CN104800172A - Carbazochrome sodium sulfonate powder injection for injection and preparation method thereof - Google Patents
Carbazochrome sodium sulfonate powder injection for injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a carbazochrome sodium sulfonate powder injection for injection and a preparation method thereof. A freeze drying powder injection of carbazochrome sodium sulfonate is basically free of freeze-drying excipients, wherein the content of carbazochrome sodium sulfonate is above 90%. When injection water for the freeze-dried powder injection is dissolved in a carbazochrome sodium sulfonate 10 mg/ml concentration solution, the pH value of the solution ranges from 5.0 to 6.0. The carbazochrome sodium sulfonate powder injection for injection can be applied to bleeding of the urinary system, the upper gastrointestinal tract, the respiratory tract and obstetrical and gynecological diseases, has a remarkable curative effect on bleeding of the urinary system, can be applied to traumatic bleeding and operation bleeding, and has an excellent physicochemical property.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of haemostatic medicament, particularly relate to a kind of injection carbazochrome sodium sulfonate injectable powder pharmaceutical composition with excellent properties.The invention still further relates to the preparation method of this injection carbazochrome sodium sulfonate injectable powder.It is hemorrhage that this injection carbazochrome sodium sulfonate injectable powder can be used for urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease.Injection carbazochrome sodium sulfonate injectable powder is comparatively remarkable to urinary system bleeding, also can be used for wound and operative hemorrhage.The injection carbazochrome sodium sulfonate injectable powder that the present invention prepares has excellent physicochemical property.
Background technology
Carbazochrome sodium sulfonate, have another name called new carbazochrome salicylate, its chemical name is: 1-methyl-6-oxo-2,3,5,6-tetrahydro indole-5-semicarbazone-2-sulfonate sodium trihydrate, English Carbazochrome Sodium Sulfonate by name, molecular formula: C10H11N4O5SNa3H2O, molecular weight: 376.32, structural formula is as follows:
Carbazochrome sodium sulfonate can reduce the permeability of blood capillary, promote blood capillary fracture end retraction effect, be usually used in capillary permeability increase and produce multiple hemorrhage.
Carbazochrome sodium sulfonate can be developed by day Honda limit pharmacy strain formula the earliest, and recorded as Pharmacopeia of Japan the 12 edition (1992) by Japanese health ministry, Pharmacopeia of Japan the 16 edition also records.Carbazochrome sodium sulfonate is Vascular haemostasis medicine of new generation, is the blood vessel hardening agent that there is clinical value a kind of pole.It is the derivant of carbazochrome, and molecular machinery induces one sodium group, and the dissolubility overcoming carbazochrome is little, by the shortcoming of salicylic acid hydrotropy, thus must create obvious haemostatic effect.Carbazochrome sodium sulfonate can increase the resistance of blood capillary to damage, reduces the permeability of blood capillary, promotes the retraction of blood capillary fracture end and stops blooding.Carbazochrome sodium sulfonate can strengthen blood capillary elasticity, reduce the permeability of blood capillary, promote the retraction effect of blood capillary fracture end, stablize the acid mucopolysaccharide in blood capillary and surrounding tissue, the remarkable shortening bleeding time, promoting the activity of thrombin and the dissolving of fibronectin, and then make bleeding part form thrombosis and reach hemostasis, is effective hemorrhage of the massive hemorrhage that capillary permeability increases and the multiple hemorrhage and a variety of causes of generation causes.And carbazochrome sodium sulfonate is not containing bigcatkin willow acid groups, there is not generation " haemolysis " problem, do not affect hemopoietic function, meanwhile, nonirritant, drug safety, can life-time service, water solublity is strong, and toxicity is extremely low, do not affect blood coagulation mechanism, onset is rapid, persistent, applied widely, be a kind of Vascular haemostasis medicine of new generation, be a kind of blood vessel hardening agent having clinical value, clinical demand amount is large.
