CN104800172B - Injection Carbazochrome Sodium Sulfonate powder-injection and preparation method - Google Patents
Injection Carbazochrome Sodium Sulfonate powder-injection and preparation method Download PDFInfo
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- CN104800172B CN104800172B CN201510272724.6A CN201510272724A CN104800172B CN 104800172 B CN104800172 B CN 104800172B CN 201510272724 A CN201510272724 A CN 201510272724A CN 104800172 B CN104800172 B CN 104800172B
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- injection
- freeze
- sodium sulfonate
- drying powder
- powder
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- 238000002347 injection Methods 0.000 title claims abstract description 155
- 239000007924 injection Substances 0.000 title claims abstract description 155
- 229960004353 carbazochrome sodium sulfonate Drugs 0.000 title claims abstract description 117
- HLFCZZKCHVSOAP-WXIWBVQFSA-M sodium;(5e)-5-(carbamoylhydrazinylidene)-1-methyl-6-oxo-2,3-dihydroindole-2-sulfonate Chemical compound [Na+].NC(=O)N\N=C/1C(=O)C=C2N(C)C(S([O-])(=O)=O)CC2=C\1 HLFCZZKCHVSOAP-WXIWBVQFSA-M 0.000 title claims abstract description 114
- 238000002360 preparation method Methods 0.000 title abstract description 45
- 238000004108 freeze drying Methods 0.000 claims abstract description 109
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 90
- 239000000243 solution Substances 0.000 claims abstract description 58
- 239000008215 water for injection Substances 0.000 claims abstract description 55
- 239000000843 powder Substances 0.000 claims abstract description 34
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims description 81
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 38
- 239000003607 modifier Substances 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 27
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 26
- 239000004695 Polyether sulfone Substances 0.000 claims description 25
- 229920006393 polyether sulfone Polymers 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000005262 decarbonization Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 238000011049 filling Methods 0.000 claims description 16
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- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
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- 230000000694 effects Effects 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
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- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 230000008901 benefit Effects 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
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- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
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- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
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- 239000003513 alkali Substances 0.000 description 2
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- PDZKPUQLQNDXMQ-UHFFFAOYSA-M sodium 5-(carbamoyldiazenyl)-6-hydroxy-1-methyl-2,3-dihydroindole-2-sulfonate Chemical compound CN1C(CC2=CC(=C(C=C21)O)N=NC(=O)N)S(=O)(=O)[O-].[Na+] PDZKPUQLQNDXMQ-UHFFFAOYSA-M 0.000 description 1
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- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to injection Carbazochrome Sodium Sulfonate powder-injection and preparation method.The freeze-drying powder-injection of Carbazochrome Sodium Sulfonate of the present invention, it is substantially not added with freeze-dried excipient, wherein the content of Carbazochrome Sodium Sulfonate is more than 90%, and the pH value of the solution is in the range of 5.0~6.0 when the freeze drying powder injection is dissolved into the solution of the concentration of 10mg/ml containing Carbazochrome Sodium Sulfonate with water for injection.Injection Carbazochrome Sodium Sulfonate powder-injection of the present invention can be used for urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease bleeding.Injection Carbazochrome Sodium Sulfonate powder-injection of the present invention is more notable to urinary system bleeding, also available for wound and operative hemorrhage.The injection Carbazochrome Sodium Sulfonate powder-injection that the present invention is prepared has excellent physicochemical property.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of haemostatic medicament, more particularly to a kind of to have superiority
The injection Carbazochrome Sodium Sulfonate powder-injection pharmaceutical composition of matter.The invention further relates to the preparation side of the injection Carbazochrome Sodium Sulfonate powder-injection
Method.The injection Carbazochrome Sodium Sulfonate powder-injection can be used for urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease bleeding.Injection
It is more notable to urinary system bleeding with Carbazochrome Sodium Sulfonate powder-injection, also available for wound and operative hemorrhage.It is prepared by the present invention
Obtained injection Carbazochrome Sodium Sulfonate powder-injection has excellent physicochemical property.
Background technology
Carbazochrome Sodium Sulfonate, also known as new adrenobazonum, its chemical name is：1- methyl -6- oxo -2,3,5,6- tetrahydro indoles -5-
Semicarbazone -2- sulfonate sodium trihydrates, English entitled Carbazochrome Sodium Sulfonate, molecular formula：
C10H11N4O5SNa3H2O, molecular weight：376.32, structural formula is as follows：
Carbazochrome Sodium Sulfonate can reduce the permeability of capillary, promote the retraction effect of capillary fracture end, be usually used in hair
A variety of bleedings that thin vasopermeability increases and produced.
