CN104490796B - Injection dexamethasone sodium phosphate pharmaceutical composition and preparation method - Google Patents
Injection dexamethasone sodium phosphate pharmaceutical composition and preparation method Download PDFInfo
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- CN104490796B CN104490796B CN201410798472.6A CN201410798472A CN104490796B CN 104490796 B CN104490796 B CN 104490796B CN 201410798472 A CN201410798472 A CN 201410798472A CN 104490796 B CN104490796 B CN 104490796B
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Abstract
The present invention relates to injection dexamethasone sodium phosphate pharmaceutical composition and preparation method.In particular it relates to a kind of injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition, wherein comprising dexamethasone sodium phosphate and freeze-dried excipient, the freeze-dried excipient is selected from：Mannitol, glycine, lactose, sorbierite, sucrose and combinations thereof；The weight ratio of the dexamethasone sodium phosphate and mannitol is 1：(1~50).Injection hexadecadrol sodium phosphate freeze-dried powder injection of the present invention can be used for anaphylaxis and auto-immune inflammatory disease treatment, particularly it is used for CTD, activity rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial astehma, serious dermatitis, ulcerative colitis, acute leukemia etc., some severe infections and poisoning, the complex treatment of malignant lymphoma are also used for, and for some severe infections and poisoning, the complex treatment of malignant lymphoma.Injection hexadecadrol sodium phosphate freeze-dried powder injection of the present invention has excellent pharmaceutical properties as used in the description.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to one kind for anaphylaxis and auto-immune inflammatory disease treatment,
Particularly it is used for CTD, activity rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial astehma, tight
Pipe inflammation, ulcerative colitis, acute leukemia etc., are also used for some severe infections and poisoning, the Synthetic of malignant lymphoma
Treat, and for some severe infections and poisoning, the pharmaceutical composition of the complex treatment of malignant lymphoma, it is more particularly to a kind of
For anaphylaxis and auto-immune inflammatory disease treatment, particularly it is used for CTD, activity rheumatism, class wind
Wet arthritis, lupus erythematosus, serious bronchial astehma, serious dermatitis, ulcerative colitis, acute leukemia etc., are also used for
Some severe infections and poisoning, the complex treatment of malignant lymphoma, and for some severe infections and poisoning, malignant lymphoma
Complex treatment freeze-drying powder-injection pharmaceutical composition, more particularly to a kind of injection dexamethasone sodium phosphate medicine group
Compound, the invention further relates to the preparation method of the injection dexamethasone sodium phosphate pharmaceutical composition.
Background technology
Dexamethasone (Dexamethasone), chemical name：16 Alpha-Methyl -11 β, 17 α, 21- trihydroxies -9 α-pregna-fluorides -
Isosorbide-5-Nitrae-diene -3,20- diketone, its chemical structural formula, chemical formula and molecular weight are as follows：
Dexamethasone is Aeroseb-Dex, with anti-inflammatory, antiallergy, antirheumatic, immunosuppressive action.Its master
It is the reaction by mitigating and preventing tissue to inflammation to want mechanism of action, so as to the performance for reducing inflammation.It is thin by suppressing inflammation
Born of the same parents, including macrophage and leucocyte gathering in inflammation part, and suppress phagocytosis, the release of lysosomal enzyme and inflammation
The synthesis and release of chemical intermediary and play antiinflammatory action.Dexamethasone is prevented from or suppresses cell-mediated immune simultaneously
Reaction, the allergic reaction of retardance, the number for reduce T lymphocytes, monocyte, biting acidic cell, reduce immune globulin with
The binding ability of cell surface receptor, and suppress the synthesis and release of interleukin, so as to reduce T lymphocytes to lymphoblast
Conversion, and mitigate the extension of primary immune response.Dexamethasone also reduces immune thing of checking by basilar memebrane, and can reduce complement
The concentration of composition and immunoglobulin.
Dexamethasone is widely used in the treatment of anaphylaxis and auto-immune inflammatory disease, it may also be used for prevention neonate
The diagnosis of Respiratory Distress Syndrome(RDS), reduction intracranial hypertension and Cushing's syndrome is in cause of disease antidiastole.
Therefore can not be dissolved in water due to dexamethasone needs the preparation such as injection, eye drops of dissolving for some
Deng people are often prepared into the sodium salt of phosphate, i.e. dexamethasone sodium phosphate (Dexamethasone Sodium
Phosphate), the chemical name of dexamethasone sodium phosphate：16 Alpha-Methyl -11 β, 17 α, -9 α of 21- trihydroxies-pregna-fluoride -1,4- two
Alkene -3,20- diketone -21- organic phosphate disodium salts, its chemical structural formula, chemical formula and molecular weight are as follows：
Current dexamethasone sodium phosphate is used for the main of clinic injection with small volume, powder-injection, eye drops etc., and it is former
Material, injection with small volume and eye drops oneself recorded by Chinese Pharmacopoeia 2010 editions (two).
Dexamethasone sodium phosphate chance light, wet, air are extremely unstable, are such as made powder-injection, because water content is low, and the powder
Injection is present in vacuum, and product is difficult to be oxidized, without steam sterilizing in the powder-injection preparation process, it is to avoid this product is because of hyperpyrexia
And decomposed metamorphic, increased the stability of medicine.Compared with liquid drugs injection, transport more facilitates freeze-dried powder, and condition of storage is more
Gently, quality is more stablized.However, powder-injection equally exists some mass defects, such as it is believed that filling in rice on the marketly
Loose sodium phosphate freeze-dried powder injection clarity is not high, easily produces opalescence.Additionally, the ground plug of the report such as Ma Fuying Company in Chongqing production
The loose phosphoric acid sodium injection of rice occurs the problem of incompatibility when with formula mannitol injection liquid compatibility.In addition, dexamethasone phosphoric acid
The chemical stability that the chemical stability of preparation of sodium is for example characterized with its impurity I is also to need what is paid special attention to, such as current edition
Chinese Pharmacopoeia should be less than 1.0% to regulation impurity I in parenteral solution.
Prior art discloses the preparation method of many Dexamethasone sodium phosphate powder injections.For example, CN1559413A
(200410016686.X, Hu Xiuai) discloses a kind of hexadecadrol sodium phosphate freeze-dried powder injection and preparation method, its composition master
To include dexamethasone sodium phosphate, freeze-dried powder supporting agent, antioxidant and pH adjusting agent, its parts by weight is:Dexamethasone phosphoric acid
1 part of sodium, 0~500 part of freeze-dried powder supporting agent, 1 part of antioxidant, appropriate pH adjusting agent.Every bottle of freeze drying powder injection phosphorus containing dexamethasone
Sour 1~50mg of sodium, preferably 2~20mg.The invention belongs to adrenal cortex hormones drug, due to dexamethasone sodium phosphate pair
Light, wet, air are extremely unstable, using the dosage form-freeze drying powder injection of the invention, than liquid drugs injection good stability.It is believed that should
The preparation process is simple for providing is invented, product quality is easily-controllable, and storage and transport more facilitate.
