CN103284959A - Posaconazole freeze-dried powder injection and preparation method thereof - Google Patents
Posaconazole freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN103284959A CN103284959A CN2012100404595A CN201210040459A CN103284959A CN 103284959 A CN103284959 A CN 103284959A CN 2012100404595 A CN2012100404595 A CN 2012100404595A CN 201210040459 A CN201210040459 A CN 201210040459A CN 103284959 A CN103284959 A CN 103284959A
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- posaconazole
- acid
- lyophilized injectable
- injectable powder
- cyclodextrin
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Abstract
The invention discloses a posaconazole freeze-dried powder injection and a preparation method thereof. The powder injection comprises an active therapeutic ingredient of posaconazole, a solubilizer of cyclodextrin and a pH conditioning agent. An acid is added in preparation processes to form a salt for solubilization. A mixed solvent comprising an organic solvent and injection water is employed, wherein the concentration of posaconazole in the mixed solvent is 2.5 to 15g/ml, the organic solvent is 3.0 to 10.0% by volume, and the balance is the injection water. In the preparation processes, the posaconazole and the acid are stirred or mixed, the organic solvent is added, the mixture is heated stirred or ultrasonically treated to be uniform, the cyclodextrin solution is added, mixture is stirred to be a clear solution, the pH value of the mixture is adjusted, the injection water is added to a constant volume, pyrogens are removed, and then aseptic filtration, subpackaging and freeze-drying are performed. The posaconazole freeze-dried powder injection of the invention has advantages that: the content of the active therapeutic ingredient is high, the stability is excellent, the powder injection is convenient for transport and storage, and the application of the posaconazole in the field of preparations is expanded.
Description
Technical field
The present invention relates to antifungal lyophilized injectable powder of a kind of posaconazole and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Posaconazole (Posaconzole) is the oral broad-spectrum antifungal new drug of novel triazole type by the exploitation of Schering Plough company, chemical name is 4-[4-[4-[4-[[(3R, 5R)-5-(2,4 difluorobenzene base)-5-(1,2,4-triazol-1-yl methyl) oxa-penta ring-3-yl] methoxyl group] phenyl] piperazine-1-yl] phenyl]-2-[(2S, 3S)-and 2-hydroxyl penta-3-yl]-1,2,4-triazole-3-ketone, chemical constitution is as follows
Gone on the market by drugs approved by FDA in JIUYUE, 2006, the listing dosage form is oral suspensions, and commodity are called Noxafil, and concentration is 40 mg/L.This chemical compound has good antibacterial activity to Candida, and is especially effective to the intractable or invasive infections with fungi (as aspergillosis, Fusarium and zygomycete, coccidioides immitis) of Polyenes and other triazole type drug resistances.Compare with other antifungal agent, he has following advantage: (1) has a broad antifungal spectrum, and activity is better than same veriety; (2) compare with existing antifungal agent, untoward reaction is light; (3) less drug interaction.
Patent documentation CN1499930A discloses a kind of oral suspensions again, after adding thickening agent and non-ionic surface active agent, make the posaconazole bioavailability be improved, but this liquid preparation only can be with oral mode dispenser, the application on the patient with severe symptoms who is difficult to swallow is restricted.In addition, oral suspensions also is subjected to very big restriction suffering from patient's the application that aggressive infects, need reach as early as possible minimum stable state medicine paddy concentration.Patent documentation CN1988887A discloses and has a kind ofly stablized, can be used for intravenous posaconazole suspension by phospholipid, but the concentration of posaconazole is lower in this suspension, and also there is the problem of poor stability, transportation and storage inconvenience in suspensoid than other dosage forms itself.
So how to enrich the application form of posaconazole, obtain a kind of posaconazole content height, good stability is convenient to the posaconazole formulations form transporting and store, becomes a technical problem that needs to be resolved hurrily.
Summary of the invention
In view of the above problems, the invention provides a kind of antifungal freeze-dried powder that contains posaconazole and preparation method thereof.
Lyophilized injectable powder of the present invention contains treatment effective ingredient posaconazole, solubilizing agent cyclodextrin and pH regulator agent.The solvent that uses in preparation process is the mixed solvent of organic solvent and water for injection composition, wherein posaconazole is 2.5 ~ 15 mg/mL in the concentration of mixed solvent, the organic solvent that uses is ethanol or the tert-butyl alcohol, the organic solvent volume accounts for the 3.0%-10.0% of total liquor capacity, and surplus is water for injection.The weight ratio of posaconazole and cyclodextrin is 1:5 ~ 40, preferred 1:10 ~ 20, and the cyclodextrin of use is selected from HP-or sulphur butyl-beta-schardinger dextrin-.