Carbazochrome Sodium Sulfonate can be developed by day Honda side pharmacy strain formula earliest, be recorded by Japanese health ministry such as Pharmacopeia of Japan the
12 editions (1992), Pharmacopeia of Japan the 16th edition is also recorded.Carbazochrome Sodium Sulfonate is Vascular haemostasis medicine of new generation, is a kind of pole
There is the blood vessel hardening agent of clinical value.It is the derivative of adrenobazone, and induce one sodium group on molecular machinery, overcomes
The solubility of adrenobazone is small, it is necessary to by the shortcoming of salicylic acid hydrotropy, so as to generate obvious haemostatic effect.Carbazochrome Sodium Sulfonate energy
Increase resistance of the capillary to damage, reduce the permeability of capillary, promote the retraction of capillary fracture end and stop
Blood.Carbazochrome Sodium Sulfonate can strengthen capillary elasticity, reduce the permeability of capillary, and the retraction for promoting capillary fracture end is made
With the acid mucopolysaccharide in stable capillary and surrounding tissue significantly shortens the bleeding time, promotes the active and fibre of fibrin ferment
The dissolving of fibrillarin member, and then make bleeding part formation thrombus and reach hemostasis, it is that capillary permeability increases and produced
Effective hemostatic of massive haemorrhage caused by a variety of bleedings and a variety of causes.And Carbazochrome Sodium Sulfonate is free of salicylic acid group, in the absence of production
Raw " haemolysis " problem, does not influence hematopoiesis function, meanwhile, nonirritant, drug safety can be used for a long time, water-soluble strong, toxicity pole
It is low, blood coagulation mechanism is not influenceed, is worked rapid, persistent is applied widely, is a kind of Vascular haemostasis medicine of new generation, is a kind of
Has the blood vessel hardening agent of clinical value, clinical demand amount is big.
Carbazochrome Sodium Sulfonate is clinically used for urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease bleeding, also available for outer
Wound and operative hemorrhage.The less stable of Carbazochrome Sodium Sulfonate, is easily influenceed by temperature, oxygen, light, and occurs to degrade or it
The change of his physicochemical property, influence even increases the security risk used using curative effect.
The common formulations that Carbazochrome Sodium Sulfonate is clinically used have the injections such as tablet and powder-injection.The injection of Carbazochrome Sodium Sulfonate
Existing many document reports.For example, the B of CN 101254174 (200710191009.5) disclose a kind of the lyophilized of Carbazochrome Sodium Sulfonate
Powder-injection, it is characterized in that being added sweet by adding thiocarbamide and/or sodium formaldehyde sulphoxylate with improving the stability of Carbazochrome Sodium Sulfonate
Reveal the solubility that alcohol improves lyophilized formulations, the freeze drying powder injection steady quality of the Carbazochrome Sodium Sulfonate prepared.Particularly provide
A kind of freeze drying powder injection of Carbazochrome Sodium Sulfonate, it is characterized in that containing following component and weight ratio：1 part of Carbazochrome Sodium Sulfonate, thiocarbamide and/or first
Aldehyde closes 0.001~0.05 part of sodium bisulphite, 0.01~0.8 part of mannitol, 0~10 part of excipient, and wherein excipient is selected from low
One or more in dextrosan glycosides, fructose, xylose, rhamnose, galactolipin, arabinose, glucuronic acid, glucose.
The B of CN 102018675 (200910212269.5) disclose a kind of carbazochrome sodium sulfonate freeze-dried powder injection agent and its preparation side
Method, the carbazochrome sodium sulfonate freeze-dried powder injection agent is made up of Carbazochrome Sodium Sulfonate, mannitol and buffer salt, prepares solvent for water for injection.Through big
Amount experiment, only plus buffer salt just solve that carbazochrome sodium sulfonate freeze-dried powder injection pH value in preparation process is unstable and storage process in it is clear
Underproof problem is spent clearly.Formulation and technology of the present invention overcomes prior art weak point, and there is provided a kind of prescription is simple, quality is protected
Demonstrate,prove, stability is good, can be applied to the carbazochrome sodium sulfonate freeze-dried powder injection of clinic.Its advantage：1. prescription is simple, and main ingredient card network is removed in prescription
Outside sulphur sodium, auxiliary material only mannitol, buffer salt；2. former, auxiliary material is State Food and Drug Administration's rule used in prescription
Fixed pharmaceutical injection level, eliminate the unpredictable adverse reaction risk that non-pharmaceutic adjuvant is brought；3. stability is good, transport and
Storage is more convenient；4. through the special pearl safety testing such as anaphylaxis, hemolytic, blood vessel irritation, haemolysis and aggegation, stimulation are had no
Property, allergic reaction.
The B of CN 102210656 (201110092416.7) disclose a kind of pharmaceutical composition containing carbazochrome sodium sulfonate compound
And preparation method thereof, this contains the pharmaceutical composition of carbazochrome sodium sulfonate compound by Carbazochrome Sodium Sulfonate, mannitol, dextran and hydroxide
Sodium is constituted.The pharmaceutical composition containing carbazochrome sodium sulfonate compound can overcome existing Carbazochrome Sodium Sulfonate powder-injection stability it is poor, dissolving
Low problem is spent, is more suitable for Clinical practice.
The B of CN 102525908 (201210042805.3) are related to Carbazochrome sodium sulfonate pharmaceutical composition, by 20~80 parts by weight
Carbazochrome Sodium Sulfonate, the lactose of 40~120 parts by weight, the PLURONICS F87 of 3~6 parts by weight, the glutathione of 1~4 parts by weight,
The natrium adetate of 0.05~0.2 parts by weight and the water for injection of 2000 parts by weight are prepared from.The Carbazochrome Sodium Sulfonate medicine group
The formulation of compound is freeze-dried powder or liquid drugs injection parenteral solution.The present invention is using lactose, PLURONICS F87, glutathione and edetic acid(EDTA)
Disodium is used as auxiliary material.Wherein mannitol is as excipients, and poloxamer is as cosolvent, stabilizer, glutathione and edetic acid(EDTA)
Disodium is used as antioxidant and metal-chelator.