Carbazochrome sodium sulfonate is hemorrhage for urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease clinically, also can be used for wound and operative hemorrhage.The less stable of carbazochrome sodium sulfonate, is easily subject to the impact of temperature, oxygen, light, and the change of degraded or other physicochemical properties occurs, and impact uses curative effect even to increase the security risk of use.
The common formulations that carbazochrome sodium sulfonate uses clinically has the injection such as tablet and injectable powder.The injection of carbazochrome sodium sulfonate has many bibliographical informations.Such as, CN 101254174 B (200710191009.5) discloses a kind of lyophilized injectable powder of carbazochrome sodium sulfonate, it is characterized in that by adding thiourea and/or sodium formaldehyde sulphoxylate to improve the stability of carbazochrome sodium sulfonate, add the dissolubility that mannitol improves lyophilized formulations, the lyophilized injectable powder steady quality of the carbazochrome sodium sulfonate prepared.Particularly provide a kind of lyophilized injectable powder of carbazochrome sodium sulfonate, it is characterized in that containing following component and weight ratio: carbazochrome sodium sulfonate 1 part, thiourea and/or sodium formaldehyde sulphoxylate 0.001 ~ 0.05 part, 0.01 ~ 0.8 part, mannitol, excipient 0 ~ 10 part, wherein excipient is selected from one or more in oligomeric dextran, fructose, xylose, rhamnose, galactose, arabinose, glucuronic acid, glucose.
CN 102018675 B (200910212269.5) discloses a kind of carbazochrome sodium sulfonate freeze-dried powder injection agent and preparation method thereof, and this carbazochrome sodium sulfonate freeze-dried powder injection agent is made up of carbazochrome sodium sulfonate, mannitol and buffer salt, and preparing solvent is water for injection.Through lot of experiments, only add buffer salt and just solve the underproof problem of clarity in the unstable and storage process of carbazochrome sodium sulfonate freeze-dried powder injection pH value in preparation process.Formulation and technology of the present invention overcomes prior art weak point, provides that a kind of prescription is simple, quality assurance, good stability, can be applicable to clinical carbazochrome sodium sulfonate freeze-dried powder injection.Its advantage: 1. prescription is simple, and in prescription except principal agent carbazochrome sodium sulfonate, adjuvant is mannitol, buffer salt only; 2. in prescription use former, adjuvant to be pharmaceutical injection level that State Food and Drug Administration specifies, eliminate the unpredictable untoward reaction risk that non-pharmaceutic adjuvant brings; 3. good stability, transports and stores more convenient; 4. through special pearl safety testings such as anaphylaxis, hemolytic, blood vessel irritations, haemolysis and coagulation, zest, anaphylactic reaction is had no.
CN 102210656 B (201110092416.7) discloses a kind of pharmaceutical composition containing carbazochrome sodium sulfonate compound and preparation method thereof, should be made up of containing the pharmaceutical composition of carbazochrome sodium sulfonate compound carbazochrome sodium sulfonate, mannitol, dextran and sodium hydroxide.Should can overcome the problems such as existing carbazochrome sodium sulfonate injectable powder poor stability, dissolubility are low containing pharmaceutical composition of carbazochrome sodium sulfonate compound, be more suitable for Clinical practice.
CN 102525908 B (201210042805.3) relates to Carbazochrome sodium sulfonate pharmaceutical composition, is prepared from by the water for injection of the PLURONICS F87 of the lactose of the carbazochrome sodium sulfonate of 20 ~ 80 weight portions, 40 ~ 120 weight portions, 3 ~ 6 weight portions, the glutathion of 1 ~ 4 weight portion, the disodium edetate of 0.05 ~ 0.2 weight portion and 2000 weight portions.The dosage form of described Carbazochrome sodium sulfonate pharmaceutical composition is freeze-dried powder or liquid drugs injection injection.The present invention adopts lactose, PLURONICS F87, glutathion and disodium edetate as adjuvant.Wherein mannitol is as excipient, and poloxamer is as cosolvent, stabilizing agent, and glutathion and disodium edetate are as antioxidant and metal-chelator.