The dissolubility of posaconazole in water is very low, so according to its weakly alkaline chemical property, in preparation process, stoichiometric non-toxic organic acid or mineral acid and posaconazole salify hydrotropy have been added, wherein, organic acid is citric acid or tartaric acid, and mineral acid is hydrochloric acid or phosphoric acid, and posaconazole is 1:0.3 ~ 2.0 with the weight ratio of acid.
Particularly, the preparation process of this freeze-dried powder is as follows:
1) posaconazole is added acid and stir into pasty state or mixing, add organic solvent, heated and stirred or ultrasonic even;
2) get the water for injection stirring and dissolving that cyclodextrin adds medicinal liquid cumulative volume 1/3 ~ 2/3 in addition, pour into again in the above-mentioned solution, be stirred to clear and bright;
3) regulator solution pH adds injection water standardize solution;
4) through depyrogenation, aseptic filtration, packing, lyophilization namely.
During above-mentioned regulator solution pH, select pH regulator agent commonly used for use, alkaline conditioner such as available hydrogen sodium oxide, potassium hydroxide or hydrochloric acid, sulphuric acid etc. are acid adjusts, the preferred sodium hydroxide of alkaline conditioner, the preferred hydrochloric acid of acid regulator, general regulator solution pH is 4 ~ 7, preferred 4.5 ~ 6.
Adopt the method depyrogenation of activated carbon adsorption, namely add the needle-use activated carbon of total liquor capacity 0.05%, leave standstill 15 minutes after, carry out aseptic filtration, packing, lyophilization again.The lyophilization step is as follows: the drug solution that branch installs is put into freeze drying box, close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed, when treating that sample temperature is down to-45 ℃ ~-35 ℃, stop the flaggy refrigeration, the open cold condenser, when condenser temperature reaches-50 ℃ ~-40 ℃, open vacuum system, begin the distillation that heats up, the control sample temperature per hour rises 2 ~ 3 ℃, when rising, sample temperature reaches 10 degree when above, the control sample temperature per hour rises 4 ~ 5 ℃, and the temperature of final drying sample is 25 ~ 35 ℃, keeps this temperature 4 ~ 6 hours, get final product tamponade, outlet.
Posaconazole lyophilized injectable powder according to above proportioning and method preparation can pass through venous transfusion, vein, muscle or hypodermic form dispenser.The dispenser scope be every day every kg body weight 0.25mg to every kg body weight 30mg every day, preferred every day every kg body weight 1mg to every day every kg body weight be 10mg.The amount that this dosage form contains effective composition posaconazole is recommended as 100 ~ 250 mg/ and props up.Each accurately dosage and frequency are different and different according to the fungal infection order of severity of patient's sex, age and treatment situation and diagnosis.
The posaconazole antifungal lyophilized injectable powder that the present invention obtains has solved posaconazole owing to the problem that is difficult for the molten poor stability that causes; The product appearance of gained is plentiful, fine and smooth, quality is loose, adds can dissolve rapidly behind the water to recover the medicinal liquid primary characteristic; And lyophilized injectable powder itself has stable performance, transportation and store characteristic easily; Clinically, use with the form of injection, transfusion, both improved the curative effect of medicine, enlarged the scope of dosage form again, satisfied the needs for the treatment of.
The specific embodiment:
Below continue by the specific embodiment that the present invention will be described, various replacements or combination according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment 1-10:
Medicinal liquid by following consumption preparation posaconazole lyophilized injectable powder:
Preparation method: posaconazole is added acid stirring or mixing, add organic solvent, be heated to 25 ~ 75 ℃ of stirring and dissolving or ultrasonic even; Other gets the water for injection stirring and dissolving that cyclodextrin adds medicinal liquid cumulative volume 1/3 ~ 2/3, pours in the above-mentioned solution again, is stirred to clear and bright; With sodium hydroxide or hydrochloric acid solution regulator solution pH, add the injection water and be settled to 200 mL.Through observing, embodiment 1-7, dissolving is good, wherein do not add cyclodextrin embodiment 8, do not add the embodiment 9 of acid and do not add the embodiment 10 dissolving situations of organic solvent poorer than embodiment 1-7.In order to further specify the present invention, hereinafter choose embodiment 2, implement 4 and the condition of embodiment 6 enlarge inventory to 10 times, be respectively embodiment 11, embodiment 12 and embodiment 13.