The A of CN 102961330 (201210551637.0) disclose a kind of preparing process of carbazochrome sodium sulfonate for injection, overcome with
Defect toward the traditional preparing process of carbazochrome sodium sulfonate for injection is there is provided a kind of cost is low, high income, and final product quality is more stable to match somebody with somebody
Technique processed：(1) mannitol is added in the about water for injection of amount of preparation 25%, heating is completely dissolved it, adds amount of preparation
0.2% (W/V) medical charcoal, boils 30 minutes, decarbonization filtering；(2) take the water for injection of amount of preparation 30%, be cooled to 40 DEG C with
Under, anhydrous Carbazochrome Sodium Sulfonate is added, stirring is completely dissolved it, and solution is added in mannitol filtrate and is well mixed；(3) 10% is used
Sodium hydroxide solution regulating liquid medicine pH value to 5.5~6.0, inject water to amount of preparation, stir, repetition measurement pH value exists
5.5~6.0, successively through 0.45 μm, 0.22 μm of filtering with microporous membrane, after censorship semi-finished product are qualified, hand over filling process.
However, existing injection carbazochrome sodium sulfonate freeze-dried powder injection agent product, including document report and commercially available product,
Use larger amount of auxiliary material, adding for these auxiliary materials can bring many hidden danger for the quality of product, such as freeze drying powder injection more
Usual excipients mannitol, it will usually introduce thermal source to product.Therefore, those skilled in the art still expect to have use as few as possible
Even substantially the method for freeze-drying powder-injection is prepared without auxiliary material particularly excipient, and expect that this powder-injection has
The property that powder-injection is generally expected is such as plastic property.
The content of the invention
Lack with or even prepared substantially without auxiliary material particularly excipient as far as possible it is an object of the invention to provide a kind of
The method of freeze-drying powder-injection, and expect that this powder-injection has property that powder-injection generally expects such as plastic property.
Present inventors have surprisingly discovered that, obtained powder-injection is prepared by the method for the present invention and is not only particularly substantially without auxiliary material
Excipient, and obtained freeze-drying powder needle set has excellent physicochemical property.The present invention is accomplished based on this discovery.
Therefore, first aspect present invention provides a kind of freeze-drying powder-injection of Carbazochrome Sodium Sulfonate, it is substantially not added with
Freeze-dried excipient.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, it is packed by cillin bottle.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, it is packed by cillin bottle, and
And be in round pie in cillin bottle.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, the content of wherein Carbazochrome Sodium Sulfonate is more than
90%, 95% is greater than, 98% is greater than, 99% is greater than.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, wherein moisture are less than 10%,
Preferably shorter than 8%, preferably shorter than 7%, more preferably less than 5%.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, wherein also including acid-base modifier.
In one embodiment, described acid-base modifier be selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate,
Potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.In one embodiment, described acid
Alkali conditioning agent is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It is well known that the freeze-drying powder-injection obtained through cryogenic freezing-vacuum drying (is often referred to simply as freeze-dried powder
Agent or freeze-dried powder), it is that each material solvent is dissolved into (being dissolved with water) first, is configured to a solution, so
After the solution is carried out cryogenic freezing, then a kind of substantially anhydrous (the typically water vacuumized, distilled, dried and obtain
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered thing or block 5%).Therefore, this is consolidated
The acid-base value of body lyophilized products generally adjusts the pH value of solution to control by process for preparation；Or can by prescription adjust so that
The solid lyophilized products of acquisition control the pH value of the dissolving/dilution to control (referred to herein as to control under defined dissolving/dilute strength
The acid-base value of solid lyophilized products processed)；Latter means are generally more generally used, such as contained many freeze drying powder injections in pharmacopeia
The acid-base value of product is controlled in this way, and this mode controls the acid-base value of product generally can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.The present invention is equally applicable to, according to first party of the present invention
Freeze drying powder injection described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 5.0~6.0 when agent is dissolved into the solution of the concentration of 10mg/ml containing Carbazochrome Sodium Sulfonate with water for injection
Amount, the amount of the pH value of such as solution in the range of 5.0~5.5.
The freeze-drying powder-injection of any embodiment according to a first aspect of the present invention, its substantially press include it is following
Prepared by step：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate water for injection is added, is stirred to dissolve,
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.0~6.0, preferably pH5.0~5.5；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, and tamponade is produced.
The freeze-drying powder-injection of any embodiment, appropriate wherein described in step (a) according to a first aspect of the present invention
Water for injection is the water for injection of 60~70% amounts of prescription full dose.The freezing of any embodiment according to a first aspect of the present invention
Dry powder-injection, wherein in the water for injection in step (a) be added with 2~10% (v/v) absolute ethyl alcohol, for example added with
3~7% (v/v) absolute ethyl alcohol.Oneself is passed through surprisingly it has been found that adding a little ethanol into decoction in this step contributes to
Acquisition dissolubility is excellent and with the powder-injection of good lyophilized form.
The freeze-drying powder-injection of any embodiment, active wherein described in step (b) according to a first aspect of the present invention
The addition of charcoal is the amount that concentration of activated carbon reaches 0.05~0.15% in decoction.
The freeze-drying powder-injection of any embodiment, is stirred wherein described in step (b) according to a first aspect of the present invention
It is 10~20min of stirring and adsorbing, such as stirring and adsorbing 15min.