CN101703484A (200910250340.9, rich original) discloses a kind of hexadecadrol sodium phosphate freeze-dried powder injection
Preparation method, comprises the following steps：After mannitol is dissolved, activated carbon is added, filtered after boiling, add dexamethasone phosphoric acid
Sodium, is configured to liquid；Liquid is through pre-freeze, primary freeze drying, secondary freeze drying；Then hydraulic pressure is jumped a queue, rolls lid, packaging.According to
The advantage for believing the invention is to improve preparating liquid and freeze drying process, and the content of dexamethasone sodium phosphate is not influenceed, and
And single batch of yield can be improved, and while shortening freeze-drying time, product stability, and energy-saving and production-increase are improve, reduce production
Cost.
CN102293757A (201110252599.4, good recipe) discloses a kind of freezing-drying powder-injection contg. dexamethasone combination
Thing, it is characterized in that the composition before lyophilized includes dexamethasone sodium phosphate, sweet dew alcohol and water, its ratio is 2~5 weight portions：10
~40 weight portions：0.5~1.2 parts by volume；It is believed that the present invention is simple, product quality is easily-controllable, is suitable to large-scale production,
And storage and transport more facilitate；And it is believed that the invention has good stability compared with liquid drugs injection product, quality is high, the storage cycle is long
Advantage.
CN103371980A (201210132758.1, gold credit) discloses a kind of hexadecadrol sodium phosphate freeze-dried powder injection,
Formula is every bottle and contains dexamethasone sodium phosphate 1-20mg, excipient 20-150mg, and pH adjusting agent, the powder-injection is to be formulated
Middle composition be dissolved in it is freeze-dried again after solvent be prepared from, it is characterized in that described solvent is the water for injection containing ethanol, match somebody with somebody
Composition in side is dissolved in the ethanol that the liquid being made after solvent contains percent by volume 5-10%.But art methods system
Standby powder-injection can not but overcome above mentioned problem.
Therefore, Decadrol such as its freeze dried powder pin for having excellent quality is still expected in this area
Agent, such as its impurity content it is relatively low and/or its be not in incompatibility and/or when with liquid be not in opalescence ground
Sai meter Song sodium phosphate freeze-dried powder injection agent is provided in clinic.
The content of the invention
It is an object of the invention to provide a kind of hexadecadrol sodium phosphate freeze-dried powder injection, the dexamethasone sodium phosphate is expected
Freeze drying powder injection has excellent pharmaceutical properties for example with excellent quality and/or excellent quality stability.People is gone out
Expect ground to find, the hexadecadrol sodium phosphate freeze-dried powder injection prepared by the present invention at least obtains the sheet of one side
The pharmaceutical properties that field is expected with regard to this product.The present invention is accomplished based on this discovery.
Therefore, first aspect present invention provides a kind of injection hexadecadrol sodium phosphate freeze-dried powder injection drug regimen
Thing, wherein comprising dexamethasone sodium phosphate and freeze-dried excipient.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the freeze-dried excipient is selected from：Mannitol, glycine, lactose, sorbierite, sucrose and combinations thereof.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the freeze-dried excipient includes mannitol.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the weight ratio of the dexamethasone sodium phosphate and mannitol is 1：(1~50).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the weight ratio of the dexamethasone sodium phosphate and mannitol is 1：(2~30).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the weight ratio of the dexamethasone sodium phosphate and mannitol is 1：(2.5~25).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the freeze-dried excipient also includes glycine.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the mannitol is 1 with the weight ratio of glycine：(0.1~0.5).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the mannitol is 1 with the weight ratio of glycine：(0.2~0.4).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the mannitol is 1 with the weight ratio of glycine：(0.2~0.3).It has been unexpectedly discovered that working as mannitol
When being used with glycine combination, can not only avoid being produced when with liquid the problem of opalescence, and can avoid being noted with mannitol
The incompatibility problem of liquid compatibility is penetrated, more surprisingly the powder-injection of this formula is special miscellaneous with the extension of its storage period
Matter increases slow, and only could realize above-mentioned purpose when mannitol and both glycine are used simultaneously；Particularly, these
Function of the conventional freeze-dried excipient in this area is to confer to the specific shape of freeze drying powder injection, but they are in the present invention
Existing technique effect is but completely unrelated with its conventional func.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, it is unit dosage formulation.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, it is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 1-50mg.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, it is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 1-30mg.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, it is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 2-20mg.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, it is unit dosage formulation, the amount of the dexamethasone sodium phosphate included in each unit formulation is 2mg, 5mg,
10mg, 15mg or 20mg.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, when it is made in every 1ml solution the solution containing dexamethasone sodium phosphate 10mg of water dissolves, the pH value of the solution is 7.5
To 8.5.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein also including acid-base modifier.In one embodiment, the species of the acid-base modifier is not particularly limited,
As long as it can adjust the pH value of the freeze drying powder injection (and/or will prepare intermediate during the freeze drying powder injection is prepared)
Save to desired scope.In one embodiment, the acid-base modifier is selected from NaOH, potassium hydroxide, phosphoric acid
Sodium dihydrogen, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the consumption of the acid-base modifier is so that described pharmaceutical composition with water for injection redissolve to substantially with it is cold
Dry preceding solution identical volume is freezed, resulting solution is surveyed according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010
Fixed, the pH value of the solution is 7.5 to 8.5.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein the consumption of the acid-base modifier is so that the dissolving of described pharmaceutical composition water for injection is made every 1ml solution
In containing dexamethasone sodium phosphate 10mg solution when, according under Chinese Pharmacopoeia annex VI H of version two in 2010 method survey
Fixed, the pH value of the solution is 7.5 to 8.5.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, its solid content in solution before freeze-drying be 2~20% (w/v), such as 3~15% (w/v), such as 3~
10% (w/v).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
The weight sum of compound, wherein dexamethasone sodium phosphate and freeze-dried excipient accounts for 2~20% (w/ of liquor capacity before freeze-drying
V), such as 3~15% (w/v), such as 3~10% (w/v).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, its with water for injection redissolve to substantially with freeze-drying before solution identical volume, the solid content in resulting solution contains
It is 2~20% (w/v) to measure, such as 3~15% (w/v), such as 3~10% (w/v).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, its with water for injection redissolve to substantially with freeze-drying before solution identical volume, wherein dexamethasone sodium phosphate and
The weight sum of freeze-dried excipient accounts for 2~20% (w/v), such as 3~15% (w/v), such as 3~10% for redissolving liquor capacity
(w/v)。
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein moisture are less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3%.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, it is substantially to be prepared by including the steps：
A () takes the active component and freeze-dried excipient of recipe quantity, add appropriate water for injection, makes dissolving, adds work
Property charcoal, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier (such as acid solution or aqueous slkali) if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
The filtered filtrate of compound, wherein step (c) gained, wherein solid content are 2~20% (w/v), such as 3~15% (w/
V), such as 3~10% (w/v).