CN 102961330 A (201210551637.0) discloses a kind of preparing process of carbazochrome sodium sulfonate for injection, overcome the defect of carbazochrome sodium sulfonate for injection tradition preparing process in the past, there is provided that a kind of cost is low, yield is high, the preparing process that end product quality is more stable: mannitol adds in the water for injection of about amount of preparation 25% by (1), heating makes it dissolve completely, add the medicinal charcoal of amount of preparation 0.2% (W/V), boil 30 minutes, decarbonization filtering; (2) get the water for injection of amount of preparation 30%, be cooled to less than 40 DEG C, add anhydrous carbazochrome sodium sulfonate, stir and make it dissolve completely, solution is added mix homogeneously in mannitol filtrate; (3) regulate liquid PH value to 5.5 ~ 6.0 with the sodium hydroxide solution of 10%, inject water to amount of preparation, stir, repetition measurement pH value is 5.5 ~ 6.0, successively through 0.45 μm, 0.22 μm filtering with microporous membrane, after censorship semi-finished product are qualified, hand over fill operation.
But; existing injection carbazochrome sodium sulfonate freeze-dried powder injection agent product; that comprise bibliographical information and commercially available product; the adjuvant that many uses are relatively large; the membership that adds of these adjuvants is that the quality of product brings many hidden danger; the usual excipients mannitol of such as lyophilized injectable powder, can introduce thermal source to product usually.Therefore, those skilled in the art still expect to have the least possible use even substantially without adjuvant particularly excipient prepare the method for lyophilization injectable powder, and expect the character such as plastic property etc. that this injectable powder has injectable powder and usually expects.
Summary of the invention
The object of the present invention is to provide a kind of the least possible use even substantially without adjuvant particularly excipient prepare the method for lyophilization injectable powder, and expect the character such as plastic property etc. that this injectable powder has injectable powder and usually expects.The present inventor have been surprisingly found that, the injectable powder prepared by the inventive method does not only add adjuvant particularly excipient substantially, and obtained freeze-drying powder needle set has excellent physicochemical property.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides a kind of lyophilization injectable powder of carbazochrome sodium sulfonate, and it does not add freeze-dried excipient substantially.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, it is packed by cillin bottle.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, it is packed by cillin bottle, and in round pie in cillin bottle.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein the content of carbazochrome sodium sulfonate is greater than 90%, such as, be greater than 95%, such as, be greater than 98%, such as, be greater than 99%.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
The lyophilization injectable powder of arbitrary embodiment, wherein also comprises acid-base modifier according to a first aspect of the present invention.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 7%, be particularly usually less than 5%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 5.0 ~ 6.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing carbazochrome sodium sulfonate 10mg/ml concentration, the amount of pH value in 5.0 ~ 5.5 scopes of such as this solution.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, it is prepare by comprising following step substantially:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 ~ 6.0 with acid-base modifier, preferred pH5.0 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose.The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, be added with the dehydrated alcohol of 2 ~ 10% (v/v) in water for injection wherein in step (a), such as, be added with the dehydrated alcohol of 3 ~ 7% (v/v).Oneself is through have been surprisingly found that, in medicinal liquid, adding a little ethanol in this step, to contribute to obtaining dissolubility excellent and have the injectable powder of good lyophilizing form.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 15 ~ 25mg/ml (such as 20mg/ml).
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
Further, second aspect present invention provides the method for the lyophilization injectable powder described in the arbitrary embodiment of lyophilization injectable powder such as first aspect present invention preparing carbazochrome sodium sulfonate, and it consists essentially of following steps:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 ~ 6.0 with acid-base modifier, preferred pH5.0 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein gained lyophilization injectable powder does not add freeze-dried excipient substantially.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein gained lyophilization injectable powder is packed by cillin bottle.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein gained lyophilization injectable powder is packed by cillin bottle, and in round pie in cillin bottle.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein in gained lyophilization injectable powder, the content of carbazochrome sodium sulfonate is greater than 90%, such as, be greater than 95%, such as, be greater than 98%, such as, be greater than 99%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein also comprises acid-base modifier in gained lyophilization injectable powder.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose.The method of arbitrary embodiment according to a second aspect of the present invention, is added with the dehydrated alcohol of 2 ~ 10% (v/v) in the water for injection wherein in step (a), such as, be added with the dehydrated alcohol of 3 ~ 7% (v/v).Oneself is through have been surprisingly found that, in medicinal liquid, adding a little ethanol in this step, to contribute to obtaining dissolubility excellent and have the injectable powder of good lyophilizing form.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 15 ~ 25mg/ml (such as 20mg/ml).
