CN102743396B - Cortical hormone alkali metal phosphate composition - Google Patents
Cortical hormone alkali metal phosphate composition Download PDFInfo
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- CN102743396B CN102743396B CN201110101294.3A CN201110101294A CN102743396B CN 102743396 B CN102743396 B CN 102743396B CN 201110101294 A CN201110101294 A CN 201110101294A CN 102743396 B CN102743396 B CN 102743396B
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Abstract
The invention relates to a cortical hormone alkali metal phosphate composition, which is prepared by a spray-drying method, and contains the following auxiliary materials by calculating the composition containing 1g Cortical hormone alkali metal phosphate: 0-100g of excipient, 0.01-59g of disodium hydrogen phosphate and 0-0.5g of sodium dihydrogen phosphate.
Description
Technical field:
The present invention relates to a kind of 17-hydroxy-11-dehydrocorticosterone preparation, particularly a kind of spraying dry cortical hormone alkali metal phosphate composition.
Background technology:
Glucocorticoid, there is antiinflammatory, antiallergic, rheumatism, immunosuppressive action, be widely used in treatment anaphylaxis and auto-immune inflammatory disease, as connective tissue disease, activeness rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, serious dermatitis, ulcerative colitis, acute leukemia etc., also for some severe infections and Comprehensive Treatment that is poisoning, malignant lymphoma.Because glucocorticoid mostly is the organic compound of indissoluble, therefore for the ease of being prepared into injection, many preparations become glucocorticoid alkali metal phosphate soluble in water, common are cortical hormone alkali metal phosphate, as betamethasone sodium phosphate, Inflamase etc., can make injection or injectable powder, adopt injection dosage form to carry out high temperature sterilize after filling due to needs, high temperature easily causes finished product rate to reduce.Easily there is degradation reaction in aqueous in cortical hormone alkali metal phosphate such as dexamethasone phosphate, is first hydrolysis, separates out, then dexamethasone C21 position-CH
2oH is oxidized, solution turned yellow.After placing a period of time, the impurity of appearance is more, can exceed and meet 2010 editions pharmacopeia to the requirement of impurity.
Chinese patent application 200810053768.x discloses a kind of dexamethasone sodium phosphate crude drug and production technology thereof, have employed drying process with atomizing in this application and produce dexamethasone sterile bulk drug, but adopt sterile bulk drug prepared by this application technique, when preparing injection, preparation steps required compared with common raw material medicine is substantially identical, there is no obvious advantage.
Chinese patent application 200410016686.x discloses a kind of hexadecadrol sodium phosphate freeze-dried powder injection, have employed sodium sulfite sodium sulfite, sodium thiosulfate, cysteine hydrochloride etc. as stabilizing agent, mannitol, lactose, sorbitol are as frozen-dried supporting agent.But lyophilized injectable powder prepared by this application, produces higher related substance in 60 DEG C of high temperature Acceleration study of 10 days.
Chinese patent application 200910250340.9 also discloses a kind of hexadecadrol sodium phosphate freeze-dried powder injection, but we find, according to technique disclosed in this application description, the temperature 4-6 DEG C of eutectic point lower than this medicinal liquid when preparing injectable powder time primary freeze drying (subliming by heating), according to " pharmaceutics " (Xi Nianzhu, People's Health Publisher, April nineteen ninety-five the third edition, 208-211) point out, eutectic point can not be exceeded in subliming by heating phase temperature, otherwise easily there is the problems such as spray bottle, illustrate when higher than the preparation therefore cannot carrying out freeze-dried powder in eutectic point.Even if this temperature reduced, when other process conditions are constant, obtained injectable powder outward appearance is also poor, and the related substance produced when high temperature Acceleration study is also higher.
Summary of the invention
For overcoming the defect of injection prepared by cortical hormone alkali metal phosphate, we provide a kind of cortical hormone alkali metal phosphate composition, the discovery that we are surprised, when when preparing cortical hormone alkali metal phosphate composition, add sodium dihydrogen phosphate and/or sodium hydrogen phosphate (sodium hydrogen phosphate and sodium dihydrogen phosphate can be referred to as phosphate in the present invention), carry out spraying dry after being jointly dissolved in solvent, the stable content of cortical hormone alkali metal phosphate in compositions can be improved significantly.Optionally, add cyclodextrin or derivatives thereof again adding on phosphatic basis, the stable content of cortical hormone alkali metal phosphate in compositions can be improved more significantly.