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein step (a) the appropriate water for injection are about the 50~80% of water for injection recipe quantity.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
It refers to add water to the concentration for causing active component in solution that compound, wherein step (b) benefit inject water to its recipe quantity
Up to 2~20mg/ml.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, wherein step (a) activated carbon dosage are the 0.05%~1% of solution weight, preferably 0.05%~0.5%.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Compound, acid solution and aqueous slkali are to use the aqueous solution being configured to selected from following pH adjusting agent wherein described in step (b)：Hydrogen
Sodium oxide molybdena, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphur
Acid or its combination.The concentration of these aqueous solution is well known to a person skilled in the art such as 1~10%, such as 2%~5%.
The injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group of any embodiment according to a first aspect of the present invention
Moisture is excellent less than 10%, preferably shorter than 8% in gained freeze-drying material after removing moisture in compound, wherein step (c)
Choosing is less than 5%, more preferably less than 3%.
Further, second aspect present invention is provided and prepares injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group
Compound (such as injection hexadecadrol sodium phosphate freeze-dried powder injection drug regimen described in first aspect present invention any embodiment
Thing) method, described pharmaceutical composition include dexamethasone sodium phosphate and freeze-dried excipient；The method is comprised the following steps：
A () takes the active component and freeze-dried excipient of recipe quantity, add appropriate water for injection, makes dissolving, adds work
Property charcoal, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier (such as acid solution or aqueous slkali) if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Dexamethasone sodium phosphate and freeze-dried excipient are included in powder-injection pharmaceutical composition.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Freeze-dried excipient is selected from described in powder-injection pharmaceutical composition：Mannitol, glycine, lactose, sorbierite, sucrose and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Freeze-dried excipient described in powder-injection pharmaceutical composition includes mannitol.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The weight ratio of dexamethasone sodium phosphate and mannitol described in powder-injection pharmaceutical composition is 1：(1~50).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The weight ratio of dexamethasone sodium phosphate and mannitol described in powder-injection pharmaceutical composition is 1：(2~30).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The weight ratio of dexamethasone sodium phosphate and mannitol described in powder-injection pharmaceutical composition is 1：(2.5~25).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Freeze-dried excipient described in powder-injection pharmaceutical composition also includes glycine.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Mannitol described in powder-injection pharmaceutical composition is 1 with the weight ratio of glycine：(0.1~0.5).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Mannitol described in powder-injection pharmaceutical composition is 1 with the weight ratio of glycine：(0.2~0.4).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Mannitol described in powder-injection pharmaceutical composition is 1 with the weight ratio of glycine：(0.2~0.3).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 1-
50mg。
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 1-
30mg。
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 2-
20mg。
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is
2mg, 5mg, 10mg, 15mg or 20mg.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
When powder-injection pharmaceutical composition is made in every 1ml solution the solution containing dexamethasone sodium phosphate 10mg of water dissolves, the solution
PH value is 7.5 to 8.5.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Also include acid-base modifier in powder-injection pharmaceutical composition.In one embodiment, the species of the acid-base modifier is not received
Especially limitation, as long as its can by the freeze drying powder injection (and/or prepare the freeze drying powder injection during will prepare in the middle of
Thing) pH value adjust to desired scope.In one embodiment, the acid-base modifier is selected from NaOH, hydrogen
Potassium oxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its group
Close.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The consumption of acid-base modifier is described in powder-injection pharmaceutical composition so that described pharmaceutical composition water for injection is redissolved to base
In sheet with freeze-drying before solution identical volume, resulting solution is according under Chinese Pharmacopoeia annex VI H of version two in 2010
Method is determined, and the pH value of the solution is 7.5 to 8.5.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The consumption of acid-base modifier is described in powder-injection pharmaceutical composition so that the dissolving of described pharmaceutical composition water for injection is made
When containing the solution of dexamethasone sodium phosphate 10mg in per 1ml solution, according under Chinese Pharmacopoeia annex VI H of version two in 2010
Method determine, the pH value of the solution is 7.5 to 8.5.
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Solid content of the powder-injection pharmaceutical composition in solution before freeze-drying is 2~20% (w/v), such as 3~15% (w/
V), such as 3~10% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The weight sum of dexamethasone sodium phosphate and freeze-dried excipient accounts for 2 of liquor capacity before freeze-drying in powder-injection pharmaceutical composition
~20% (w/v), such as 3~15% (w/v), such as 3~10% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition with water for injection redissolve to substantially with freeze-drying before solution identical volume, in resulting solution
Solid content is 2~20% (w/v), such as 3~15% (w/v), such as 3~10% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition with water for injection redissolve to substantially with freeze-drying before solution identical volume, wherein dexamethasone
The weight sum of sodium phosphate and freeze-dried excipient accounts for 2~20% (w/v), such as 3~15% (w/v), example for redissolving liquor capacity
Such as 3~10% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Moisture is less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3% in powder-injection pharmaceutical composition.
The filtered filtrate of the method for any embodiment according to a second aspect of the present invention, wherein step (c) gained, wherein
Solid content is 2~20% (w/v), such as 3~15% (w/v), such as 3~10% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein step (a) the appropriate water for injection are notes
Penetrate about 50~80% with water recipe quantity.
The method of any embodiment according to a second aspect of the present invention, wherein step (b) benefit injects water to it
Recipe quantity refers to add water to cause the concentration of active component in solution up to 2~20mg/ml.
The method of any embodiment according to a second aspect of the present invention, wherein step (a) activated carbon dosage is solution
The 0.05%~1% of weight, preferably 0.05%~0.5%.
The method of any embodiment, acid solution and aqueous slkali wherein described in step (b) according to a second aspect of the present invention
It is to use the aqueous solution being configured to selected from following pH adjusting agent：NaOH, potassium hydroxide, sodium dihydrogen phosphate, phosphoric acid hydrogen two
Sodium, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.The concentration of these aqueous solution is ability
Known to field technique personnel, such as 1~10%, such as 2%~5%.
The method of any embodiment, wherein removes gained freezing after moisture according to a second aspect of the present invention in step (c)
Moisture is less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3% in dried material.
Further, third aspect present invention provides control injection hexadecadrol sodium phosphate freeze-dried powder injection medicine group
The method that impurity gathers way in compound.
The method of any embodiment according to a third aspect of the present invention, wherein the impurity is impurity I.I.e. 2010 versions
《Chinese Pharmacopoeia》With ground in the high performance liquid chromatography of the Related substances separation in two dexamethasone sodium phosphate injections of page 251
Sai meter Song sodium phosphates peak relative retention time is about 0.25 impurity, or perhaps such as the present invention【HPLC methods】With【Relevant material
Inspection technique】Identified and dexamethasone sodium phosphate peak relative retention time is about 0.25 impurity.
The method of any embodiment according to a third aspect of the present invention, the method includes being freezed using dexamethasone sodium phosphate
Excipient is prepared into freeze-drying powder-injection together.
The method of any embodiment according to a third aspect of the present invention, wherein the freeze-dried excipient is selected from：It is mannitol, sweet
Propylhomoserin, lactose, sorbierite, sucrose and combinations thereof.
The method of any embodiment according to a third aspect of the present invention, wherein the freeze-dried excipient includes mannitol.
