.
Preparation method: undertaken by patented method, bottled with the brown ampoule of 2ml, and inflated with nitrogen, 110 ℃ of pressure sterilizing 10min.
Reference examples 4: embodiment 4 preparations contain the liquid preparation of nitrous sodium ferricyanide among the referenced patent JP7126017
Prescription (by 1000ml):
Nitrous sodium ferricyanide 3g
Disodium hydrogen phosphate,anhydrous 0.1g
Citric acid 0.06g
Water for injection adds to 1000ml.
Preparation method: undertaken by patented method, bottled with the brown ampoule of 2ml, and inflated with nitrogen, 110 ℃ of pressure sterilizing 10min.
Reference examples 5: preparation contains the liquid preparation of nitrous sodium ferricyanide by the following method
Prescription (by 1000ml):
Nitrous sodium ferricyanide 3g
Water for injection adds to 1000ml.
Preparation method: the nitrous sodium ferricyanide is undertaken by the method for reference examples 4 after dissolving back and standardize solution with water for injection, and is bottled with the brown ampoule of 2ml, and inflated with nitrogen, but do not sterilize.
Investigate sample: the sample of embodiment 1～embodiment 10, the sample of reference examples 1～example 5.。
Investigate index and method: whether placed 48 hours down in room temperature (24 ℃) after (1) each sample preparation, investigating has precipitate and content (the nitrous sodium ferricyanide is in dihydrate); (2) each sample investigates after 2 hours in heating under 100 ℃ whether precipitate is arranged.
Precipitate: whether the solution in the perusal ampoule has precipitation.
Content (nitrous sodium ferricyanide): measure according to the high performance liquid chromatography under " Sodium Nitroprussidefor Injection " the kind assay item among the American Pharmacopeia USP28.The result is to contain weight (mg/ml) expression of nitrous sodium ferricyanide among the every 1ml of each sample.
Result of the test sees Table 1.
Table 1 contains the quality investigation result of the liquid preparation of nitrous sodium ferricyanide
The result shows that 10 embodiment samples of the present invention and the perusal of reference examples sample all do not have precipitation.The sample of each sample of the present invention and reference examples 1～4 does not have precipitation after heating 2 hours under 100 ℃, and the sample of reference examples 5 has very significantly precipitation.Nitrous sodium ferricyanide content (in mg/ml) and the theoretical concentration basically identical that feeds intake in the medicinal liquid.
In addition, the liquid preparation that contains the nitrous sodium ferricyanide of the present invention, wherein used various adjuvants all are the adjuvants of medicine preparation routine, can not have safety issue.Therefore the safety of liquid preparation of the present invention with good clinical drug.
(1) sample of laboratory sample: embodiment 1～10, the sample of reference examples 1～5.
(2) investigation method:
Room temperature keeps sample: get each sample, placed 24 months at lucifuge, 24 ± 2 ℃ room temperature place, respectively at 0 month, January, February, March, June, December, sampling in 18 months, 24 months, observe precipitate with reference to the method in the experimental example 1.The content of nitrous sodium ferricyanide (mg/ml) in the working sample.With 0 month result was benchmark (100%), asked the remaining rate (%) of calculating master's composition in June (percent of drug content (mg/ml) in medicinal liquid when drug content (mg/ml) was divided by 0 month in the medicinal liquid when being June, down with).
High temperature keeps sample: get each sample, placed 6 months in lucifuge, 40 ± 2 ℃ calorstat, respectively at 0 month, January, February, March, sampling in June, observe precipitate with reference to the method in the experimental example 1.The content of nitrous sodium ferricyanide (mg/ml) in the working sample.With 0 month result was benchmark (100%), asked the remaining rate (%) of calculating master's composition in June.
Result of the test sees Table 2.
Table 2 contains the investigation result that keeps sample for a long time of the liquid preparation of nitrous sodium ferricyanide
Annotate: " * " expression does not produce precipitation, and " √ " expression has precipitation to generate.
As seen the result compares with the sample of reference examples from table, and the liquid preparation that contains the nitrous sodium ferricyanide of the present invention has good stable.After placing 24 months under placement 6 months and the room temperature condition under 40 ℃ of conditions, it is stable that sample still keeps, and satisfies the basic requirement to stability of liquid preparation.
Claims (10)
1. a liquid preparation is characterized in that, wherein contains:
(a) sodium nitroprusside of effective dose in the treatment,
(b) the medicinal solvent of alcohol and
(c) water for injection of 0%～40% (v/v);
The medicinal solvent of described alcohol is by the following alcohol solvent composition of being selected from of more than one: ethanol, 1,2-propylene glycol, glycerol, polyethylene glycols, isopropyl alcohol; And described polyethylene glycols is that molecular weight is 200～600 Polyethylene Glycol.
2. liquid preparation as claimed in claim 1 is characterized in that described ethanol is dehydrated alcohol.
3. as any described liquid preparation of claim 1～2, it is characterized in that wherein also contain acceptable accessories, described adjuvant is selected from acid-base modifier, light stabilizer, metal chelating agent.
4. as any described liquid preparation of claim 1～2,, wherein contain by every 1000ml:
(a) sodium nitroprusside 0.5g～150g
(b) water for injection 0ml～250ml
(c) acid-base modifier 0g～10g
(d) light stabilizer 0g～10g
(e) metal chelating agent 0g～2g
(f) the medicinal solvent of alcohol adds to 1000ml.
5. liquid preparation as claimed in claim 4, wherein said light stabilizer are the combinations that is selected from following one or more: card network sulphur is received, the xanthine dinucleotide disodium salt.
6. as any described liquid preparation of claim 1～2,, wherein contain by every 1000ml:
(a) sodium nitroprusside 1g～100g
(b) water for injection 0ml～250ml
(c) acid-base modifier 0g～5g
(d) light stabilizer 0g～5g
(e) metal chelating agent 0g～1g
(f) the medicinal solvent of alcohol adds to 1000ml.
7. liquid preparation as claimed in claim 6, wherein said light stabilizer are the combinations that is selected from following one or more: card network sulphur is received, the xanthine dinucleotide disodium salt.
8. the preparation method of liquid preparation as claimed in claim 1, comprising following steps:
(1) get sodium nitroprusside, add an amount of medicinal solvent of alcohol, stirring and dissolving,
(2) add other pharmaceutic adjuvant, stirring and dissolving,
(3) add the full dose of the medicinal solvent of alcohol, stir to the dosing volume,
(4) solution is filtered to clarification, is divided in the medicinal glass bottle again, seal, and sterilization, promptly.
9. the purposes of liquid preparation as claimed in claim 1 in the preparation intravenous injection medicine.
10. purposes as claimed in claim 9 is characterized in that, described liquid preparation is with after the intravenous drip liquid dilution that grade is oozed or height oozes, but is used to prepare the medicine of intravenous drip.
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Non-Patent Citations (4)
| Title |
|---|
| 硝普钠水溶液稳定体系的研究. 宋保林等.徐州师范学院学报（自然科学版），第1期. 1984 |
| 硝普钠水溶液稳定体系的研究. 宋保林等.徐州师范学院学报（自然科学版），第1期. 1984 * |
| 硝普钠的应用，稳定性及其制剂. 冯仰华.医院药学杂志，第1卷第1期. 1981 |
| 硝普钠的应用，稳定性及其制剂. 冯仰华.医院药学杂志，第1卷第1期. 1981 * |
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