The invention provides a kind of compositions containing formula (I) compound, it is characterized in that described compositions is prepared with spray drying process, in the compositions containing 1g formula (I) compound, also containing, for example lower adjuvant:
Excipient 0-100g;
Sodium hydrogen phosphate 0.01-59g, sodium dihydrogen phosphate 0-0.5g.
Described general formula (I) compound is that cortical hormone alkali metal phosphate is as follows:
Wherein M is alkali metal, is selected from Na, K, is preferably Na
R2=H ,-COR2, R2 are alkyl within six carbon or furyl,
R3=H or methyl,
R4=H or halogen,
R5=H, halogen or methyl,
1,2 represented by dotted arrows singly-bounds or double bonds.
Preferably
R2=H ,-COR2, R2 are alkyl within three carbon or 2-furyl,
R3=H or methyl,
R4=H or F,
R5=H, F or methyl,
1,2 represented by dotted arrows singly-bounds or double bonds.
More preferably
R2=H ,-COR2, R2 are methyl or 2-furyl,
R3＝H，
R4=H or F,
R5=H or methyl,
1,2 represented by dotted arrows singly-bounds or double bonds.
Further preferably
R2=H ,-COR2, R2 are methyl,
R3＝H，
R4=H or F,
R5=H or methyl,
1,2 represented by dotted arrows double bonds.
The preparation method of described formula (I) compound, with formula (II) compound for substrate, reacts according to method disclosed in Chinese patent application 200710061255.9 description embodiment nine and pyrophosphoryl chloride and alkali metal hydroxide and prepares.
Its Chinese style (I) compound is selected from one or more in betamethasone sodium phosphate, Inflamase, dexamethasone sodium phosphate.
Described excipient, is selected from one or more in glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, one or more in preferred mannitol, lactose, sorbitol.
Described excipient content, in the compositions often containing 1g formula (I) compound, is selected from 0-59g, is preferably 0-35.4g.
Described phosphate content, in the compositions often containing 1g formula (I) compound, preferably,
Sodium hydrogen phosphate 0.1-16g, sodium dihydrogen phosphate 0-0.3g;
More preferably
Sodium hydrogen phosphate 0.75-8g, sodium dihydrogen phosphate 0-0.1g.
Described compositions, to contain the compositions of formula (I) compound containing 1g, except aforementioned adjuvant, preferably also containing, for example lower adjuvant: cyclodextrin or derivatives thereof 0.01-60g; Preferred 0.01-20g.More preferably 0.01-6g, further preferred 0.01-3g.
Described cyclodextrin or derivatives thereof comprises: beta-schardinger dextrin-or derivatives thereof, is one or more in beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, HP-β-CD, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin, glucosyl-ss-cyclodextrin, malt sugar group-beta-cyclodextrin; Alpha-cyclodextrin or derivatives thereof; Gamma-cyclodextrin or derivatives thereof is one or more in gamma-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, hydropropyl-y-cyclodextrin.Described HP-β-CD is 2-HP-BETA-CD, 3-HP-β-CD, 2, 3-dihydroxypropyl-beta-schardinger dextrin-, 2, 6-dihydroxypropyl-beta-schardinger dextrin-, 2, 3, one or more in 6-tri-HP-β-CD, described methyl-B-cyclodextrin is selected from RAMEB (partly methylated β-cyclodextrin), random methyl-β-cyclodextrin (RandomLy methlated-β-Cyclodextrin, RM-β-CD) 2, 6-O-DM-β-CD, one or more in 2-O-methyl-B-cyclodextrin,
One or more in preferred HP-β-CD, hydropropyl-y-cyclodextrin, gamma-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, alpha-cyclodextrin, more preferably 2-HP-BETA-CD.
Described compositions, adopts spray drying process preparation.Need formula (I) compound and adjuvant to be dissolved in solvent when carrying out spraying dry, the formula of described solvent, in the product containing 1g formula (I) compound, for:
Water for injection 10-600mL, ethanol 0-90mL, ethanol content≤40% in solvent.
The formula of preferred solvent, in the product containing 1g formula (I) compound, for: water for injection 50-200mL, ethanol 0-20mL, ethanol content≤40% in solvent.