The method of any embodiment according to a third aspect of the present invention, wherein the dexamethasone sodium phosphate and mannitol
Weight ratio is 1：(1~50).
The method of any embodiment according to a third aspect of the present invention, wherein the dexamethasone sodium phosphate and mannitol
Weight ratio is 1：(2~30).
The method of any embodiment according to a third aspect of the present invention, wherein the dexamethasone sodium phosphate and mannitol
Weight ratio is 1：(2.5~25).
The method of any embodiment according to a third aspect of the present invention, wherein the freeze-dried excipient also includes glycine.
The method of any embodiment according to a third aspect of the present invention, wherein the mannitol is with the weight ratio of glycine
1：(0.1~0.5).
The method of any embodiment according to a third aspect of the present invention, wherein the mannitol is with the weight ratio of glycine
1：(0.2~0.4).
The method of any embodiment according to a third aspect of the present invention, wherein the mannitol is with the weight ratio of glycine
1：(0.2~0.3).
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 1-
50mg。
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 1-
30mg。
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is 2-
20mg。
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is unit dosage formulation, and the amount of the dexamethasone sodium phosphate included in each unit formulation is
2mg, 5mg, 10mg, 15mg or 20mg.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
When powder-injection pharmaceutical composition is made in every 1ml solution the solution containing dexamethasone sodium phosphate 10mg of water dissolves, the solution
PH value is 7.5 to 8.5.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Also include acid-base modifier in powder-injection pharmaceutical composition.In one embodiment, the species of the acid-base modifier is not received
Especially limitation, as long as its can by the freeze drying powder injection (and/or prepare the freeze drying powder injection during will prepare in the middle of
Thing) pH value adjust to desired scope.In one embodiment, the acid-base modifier is selected from NaOH, hydrogen
Potassium oxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its group
Close.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The consumption of acid-base modifier is described in powder-injection pharmaceutical composition so that described pharmaceutical composition water for injection is redissolved to base
In sheet with freeze-drying before solution identical volume, resulting solution is according under Chinese Pharmacopoeia annex VI H of version two in 2010
Method is determined, and the pH value of the solution is 7.5 to 8.5.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The consumption of acid-base modifier is described in powder-injection pharmaceutical composition so that the dissolving of described pharmaceutical composition water for injection is made
When containing the solution of dexamethasone sodium phosphate 10mg in per 1ml solution, according under Chinese Pharmacopoeia annex VI H of version two in 2010
Method determine, the pH value of the solution is 7.5 to 8.5.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Solid content of the powder-injection pharmaceutical composition in solution before freeze-drying is 2~20% (w/v), such as 3~15% (w/
V), such as 3~10% (w/v).
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
The weight sum of dexamethasone sodium phosphate and freeze-dried excipient accounts for 2 of liquor capacity before freeze-drying in powder-injection pharmaceutical composition
~20% (w/v), such as 3~15% (w/v), such as 3~10% (w/v).
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition with water for injection redissolve to substantially with freeze-drying before solution identical volume, in resulting solution
Solid content is 2~20% (w/v), such as 3~15% (w/v), such as 3~10% (w/v).
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition with water for injection redissolve to substantially with freeze-drying before solution identical volume, wherein dexamethasone
The weight sum of sodium phosphate and freeze-dried excipient accounts for 2~20% (w/v), such as 3~15% (w/v), example for redissolving liquor capacity
Such as 3~10% (w/v).
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Moisture is less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3% in powder-injection pharmaceutical composition.
The method of any embodiment according to a third aspect of the present invention, wherein the injection dexamethasone sodium phosphate is lyophilized
Powder-injection pharmaceutical composition is substantially to be prepared by including the steps：
A () takes the active component and freeze-dried excipient of recipe quantity, add appropriate water for injection, makes dissolving, adds work
Property charcoal, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier (such as acid solution or aqueous slkali) if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
The filtered filtrate of the method for any embodiment according to a third aspect of the present invention, wherein step (c) gained, wherein
Solid content is 2~20% (w/v), such as 3~15% (w/v), such as 3~10% (w/v).
The method of any embodiment according to a third aspect of the present invention, wherein step (a) the appropriate water for injection are notes
Penetrate about 50~80% with water recipe quantity.
The method of any embodiment according to a third aspect of the present invention, wherein step (b) benefit injects water to it
Recipe quantity refers to add water to cause the concentration of active component in solution up to 2~20mg/ml.
The method of any embodiment according to a third aspect of the present invention, wherein step (a) activated carbon dosage is solution
The 0.05%~1% of weight, preferably 0.05%~0.5%.
The method of any embodiment, acid solution and aqueous slkali wherein described in step (b) according to a third aspect of the present invention
It is to use the aqueous solution being configured to selected from following pH adjusting agent：NaOH, potassium hydroxide, sodium dihydrogen phosphate, phosphoric acid hydrogen two
Sodium, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.The concentration of these aqueous solution is ability
Known to field technique personnel, such as 1~10%, such as 2%~5%.
The method of any embodiment, wherein removes gained freezing after moisture according to a third aspect of the present invention in step (c)
Moisture is less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3% in dried material.
Any technical characteristic that any embodiment of either side of the present invention or the either side has is equally applicable
Any embodiment of other any embodiments or other either sides, as long as they will not be conflicting, certainly mutual
Between where applicable, if necessary can individual features be made with appropriate modification.Make into one with feature to various aspects of the present invention below
The description of step.
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 statement of the invention.Additionally, 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 explains, the term and phrase for referring to if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
It is further described to various aspects of the present invention below.
In the method for the invention step, although its description specific steps in some details or language description on
The step of described in the preparation example of following detailed description part, is otherwise varied, however, those skilled in the art are according to this
The detailed disclosure of invention full text can summarize above the method for the invention step completely.
In the present invention, if not otherwise indicated, it is according to the present invention during amount of the relevant material in the various materials of measure
【HPLC methods】Carry out.In the present invention, if not otherwise indicated, in the material for determining various compositions active component content
When, it is according to the present invention【HPLC methods】Carry out.
The preparation process of freeze-drying powder-injection is 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：
In preparing the instantiation in freeze-drying powder-injection below, if not otherwise specified, lyophilized song used
Line is freeze-drying curve A.
Moisture in freeze-drying powder-injection is generally below 10%, preferably shorter than 8%, preferably shorter than 5%, more excellent
Choosing is less than 3%.Moisture control can be controlled by appropriate adjustment freeze-drying program.Moisture in the freeze-drying powder-injection contains
Amount can be determined according to many known methods, such as dry weight-loss method.