Embodiment 11
Prescription:
Posaconazole 20 g
HP-200 g
Citric acid 35 g
Ethanol 90 mL
Water for injection adds to 2000 mL
—————————————————
Make 80 altogether
Preparation method: posaconazole and citric acid are mixed, add ethanol, be heated to 60 ℃, stir into uniform state; Other gets cyclodextrin and adds injection water 900 mL stirring and dissolving, pours in the above-mentioned solution again, is stirred to clear and bright; Regulator solution pH is 5.0, adds injection water standardize solution; Through depyrogenation, aseptic filtration, packing, lyophilization namely.
Embodiment 12:
Prescription:
Posaconazole 20 g
Sulphur butyl-beta-schardinger dextrin-400 g
Tartaric acid 14 g
The tert-butyl alcohol 150 mL
Water for injection adds to 2000 mL
—————————————————
Make 80 altogether
Preparation method: the posaconazole tartarize is mixed, add the tert-butyl alcohol, ultrasonic one-tenth uniform state; Other gets cyclodextrin and adds injection water 1200 mL stirring and dissolving, pours in the above-mentioned solution again, is stirred to clear and bright; Regulator solution pH is 5.5, adds injection water standardize solution; Through depyrogenation, aseptic filtration, packing, lyophilization namely.
Embodiment 13:
Prescription:
Posaconazole 20 g
Sulphur butyl-beta-schardinger dextrin-600g
Citric acid 40 g
The tert-butyl alcohol 180 mL
Water for injection adds to 2000 mL
—————————————————
Make 80 altogether
Preparation method: the posaconazole adding citric acid is mixed, add the tert-butyl alcohol, stir into uniform state; Other gets cyclodextrin and adds injection water 1300 mL stirring and dissolving, pours in the above-mentioned solution again, is stirred to clear and bright; Regulator solution pH is 6.0, adds injection water standardize solution; Through depyrogenation, aseptic filtration, packing, lyophilization namely.
Claims (10)
1. lyophilized injectable powder that contains posaconazole, it is characterized in that containing posaconazole, solubilizing agent cyclodextrin and the pH regulator agent for the treatment of effective dose, and in layoutprocedure, add sour salify hydrotropy, the mixed solvent that has used organic solvent and water for injection to form, wherein posaconazole is 2.5 ~ 15 mg/mL in the concentration of mixed solvent.
2. lyophilized injectable powder according to claim 1, the weight ratio of posaconazole and cyclodextrin is 1:5 ~ 40.
3. lyophilized injectable powder according to claim 1, the preferred weight ratio of posaconazole and cyclodextrin is 1:10 ~ 20.
4. lyophilized injectable powder according to claim 1 is characterized in that cyclodextrin is selected from HP-or sulphur butyl-beta-schardinger dextrin-.
5. lyophilized injectable powder according to claim 1 is characterized in that, has used organic acid or mineral acid and posaconazole salify hydrotropy in the preparation process, and wherein posaconazole is 1:0.3 ~ 2.0 with the weight ratio of acid.
6. lyophilized injectable powder according to claim 1 or 5 is characterized in that the organic acid that uses in the preparation process is citric acid or tartaric acid, and the mineral acid that uses is hydrochloric acid or phosphoric acid.
7. lyophilized injectable powder according to claim 1 is characterized in that, has used the mixed solvent of organic solvent and water for injection in preparation process, and wherein the organic solvent volume accounts for 3.0% ~ 10.0% of total liquor capacity.
8. according to claim 1 or 7 described lyophilized injectable powders, it is characterized in that the organic solvent that uses in the preparation process is ethanol or the tert-butyl alcohol.
9. lyophilized injectable powder according to claim 1 is characterized in that, using pH regulator agent regulator solution pH in the preparation process is 4 ~ 7.