The preparation method of the described compositions containing formula (I) compound is: formula (I) compound and adjuvant are dissolved in recipe quantity water for injection, add recipe quantity ethanol again, add active carbon, 40-60 DEG C of insulation 20-30 minute, cross 0.22 μm of filter membrane removing active carbon, obtain medicinal liquid
Medicinal liquid is carried out spraying dry, and spray drying condition is as follows:
Hot air flowrate: 0.75 ~ 1.20m
3/ min
Hot air inlet temperature: 90 ~ 140 DEG C
Hot air outlet temperature: 65 ~ 95 DEG C
Heat air pressure: 90 ~ 150kpa (gauge pressure)
Medicinal liquid flow velocity: 1 ~ 20mL/min.
The compositions that technique of the present invention is obtained, direct packaging can become injection, or for the preparation of other preparations, simplify the production craft step of injection, and overcome adopt crude drug prepare lyophilized injectable powder time crude drug need be dissolved, lyophilizing, need lot of energy, production efficiency is low, the shortcoming that equipment investment is large.And compositions provided by the invention, compared with the technique preparing sterile powder for injection with the spraying dry of routine, our wonderful discovery, after adding phosphate, and do not add compared with phosphatic experimental group, compositions prepared by the present invention, in 60 DEG C of Acceleration study of 10 days, stable content, apparently higher than not adding this phosphatic spray-dried compositions, even add a small amount of phosphate, does not affect the generation of this technique effect yet.Further, we also find, when preparing spray-dried compositions, except adding phosphate, also add cyclodextrin or derivatives thereof, further can significantly improve the stable content of obtained compositions, with add cyclodextrin or derivatives thereof in prior art when preparing injection and mainly utilize the clathration of cyclodextrin to increase the different solubility of principal agent, in compositions provided by the invention, crude drug is all soluble in water, do not need the method solubilising adopting cyclodextrin inclusion compound, particularly cyclodextrin or derivatives thereof adds proportioning, preferably cyclodextrin or derivatives thereof and weight ratio 0.01-3, namely cyclodextrin or derivatives thereof and mol ratio are less than 1, even if illustrate and only add micro-cyclodextrin or derivatives thereof, also further raising stable content on phosphatic basis can added, and in prior art, when preparing clathrate, the mol ratio of cyclodextrin or derivatives thereof and active component is generally all greater than 1.And the high temperature Acceleration study result of comparative examples 2 shows, when only adding cyclodextrin or derivatives thereof, then without this technique effect, illustrate that only adding cyclodextrin or derivatives thereof does not act on this goal of the invention of stable content improving spray-dried compositions, the reason producing technique effect is due to cyclodextrin or derivatives thereof and the coefficient result of phosphate.
Detailed description of the invention:
Embodiment in detailed description of the invention is only the technical scheme illustrating further invention, can not be interpreted as the restriction to embodiment of the present invention.In embodiment, dexamethasone sodium phosphate used, betamethasone sodium phosphate, Inflamase are Tianjin Tianyao Pharmaceutical Co., Ltd. and produce, and meet Chinese Pharmacopoeia 2010 editions standards.Spraying dry equipment used is the SD1000 type spray dryer that Japanese EYELA produces.
Embodiment 2-1
(1) cyclodextrin is dissolved in after in 20% recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in 80% recipe quantity water for injection and adds mannitol and make it to dissolve
(3) mixing after above-mentioned 2 solution being merged
(4) recipe quantity ethanol is added the rear 0.22 μm of filter element filtering of above-mentioned solution mixing degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.80m
3/ min
Inlet temperature: 100 DEG C
Outlet temperature: 65 DEG C
Atomisation pressure: 120kpa
Medicinal liquid flow velocity: 5mL/min
(5) dexamethasone sodium phosphate composition that step (4) obtains is distributed into injectable powder, specification 5mg/120.0mg (dexamethasone sodium phosphate/gross weight)
Embodiment 2-2
(1) after phosphate salt dissolves is in 20% recipe quantity water for injection, dexamethasone sodium phosphate dissolving is added
(2) by molten for mannitol residue 80% water for injection
(3) mixing after above-mentioned 2 solution being merged
(4) cross medicinal liquid is degerming through 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution.Carry out spraying dry, obtain dexamethasone sodium phosphate composition.Spray condition is with embodiment 2-1
(5) dexamethasone sodium phosphate composition that step (4) obtains is distributed into injectable powder, specification 5mg/70.0mg (dexamethasone sodium phosphate/gross weight)
Embodiment 3-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection and adds mannitol and make it to dissolve
(3) mixing after above-mentioned 2 solution being merged
(4) recipe quantity ethanol being added above-mentioned solution, to cross 0.22 μm of filter element filtering degerming, carries out spraying dry, obtain betamethasone sodium phosphate compositions after mixing.
