CN1615870A - Itraconazole freeze-dried powder injection and preparing method - Google Patents
Itraconazole freeze-dried powder injection and preparing method Download PDFInfo
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- CN1615870A CN1615870A CN 200410078134 CN200410078134A CN1615870A CN 1615870 A CN1615870 A CN 1615870A CN 200410078134 CN200410078134 CN 200410078134 CN 200410078134 A CN200410078134 A CN 200410078134A CN 1615870 A CN1615870 A CN 1615870A
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- itraconazole
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- propylene glycol
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Abstract
The freeze-dried Itraconazole powder for injection is prepared through preparing solution with Itraconazole, hydroxypropyl-beta-cyclodextrin, propylene glycol, hydrochloric acid and sodium hydroxide; adding proper amount of diluent and freeze drying. Compared with Itraconazole injection, the present invention has the advantages of raised physical stability, no high temperature decomposing degradation of Itraconazole, loose product and fast recovering of the original solution characteristic after adding water, low water content and drying in vacuum resulting in less oxidation and high stability for long term storing, and less pollution and particle matter introduced during production.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, specifically is itraconazole lyophilized injectable powder and preparation method.
Background technology
Human fungal infection disease has three classes: shallow table, subcutaneous and systemic fungal infection, and the first two class has obtained better prevention, and only systemic fungal infection still is thorny so far.The characteristics of systemic fungal infection are difficult diagnosiss, and disease progression is fast, the mortality rate height, and active drug is few, the therefore clinical antifungal agent that has efficient, low toxicity and act on characteristics such as rapid that presses for.U.S. Abbott releases Itraconazole injection, has solved an expectation galenic pharmacy difficult problem for a long time, can quiet mode administration, so not only kept efficient, the broad-spectrum characteristics of itraconazole antibacterial action, and also have good safety and use motility.But the less stable of injection is separated out principal agent easily, and is thermo-labile, easily freezes, and transportation is stored all inconvenient.Therefore, we have developed Itraconazole freeze-dried powder injection, have evaded the shortcoming of Itraconazole injection, and have kept advantages such as injection is efficient, quick-acting.
Introduction according to the Itraconazole injection description among the U.S. PDR, the HP-of this injection employing 40% is as the solubilizing agent of itraconazole, but adopt the itraconazole lyophilized injection of the HP-of this ratio as the solubilizing agent preparation, precipitating blended the time with sodium chloride injection, the inventor finds a wonderful phenomenon by further a large amount of tests, the consumption that improves HP-reaches 40%～60% o'clock lyophilized products and clarify the nothing precipitation when diluting with sodium chloride injection, such phenomenon is in the not similarly instruction and explaining of pharmaceutics teaching material and pertinent literature, and those skilled in the art can't be according to the recipe quantity of inferring the HP-of Itraconazole freeze-dry pin about the injection prescription of the Itraconazole injection description among the U.S. PDR.
Summary of the invention
The purpose of this invention is to provide a kind of itraconazole lyophilized injectable powder.Compare with Itraconazole injection, have the following advantages: 1, itraconazole is difficult for moltenly in water, has just avoided itraconazole owing to being difficult for the bad problem of the molten physical stability that causes after making lyophilized injectable powder.2, can avoid itraconazole in preparation process, to decompose rotten because of hyperpyrexia.3, the product quality of gained is loose, and adding behind the water rapidly, dissolving recovers the original characteristic of medicinal liquid.4, water content is low, and simultaneously drying is carried out in a vacuum, so be difficult for oxidation, good stability helps the long term store of product.5, opportunities for contamination reduces relatively in the production process, so the particle matter in the product lacks than additive method.