The method of arbitrary embodiment according to a second aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein in step (e) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
State on the invention in the step of preparation method, although its concrete steps described in some details or the language step described in preparation example that describes up and down literary composition detailed description of the invention part distinguish to some extent, but those skilled in the art can summarize the above method step completely according to the open in detail of the present invention's full text.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Have been found that the injection carbazochrome sodium sulfonate lyophilization injectable powder that the inventive method prepares has beat all advantage.Such as be embodied in following stability test and pyrogen test two aspects:
Stability test: whole injectable powder that Examples below 1 to embodiment 15 prepares, is placed in 42 DEG C of places and places May to carry out high-temperature treatment test; For each injectable powder, related substance when using [HPLC method] to measure this injectable powder 0 month time and in May (relative to main constituent) content, particularly follows the tracks of and calculates the content of impurity 3 (being called a kind of degradation impurity according to the blue document of Xu Lan); The content being calculated as follows impurity 3 increases percent (%, can referred to as " impurity 3 increment "):
Above-mentioned whole injectable powder uses same batch card network sulphur sodium raw materials medicine to prepare, impurity 3 content of whole injectable powder 0 month time is substantially suitable, all in 0.08 ~ 0.11% scope, but after being through above-mentioned high-temperature treatment, different sample presents visibly different impurity 3 situation of change.Specifically, impurity 3 increment (%) of the whole injectable powder of embodiment 12 ~ 15 gained is all in 78 ~ 153% scopes, and impurity 3 increment (%) of the whole injectable powder of embodiment 1-11 gained is all in 17 ~ 31% scopes.
Pyrogen test: according to the pyrogen test of current edition Chinese Pharmacopoeia two annex MD, pyrogen test is carried out to whole 9 injectable powder that Examples below 6 to embodiment 10 and embodiment 12 to embodiment 15 prepare.For each powder pin sample, the body temperature calculating its 3 rabbit raises sum.Result: 3 rabbit body temperatures of the whole injectable powder of embodiment 12 to embodiment 15 raise sums all within the scope of 0.85 ~ 1.06 DEG C (although qualified in defective limit), 3 rabbit body temperatures of the whole injectable powder of embodiment 6 to embodiment 10 raise sums all within the scope of 0.17 ~ 0.33 DEG C.
In the present invention, preferred lyophilized injectable powder of the present invention after make the solution containing active component 10mg in every 1ml with water, then measures the acid-base value of this freeze-dried powder according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items and pH value algoscopy.
The preparation process of lyophilization injectable powder well known to a person skilled in the art pharmaceutical technology, such as following kind of the schematic freeze-drying curve of two shown in freeze-drying curve A and freeze-drying curve B:
Hereafter preparing in the instantiation in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Water content in lyophilization injectable powder is general below 8%, preferably lower than 7%, more preferably less than 5%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.
In the present invention, in order to regulate the pH value of medicinal liquid where necessary, suitable pH adjusting agent can be added in compositions.Although the present inventor only regulates with not having the strong acid of buffer capacity or strong base solution such as a sodium hydrate aqueous solution and aqueous hydrochloric acid solution, but, those skilled in the art understand, if the pH requirement of system can be met with this pH adjusting agent process of not having buffer capacity, the pH adjusting agent then with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can adjust ph, and can stablize pH value.Therefore arbitrary pH adjusting agent listed by the present invention or its combination include in spirit and scope of the invention.
When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 10%, more more preferably 1 ~ 5%.Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 10%, more more preferably 1 ~ 5%.