Spray drying condition is as follows:
Hot air flowrate: 1.05m
3/ min
Inlet temperature: 100 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 120kpa
Medicinal liquid flow velocity: 8mL/min
(5) the betamethasone sodium phosphate compositions that step (4) obtains is distributed into injectable powder, specification 5mg/110.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 3-2
(1) after phosphate salt dissolves is in half recipe quantity water for injection, betamethasone sodium phosphate dissolving is added
(2) by molten for mannitol residue water for injection
(3) mixing after above-mentioned 2 solution being merged
(4) cross medicinal liquid is degerming through 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution.Carry out spraying dry, obtain betamethasone sodium phosphate compositions.Spray drying condition is with embodiment 3-1
(5) the betamethasone sodium phosphate compositions that step (4) obtains is distributed into injectable powder, specification 5mg/95mg (betamethasone sodium phosphate/gross weight).
Embodiment 4-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add mannitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.75m
3/ min
Inlet temperature: 140 DEG C
Outlet temperature: 95 DEG C
Atomisation pressure: 150kpa
Medicinal liquid flow velocity: 10mL/min
(5) dexamethasone sodium phosphate composition that step (4) obtains is distributed into injectable powder, specification 5mg/100.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 4-2
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add mannitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.Spray drying condition is with embodiment 4-1
(5) dexamethasone sodium phosphate composition that step (4) obtains is distributed into injectable powder, specification 5mg/100.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 5-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add mannitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.75m
3/ min
Inlet temperature: 90 DEG C
Outlet temperature: 65 DEG C
Atomisation pressure: 90kpa
Medicinal liquid flow velocity: 3mL/min
(5) dexamethasone sodium phosphate composition that step (4) obtains is distributed into injectable powder, specification 5mg/100.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 5-2
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add lactose after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.
Spray drying condition is with embodiment 5-1
(5) the betamethasone sodium phosphate compositions that step (4) obtains is distributed into injectable powder, specification 5mg/100.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 5-3
(1) after phosphate salt dissolves is in half recipe quantity water for injection, betamethasone sodium phosphate dissolving is added
(2) by molten for lactose residue water for injection
(3) mixing after above-mentioned 2 solution being merged
(4) cross medicinal liquid is degerming through 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution.Carry out spraying dry, obtain betamethasone sodium phosphate compositions.Spray drying condition is with embodiment 5-1.
(5) the betamethasone sodium phosphate compositions that step (4) obtains is distributed into injectable powder, specification 5mg/50.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 6-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add mannitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.
Spray drying condition is as follows:
Hot air flowrate: 1.20m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 120kpa
Medicinal liquid flow velocity: 20mL/min
(5) by the betamethasone sodium phosphate compositions that step (4) obtains, injectable powder is distributed into, specification 2mg/120.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 6-2
(1) after phosphate salt dissolves is in half recipe quantity water for injection, betamethasone sodium phosphate dissolving is added
(2) by molten for mannitol residue water for injection
(3) mixing after above-mentioned 2 solution being merged
(4) cross medicinal liquid is degerming through 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution.Carry out spraying dry, obtain betamethasone sodium phosphate compositions.Spray drying condition is with embodiment 6-1.
(5) the betamethasone sodium phosphate compositions that step (4) obtains is distributed into injectable powder, specification 2mg/120.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 7-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add mannitol after being merged by above-mentioned 2 solution and make it to dissolve (pH value: 4.00)
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.95m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 120kpa
Medicinal liquid flow velocity: 10mL/min
(5) by the dexamethasone sodium phosphate composition that step (4) obtains, injectable powder is distributed into, specification 5mg/200.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 7-2
(1) after phosphate salt dissolves is in half recipe quantity water for injection, dexamethasone sodium phosphate dissolving is added
(2) by molten for mannitol residue water for injection
(3) mixing after above-mentioned 2 solution being merged
(4) cross medicinal liquid is degerming through 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution.Carry out spraying dry, obtain dexamethasone sodium phosphate composition.Spray drying condition is with embodiment 7-1.