When freeze drying powder injection of the present invention is prepared, in the liquid prepared, solid content is 2~20% (w/v), for example
3~15% (w/v), such as 3~10% (w/v).Because freeze drying powder injection is typically to carry out freeze-drying in tubulose cillin bottle
Obtain, skilled artisan understands that this product is obtaining finished product even before for doctor's use, be typically each presented one
Round pie, although lecture is fewer than the volume of original aqueous solution in the volume theory of the cake (slightly reducing), however it is generally this
Diminution will not generally narrow down to raw water liquor capacity 50%, it will usually between the 80-120% of raw water liquor capacity, more generally
Between the 90-100% of raw water liquor capacity, and raw water liquid level of solution vestige (main body can be observed from finished product cillin bottle
Pie because freeze reduce after remain in liquid level vestige in bottle wall, even if dried frozen aquatic products in cillin bottle is for example touched because of a variety of causes
The reason such as hit and be in powdered, still can generally retain original liquid level vestige), vestige can also estimate the freezing and do accordingly
Aqueous solution volume of the dry composition before freeze-drying.Therefore, although the present invention is to provide a kind of substantially anhydrous freezing
Powder-injection is dried, but it still can be substantially estimated according to the powder-injection when preparing, at least start it in freeze-drying
Preceding medicine liquid volume, the weight for drying end-product in the volume estimated according to this and cillin bottle can be also calculated in system
During standby freeze drying powder injection of the present invention, the content of the solid content in the liquid prepared.Therefore, jelly according to a first aspect of the present invention
Dry powder injection, its prepare when liquid solid content for 2~20% (w/v), such as 3~15% (w/v), such as 3~
10% (w/v).
Term " solid content " refer to solid matter (such as reactive compound of the present invention and whole excipient used,
Weight/gram) be added in solvent (such as water for injection), obtain a solution after dissolving, the weight of the solid matter divided by
The percentage (weight/volume percentage, such as g/100ml) of whole liquor capacity.
In the present invention, symbol %, according to the linguistic context that it is used, can have skilled addressee readily understands that
Implication.For example when solid content is referred to, 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, below 8%, now symbol % represents weight to such as moisture
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % represents weight/volume percentage
Number；In solid dispersion in solids or during liquid dispersion (such as the water content of powder pin) in solids, % 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 liquid of the invention is prepared, the e.g., from about miillpore filter of 0.45um can be used
Coarse filtration filtering is carried out, before liquid is filled in cillin bottle, it is possible to use e.g., from about the miillpore filter of 0.22um carries out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
Powder-injection of the invention, it is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably 20
In second, more preferably in 15 seconds.
Freeze drying powder injection of the invention, it is made in every 1ml solution and basis containing reactive compound 10mg of water
Method under Chinese Pharmacopoeia annex VI H of version two in 2010 is determined, and the pH value of the solution is 7.5 to 8.5.
The freeze drying powder injection that the present invention is provided can be preserved at least 24 months in cool dark place, can be met general freezing and be done
The Storage Requirement of dry powder-injection.
It has been found that freeze-drying powder-injection of the present invention has good pharmaceutical properties for example with excellent chemically stable
Property.
Freeze-drying powder-injection of the present invention clinically can be used for anaphylaxis and auto-immune inflammatory disease.It is used for
CTD, activity rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial astehma, serious dermatitis, ulcer
Property colitis, acute leukemia etc., are also used for some severe infections and poisoning, the complex treatment of malignant lymphoma.
Injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition of the present invention usage and dosage clinically is usual
It is as follows：General dosage, is injected intravenously 2~20mg every time；During drip-feed, should be diluted with 5% glucose injection, can be 2~6 small
When repeat administration to stable disease, but heavy dose of successive administration is usually no more than 72 hours.Can also be used to alleviate malignant tumour institute
The encephaledema of cause, first dose of intravenous injection 10mg, subsequent every 4mg of intramuscular injection in 6 hours, general 12~24 hours patients can have inclination
Turn, gradually decrement after 2~4 days, be discontinued within 5~7 days.To inoperable brain tumor, first dose can intravenous injection 50mg, later every 2
Hour repeats to give 8mg, reduces to daily 2mg after a couple of days again, and point 2~3 veins give.For each 5mg of intrathecal injection, interval
Injection in 1~3 week is once；General 0.8~the 4mg every time of intraarticular injection, depending on articular cavity size.
Dexamethasone sodium phosphate is Aeroseb-Dex, and with anti-inflammatory, antiallergy is antitoxin to wait effect, can be used for
The allergy such as infectious serious adrenocortical insufficiency, CTD, serious bronchitis asthma.Dexamethasone
Sodium phosphate has antiinflammatory action：This product mitigates and prevents reaction of the tissue to inflammation, so as to the performance for reducing inflammation.Can suppress
Inflammatory cell, including macrophage and leucocyte gathering in inflammation part, and suppress phagocytosis, the release of lysosomal enzyme with
And the synthesis and release of inflammation chemistry intermediary.Dexamethasone sodium phosphate also has antiallergy, immunosuppressive action：Including preventing
Or suppressing cell-mediated immune response, the allergic reaction of retardance reduces T lymphocytes, monocyte, bites acidic cell
Number, reduces the binding ability of immunoglobulin and cell surface receptor, and suppresses the synthesis and release of interleukin, so as to reduce
T lymphocytes mitigate the extension of the primary immune response of feelings to lymphoblastic transformation.This product is also reduced immune to be checked thing and passes through
Basilar memebrane, and the concentration of complement component and immunoglobulin can be reduced.
Injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition of the present invention presents gratifying pharmacy effect
Really.
Specific embodiment
The present invention can be conducted further description 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 to used in experiment to material and test method carry out generality
And/or specific description.Although for realize many materials that the object of the invention used 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 limiting this hair
It is bright.
Hereafter preparation process in order to citing purpose, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize the method that the present invention prepares freeze drying powder injection that obtains according to existing knowledge completely.Under
Face prepares in various compositions with liquid, and if not otherwise indicated, every batch is always 5000ml with liquid measure；But list formula and prepare
During process, for powder-injection, formula and preparation method are illustrated with the composition of every bottle of active component and other materials of corresponding weight portion
(especially for embodiment 1-7 and embodiment 11-14).When with liquid, when using acid-base modifier (i.e. pH adjusting agent)
When, it is 1M hydrochloric acid solutions or 1M sodium hydroxide solutions, on the basis of the auxiliary agent has been used, the amount of the acid-base modifier is
Make the pH value of the liquid before freeze-drying in the range of 7.8~8.2.
In tests below, if not otherwise indicated, during using charcoal absorption, consumption is the amount commonly used in production, i.e.,
0.1% (adding activated carbon 0.1g in i.e. per 100ml liquids).In tests below, when preparing freeze drying powder injection, the activity for using
Composition is that (it is according to the present invention with a collection of bulk drug【HPLC methods】Checked, impurity I contents 0.14%), unless otherwise indicated.
In the present invention, used during relevant material in measure powder-injection following【HPLC methods】With【Related substances separation method】
Carry out.
【HPLC methods】：
Determined according to high performance liquid chromatography (the two annex VD of version Chinese Pharmacopoeia in 2010)；
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；With triethylamine solution
(triethylamine 7.5ml is taken, 1000ml is diluted with water to, with ± the 0.05)-methanol-acetonitrile (55 of phosphorus acid for adjusting pH value to 3.0：40：5)
It is mobile phase；Detection wavelength is 242nm；
Take dexamethasone sodium phosphate and dexamethasone, plus methyl alcohol dissolve and dilute be made it is each molten containing about 10 μ g in every 1ml
Liquid, takes 20 μ l injection liquid chromatographs, records chromatogram, and number of theoretical plate is calculated by dexamethasone sodium phosphate peak and is not less than 7000,
Dexamethasone sodium phosphate peak should be greater than 4.4 with the separating degree at dexamethasone peak.