In the present invention, symbol %, according to the linguistic context that it uses, can have the implication of those skilled in the art's easy understand.Such as when mentioning solid content, this symbol represents the percent (w/v, such as g/100ml) of weight/volume; Again such as when mentioning " water content " in lyophilization injectable powder, such as water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, solid dispersal in a liquid time, % represents weight/volume percent; Solid dispersal in solids or liquid dispersion in solids (such as the water content of powder pin) time, % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparing medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of example 0.45um according to appointment can carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane of example 0.22um according to appointment can carry out fine straining and filter with degerming, can filter repeatedly if desired.
According to lyophilized injectable powder of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that such as XiLin is bottled), and in per unit dosage, the amount of reactive compound can such as but not limited to about 10mg, about 20mg, about 40mg, about 60mg, about 80mg, about 100mg.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and typically the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.
According to lyophilized injectable powder of the present invention, its with water make in every 1ml containing reactive compound 10mg solution and according under Chinese Pharmacopoeia version in 2010 two annex VI H items method measure, the pH value of this solution is 5.0 ~ 6.0.In one embodiment, pH value is 5.0 ~ 5.5.
Lyophilized injectable powder provided by the invention can be preserved at least 24 months at place dry below 25 DEG C, can meet the Storage Requirement of general lyophilization injectable powder.
Obtained freeze-drying injectable powder of the present invention particularly lyophilization injectable powder is generally white or the lyophilizing block of off-white color or its fragment or its powder, odorless, bitter in the mouth, soluble in water.
Carbazochrome sodium sulfonate (Carbazochrome Sodium Sulfonate), English language Chemical name: sodium 5-(carbamoylhydrazono) 2,3,5,6-tetrahydro-1-methyl-6-oxo-1h-indole-2-sulphonate; (5E)-3-hydroxy-1-methyl-2,3-dihydro-1H-indole-5,6-dione5-semicarbazone; Sodium (5E)-5-(carbamoylhydrazono)-1-methyl-6-oxo-2,3,5,6-tetrahydro-1H-indole-2-sulfonate; Sodium (5Z)-5-(carbamoylhydrazono)-1-methyl-6-oxo-2,3,5,6-tetrahydro-1H-indole-2-sulfonate etc.Chinesization formal name used at school: Carbazochrome Sodium Sulfonate.
It is hemorrhage that carbazochrome sodium sulfonate is adapted to urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease, comparatively remarkable to urinary system bleeding, also can be used for wound and operative hemorrhage.Carbazochrome sodium sulfonate can increase the resistance of blood capillary to damage, reduces the permeability of blood capillary, promotes the retraction of blood capillary fracture end and stops blooding.Acute toxicity test: mice intramuscular injection LD50>1000mg/kg; Maximum non-lethal dose test: MNLD>2000mg/kg; Irritation test: have no obvious tissue degeneratiaon downright bad; Hemolytic test: have no erythrocyte fragmentation or cohesion, show without haemolysis.
Pharmacokinetics aspect, after the oral carbazochrome sodium sulfonate 150mg of health adult man, in 0.5 ~ 1 hour blood, Cmax reaches 25ng/ml, and the half-life (t1/2) is 1.5 hours, within 0.5 ~ 1 hour, reach urine drug concentration after oral the highest, excretion in about 24 hours is complete.
Detailed description of the invention
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.Any conceive according to the present invention done be only pro forma but not substantial equivalent transformation and all should be considered as technical scheme category of the present invention.
In example below, if not otherwise indicated, be the carbazochrome sodium sulfonate crude drug (it meets the quality standard of Pharmacopeia of Japan 16 editions the 533rd page of carbazochrome sodium sulfonate recorded) of same batch of use when preparing injectable powder.