(5) dexamethasone sodium phosphate composition that step (4) obtains is distributed into injectable powder, specification 5mg/185.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 8-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection and adds mannitol and make it to dissolve
(3) mixing after above-mentioned 2 solution being merged
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.
Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 108 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 120kpa
Medicinal liquid flow velocity: 1mL/min
(5) by the betamethasone sodium phosphate compositions that step (4) obtains, injectable powder is distributed into, specification 10.0mg/65.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 8-2
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add sorbitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.
Spray drying condition is as follows with embodiment 8
(5) by the betamethasone sodium phosphate compositions that step (4) obtains, injectable powder is distributed into, specification 10.0mg/65.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 8-3
(1) phosphate is dissolved in recipe quantity water for injection, adds betamethasone sodium phosphate and make it to dissolve;
(2) add lactose and make it to dissolve
(3) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.Spray drying condition is with embodiment 8-1
(4) by the betamethasone sodium phosphate compositions that step (3) obtains, injectable powder is distributed into, specification 10.0mg/45.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 9-1
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add sorbitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 100kpa
Medicinal liquid flow velocity: 5mL/min
(5) by the dexamethasone sodium phosphate composition that step (4) obtains, injectable powder is distributed into, specification 10.0mg/130.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 9-2
(1) phosphate is dissolved in recipe quantity water for injection, adds dexamethasone sodium phosphate and make it to dissolve;
(2) add mannitol and make it to dissolve
(2) add lactose and make it to dissolve
(3) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.Spray drying condition is with embodiment 9-1
(4) by the betamethasone sodium phosphate compositions that step (3) obtains, injectable powder is distributed into, specification 20.0mg/140.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 10-1
(1) cyclodextrin is dissolved in after in 10% recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) phosphate is dissolved in residue recipe quantity water for injection
(3) mixing after above-mentioned 2 solution being merged
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain betamethasone sodium phosphate compositions.Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 100kpa
Medicinal liquid flow velocity: 5mL/min
(5) by the betamethasone sodium phosphate compositions that step (4) obtains, injectable powder is distributed into, specification 20.0mg/120.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 10-2
(1) phosphate is dissolved in after in recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) degerming by crossing 0.22 μm of filter element filtering after above-mentioned solution mixing, carry out spraying dry, obtain betamethasone sodium phosphate compositions.
Spray drying condition is with embodiment 10-1
(3) by the betamethasone sodium phosphate compositions that step (2) obtains, injectable powder is distributed into, specification 2.0mg/120.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 11-1
(1) phosphate is dissolved in after in recipe quantity water for injection and adds betamethasone sodium phosphate dissolving
(2) degerming by crossing 0.22 μm of filter element filtering after above-mentioned solution mixing, carry out spraying dry, obtain betamethasone sodium phosphate compositions.
Spray drying condition is with embodiment 10-1
(3) by the betamethasone sodium phosphate compositions that step (2) obtains, injectable powder is distributed into, specification 2.0mg/120.0mg (betamethasone sodium phosphate/gross weight).
Embodiment 11-1
(1) cyclodextrin is dissolved in after in 90% recipe quantity water for injection and adds dexamethasone sodium phosphate dissolving
(2) phosphate is dissolved in after in residue water for injection and adds dexamethasone sodium phosphate dissolving
Degerming by crossing 0.22 μm of filter element filtering after above-mentioned solution mixing, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 100kpa
Medicinal liquid flow velocity: 5mL/min
(3) by the dexamethasone sodium phosphate composition that step (2) obtains, injectable powder is distributed into, specification 1.0mg/60.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 11-2
(1) mannitol is dissolved in 50% recipe quantity water for injection
(2) by phosphate, be dissolved in residue water for injection in after add dexamethasone sodium phosphate dissolve
Degerming by crossing 0.22 μm of filter element filtering after above-mentioned solution mixing, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is with embodiment 11-1
(3) by the dexamethasone sodium phosphate composition that step (2) obtains, injectable powder is distributed into, specification 20mg/40.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 12-1
(1) be dissolved in by lactose in 90% recipe quantity water for injection, water for injection is warming up to 40-60 DEG C
(2) phosphate, cyclodextrin are dissolved in after in residue water for injection and add dexamethasone sodium phosphate dissolving
Degerming by crossing 0.22 μm of filter element filtering after above-mentioned solution mixing, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 100kpa
Medicinal liquid flow velocity: 5mL/min
(3) by the dexamethasone sodium phosphate composition that step (2) obtains, injectable powder is distributed into, specification 1.0mg/100.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 12-2
(1) be dissolved in by lactose in 90% recipe quantity water for injection, water for injection is warming up to 40-60 DEG C
(2) phosphate is dissolved in after in residue water for injection and adds dexamethasone sodium phosphate dissolving
Degerming by crossing 0.22 μm of filter element filtering after above-mentioned solution mixing, carry out spraying dry, obtain dexamethasone sodium phosphate composition.Spray drying condition is with embodiment 12-1
(3) by the dexamethasone sodium phosphate composition that step (2) obtains, injectable powder is distributed into, specification 1.0mg/100.0mg (dexamethasone sodium phosphate/gross weight).