The freeze-drying powder-injection of any embodiment, is filtered wherein described in step (b) according to a first aspect of the present invention
Taking off the mode of charcoal is：With aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration.
The freeze-drying powder-injection of any embodiment, is wherein added described in step (c) according to a first aspect of the present invention
Water for injection to prescription full dose refers to add water for injection until activity component concentration is 15~25mg/ml (such as 20mg/ml)
Amount.
The freeze-drying powder-injection of any embodiment, degerming wherein described in step (d) according to a first aspect of the present invention
Filtering is to carry out aseptic filtration using 0.22um polyether sulfone filter core.
Further, second aspect of the present invention, which is provided, prepares the freeze-drying powder-injection of the Carbazochrome Sodium Sulfonate such as present invention the
The method of freeze-drying powder-injection described in one side any embodiment, it consists essentially of following steps：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate water for injection is added, is stirred to dissolve,
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.0~6.0, preferably pH5.0~5.5；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, and tamponade is produced.
The method of any embodiment according to a second aspect of the present invention, wherein gained freeze-drying powder-injection does not add substantially
Plus freeze-dried excipient.
The method of any embodiment according to a second aspect of the present invention, wherein gained freeze-drying powder-injection is close by cillin bottle
Package is filled.
The method of any embodiment according to a second aspect of the present invention, wherein gained freeze-drying powder-injection is close by cillin bottle
Package is filled, and is in round pie in cillin bottle.
The method of any embodiment according to a second aspect of the present invention, wherein Carbazochrome Sodium Sulfonate in gained freeze-drying powder-injection
Content be more than 90%, be greater than 95%, be greater than 98%, be greater than 99%.
The method of any embodiment according to a second aspect of the present invention, wherein also including acid in gained freeze-drying powder-injection
Alkali conditioning agent.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, phosphorus
Sour disodium hydrogen, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.In one embodiment,
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
The method of any embodiment according to a second aspect of the present invention, appropriate water for injection is wherein described in step (a)
The water for injection of 60~70% amounts of prescription full dose.The method of any embodiment, wherein step according to a second aspect of the present invention
(a) 2~10% (v/v) absolute ethyl alcohol, such as anhydrous second added with 3~7% (v/v) are added with the water for injection in
Alcohol.Oneself contributes to acquisition dissolubility excellent and tool by warp surprisingly it has been found that adding a little ethanol into decoction in this step
There is the powder-injection of good lyophilized form.
The method of any embodiment, the addition of activated carbon wherein described in step (b) according to a second aspect of the present invention
It is the amount that concentration of activated carbon reaches 0.05~0.15% in decoction.
The method of any embodiment according to a second aspect of the present invention, stirring is stirring and adsorbing wherein described in step (b)
10~20min, such as stirring and adsorbing 15min.
The method of any embodiment, the mode of filtering decarbonization wherein described in step (b) according to a second aspect of the present invention
It is：With aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration.
The method of any embodiment, mends wherein described in step (c) and injects water to according to a second aspect of the present invention
Prescription full dose refers to add water for injection the amount until activity component concentration is 15~25mg/ml (such as 20mg/ml).
The method of any embodiment according to a second aspect of the present invention, aseptic filtration is to use wherein described in step (d)
0.22um polyether sulfone filter core carries out aseptic filtration.
The method described in any embodiment, wherein removes gained after moisture according to a second aspect of the present invention in step (e)
It is freeze-dried moisture in material and is less than 10%, preferably shorter than 8%, preferably shorter than 7%, more preferably less than 5%.
In the step of above-mentioned preparation method of the invention, although specific steps that it is described are in some details or language
The step of described in preparation example in description with following detailed description part, is otherwise varied, however, people in the art
Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.
The invention will be further described below.
All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary
Offer expressed implication with it is of the invention inconsistent when, be defined by the statement of the present invention.In addition, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explained that the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
It has been found that the injection Carbazochrome Sodium Sulfonate freeze-drying powder-injection that the inventive method is prepared have it is unexpected
Advantage.For example it is embodied in two aspects of following stability test and pyrogen test：
Stability test：Whole powder-injection that Examples below 1 to embodiment 15 is prepared, are placed at 42 DEG C and place 5
Month to carry out high-temperature treatment experiment；For each powder-injection, use【HPLC methods】The powder-injection is determined at 0 month and in May
When relevant material (relative to principal component) content, particularly track and calculate impurity 3 and (be called one kind according to the blue documents of Xu Lan
Degradation impurity) content；The content increase percentage of impurity 3 is calculated as follows (% may be simply referred to as " increment of impurity 3 ")：
Above-mentioned whole powder-injection are prepared using same batch card network sulphur sodium raw materials medicine, and whole powder-injection are miscellaneous at 0 month
The content of matter 3 is substantially suitable, in the range of 0.08~0.11%, but after above-mentioned high-temperature treatment, different samples present bright
The aobvious different situation of change of impurity 3.Specifically, the increment of impurity 3 (%) of the whole powder-injection of the gained of embodiment 12~15 exists
In the range of 78~153%, the increment of impurity 3 (%) of whole powder-injection is in the range of 17~31% obtained by embodiment 1-11.