In example below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is when making to prepare injectable powder, make the pH value of the solution prepared before lyophilization be adjusted to a certain setting or scope, this setting or scope are value or the scopes that lyophilization gained dry powder water for injection is diluted to the pH value that the solution containing active component 10mg/ml measures.The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder completely according to existing knowledge.Dosing is prepared in various compositions below, and if not otherwise indicated, the total dosing amount often criticized is 10000ml, but when listing formula, the amount all containing carbazochrome sodium sulfonate 40mg in every bottle is illustrated.
assay method:
The assay of various sample (comprising injectable powder of the present invention) and determination of related substances can be carried out (can be described as herein [HPLC method]) according to following methods:
[HPLC method]: with reference to the blue document (Xu Lanlan of Xu Lan, Deng, the related substance of high effective liquid chromatography for measuring carbazochrome sodium sulfonate injection, Chinese Pharmaceutical Journal, 2014,49 (12): 1073) method is carried out, and particularly carries out with reference to 2.1 joint liquid phase chromatogram conditions wherein and uses 220nm determined wavelength; Concrete liquid phase chromatogram condition is:
Chromatographic column: HP-ODS Hypersil post (4.6mm × 250mm, 5um); Mobile phase A: 0.01mol/L ammonium dihydrogen phosphate (with phosphorus acid for adjusting pH to 3.0)-acetonitrile (94:6), Mobile phase B: acetonitrile; Linear gradient elution, program is 0 ~ 10min, B volume fraction is 0%, and 10 ~ 30min, B volume fraction is 0% ~ 50%, and 30 ~ 35min, B volume fraction is 50%; Determined wavelength: 220nm; Column temperature: 40 DEG C; Flow velocity: 1.0mL/min; Sample size: 10uL; Theoretical cam curve calculates by carbazochrome sodium sulfonate peak and is not less than 2500;
Sample thief is appropriate, adds mobile phase A and dissolves and make the solution about containing active component 0.5mg in every 1mL, as need testing solution; Precision measures 1mL, puts in 100mL measuring bottle, is diluted to scale with mobile phase, shake up, in contrast solution; Get contrast solution and need testing solution sample introduction respectively, detect in 220 wavelength places, record chromatogram; Analysing impurity belongs to and calculates impurity level.Use and be somebody's turn to do [HPLC method] also can measure active component in injectable powder with calculated by peak area content by external standard method.
embodiment 1: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (65% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.1%) in previous step gained medicinal liquid, stir (making absorption 15min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 2: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2.67ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (70% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.05%) in previous step gained medicinal liquid, stir (making absorption 20min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 7%), tamponade, to obtain final product.
embodiment 3: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 1.6ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (60% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.15%) in previous step gained medicinal liquid, stir (making absorption 10min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.3 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 6%), tamponade, to obtain final product.
embodiment 4: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2.5ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (65% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.12%) in previous step gained medicinal liquid, stir (making absorption 18min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.3 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization (freeze-drying curve B) removes moisture (moisture is lower than 6%), tamponade, to obtain final product.
embodiment 5: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (62% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.08%) in previous step gained medicinal liquid, stir (making absorption 14min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.2 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 6: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (65% of prescription full dose) water for injection (being added with the dehydrated alcohol of 5% (v/v) in this water for injection), be stirred to dissolve;
B () adds active carbon (0.1%) in previous step gained medicinal liquid, stir (making absorption 15min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 7: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2.67ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (70% of prescription full dose) water for injection (being added with the dehydrated alcohol of 3% (v/v) in this water for injection), be stirred to dissolve;
B () adds active carbon (0.05%) in previous step gained medicinal liquid, stir (making absorption 20min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 7%), tamponade, to obtain final product.
embodiment 8: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 1.6ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (60% of prescription full dose) water for injection (being added with the dehydrated alcohol of 7% (v/v) in this water for injection), be stirred to dissolve;
B () adds active carbon (0.15%) in previous step gained medicinal liquid, stir (making absorption 10min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.3 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 6%), tamponade, to obtain final product.
embodiment 9: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2.5ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (65% of prescription full dose) water for injection (being added with the dehydrated alcohol of 5% (v/v) in this water for injection), be stirred to dissolve;
B () adds active carbon (0.12%) in previous step gained medicinal liquid, stir (making absorption 18min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.3 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization (freeze-drying curve B) removes moisture (moisture is lower than 6%), tamponade, to obtain final product.