Embodiment 13-1
(1) lactose is dissolved in half recipe quantity water for injection
(2) phosphate is dissolved in half recipe quantity water for injection and adds Inflamase dissolving
(3) above-mentioned 2 solution are merged
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain Inflamase compositions.
Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 115 DEG C
Outlet temperature: 85 DEG C
Atomisation pressure: 100kpa
Medicinal liquid flow velocity: 5mL/min
(5) by the Inflamase compositions that step (4) obtains, injectable powder is distributed into, specification 20.0mg/60.0mg (Inflamase/gross weight).
Embodiment 13-2
(1) cyclodextrin is dissolved in after in half recipe quantity water for injection and adds Inflamase dissolving
(2) phosphate is dissolved in half recipe quantity water for injection
(3) add lactose after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain Inflamase compositions.Spray drying condition is as follows: with embodiment 13-1
(5) by the Inflamase compositions that step (4) obtains, injectable powder is distributed into, specification 20.0mg/60.0mg (Inflamase/gross weight).
Comparative examples 1
(1) cyclodextrin is dissolved in after in recipe quantity 80% water for injection and adds dexamethasone sodium phosphate dissolving, and regulate pH to 8.2 with 1mol/L sodium hydroxide solution
(2) add mannitol after supplying recipe quantity water for injection and make it to dissolve
(3) cross 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution degerming, carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.75m
3/ min
Inlet temperature: 90 DEG C
Outlet temperature: 60 DEG C
Atomisation pressure: 90kpa
Medicinal liquid flow velocity: 3mL/min
(4) dexamethasone sodium phosphate composition that step (3) obtains is distributed into injectable powder, specification 10.0mg/200.0mg (dexamethasone sodium phosphate/gross weight).
Comparative examples 2
(1) dexamethasone sodium phosphate is added after in 80% recipe quantity water for injection and dissolve
(2) regulate pH to 8.3 with the sodium hydroxide solution of 1mol/L, supply the water for injection of surplus
(3) add mannitol after being merged by above-mentioned 2 solution and make it to dissolve
(4) cross medicinal liquid is degerming through 0.22 μm of filter element filtering after recipe quantity ethanol being added the mixing of above-mentioned solution.Carry out spraying dry, obtain dexamethasone sodium phosphate composition.
Spray drying condition is as follows:
Hot air flowrate: 0.90m
3/ min
Inlet temperature: 108 DEG C
Outlet temperature: 75 DEG C
Atomisation pressure: 100kpa
Medicinal liquid flow velocity: 6mL/min
(5) dexamethasone sodium phosphate composition that step (4) obtains divided be packaged into injectable powder, (5.0mg/120.0mg dexamethasone sodium phosphate/gross weight).
Comparative examples 3
Dexamethasone sodium phosphate 10g
Water for injection 150g
(1) dexamethasone sodium phosphate of recipe quantity is dissolved in the water for injection of recipe quantity, is stirred to and entirely moltenly obtains medicinal liquid (1).