Pyrogen test：According to two annex MD of current edition Chinese Pharmacopoeia pyrogen test, to Examples below 6 to embodiment
10 and all 9 powder-injection for preparing of embodiment 12 to embodiment 15 carry out pyrogen tests.For each powder pin sample,
Calculate the body temperature rise sum of its 3 rabbit.As a result：Embodiment 12 to the whole powder-injection of embodiment 15 3 rabbit body temperature liters
High sum is (close to unqualified limit although qualified) in the range of 0.85~1.06 DEG C, and embodiment 6 to embodiment 10 is all
3 rabbit body temperatures of powder-injection raise sum in the range of 0.17~0.33 DEG C.
In the present invention, it is preferred to freeze drying powder injection of the present invention be made of water in every 1ml after the solution of the 10mg containing active component,
It is the acid-base value that pH value determination method determines the freeze-dried powder further according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010.
The preparation process of freeze-drying powder-injection is that well known to a person skilled in the art pharmaceutical technology, such as following lyophilized song
Two kinds of schematical freeze-drying curves shown in line A and freeze-drying curve B：
Prepare below in the instantiation in freeze-drying powder-injection, if not otherwise specified, lyophilized song used
Line is freeze-drying curve A.
Water content in freeze-drying powder-injection is general below 8%, preferably shorter than 7%, more preferably less than 5%.Water
Sub-control system can be controlled by suitably adjusting freeze-drying program.Moisture in the freeze-drying powder-injection can be according to many
Known method is determined, such as dry weight-loss method.
In the present invention, for the pH value of regulating liquid medicine when necessary, appropriate pH regulations can be added into composition
Agent.Although the present inventor is only with strong acid or the strong base solution such as sodium hydrate aqueous solution and aqueous hydrochloric acid solution for not having buffer capacity
It is adjusted, if however, it will be appreciated by those skilled in the art that body can be met with this pH adjusting agent processing for not having buffer capacity
The pH requirements of system, then the pH adjusting agent with buffer capacity will be better able to realize the object of the invention, therefore these buffers are not
But pH value can be adjusted, and can stable pH value.Therefore the listed any pH adjusting agent of the present invention or its combination are included in this hair
In bright spirit and scope.
When preparing freeze drying powder injection of the present invention, in the decoction prepared, solid content be for 1~20% (w/v), it is excellent
1~15% (w/v) is selected, even more preferably 1~10%, even more preferably 1~5%.Because freeze drying powder injection is typically in tubulose XiLin
It is freeze-dried in bottle, skilled artisan understands that this product is obtaining finished product or even using it for doctor
Before, a round pie is typically each presented, (is slightly contracted although lecture is fewer than the volume of original aqueous solution in the volume theory of the cake
It is small), but generally this diminution will not generally narrow down to raw water liquor capacity 50%, it will usually in the 80- of raw water liquor capacity
Between 120%, between the 90-100% for being more typically in raw water liquor capacity, and it is molten that raw water can be observed out of finished product cillin bottle
Liquid liquid level vestige is (main body pie because remaining in the liquid level vestige in bottle wall after lyophilized reduce, even if the dried frozen aquatic products in cillin bottle
It is in powdered because of a variety of causes reason such as colliding, still can generally retains original liquid level vestige), vestige is also accordingly
Aqueous solution volume of the freeze-dried composition before freeze-drying can be estimated.Therefore, although the present invention is to provide one
Substantially anhydrous freeze-drying powder-injection is planted, but it still can be substantially estimated according to the powder-injection when preparing, at least
The weight of drying end-product in medicine liquid volume before freeze-drying starts, the volume estimated according to this and cillin bottle
Amount, can also be calculated when preparing freeze drying powder injection of the present invention, the content of the solid content in the decoction prepared.Therefore, according to
The freeze drying powder injection of first aspect present invention, its solid content of decoction when preparing is for 1~20% (w/v), preferably 1
~15% (w/v), even more preferably 1~10%, even more preferably 1~5%.
In the present invention, symbol %, according to its used linguistic context, can have skilled addressee readily understands that
Implication.For example when referring to solid content, the symbol represents the percentage (w/v, such as g/100ml) of weight/volume；And example
Such as in " water content " in referring to freeze-drying powder-injection, such as water content is below 8%, and now symbol % represents weight
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % represents weight/volume percentage
Number；Scattered in solids or during liquid dispersion (such as the water content of powder pin) in solids in solid, % represents w/w
Percentage.In other cases, unless otherwise noted, symbol % represents w/w percentage.
It is as well known to those skilled in the art when preparing the decoction of the present invention, e.g., from about 0.45um miillpore filter can be used
Coarse filtration filtering is carried out, before decoction is filled in cillin bottle, e.g., from about 0.22um miillpore filter can be used to carry out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
According to the freeze drying powder injection of the present invention, it is freeze-drying powder-injection.In one embodiment, the freeze-drying
Powder-injection is that the amount of reactive compound in single-dose preparations (such as the bottled powder-injection in XiLin), per unit dosage can be such as
But it is not limited to about 10mg, about 20mg, about 40mg, about 60mg, about about 80mg, 100mg.
According to the freeze drying powder injection of the present invention, it is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably
In 20 seconds, more preferably in 15 seconds.
According to the freeze drying powder injection of the present invention, the solution and basis of the 10mg containing reactive compound in every 1ml is made of water for it
Method under Chinese Pharmacopoeia annex VI H of version two in 2010 is determined, and the pH value of the solution is 5.0~6.0.In an implementation
In scheme, pH value is 5.0~5.5.
The freeze drying powder injection that the present invention is provided can be preserved at least 24 months below 25 DEG C at drying, can meet one
As freeze-drying powder-injection Storage Requirement.