10. lyophilized injectable powder according to claim 1, its preparation method is:
Posaconazole is added sour the stirring or mixing, add organic solvent, heated and stirred dissolving or ultrasonic even; Other gets the water for injection stirring and dissolving that cyclodextrin adds medicinal liquid cumulative volume 1/3 ~ 2/3, pours in the above-mentioned solution again, is stirred to clear and bright; Regulator solution pH adds injection water standardize solution; Through depyrogenation, aseptic filtration, packing, lyophilization namely.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210040459.5A CN103284959B (en) | 2012-02-22 | 2012-02-22 | Posaconazole freeze-dried powder injection and preparation method thereof |
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| CN201210040459.5A CN103284959B (en) | 2012-02-22 | 2012-02-22 | Posaconazole freeze-dried powder injection and preparation method thereof |
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| CN103284959B CN103284959B (en) | 2015-06-03 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546724A (en) * | 2013-10-12 | 2015-04-29 | 博瑞生物医药技术(苏州)有限公司 | Solid dispersion of antifungal agent |
| CN105287403A (en) * | 2014-08-02 | 2016-02-03 | 陕西合成药业股份有限公司 | Freeze-drying composition of posaconazole prodrug and preparation method and application of freeze-drying composition of posaconazole prodrug |
| CN105879041A (en) * | 2014-11-14 | 2016-08-24 | 北京赛林泰医药技术有限公司 | Posaconazole oral solution and preparation method thereof |
| CN106265534A (en) * | 2015-05-25 | 2017-01-04 | 江苏正大丰海制药有限公司 | A kind of preparation method of posaconazole lyophilized injectable powder |
| CN106511262A (en) * | 2015-09-11 | 2017-03-22 | 上海美悦生物科技发展有限公司 | Posaconazole oral solution and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1555796A (en) * | 2004-01-07 | 2004-12-22 | 海南康力元药业有限公司 | Fluorokongzole powder for injection and its preparation method |
| CN1596897A (en) * | 2004-07-26 | 2005-03-23 | 范敏华 | Itraconazole injection and its preparation method |
| CN1615870A (en) * | 2004-09-17 | 2005-05-18 | 北京博尔达生物技术开发有限公司 | Itraconazole freeze-dried powder injection and preparing method |
| CN1988887A (en) * | 2004-05-28 | 2007-06-27 | 先灵公司 | Injectable pharmaceutical suspension comprising posaconazole |
| CN102836128A (en) * | 2011-06-25 | 2012-12-26 | 博瑞生物医药技术(苏州)有限公司 | Method for preparing ultrafine particles of water-insoluble or insoluble medicine |
-
2012
- 2012-02-22 CN CN201210040459.5A patent/CN103284959B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555796A (en) * | 2004-01-07 | 2004-12-22 | 海南康力元药业有限公司 | Fluorokongzole powder for injection and its preparation method |
| CN1988887A (en) * | 2004-05-28 | 2007-06-27 | 先灵公司 | Injectable pharmaceutical suspension comprising posaconazole |
| CN1596897A (en) * | 2004-07-26 | 2005-03-23 | 范敏华 | Itraconazole injection and its preparation method |
| CN1615870A (en) * | 2004-09-17 | 2005-05-18 | 北京博尔达生物技术开发有限公司 | Itraconazole freeze-dried powder injection and preparing method |
| CN102836128A (en) * | 2011-06-25 | 2012-12-26 | 博瑞生物医药技术(苏州)有限公司 | Method for preparing ultrafine particles of water-insoluble or insoluble medicine |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546724A (en) * | 2013-10-12 | 2015-04-29 | 博瑞生物医药技术(苏州)有限公司 | Solid dispersion of antifungal agent |
| CN105287403A (en) * | 2014-08-02 | 2016-02-03 | 陕西合成药业股份有限公司 | Freeze-drying composition of posaconazole prodrug and preparation method and application of freeze-drying composition of posaconazole prodrug |
| CN105879041A (en) * | 2014-11-14 | 2016-08-24 | 北京赛林泰医药技术有限公司 | Posaconazole oral solution and preparation method thereof |
| CN106265534A (en) * | 2015-05-25 | 2017-01-04 | 江苏正大丰海制药有限公司 | A kind of preparation method of posaconazole lyophilized injectable powder |
| CN106511262A (en) * | 2015-09-11 | 2017-03-22 | 上海美悦生物科技发展有限公司 | Posaconazole oral solution and preparation method thereof |
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| CN103284959B (en) | 2015-06-03 |
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