(2) medicinal liquid (1) is carried out spraying dry, obtain dexamethasone sodium phosphate crude drug.Spray drying condition is as follows:
Hot air flowrate: 0.65m
3/ min
Hot air inlet temperature: 115 DEG C
Outlet temperature: 90 DEG C
Medicinal liquid flow velocity: 5ml/min
Heat air pressure (gauge pressure): 130kpa
(3) step (2) is obtained dexamethasone sodium phosphate crude drug directly to divide and be packaged into injectable powder.Specification 10mg/ props up
Stable content contrast experiment:
The injectable powder that the compositions subpackage that Example 1 to embodiment 10 and comparative example 1-3 obtain obtains, adopt each 20, (5mg/ props up to get commercially available hexadecadrol sodium phosphate freeze-dried powder injection, Ma'an Mountain of Anhui BBCA Pharmaceuticals Co., Ltd. pharmaceutical factory) and betamethasone sodium phosphate lyophilized injectable powder (5.26mg/ props up, Chengdu Tiantaishan Pharmaceutical Co., Ltd.) 20, be divided into commercially available 1 (dexamethasone sodium phosphate) and commercially available 2 (betamethasone sodium phosphate) all samples lucifuge packaging, putting (60 ± 2) DEG C, keep in Dark Place in thermostatic container 10 days sampling and measuring, 10 sample detection cortical hormone alkali metal phosphate content are got respectively at random before detection and after 10 days, to detect front average content for 100%, determine experimental result after 10 days, and t inspection is carried out to result.The results are shown in following table (
n=10)
High temperature stable content contrast experiment show, only add phosphate and do not add the embodiment of cyclodextrin or derivatives thereof, at spraying dry and after subpackage, stable content is obviously higher than the comparative examples 2 only adding excipient and the comparative examples 1 adding HP-β-CD and mannitol, and do not add the spraying dry dexamethasone sodium phosphate crude drug (comparative examples 3) of adjuvant direct packaging, be also significantly higher than commercially available freeze-drying prods.Particularly only add micro-phosphatic 9-2, its stable content also will be significantly higher than comparative example 1 and comparative example 2, and commercially available freeze-drying prods.Illustrate that trace just can play the significant effect improving spray dried products stability phosphatic adding.And except excipient, only adding relatively large phosphatic embodiment 10-2, the degree that its stable content improves gap compared with embodiment 9-2 is also little.And, add cyclodextrin or derivatives thereof and each embodiment phosphatic simultaneously, at spraying dry and after subpackage, stable content is obviously higher than and only adds phosphate and the embodiment not adding cyclodextrin or derivatives thereof, particularly only add embodiment 6-1 and the embodiment 4-1 of micro-cyclodextrin or derivatives thereof, stable content with only add compared with phosphatic embodiment, there has also been and significantly improve.Explanation is when to add phosphate and cyclodextrin or derivatives thereof simultaneously, the synergy improving product content stability can be produced, and adding of the cyclodextrin or derivatives thereof of relatively low amount can produce synergy with phosphate, improve the stable content of formulation products.
Claims (20)
1. the compositions containing formula (I) compound, is characterized in that described compositions is prepared with spray drying process, in the compositions containing 1g formula (I) compound, also containing, for example lower adjuvant: excipient 0-100g; Sodium hydrogen phosphate 0.01-59g, sodium dihydrogen phosphate 0-0.5g;
（I）
M is selected from Na, K; R2=H, R3=H or methyl, R4=H or halogen, R5=H; 1,2 represented by dotted arrows double bonds,
The spray drying preparation adopted is for be dissolved in recipe quantity water for injection by formula (I) compound and adjuvant, add recipe quantity ethanol again, add active carbon, 40-60 DEG C of insulation 20-30 minute, cross 0.22 μm of filter membrane removing active carbon, obtain medicinal liquid, carry out spraying dry, spray drying condition is as follows: hot air flowrate: 0.75 ~ 1.20m3/min hot air inlet temperature: 90 ~ 140 DEG C of hot air outlet temperature: 65 ~ 95 DEG C of heat air pressures: 90 ~ 150kpa gauge pressure medicinal liquid flow velocity: 1 ~ 20ml/min.
2. compositions as claimed in claim 1, is characterized in that described formula (I) compound, is selected from one or more in betamethasone sodium phosphate, Inflamase, dexamethasone sodium phosphate.
3. as claim 1-2 arbitrarily as described in compositions, it is characterized in that one or more that described excipient is selected from glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran.
4. compositions as claimed in claim 3, is characterized in that one or more that described excipient is selected from mannitol, lactose, sorbitol.
5. compositions as claimed in claim 1, is characterized in that described excipient content, in the compositions often containing 1g formula (I) compound, is preferably 0-56.9g.
6. compositions as claimed in claim 5, is characterized in that described excipient content, in the compositions often containing 1g formula (I) compound, is preferably 0-35.4g.