【Related substances separation method】：
Take powder-injection, plus mobile phase quantitatively dilutes the solution being made in every 1ml containing about dexamethasone sodium phosphate 0.5mg, makees
It is need testing solution；Precision measures lml, puts in 100ml measuring bottles, and scale is diluted to mobile phase, shakes up, as contrast solution；
Use【HPLC methods】, the μ l of contrast solution 20 injection liquid chromatographs are taken, detection sensitivity is adjusted, make principal component chromatogram
The peak height at peak is about the 20% of full scale；Precision measures need testing solution and each 20 μ l of contrast solution again, is injected separately into liquid phase color
Spectrometer, 2 times of record chromatogram to principal component peak retention time；
It is (miscellaneous if any the impurity for being about 0.25 with dexamethasone sodium phosphate peak relative retention time in need testing solution chromatogram
Matter I) peak, the content of impurity I is calculated with reference to contrast solution.For dexamethasone sodium phosphate ejection preparation, typically wherein
Impurity I contents should require (to be not more than the main peak area of contrast solution) less than 1.0%.
Embodiment 1：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 10mg,
Mannitol 50mg,
Glycine 12.5mg,
With liquid water for injection 1ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 70%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
Embodiment 2：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 2mg,
Mannitol 50mg,
Glycine 15mg,
With liquid water for injection 1ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 60%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
Embodiment 3：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 20mg,
Mannitol 50mg,
Glycine 10mg,
With liquid water for injection 1ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 80%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
Embodiment 4：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 10mg,
Mannitol 50mg,
Glycine 12.5mg,
With liquid water for injection 0.725ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 50%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
Embodiment 5：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 10mg,
Mannitol 50mg,
Glycine 12.5mg,
With liquid water for injection 2.41ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 70%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
Embodiment 6：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 5mg,
Mannitol 50mg,
Glycine 12.5mg,
With liquid water for injection 2ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 70%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
Embodiment 7：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Formula：
Dexamethasone sodium phosphate 2.5mg,
Mannitol 50mg,
Glycine 12.5mg,
With liquid water for injection 1.2ml；
Preparation method：
A () takes the active component and freeze-dried excipient of recipe quantity, add the water for injection of recipe quantity 70%, makes dissolving, then
Add activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture (making moisture be less than 3%),
Tamponade, obtains final product.
The present embodiment carries out freeze-drying using freeze-drying curve B.
Embodiment 11：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
The formula and preparation method of embodiment 1-7 are respectively referred to, different is only not use glycine therein, obtain 7 batches
Secondary powder-injection, can be designated as respectively E111 (reference implementation example 1 be obtained, also there is similar meaning below), E112, E113, E114,
E115、E116、E117。
Embodiment 12：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
The formula and preparation method of embodiment 1-7 are respectively referred to, different is only that glycine therein is replaced with into the sweet of equivalent
Dew alcohol, obtains 7 powder-injection of batch, can respectively be designated as E121, E122, E123, E124, E125, E126, E127.
Embodiment 13：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
The formula and preparation method of embodiment 1-7 are respectively referred to, different is only not use mannitol therein, obtain 7 batches
Secondary powder-injection, can respectively be designated as E131, E132, E133, E134, E135, E136, E137.
Embodiment 14：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
The formula and preparation method of embodiment 1-7 are respectively referred to, different is only that mannitol therein is replaced with into the sweet of equivalent
Propylhomoserin, obtains 7 powder-injection of batch, can respectively be designated as E141, E142, E143, E144, E145, E146, E147.
Embodiment 15：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition (gained powder pin can be described as #413E5)
(1) prescription
(2) preparation method
Solution is prepared：Recipe quantity mannitol and sodium hydrogensulfite are taken, the note for having led to nitrogen of total amount of preparation 70% is dissolved in
Penetrate with water, it is 8.0~8.4 to adjust pH with pH adjusting agent, plus recipe quantity dexamethasone sodium phosphate stirring and dissolving, plus amount of preparation
0.05% activated carbon is stirred at room temperature 30 minutes, filtering to clear and bright, with standby after 0.22 μm of miillpore filter aseptic filtration：
Freeze-drying：Above-mentioned refined filtration liquid is taken, is sub-packed in 7ml glass tube vials by every bottle of 2ml (20mg specifications), glass tube vial is put cold
On the flaggy of lyophilizer product room, 4 hours are incubated in -45 DEG C, open water vessel refrigeration switch, after pre-freeze insulation terminates, opened
Vavuum pump is opened, when vacuum reading is down to below 20 handkerchiefs, flaggy temperature is gradually risen to -5 DEG C, 10 hours are incubated, 0 is warming up to
DEG C continue be incubated 3 hours, when products temperature and flaggy temperature it is close when, continue raise flaggy temperature to 30 DEG C and insulation 3 hours,
Terminate to freeze when products temperature is again close to flaggy temperature, vacuum falls lid, tamponade, packaging.
Embodiment 16：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition (gained powder pin can be described as #484E2)
Formula：Dexamethasone sodium phosphate 50g, mannitol 200g, water for injection are added to 10L.
Preparation method：(1) preparating liquid：200g mannitol is quantitatively weighed, 3L waters for injection are added, stirred to being completely dissolved, pressed
Full dose volume adds the activated carbon of 1.0g/L, after boiling 15min, filters carbon removal；Add 5L waters for injection, 50g dexamethasone phosphorus
Sour sodium, is completely dissolved it, measures liquid pH value for 8.02, and benefit injects water to 10L, through the degerming of 0.22 μm of miillpore filter
Filter is filtered to basin, is configured to liquid, standby；(2) freeze-drying：By the condenser temperature of freeze drier (FCM50D types)
Less than -40 DEG C are down in advance, above-mentioned liquid is sub-packed in 2mL glass tube vials by every bottle of 1mL (5mg specifications), be put into freeze drier
Product room flaggy, less than -35 DEG C are reduced in 1h by flaggy temperature, keep low-temperature condition 2h, carry out pre-freeze；Open vacuum
Pump, adjusts the vacuum of freeze drier to below 20Pa, and flaggy temperature is risen into 5 DEG C in 1h, is incubated 4h, is once done
It is dry；Then flaggy temperature is risen to 15 DEG C by control vacuum in 10~20Pa in 1h, is incubated 2h, is then further continued for intensification 1h
It is 38 DEG C to flaggy temperature, is incubated 4h.(lyophilized total time is 16h).(3) freeze after terminating, carry out hydraulic pressure and jump a queue, roll lid, bag
Dress.
Embodiment 17：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition (gained powder pin can be described as #757E1)
Formula：Dexamethasone sodium phosphate：5g, mannitol：40g, inject water to：1000ml.