The present invention makes solution by itraconazole, HP-, propylene glycol, hydrochloric acid, sodium hydroxide, can add proper amount of diluting, obtained by freeze drying.Wherein the consumption of itraconazole is for 0.2～5% of the prescription solution amount, and preferred 0.5～2%, the HP-consumption is 40%～60%, preferred 45%～55% of the prescription solution amount.Introduction according to the Itraconazole injection description among the U.S. PDR, the HP-of this injection employing 40% is as the solubilizing agent of itraconazole, but adopt the itraconazole lyophilized injection of the HP-of this ratio as the solubilizing agent preparation, precipitating blended the time with sodium chloride injection, the inventor finds a wonderful phenomenon by further a large amount of tests, and the consumption that improves HP-reaches 40%～60% o'clock lyophilized products and clarify the nothing precipitation when diluting with sodium chloride injection.Described diluent is selected from mannitol, lactose, dextran, glucose, glycine, gelatin hydrolysate, polyvidone etc., and the consumption of diluent accounts for 0%～15% of prescription solution amount.Preferred 4%～8%.The prescription solution amount consumption of propylene glycol is 2%～4%, and is preferred 2.2%～2.8%, and the consumption of hydrochloric acid is 0.2～0.8%, preferred 0.3～0.5% of the prescription solution amount.
Preparation technology is: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring or ultrasonic dissolution become clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.
The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 4 hours.
2) sublimation drying:
A sublimed method: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
Freezing and sublimation method repeatedly: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, close fridge, slowly heat by the heating system under the dividing plate, when temperature rises to-20 ℃, open fridge, temperature is descended, when reducing to-45 ℃, temperature closes fridge, slowly heat by the heating system under the dividing plate, so repeatedly, the sublimation drying time is 35 hours.
3) dry again: the drying stage temperature is controlled at 20 ℃ again, and be 12 hours drying time again.
The products appearance that the present invention makes is plentiful, fine and smooth, dissolution velocity is fast again, is convenient to clinical use.
Following examples are used for further specifying the present invention, rather than limitation of the scope of the invention.
Embodiment 1
Prescription: itraconazole 250g
HP-10000g
Propylene glycol 625ml
Hydrochloric acid 95ml
Mannitol 1000g
Water for injection adds to 25000ml
Make 1000 altogether
Method for making: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, ultrasonic dissolution becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and bright, add mannitol, stirring and dissolving transfers pH to 4.5 to supply water yield ultrafiltration with sodium hydroxide, packing, lyophilization.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 3.5 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
3) dry again: the drying stage temperature is controlled at below 15 ℃ again, and be 12 hours drying time again.
Embodiment 2
Prescription: itraconazole 250g
HP-12500g
Propylene glycol 625ml
Hydrochloric acid 95ml
Water for injection adds to 25000ml
Make 1000 altogether
Method for making: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring and dissolving becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 3.5 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
3) dry again: the drying stage temperature is controlled at below 15 ℃ again, and be 12 hours drying time again.
Embodiment 3
Prescription: itraconazole 250g
HP-15000g
Propylene glycol 625ml
Hydrochloric acid 95ml
Water for injection adds to 25000ml
Make 1000 altogether
Method for making: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring and dissolving becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 3.5 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
3) dry again: the drying stage temperature is controlled at below 15 ℃ again, and be 12 hours drying time again.
Embodiment 4
Prescription: itraconazole 250g
HP-11250g
Propylene glycol 625ml
Hydrochloric acid 95ml
Water for injection adds to 25000ml
Make 1000 altogether
Method for making: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring and dissolving becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 3.5 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
3) dry again: the drying stage temperature is controlled at below 15 ℃ again, and be 12 hours drying time again.
Embodiment 5
Prescription: itraconazole 250g
HP-13750g
Propylene glycol 625ml
Hydrochloric acid 95ml
Water for injection adds to 25000ml
Make 1000 altogether
Method for making: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring and dissolving becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 3.5 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
3) dry again: the drying stage temperature is controlled at below 15 ℃ again, and be 10 hours drying time again.
Embodiment 6
Prescription: itraconazole 250g
HP-12500g
Propylene glycol 625ml
Hydrochloric acid 95ml
Water for injection adds to 25000ml
Make 2000 altogether
Method for making: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring and dissolving becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 3.5 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 15 hours.