7. compositions as claimed in claim 1, is characterized in that described phosphate content, in the compositions often containing 1g formula (I) compound, is preferably sodium hydrogen phosphate 0.1-16g, sodium dihydrogen phosphate 0-0.3g.
8. compositions as claimed in claim 7, is characterized in that described phosphate content, in the compositions often containing 1g formula (I) compound, is preferably sodium hydrogen phosphate 0.75-8g, sodium dihydrogen phosphate 0-0.1g.
9. compositions as claimed in claim 1, is characterized in that the compositions often containing 1g formula (I) compound, preferably also containing, for example lower adjuvant: cyclodextrin or derivatives thereof 0.01-60g.
10. compositions as claimed in claim 9, is characterized in that the compositions often containing 1g formula (I) compound, preferably containing cyclodextrin or derivatives thereof 0.01-20g.
11. compositionss as claimed in claim 10, is characterized in that the compositions often containing 1g formula (I) compound, preferably containing cyclodextrin or derivatives thereof 0.01-6g.
12. compositionss as claimed in claim 10, is characterized in that the compositions often containing 1g formula (I) compound, preferably containing cyclodextrin or derivatives thereof 0.01-3g.
13. as arbitrary in claim 10-12 as described in compositions, it is characterized in that described cyclodextrin or derivatives thereof is selected from beta-schardinger dextrin-or derivatives thereof, alpha-cyclodextrin or derivatives thereof, one or more in gamma-cyclodextrin or derivatives thereof.
14. compositionss as claimed in claim 13, is characterized in that described beta-schardinger dextrin-or derivatives thereof is one or more in beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, HP-β-CD, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin, glucosyl-ss-cyclodextrin, malt sugar group-beta-cyclodextrin.
15. compositionss as claimed in claim 14, it is characterized in that described HP-β-CD is that HP-β-CD is selected from 2-HP-BETA-CD, 3-HP-β-CD, 2,3-dihydroxypropyl-beta-schardinger dextrin-, 2,6-dihydroxypropyl-beta-schardinger dextrin-, 2, one or more in 3,6-tri-HP-β-CD.
16. compositionss as claimed in claim 14, is characterized in that one or more that described methyl-B-cyclodextrin is selected from RAMEB, arbitrarily methyl-β-cyclodextrin 2,6-O-DM-β-CD, 2-O-methyl-B-cyclodextrin.
17. compositionss as claimed in claim 13, is characterized in that one or more in the described preferred HP-β-CD of cyclodextrin or derivatives thereof, hydropropyl-y-cyclodextrin, gamma-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, alpha-cyclodextrin.
18. compositionss as claimed in claim 17, is characterized in that the described preferred 2-HP-BETA-CD of cyclodextrin or derivatives thereof.
19. compositionss as claimed in claim 1, prepared by employing spray drying process, formula (I) compound and adjuvant is needed to be dissolved in solvent when carrying out spraying dry, the formula of described solvent is in the product containing 1g formula (I) compound, for: water for injection 10-600ml, ethanol 0-90 mL, ethanol content≤40% in solvent.
20. compositionss as claimed in claim 19, is characterized in that the formula of described solvent is in the product containing 1g formula (I) compound, for: water for injection 50-200mL, ethanol 0-20mL, ethanol content≤40% in solvent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101120915A (en) * | 2006-08-10 | 2008-02-13 | 天津药业集团新郑股份有限公司 | Dexamethasone sodium phosphate injection |
| CN101623291A (en) * | 2008-07-07 | 2010-01-13 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate injection |
| 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 |
| CN101926760A (en) * | 2009-06-24 | 2010-12-29 | 天津金耀集团有限公司 | Dexamethasone injecta coated with 2-hydroxypropyl-beta-cyclodextrin |
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2011
- 2011-04-22 CN CN201110101294.3A patent/CN102743396B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101120915A (en) * | 2006-08-10 | 2008-02-13 | 天津药业集团新郑股份有限公司 | Dexamethasone sodium phosphate injection |
| CN101623291A (en) * | 2008-07-07 | 2010-01-13 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate injection |
| CN101926760A (en) * | 2009-06-24 | 2010-12-29 | 天津金耀集团有限公司 | Dexamethasone injecta coated with 2-hydroxypropyl-beta-cyclodextrin |
| 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 |
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