Obtained freeze-drying powder-injection of the present invention particularly freeze-drying powder-injection is usually white or the lyophilized bulk of off-white color
Thing or its fragment or its powder, odorless, bitter are 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..Chinese chemical name：1- methyl -6- oxo -2,3,5,6- tetrahydro indoles -
5- semicarbazone -2- sodium sulfonates.
Carbazochrome Sodium Sulfonate is adapted to urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease bleeding, to urinary system bleeding
Curative effect is more notable, also available for wound and operative hemorrhage.Carbazochrome Sodium Sulfonate can increase resistance of the capillary to damage, reduction
The permeability of capillary, promotes the retraction of capillary fracture end and stops blooding.Acute toxicity test：Mouse intramuscular injection LD50>
1000mg/kg；Maximum non-lethal dose experiment：MNLD>2000mg/kg；Irritation test：Have no obvious tissue degeneratiaon's necrosis；It is molten
Blood test：Red blood cell rupture or cohesion are had no, shows no haemocylolysis.
It is maximum in 0.5~1 hour blood after the oral Carbazochrome Sodium Sulfonate 150mg of health adult man in terms of pharmacokinetics
Concentration reaches 25ng/ml, and half-life period (t1/2) is 1.5 hours, and up to urine drug concentration highest, about 24 is small within oral latter 0.5~1 hour
When excretion finish.
Embodiment
The present invention can be further described by the following examples, however, the scope of the present invention is not limited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out general to the material and test method that are arrived used in experiment
And/or specific description.Although for realize many materials used in the object of the invention and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.Following examples further illustrate the present invention, rather than limit this hair
It is bright.Any only formal rather than substantial equivalent transformation according to made by present inventive concept is regarded as the present invention
Technical scheme category.
In following example, used with a batch of Carbazochrome Sodium Sulfonate raw material if not otherwise indicated, when preparing powder-injection
Medicine (it meets the quality standard of the Pharmacopeia of Japan 16 edition Carbazochrome Sodium Sulfonate recorded of page 533).
In following example, the pH adjusting agent (in the present invention that is, acid-base modifier) used, unless otherwise noted,
It is 1M sodium hydroxide solutions or 1M hydrochloric acid solutions, its consumption is make to be prepared before freeze-drying molten when making to prepare powder-injection
The pH value of liquid is adjusted to a certain setting or scope, and the setting or scope are that freeze-drying gained dry powder is diluted with water for injection
The value or scope of the pH value determined into the solution of the 10mg/ml containing active component.Hereafter preparation process is for the purpose of citing, and
Comparability based on each citing and make some specific description, those skilled in the art completely can be therefrom according to existing knowledge
Summarize the method that the present invention prepares freeze drying powder injection that obtains.Prepared below with liquid in various compositions, if not otherwise indicated, often
What is criticized is always 10000ml with liquid measure, but when listing formula, is illustrated by every bottle of amount containing 40mg in terms of Carbazochrome Sodium Sulfonate.
Assay method：
The assay and relevant substance-measuring of various samples (including powder-injection of the present invention) can be carried out according to following methods
(referred to herein as【HPLC methods】)：
【HPLC methods】：With reference to the blue document (Xu Lanlan, etc. high effective liquid chromatography for measuring Carbazochrome Sodium Sulfonate injection of Xu Lan
Relevant material, Chinese Pharmaceutical Journal, 2014,49 (12)：1073) method is carried out, with particular reference to therein 2.1 section liquid chromatograies
Condition carries out and uses 220nm Detection wavelengths；Specifically liquid phase chromatogram condition is：
Chromatographic column：HP-ODS Hypersil posts (4.6mm × 250mm, 5um)；Mobile phase A：0.01mol/L biphosphates
Ammonium salt solution (with phosphorus acid for adjusting pH to 3.0)-acetonitrile (94：6), Mobile phase B：Acetonitrile；Linear gradient elution, program be 0~
10min, B volume fraction are 0%, 10~30min, and B volume fractions are 0%~50%, 30~35min, and B volume fractions are
50%；Detection wavelength：220nm；Column temperature：40℃；Flow velocity：1.0mL/min；Sample size：10uL；Theoretical cam curve presses Carbazochrome Sodium Sulfonate
Peak, which is calculated, is not less than 2500；
Take sample appropriate, plus mobile phase A dissolves and the solution in every 1mL containing about active component 0.5mg is made, as trying
Product solution；Precision measures 1mL, puts in 100mL measuring bottles, scale is diluted to mobile phase, shake up, be used as contrast solution；Take respectively
Contrast solution and need testing solution sample introduction, are detected at 220 wavelength, record chromatogram；Analysing impurity belongs to and calculates impurity level.
Use this【HPLC methods】The content of active component in powder-injection can also be determined with calculated by peak area by external standard method.
Embodiment 1：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 65% of prescription full dose) water for injection is added, is stirred to dissolve,
(b) activated carbon (0.1%) is added in rapid gained decoction one step up, stirred (making absorption 15min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.0；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 5%), and tamponade is produced.
Embodiment 2：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2.67ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 70% of prescription full dose) water for injection is added, is stirred to dissolve,
(b) activated carbon (0.05%) is added in rapid gained decoction one step up, stirred (making absorption 20min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.5；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 7%), and tamponade is produced.