3) dry again: the drying stage temperature is controlled at below 15 ℃ again, and be 12 hours drying time again.
Claims (9)
1, a kind of freeze-dried composition of Itraconazole azoles is characterized in that making solution by itraconazole, HP-, propylene glycol, hydrochloric acid, sodium hydroxide, obtained by freeze drying.
2, pharmaceutical composition according to claim 1 is characterized in that the consumption of itraconazole is 0.2～5% of prescription solution amount.
3, pharmaceutical composition according to claim 1 is characterized in that the consumption of itraconazole is 0.5～2% of prescription solution amount.
4, pharmaceutical composition according to claim 1 is characterized in that the HP-consumption is 40%～60% of prescription solution amount.
5, pharmaceutical composition according to claim 1 is characterized in that the HP-consumption is 45%～55% of prescription solution amount.
6, pharmaceutical composition according to claim 1 is characterized in that the propylene glycol consumption is 2%～4% of prescription solution amount.
7, pharmaceutical composition according to claim 1 is characterized in that the hydrochloric acid consumption is 0.2%～0.8% of prescription solution amount.
8, pharmaceutical composition according to claim 1 is characterized in that preparation technology: itraconazole is added hydrochloric acid stir into pasty state, add propylene glycol, stirring and dissolving becomes clear and bright solution.Other gets HP-and adds stirring and dissolving in the proper amount of water for injection, and the itraconazole propylene glycol solution is poured in the HP-solution, is stirred to clear and brightly, transfers pH to 4.5 to supply water yield ultrafiltration, packing, lyophilization with sodium hydroxide.
9, preparation technology according to claim 8 is characterized in that the dissolving method of itraconazole stirs into pasty state for itraconazole is added hydrochloric acid, adds propylene glycol, and stirring and dissolving becomes clear and bright solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410078134 CN1615870A (en) | 2004-09-17 | 2004-09-17 | Itraconazole freeze-dried powder injection and preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410078134 CN1615870A (en) | 2004-09-17 | 2004-09-17 | Itraconazole freeze-dried powder injection and preparing method |
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| Publication Number | Publication Date |
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| CN1615870A true CN1615870A (en) | 2005-05-18 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101889979A (en) * | 2010-07-05 | 2010-11-24 | 东北农业大学 | Itraconazole injection for dogs and preparation method thereof |
| CN102379844A (en) * | 2011-10-31 | 2012-03-21 | 广州维美投资有限公司 | Itraconazole isomer injection |
| CN102499909A (en) * | 2011-12-27 | 2012-06-20 | 哈尔滨三联药业有限公司 | Itraconazole dispersible tablets and preparation method thereof |
| CN103284959A (en) * | 2012-02-22 | 2013-09-11 | 重庆圣华曦药业股份有限公司 | Posaconazole freeze-dried powder injection and preparation method thereof |
-
2004
- 2004-09-17 CN CN 200410078134 patent/CN1615870A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101889979A (en) * | 2010-07-05 | 2010-11-24 | 东北农业大学 | Itraconazole injection for dogs and preparation method thereof |
| CN102379844A (en) * | 2011-10-31 | 2012-03-21 | 广州维美投资有限公司 | Itraconazole isomer injection |
| CN102499909A (en) * | 2011-12-27 | 2012-06-20 | 哈尔滨三联药业有限公司 | Itraconazole dispersible tablets and preparation method thereof |
| CN102499909B (en) * | 2011-12-27 | 2013-08-07 | 哈尔滨三联药业有限公司 | Itraconazole dispersible tablets and preparation method thereof |
| CN103284959A (en) * | 2012-02-22 | 2013-09-11 | 重庆圣华曦药业股份有限公司 | Posaconazole freeze-dried powder injection and preparation method thereof |
| CN103284959B (en) * | 2012-02-22 | 2015-06-03 | 重庆圣华曦药业股份有限公司 | Posaconazole freeze-dried powder injection and preparation method thereof |
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