Preparation method：Dexamethasone sodium phosphate, mannitol, plus the parts by volume of water for injection 800 are weighed by formula ratio, heating stirring makes
Dissolving, add 0.2% needle-use activated carbon, mix, stirring, 40 DEG C~100 DEG C be incubated 10 minutes~30 minutes, coarse filtration takes off charcoal,
Filtrate is mended and injects water to 1000 parts by volume, intermediate after the assay was approved, then with 0.22 μm of filter membrane refined filtration, quantitative filling in
In 2ml cillin bottles, half moulding plug is put in freeze drying box, freezes, total head plug, and outlet lock aluminium lid, packaging fills in rice with obtaining final product
Loose sodium phosphate freeze-dried powder injection.
Embodiment 18：Prepare hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition (gained powder pin can be described as #980E1)
Formula：Dexamethasone sodium phosphate 50g, mannitol 1000g, ethanol 500ml.
Preparation method：1) mannitol and ethanol of recipe quantity are dissolved in 7000ml waters for injection, add 20g activated carbons, 40-60
Degree insulation 20-30 minutes, crosses 0.22 μm of filter membrane and removes activated carbon；Dexamethasone sodium phosphate is added, stirring is completely dissolved it, mends
10000ml is injected water to, pH value is adjusted to 8.0-8.5 with phosphate buffer, by liquid by 0.22 μm of filter element filtering
It is degerming, it is sub-packed in pipe-produced glass bottle, half tamponade.2) pre-freeze, after -40 DEG C of product temperature of control, is incubated 2h.3) lyophilization,
Vavuum pump is opened, control vacuum is gradually heating to control product temperature at -10 DEG C~-8 DEG C in below 40pa, is incubated 2h, then
- 5 DEG C are warming up to, 6h is incubated.4) redrying, control vacuum heats up in below 30pa, product temperature is risen to 33-36
DEG C, freeze drying box is reached capacity vacuum, it is incubated 4h.5) vacuum is released, lid is rolled and is obtained finished product.
Test example 1：Powder-injection Performance
Whole freezing-drying powder-injection contg. dexamethasone agent prepared by above-described embodiment 1-7, embodiment 11-18 are in 40 DEG C of bars
Placed 5 months under part, impurity I contents (%) when determining each injection fluid samples respectively at 0 month and in May；
Press examination and calculate impurity I contents increase percentage (%)：
Impurity I contents increase percentage (%)=
[(- 0 month impurity I content of May impurity I content) 0 month impurity I content of ÷] × 100%
Above-mentioned " impurity I contents increase percentage " value is more big then to represent that product is more unstable.
As a result：The impurity I contents of whole freezing-drying powder-injection contg. dexamethasone agent that embodiment 1-7 is prepared increase by hundred
In the range of 25~54%, the impurity I contents of such as hexadecadrol sodium phosphate freeze-dried powder injection of embodiment 1 increase percentage to fraction
Number is 34%；
It is equal that the impurity I contents of whole freezing-drying powder-injection contg. dexamethasone agent obtained in embodiment 11-18 increase percentage
In the range of 204~287%, the impurity I contents of the sample E111 hexadecadrol sodium phosphate freeze-dried powder injections of such as embodiment 11
It is 253% to increase percentage.
Test example 2：Parenteral solution Performance
The investigation of powder-injection and formula mannitol injection liquid compatibility is carried out with reference to the document of Ma Fuying etc..
Specific method is：Strict implement sterile working, 20% formula mannitol injection liquid 5mL is taken with disposable sterilized injector,
It is sufficiently mixed with injection Dexamethasone sodium phosphate powder injection (with active ingredient 5mg), 0 hour after observation mixing, 0.5 small
When, 1 hour, 2 hours four time points whether there are white casse or White Flocculus.
Using the above method, whole powder-injection obtained in embodiment 1-7 and embodiment 11-18 are investigated.As a result：Embodiment
Four time points do not occur white casse and white flock after seven powder-injection samples of 1-7 mix with formula mannitol injection liquid
Thing, dissolves good；It was unexpectedly determined that complete obtained in whole powder-injection obtained in embodiment 11-14 and embodiment 15-18
Whether portion's powder-injection there are white casse or White Flocculus at 1 hour, 2 hours two time points, and sample segment is small 0
When, 0.5 hour two time point when there are white casse or White Flocculus.For freezing-drying powder-injection contg. dexamethasone
Agent, it has been used together clinical meaning with formula mannitol injection liquid, it is obvious that only in mannitol and glycine combination
When using, the hexadecadrol sodium phosphate freeze-dried powder injection for obtaining could be presented excellent compatibility.
Additionally, by each powder-injection of embodiment of the present invention 1-7 5% glucose injection or 0.9% sodium chloride injection
When matching somebody with somebody liquid according to method in clinical application, opalescence or the bad problem of clarity are showed no.
Additionally, each powder-injection of embodiment of the present invention 1-7 is made of water dissolves respectively containing dexamethasone in every 1ml solution
During the solution of sodium phosphate 10mg, the pH value of these solution is in the range of 7.5 to 8.5.By each powder pin of embodiment of the present invention 1-7
Agent respectively with water for injection redissolve to substantially with freeze-drying before solution identical volume, resulting solution is according to Chinese Pharmacopoeia
Method under annex VI H of version two in 2010 is determined, and the pH value of these solution is in the range of 7.5 to 8.5.By the present invention
Each powder-injection of embodiment 1-7 respectively with water for injection redissolve to substantially with freeze-drying before solution identical volume, gained
Solid content in solution in the range of 3~15% (w/v), particularly in the range of 3~10% (w/v).
Industrial applicability
Injection dexamethasone sodium phosphate pharmaceutical composition of the present invention, it can be used for anaphylaxis and LADA
Inflammatory diseases, are particularly used for CTD, activity rheumatism, rheumatoid arthritis, lupus erythematosus, tight
Weight bronchial astehma, serious dermatitis, ulcerative colitis, acute leukemia etc., are also used for some severe infections and poisoning, pernicious
The complex treatment of lymthoma, and for some severe infections and poisoning, the complex treatment of malignant lymphoma.
Claims (31)
1. a kind of injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition, wherein comprising dexamethasone sodium phosphate and jelly
Dry excipient；The freeze-dried excipient includes mannitol and glycine, and the weight ratio of the two is 1：(0.2~0.3)；Fill in describedly
The weight ratio of the loose sodium phosphate of rice and mannitol is 1：(2.5~25).
2. pharmaceutical composition according to claim 1, it is unit dosage formulation, the ground plug included in each unit formulation
The amount of the loose sodium phosphate of rice is 2-20mg.
3. pharmaceutical composition according to claim 1, it is unit dosage formulation, the ground plug included in each unit formulation
The amount of the loose sodium phosphate of rice is 2mg, 5mg, 10mg, 15mg or 20mg.
4. pharmaceutical composition according to claim 1, it is made 10mg containing dexamethasone sodium phosphate in every 1ml solution with water dissolves
Solution when, the pH value of the solution is 7.5 to 8.5.
5. pharmaceutical composition according to claim 1, wherein also including acid-base modifier.
6. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is noted
Penetrate with water redissolve arrive with freeze-drying before solution identical volume, resulting solution is according to two annex VI of Chinese Pharmacopoeia version in 2010
Method under H is determined, and the pH value of the solution is 7.5 to 8.5.
7. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is noted
Penetrate be made of water dissolves in every 1ml solution containing dexamethasone sodium phosphate 10mg solution when, according to Chinese Pharmacopoeia version two in 2010
Method under portion annex VI H is determined, and the pH value of the solution is 7.5 to 8.5.
8. pharmaceutical composition according to claim 1, its solid content in solution before freeze-drying is 3 ~ 15% (w/v).
9. pharmaceutical composition according to claim 1, its solid content in solution before freeze-drying is 3 ~ 10% (w/v).
10. pharmaceutical composition according to claim 1, the weight sum of wherein dexamethasone sodium phosphate and freeze-dried excipient accounts for cold
Freeze 3 ~ 10% (w/v) of dry preceding liquor capacity.
11. pharmaceutical compositions according to claim 1, it is redissolved with water for injection and arrived and solution identical body before freeze-drying
Product, the solid content in resulting solution is 3 ~ 10% (w/v).
12. pharmaceutical compositions according to claim 1, it is redissolved with water for injection and arrived and solution identical body before freeze-drying
Product, the weight sum of wherein dexamethasone sodium phosphate and freeze-dried excipient accounts for 3 ~ 10% (w/v) for redissolving liquor capacity.
13. pharmaceutical compositions according to claim 1, wherein moisture are less than 5%.
14. pharmaceutical compositions according to claim 1, wherein moisture are less than 3%.
15. pharmaceutical compositions according to claim 1, it is prepared by including the steps：
A () takes the active component and freeze-dried excipient of recipe quantity, add appropriate water for injection, makes dissolving, adds activated carbon,
Stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component content,
Adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；With
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product,
Wherein：
The filtered filtrate of step (c) gained, wherein solid content are 3 ~ 15% (w/v)；
Step (a) the appropriate water for injection is the 50 ~ 80% of water for injection recipe quantity；
Step (b) benefit inject water to its recipe quantity refer to add water to cause the concentration of active component in solution up to 2 ~
20mg/ml；
Step (a) activated carbon dosage is the 0.05% ~ 0.5% of solution weight；
Moisture is less than 5% in gained freeze-drying material after removing moisture in step (c).
16. methods for preparing injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition, described pharmaceutical composition includes
Dexamethasone sodium phosphate and freeze-dried excipient；The freeze-dried excipient includes mannitol and glycine, and the weight ratio of the two is 1：
(0.2~0.3)；The weight ratio of the dexamethasone sodium phosphate and mannitol is 1：(2.5~25)；The method is comprised the following steps：
A () takes the active component and freeze-dried excipient of recipe quantity, add appropriate water for injection, makes dissolving, adds activated carbon,
Stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component content,
Adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product；
Wherein, solid of the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition in solution before freeze-drying
Thing content is 3 ~ 15% (w/v).
17. methods according to claim 16, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition is single
Position dosage formulation, the amount of the dexamethasone sodium phosphate included in each unit formulation is 2-20mg.
18. methods according to claim 16, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition water
When dissolving is made in every 1ml solution the solution containing dexamethasone sodium phosphate 10mg, the pH value of the solution is 7.5 to 8.5.
19. methods according to claim 16, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition reclaimed water
Content is divided to be less than 5%.
The method that impurity gathers way in 20. control injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical compositions, the party
Method includes being prepared into freeze-drying powder-injection together using dexamethasone sodium phosphate and freeze-dried excipient；The freeze-dried excipient bag
Mannitol and glycine are included, the weight ratio of the two is 1：(0.2~0.3)；The weight ratio of the dexamethasone sodium phosphate and mannitol
It is 1：(2.5~25).
21. methods according to claim 20, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition is single
Position dosage formulation, the amount of the dexamethasone sodium phosphate included in each unit formulation is 2-20mg.
22. methods according to claim 20, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition water
When dissolving is made in every 1ml solution the solution containing dexamethasone sodium phosphate 10mg, the pH value of the solution is 7.5 to 8.5.
23. methods according to claim 20, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition is cold
It is 3 ~ 15% (w/v) to freeze the solid content in dry preceding solution.
24. methods according to claim 20, in the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
The weight sum of Sai meter Song sodium phosphates and freeze-dried excipient accounts for 3 ~ 15% (w/v) of liquor capacity before freeze-drying.
25. methods according to claim 20, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition note
Penetrate redissolved with water arrive with solution identical volume before freeze-drying, solid content in resulting solution is 3 ~ 15% (w/v).
26. methods according to claim 20, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition note
Penetrate with water redissolve arrive with freeze-drying before solution identical volume, wherein the weight of dexamethasone sodium phosphate and freeze-dried excipient it
With 3 ~ 15% (w/v) for accounting for redissolution liquor capacity.
27. methods according to claim 20, the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition reclaimed water
Content is divided to be less than 5%.
28. methods according to claim 20, wherein the injection hexadecadrol sodium phosphate freeze-dried powder injection pharmaceutical composition
Prepared by including the steps：
A () takes the active component and freeze-dried excipient of recipe quantity, add appropriate water for injection, makes dissolving, adds activated carbon,
Stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component content,
Adjusted to pH value 7.5 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
29. methods according to claim 28, step (a) the appropriate water for injection is the 50 ~ 80% of water for injection recipe quantity.
30. methods according to claim 28, it refers to add water to so that molten that step (b) benefit injects water to its recipe quantity
The concentration of active component is up to 2 ~ 20mg/ml in liquid.
31. methods according to claim 28, step (a) activated carbon dosage is the 0.05% ~ 0.5% of solution weight.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559413A (en) * | 2004-02-26 | 2005-01-05 | 胡秀爱 | Freezing-drying powder-injection contg. dexamethasone sodium phosphate, and its prepn. method |
| CN101703484A (en) * | 2009-12-04 | 2010-05-12 | 蚌埠丰原涂山制药有限公司 | Preparation method of hexadecadrol sodium phosphate freeze-dried powder injection |
| CN102293757A (en) * | 2011-08-30 | 2011-12-28 | 海南良方医药有限公司 | Dexamethasone Sodium Phosphate freeze-dried powder injection and its preparation method |
| CN103371980A (en) * | 2012-04-28 | 2013-10-30 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate freeze-dried powder injection |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559413A (en) * | 2004-02-26 | 2005-01-05 | 胡秀爱 | Freezing-drying powder-injection contg. dexamethasone sodium phosphate, and its prepn. method |
| CN101703484A (en) * | 2009-12-04 | 2010-05-12 | 蚌埠丰原涂山制药有限公司 | Preparation method of hexadecadrol sodium phosphate freeze-dried powder injection |
| CN102293757A (en) * | 2011-08-30 | 2011-12-28 | 海南良方医药有限公司 | Dexamethasone Sodium Phosphate freeze-dried powder injection and its preparation method |
| CN103371980A (en) * | 2012-04-28 | 2013-10-30 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate freeze-dried powder injection |
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