Embodiment 3：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 1.6ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 60% of prescription full dose) water for injection is added, is stirred to dissolve,
(b) activated carbon (0.15%) is added in rapid gained decoction one step up, stirred (making absorption 10min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.3；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 6%), and tamponade is produced.
Embodiment 4：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2.5ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 65% of prescription full dose) water for injection is added, is stirred to dissolve,
(b) activated carbon (0.12%) is added in rapid gained decoction one step up, stirred (making absorption 18min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.3；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying (freeze-drying curve B) removes moisture (moisture is less than 6%), and tamponade is produced.
Embodiment 5：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 62% of prescription full dose) water for injection is added, is stirred to dissolve,
(b) activated carbon (0.08%) is added in rapid gained decoction one step up, stirred (making absorption 14min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.2；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 5%), and tamponade is produced.
Embodiment 6：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 65% of prescription full dose) water for injection is added (in the water for injection
Absolute ethyl alcohol added with 5% (v/v)), it is stirred to dissolve；
(b) activated carbon (0.1%) is added in rapid gained decoction one step up, stirred (making absorption 15min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.0；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 5%), and tamponade is produced.
Embodiment 7：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2.67ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 70% of prescription full dose) water for injection is added (in the water for injection
Absolute ethyl alcohol added with 3% (v/v)), it is stirred to dissolve；
(b) activated carbon (0.05%) is added in rapid gained decoction one step up, stirred (making absorption 20min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.5；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 7%), and tamponade is produced.
Embodiment 8：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 1.6ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 60% of prescription full dose) water for injection is added (in the water for injection
Absolute ethyl alcohol added with 7% (v/v)), it is stirred to dissolve；
(b) activated carbon (0.15%) is added in rapid gained decoction one step up, stirred (making absorption 10min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.3；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 6%), and tamponade is produced.
Embodiment 9：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2.5ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 65% of prescription full dose) water for injection is added (in the water for injection
Absolute ethyl alcohol added with 5% (v/v)), it is stirred to dissolve；
(b) activated carbon (0.12%) is added in rapid gained decoction one step up, stirred (making absorption 18min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.3；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying (freeze-drying curve B) removes moisture (moisture is less than 6%), and tamponade is produced.
Embodiment 10：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
Formula：
Carbazochrome Sodium Sulfonate：40mg,
Acid-base modifier：In right amount, settings of the regulation pH into following preparation method,
Water for injection：To 2ml
Preparation method：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, appropriate (the 62% of prescription full dose) water for injection is added (in the water for injection
Absolute ethyl alcohol added with 5% (v/v)), it is stirred to dissolve；
(b) activated carbon (0.08%) is added in rapid gained decoction one step up, stirred (making absorption 14min), filtering decarbonization
(with aperture be 1um titanium rod decarburization filtering after, then with 0.45um polyether sulfone filter core by decoction coarse filtration)；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component contains
Amount, if necessary (or optionally) adjusted with acid-base modifier to pH5.2；
(d) it is filling in cillin bottle by decoction aseptic filtration (carrying out aseptic filtration with 0.22um polyether sulfone filter core)；
(e) freeze-drying removes moisture (moisture is less than 5%), and tamponade is produced.
Embodiment 11：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection
The dispensing and preparation method of reference implementation example 6, unlike in the water for injection used in step (a) added with 12%,
20% or 30% absolute ethyl alcohol.Three batches of powder pins are made and are designated as Ex111, Ex112, Ex113 respectively.
Above example 1 is into the gained powder-injection of embodiment 11：The whole samples of embodiment 11 can not form regular
Round pie, and there is serious spray bottle phenomenon；Embodiment 1-5 whole samples have severe atrophy, and every bottle adds water
Still it can not be completely dissolved after 3min when 5ml dissolves；Embodiment 6-10 whole samples are respectively formed regular round pie, not withered
Contract, have no spray bottle phenomenon, every bottle add water 5ml dissolving when 25 seconds within can be completely dissolved.In addition, according to current edition Chinese Pharmacopoeia two
Remaining ethanol, has not as a result detected remnants in the gas chromatography measure embodiment 6-10 of portion's annex whole samples.Through
The content of Carbazochrome Sodium Sulfonate is more than 99% in conversion, embodiment 6-10 whole samples.
Embodiment 12：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection (#174)
Preparation technology：Take above three component to mix, add 500ml water for injection dissolving, water for injection is settled to
1000ml makes the concentration 2% of Carbazochrome Sodium Sulfonate solution.It is filling in container with 0.22 μm of miillpore filter aseptic filtration, filling amount
1ml/ branch, carries out lyophilized, tamponade, rolls lid, packaging is produced.
Embodiment 13：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection (#675)
Preparation technology：The Carlow sulphur sodium of recipe quantity is weighed, the water for injection of recipe quantity, 50 DEG C of stirring and dissolvings are added, then claim
The mannitol of recipe quantity is taken, stirring and dissolving adds citric acid-sodium citrate buffer (5mM) of recipe quantity, adds recipe quantity
Activated carbon, stir 30 minutes, first filter decarburization, then use 0.22um membrane filtrations, detect intermediate, filling, lyophilized, capping,
Examine, pack, produce carbazochrome sodium sulfonate freeze-dried powder injection finished product.
Embodiment 14：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection (#656)
1st, it is formulated (weight：g)：Carbazochrome Sodium Sulfonate 1, mannitol 0.1, dextran 2 and sodium hydroxide 0.5.