embodiment 10: prepare carbazochrome sodium sulfonate lyophilization injectable powder
formula:
Carbazochrome sodium sulfonate: 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: to 2ml
method for making:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate (62% of prescription full dose) water for injection (being added with the dehydrated alcohol of 5% (v/v) in this water for injection), be stirred to dissolve;
B () adds active carbon (0.08%) in previous step gained medicinal liquid, stir (making absorption 14min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.2 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 11: prepare carbazochrome sodium sulfonate lyophilization injectable powder
The batching of reference example 6 and method for making, unlike the dehydrated alcohol being added with 12%, 20% or 30% in the water for injection that step (a) is used.Obtained three batches of powder pins are designated as Ex111, Ex112, Ex113 respectively.
In above embodiment 1 to embodiment 11 gained injectable powder: whole samples of embodiment 11 all can not form regular round pie, and all there is serious spray bottle phenomenon; Whole samples of embodiment 1-5 all have severe atrophy, and still can not dissolve completely after 3min when the every bottle of 5ml that adds water dissolves; Can dissolve completely within 25 seconds when whole samples of embodiment 6-10 all form regular round pie, not atrophy, have no spray bottle phenomenon, the every bottle of 5ml that adds water dissolves.In addition, according to ethanol remaining in whole samples of the gas chromatography determination embodiment 6-10 of current edition Chinese Pharmacopoeia two annex, result has not all detected remnants.Through conversion, in whole samples of embodiment 6-10, the content of carbazochrome sodium sulfonate is greater than 99%.
embodiment 12: prepare carbazochrome sodium sulfonate lyophilization injectable powder (#174)
Preparation technology: get above-mentioned three components mixing, the water for injection adding 500ml dissolves, and water for injection is settled to the concentration 2% that 1000ml makes carbazochrome sodium sulfonate solution.With 0.22 μm of microporous filter membrane aseptic filtration, fill is in container, and fill amount 1ml/ props up, and carries out lyophilizing, tamponade, rolls lid, packs and get final product.
embodiment 13: prepare carbazochrome sodium sulfonate lyophilization injectable powder (#675)
Preparation technology: the Carlow sulphur sodium taking recipe quantity, adds the water for injection of recipe quantity, 50 DEG C of stirring and dissolving, take the mannitol of recipe quantity again, stirring and dissolving, adds the citric acid-sodium citrate buffer (5mM) of recipe quantity, then adds the active carbon of recipe quantity, stir 30 minutes, first filter decarburization, then use 0.22um membrane filtration, detect intermediate, fill, lyophilizing, add a cover, check, pack, obtain carbazochrome sodium sulfonate freeze-dried powder injection finished product.
embodiment 14: prepare carbazochrome sodium sulfonate lyophilization injectable powder (#656)
1, formula (weight: g): carbazochrome sodium sulfonate 1, mannitol 0.1, dextran 2 and sodium hydroxide 0.5.
2, preparation method:
1) carbazochrome sodium sulfonate of recipe quantity, mannitol and dextran are added in appropriate water for injection, be stirred to and dissolve completely, obtain solution A;
2) added in appropriate water for injection by sodium hydroxide and dissolve, then add in solution A by sodium hydroxide solution, stir, the pH value making mixed liquor is 5, obtains solution B;
3) in solution B, add the active carbon of dose volume 0.5%, after boiling 30min, carry out filtering decarbonization, collect filtrate, then use 0.2 μm of microporous filter membrane aseptic filtration, collect liquor C;
4) liquor C makes pulverous pharmaceutical composition through lyophilization.
embodiment 15: prepare carbazochrome sodium sulfonate lyophilization injectable powder (#330)
Every 2000ml consumption: anhydrous carbazochrome sodium sulfonate 20.0g, mannitol 80.0g, medicinal charcoal 4.0g, fresh water for injection adds to 2000ml.
Method for making: mannitol adds in the water for injection of about amount of preparation 25% by (1), heating makes it dissolve completely, adds the medicinal charcoal of amount of preparation 0.2% (W/V), boils 30 minutes, decarbonization filtering.
(2) get the water for injection of amount of preparation 30%, be cooled to less than 40 DEG C, add anhydrous carbazochrome sodium sulfonate, stir and make it dissolve completely, solution is added mix homogeneously in mannitol filtrate.
(3) regulate liquid PH value to 5.5 ~ 6.0 with the sodium hydroxide solution of 10%, inject water to 2000ml, stir, repetition measurement pH value is 5.5 ~ 6.0, successively through 0.45 μm, 0.22 μm filtering with microporous membrane, after censorship semi-finished product are qualified, hand over fill operation.
industrial applicability
The invention provides a kind of injection carbazochrome sodium sulfonate lyophilization injectable powder with excellent properties, and the preparation method of this injection carbazochrome sodium sulfonate lyophilization injectable powder.It is hemorrhage that injection carbazochrome sodium sulfonate lyophilization injectable powder of the present invention can be used for urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease.Carbazochrome sodium sulfonate is comparatively remarkable to urinary system bleeding, also can be used for wound and operative hemorrhage.The injection carbazochrome sodium sulfonate lyophilization injectable powder that the present invention prepares has excellent physicochemical property.
Claims (10)
1. a lyophilization injectable powder for carbazochrome sodium sulfonate, it does not add freeze-dried excipient substantially.
2. lyophilization injectable powder according to claim 1, is characterized in that:
It is packed by cillin bottle;
It is packed by cillin bottle, and in round pie in cillin bottle;
Wherein the content of carbazochrome sodium sulfonate is greater than 90%, such as, be greater than 95%, such as, be greater than 98%, such as, be greater than 99%; And/or
Wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
3. lyophilization injectable powder according to claim 1, is characterized in that:
Wherein also comprise acid-base modifier;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution;
Described acid-base modifier is 1M hydrochloric acid solution or 1M sodium hydroxide solution; And/or
The amount of described acid-base modifier is, the amount of pH value in 5.0 ~ 6.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing carbazochrome sodium sulfonate 10mg/ml concentration, the amount of pH value in 5.0 ~ 5.5 scopes of such as this solution.
4. lyophilization injectable powder according to claim 1, it is prepare by comprising following step substantially:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 ~ 6.0 with acid-base modifier, preferred pH5.0 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
5. lyophilization injectable powder according to claim 4, is characterized in that:
Appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose; Or be added with the dehydrated alcohol of 2 ~ 10% (v/v) in the water for injection further, in step (a);
The addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid;
Stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min;
The mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration;
Mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 15 ~ 25mg/ml (such as 20mg/ml); And/or
Aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
6. prepare the method for the lyophilization injectable powder of lyophilization injectable powder such as described in any one of claim 1-5 of carbazochrome sodium sulfonate, it consists essentially of following steps:
A () takes the carbazochrome sodium sulfonate of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 ~ 6.0 with acid-base modifier, preferred pH5.0 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
7. method according to claim 6, is characterized in that:
Gained lyophilization injectable powder does not add freeze-dried excipient substantially;
Gained lyophilization injectable powder is packed by cillin bottle;
Gained lyophilization injectable powder is packed by cillin bottle, and in round pie in cillin bottle; And/or
In gained lyophilization injectable powder, the content of carbazochrome sodium sulfonate is greater than 90%, such as, be greater than 95%, such as, be greater than 98%, such as, be greater than 99%.
8. method according to claim 6, is characterized in that:
Wherein also comprise acid-base modifier in gained lyophilization injectable powder;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination; And/or
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
9. method according to claim 6, is characterized in that:
Appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose; Or be added with the dehydrated alcohol of 2 ~ 10% (v/v) in the water for injection further, in step (a);
The addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid;
Stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min; And/or
The mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
10. method according to claim 6, is characterized in that:
Mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 15 ~ 25mg/ml (such as 20mg/ml);
Aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration;
In step (e) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
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| CN113425677A (en) * | 2021-08-03 | 2021-09-24 | 江苏吴中医药集团有限公司 | Carbazochrome sodium sulfonate water injection and preparation method and application thereof |
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