2nd, preparation method：
1) Carbazochrome Sodium Sulfonate, mannitol and dextran of recipe quantity are added in appropriate water for injection, stirred to completely molten
Solution, obtains solution A；
2) sodium hydroxide is added in appropriate water for injection and dissolved, then add sodium hydroxide solution in solution A, stirring
Uniformly, the pH value for making mixed liquor is 5, obtains solution B；
3) activated carbon of dose volume 0.5% is added into solution B, is boiled after 30min, filtering decarbonization is carried out, filter is collected
Liquid, then with 0.2 μm of miillpore filter aseptic filtration, collect liquor C；
4) liquor C is freeze-dried is made powdered pharmaceutical composition.
Embodiment 15：Prepare Carbazochrome Sodium Sulfonate freeze-drying powder-injection (#330)
Per 2000ml consumptions：Anhydrous Carbazochrome Sodium Sulfonate 20.0g, mannitol 80.0g, medical charcoal 4.0g, fresh water for injection add
To 2000ml.
Preparation method：(1) mannitol is added in the about water for injection of amount of preparation 25%, heating is completely dissolved it, and addition is matched somebody with somebody
The medical charcoal of amount 0.2% (W/V) processed, boils 30 minutes, decarbonization filtering.
(2) water for injection of amount of preparation 30% is taken, less than 40 DEG C are cooled to, anhydrous Carbazochrome Sodium Sulfonate is added, stirring makes its complete
Fully dissolved, solution is added in mannitol filtrate and is well mixed.
(3) 2000ml is injected water to 5.5~6.0 with 10% sodium hydroxide solution regulating liquid medicine pH value, stirred
Uniformly, repetition measurement pH value is 5.5~6.0, successively through 0.45 μm, 0.22 μm of filtering with microporous membrane, after censorship semi-finished product are qualified, hands over and fills
Fill process.
Industrial applicability
The invention provides a kind of injection Carbazochrome Sodium Sulfonate freeze-drying powder-injection with excellent properties, and the injection
With the preparation method of Carbazochrome Sodium Sulfonate freeze-drying powder-injection.Injection Carbazochrome Sodium Sulfonate freeze-drying powder-injection of the present invention can be used for secreting
Urinary system, upper digestive tract, respiratory tract and obstetrical and gynecological disease bleeding.Carbazochrome Sodium Sulfonate is more notable to urinary system bleeding, also
Available for wound and operative hemorrhage.The injection Carbazochrome Sodium Sulfonate freeze-drying powder-injection that the present invention is prepared has excellent reason
Change property.
Claims (14)
1. a kind of freeze-drying powder-injection of Carbazochrome Sodium Sulfonate, it is not added with freeze-dried excipient, and is by including the steps
Prepare：
(a) Carbazochrome Sodium Sulfonate of recipe quantity is weighed, adds in the water for injection of 60 ~ 70% amounts of prescription full dose, the water for injection and adds
There is 3 ~ 7% (v/v) absolute ethyl alcohol, be stirred to dissolve；
(b) activated carbon is added in rapid gained decoction one step up, stirred, filtering decarbonization；
(c) mend and inject water to prescription full dose, stir, determine solution ph and optional measure active component content,
Optionally adjusted with acid-base modifier to pH5.0 ~ 6.0；
(d) it is filling in cillin bottle by decoction aseptic filtration；
(e) freeze-drying removes moisture, and tamponade is produced.
2. freeze-drying powder-injection according to claim 1, it is packed by cillin bottle.
3. freeze-drying powder-injection according to claim 1, it is packed by cillin bottle, and is in cake in cillin bottle
Shape.
4. the content of freeze-drying powder-injection according to claim 1, wherein Carbazochrome Sodium Sulfonate is more than 95%.
5. freeze-drying powder-injection according to claim 1, wherein moisture are less than 5%.
6. freeze-drying powder-injection according to claim 1, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, phosphorus
Acid dihydride sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
7. freeze-drying powder-injection according to claim 1, described acid-base modifier is that hydrochloric acid solution or sodium hydroxide are molten
Liquid.
8. freeze-drying powder-injection according to claim 1, described acid-base modifier is 1M hydrochloric acid solutions or 1M hydroxides
Sodium solution.
9. freeze-drying powder-injection according to claim 1, the amount of the acid-base modifier is to note the freeze drying powder injection
Amount of the pH value of the solution in the range of 5.0 ~ 5.5 when penetrating the solution that the concentration of 10mg/ml containing Carbazochrome Sodium Sulfonate is dissolved into water.
10. freeze-drying powder-injection according to claim 1, the addition of activated carbon described in step (b) is living in decoction
Property charcoal concentration reaches 0.05 ~ 0.15% amount.
11. freeze-drying powder-injection according to claim 1, stirring is 10 ~ 20min of stirring and adsorbing described in step (b).
12. freeze-drying powder-injection according to claim 1, the mode of filtering decarbonization described in step (b) is：It is with aperture
After 1um titanium rod decarburization filtering, then with 0.45um polyether sulfone filter core by decoction coarse filtration.
13. freeze-drying powder-injection according to claim 1, benefit injects water to prescription full dose and referred to described in step (c)
Water for injection is added until activity component concentration is up to the amount in the range of 15 ~ 25mg/ml.
14. freeze-drying powder-injection according to claim 1, aseptic filtration described in step (d) is the polyethers using 0.22um
Sulfone filter core carries out aseptic filtration.
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Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |