CN1864666A - Lyophilized powder injection of levofloxacin mesylate and preparation method thereof - Google Patents

Lyophilized powder injection of levofloxacin mesylate and preparation method thereof Download PDF

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Publication number
CN1864666A
CN1864666A CN 200610019305 CN200610019305A CN1864666A CN 1864666 A CN1864666 A CN 1864666A CN 200610019305 CN200610019305 CN 200610019305 CN 200610019305 A CN200610019305 A CN 200610019305A CN 1864666 A CN1864666 A CN 1864666A
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levofloxacin
injection
excipient
water
glucose
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CN 200610019305
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吴小玉
周利娟
艾鸣哲
曹勇
吴佳
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HUBEI KEYI PHARMACEUTIC CO Ltd
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HUBEI KEYI PHARMACEUTIC CO Ltd
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Abstract

The freeze dried levofloxacin mesilate powder for injection consists of levofloxacin mesilate as active component and pharmaceutically acceptable excipient. The preparation process of the freeze dried levofloxacin mesilate powder for injection includes the following steps: dissolving excipient in water for injection, regulating pH value to 3.8-4.0, adding injection purpose active carbon and boiling through steam heating, cooling and filtering to eliminating active carbon, adding levofloxacin mesilate, regulating pH value to 3.0-4.5, adding water for injection, eliminating pyrogen, filtering, washing, drying, and freeze drying to obtain the freeze dried levofloxacin mesilate powder for injection. Or, The preparation process includes the following steps: dissolving excipient and levofloxacin mesilate in water for injection, regulating pH value to 3.0-4.5, eliminating pyrogen, filtering, washing, drying, and freeze drying to obtain the freeze dried levofloxacin mesilate powder for injection. The present invention has high stability and use convenience.

Description

Lyophilized powder injection of levofloxacin mesylate and preparation method thereof
Technical field
The present invention relates to lyophilized powder injection of levofloxacin mesylate and preparation method thereof, belong to medical technical field.
Background technology
Levofloxacin M. S. A is the fluoroquinolones anti-infectives, its molecular formula: C 18H 20FN 3O 4CH 3SO 3HH 2O, molecular weight: 475.49 chemical structural formulas are:
Figure A20061001930500031
Levofloxacin M. S. A is the mesylate of levofloxacin, and its clinical efficacy and levofloxacin are close, and its antimicrobial spectrum is identical with ofloxacin, but antibacterial action is strong 1 times, and toxicity is lower, and its clinical practice is wide, untoward reaction is little, is subjected to doctor and patient's welcome deeply.The Levofloxacin M. S. A water solublity is better, is fit to make ejection preparation.At present, there is the little pin and the infusion solutions listing of Levofloxacin M. S. A in market, but the Levofloxacin M. S. A aqueous stability is poor, meets auroral poles and easily decomposes variable color, and its little pin and infusion solutions all need keep in Dark Place.
Summary of the invention
The present invention provides a kind of lyophilized powder injection of levofloxacin mesylate and preparation method thereof at the problems referred to above exactly, and the obtained freeze-drying powder needle injection can improve stability of formulation with solid form storage transportation, extends the expiration date.The method technology that provides is simple, is suitable for large-scale production.
Technical scheme provided by the invention is: lyophilized powder injection of levofloxacin mesylate, form by active component Levofloxacin M. S. A and pharmaceutically-acceptable excipients.
Described excipient is selected from one or more in glucide, mannitol, the sodium chloride; Weight ratio between Levofloxacin M. S. A (in levofloxacin) and the excipient is 1: 1-20: 1.
The preferred glucose of excipient wherein.Weight ratio 1 between Levofloxacin M. S. A and the glucose: 1-10: 1.Weight ratio between Levofloxacin M. S. A and the glucose 5: 1.
The present invention also provides the preparation method of above-mentioned lyophilized powder injection of levofloxacin mesylate, getting excipient earlier is dissolved in the water for injection, make into the excipient solution of 50～70wt%, regulate pH to 3.8～4.0, add 0.3～1.0g needle-use activated carbon by the 100ml excipient solution, Steam Heating was boiled 30～120 minutes, cooling, and filtering decarbonization gets excipient filtrate; The Levofloxacin M. S. A raw material is added in the above-mentioned excipient filtrate, regulate pH to 3.0～4.5, adding the injection water is the Levofloxacin M. S. A solution of 10～20wt% to forming in levofloxacin concentration; Active carbon depyrogenation, membrane filtration degerming, absolute ethanol washing, vacuum drying, lyophilizing promptly get lyophilized powder injection of levofloxacin mesylate.
The present invention also can prepare as follows: excipient, Levofloxacin M. S. A are added the dissolving of injection water, regulate pH to 3.0～4.5, adding the injection water is the Levofloxacin M. S. A solution of 10～20wt% to forming in levofloxacin concentration; Active carbon depyrogenation, membrane filtration degerming, absolute ethanol washing, vacuum drying, lyophilizing promptly get lyophilized powder injection of levofloxacin mesylate.
When lyophilized powder injection of levofloxacin mesylate of the present invention uses, can add 5% glucose injection, 0.9% sodium chloride injection or 5% Dextrose and Sodium Chloride Inj. 100ml iv drip more earlier with after 5% glucose injection, 0.9% sodium chloride injection or 5% Dextrose and Sodium Chloride Inj., the 5～10ml dissolving.Lyophilized powder injection of levofloxacin mesylate of the present invention can supply intravenous drip, and the instillation time is every 100ml at least 60 minutes.This preparation should not mix quiet with bottle with other medicines, or carries out quiet in same radicular vein tube for transfusion.Recommended dose: adult 400mg every day (in levofloxacin), divide 1-2 time quiet.Severe infection patient and pathogen are to this product sensitivity chump (as bacillus pyocyaneus), and every day, maximal dose can increase to 600mg (in levofloxacin), divide 1-2 time quiet.The renal function person of going down determines dosage according to creatinine clearance rate.
Lyophilized powder injection of levofloxacin mesylate of the present invention has good stability, and characteristics easy to use have better stability than little pin and infusion solutions.
The specific embodiment
Further specify the present invention by the following examples, therefore do not limit the present invention in the described scope of embodiments.
Embodiment 1:
Get the 40g glucose and be dissolved in the water for injection (30 ℃), make into the glucose concentrated solution of 50wt%, regulate pH to 3.8～4.0 with 1mol/L hydrochloric acid, add the 0.3g needle-use activated carbon by 100ml glucose concentrated solution, Steam Heating was boiled 30 minutes, was chilled to 50 ℃, filtering decarbonization gets glucose filtrate.
With 200g (with C 18H 20FN 3O 4Meter) Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) add in the glucose filtrate, add injection water to Levofloxacin M. S. A and dissolve, regulate pH to 3.5～4.5, add the injection water to 2000g; Add the 10g needle-use activated carbon, 60 ℃ were stirred filtering decarbonization 30 minutes; Through 0.22um filter membrane coarse filtration and fine straining.By 1000 bottles of fills, lyophilizing, tamponade, Zha Gai.
Embodiment 2:
Get the 60g glucose and be dissolved in the hot water for injection (60 ℃), make into the glucose concentrated solution of 60wt%, regulate pH to 3.8～4.0 with 1mol/L hydrochloric acid, add the 0.3g needle-use activated carbon by 100ml glucose concentrated solution, Steam Heating was boiled 30 minutes, was chilled to 50 ℃, filtering decarbonization gets glucose filtrate.
With 300g (with C 18H 20FN 3O 4Meter) Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) add in the glucose filtrate, add injection water to Levofloxacin M. S. A and dissolve, regulate pH to 3.5～4.5, add the injection water to 3000g; Add the 15g needle-use activated carbon, 60 ℃ were stirred filtering decarbonization 30 minutes; Through 0.22um filter membrane coarse filtration and fine straining.By 1000 bottles of fills, lyophilizing, tamponade, Zha Gai.
Embodiment 3:
Get the 30g glucose and be dissolved in the hot water for injection (100 ℃), make into the glucose concentrated solution of 70wt%, regulate pH to 3.8～4.0 with 1mol/L hydrochloric acid, add the 0.3g needle-use activated carbon by 100ml glucose concentrated solution, Steam Heating was boiled 30 minutes, was chilled to 50 ℃, filtering decarbonization gets glucose filtrate.
With 300g (with C 18H 20FN 3O 4Meter) Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) add in the glucose filtrate, add injection water to Levofloxacin M. S. A and dissolve, regulate pH to 3.5～4.5, add the injection water to 3000g; Add the 15g needle-use activated carbon, 60 ℃ were stirred filtering decarbonization 30 minutes; Through 0.22um filter membrane coarse filtration and fine straining.By 1000 bottles of fills, lyophilizing, tamponade, Zha Gai.
Embodiment 4:
A. preparating liquid: with 150g glucose, 300g Levofloxacin M. S. A (with C 18H 20FN 3O 4Meter) adds the dissolving of injection water, regulate pH to 3.0～4.5, add the injection water to 3000g.
B. depyrogenation: get the 15g needle-use activated carbon and add in the solution that step a makes, 60 ℃ were stirred filtering decarbonization 30 minutes.
C. degerming: the medicinal liquid that obtains through step b is through 0.22um filter membrane coarse filtration and fine straining.
D. fill: with the fill of 1000 bottles of control cillin bottles.
E. lyophilizing: under-20～-50 ℃, vacuum, carry out lyophilization.Tamponade, Zha Gai promptly get lyophilized powder injection of levofloxacin mesylate.
Embodiment 5:
1000 bottles of inventorys
Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) 450g is (with C 18H 20FN 3O 4Meter)
Glucose 30g
Water for injection adds to 3000g
Get the 30g glucose and be dissolved in the hot water for injection (60 ℃), make into the glucose concentrated solution of 70wt%, regulate pH to 3.8～4.0 with 1mol/L hydrochloric acid, add the 1.0g needle-use activated carbon by 100ml glucose concentrated solution, Steam Heating was boiled 120 minutes, was chilled to 50 ℃, filtering decarbonization gets glucose filtrate.
With 450g (with C 18H 20FN 3O 4Meter) Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) add in the glucose filtrate, add injection water to Levofloxacin M. S. A and dissolve, regulate pH to 3.5～4.5, add the injection water to 3000g; Add the 15g needle-use activated carbon, 60 ℃ were stirred filtering decarbonization 30 minutes; Through 0.22um filter membrane coarse filtration and fine straining.By 1000 bottles of fills, lyophilizing, tamponade, Zha Gai.
Embodiment 6:
1000 bottles of inventorys
Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) 450g is (with C 18H 20FN 3O 4Meter)
Glucose 60g
Water for injection adds to 3000g
Preparation method is with embodiment 2.
Embodiment 7:
1000 bottles of inventorys
Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) 450g is (with C 18H 20FN 3O 4Meter)
Glucose 150g
Water for injection adds to 3000g
Preparation method is with embodiment 2.
Embodiment 8:
1000 bottles of inventorys
Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) 600g is (with C 18H 20FN 3O 4Meter)
Glucose 30g
Water for injection adds to 3000g
Preparation method is with embodiment 2.
Embodiment 9:
1000 bottles of inventorys
Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) 600g is (with C 18H 20FN 3O 4Meter)
Glucose 600g
Water for injection adds to 3000g
Preparation method is with embodiment 2.
Embodiment 10:
1000 bottles of inventorys
Levofloxacin M. S. A (C 18H 20FN 3O 4CH 3SO 3HH 2O) 600g is (with C 18H 20FN 3O 4Meter)
Glucose 150g
Water for injection adds to 3000g
Preparation method is with embodiment 2.
The present invention illustrates beneficial effect of the present invention by following test:
A. the comparison of excipient
1. test objective:
Mannitol, glucose are lyophilizing pin excipient commonly used, and the eutectic point of mannitol is-1.0 ℃, and the eutectic point of glucose is-3 ℃, respectively with mannitol, glucose and Levofloxacin M. S. A compatibility, investigate compatibility stability.
2. test method
Mannitol is mixed with 20% solution, adds Levofloxacin M. S. A, make into 0.5g/L, placed 7 days under-5 ℃ of conditions.
In addition glucose is mixed with 20% solution, adds Levofloxacin M. S. A, make into 0.5g/L, placed 7 days under-5 ℃ of conditions.
3. result of the test
Produce precipitation behind 20% mannitol solution and the Levofloxacin M. S. A compatibility.Still be settled solution behind glucose solution and the Levofloxacin M. S. A compatibility, do not produce precipitation.
4. conclusion
There are not obvious incompatibility in glucose and Levofloxacin M. S. A between the two, and glucose more is applicable in the lyophilized powder injection of levofloxacin mesylate prescription than mannitol as excipient.
B. lyophilized powder injection of levofloxacin mesylate, the little pin of Levofloxacin M. S. A, Levofloxacin M. S. A infusion solutions stability are relatively
1. sample: lyophilized powder injection of levofloxacin mesylate, lot number: 030609, specification: 0.2g, control antibiotic glass bottle dress, Hubei KeYi Pharmacentic Co., Ltd. produces.
The little pin of Levofloxacin M. S. A, lot number: 031030470, specification: 2ml:0.2g, colourless ampoule is bottled, and He'nan Tianfang Pharmaceutical Co., Ltd produces.
The Levofloxacin M. S. A infusion solutions, lot number: 0310152, specification: 100ml:0.2g, colourless transfusion bottle, the Beijing Double-Crane Pharmaceutical Co., Ltd produces.
2. experimental condition:
Light: illumination 4500 ± 5001x, sample put in 4500 ± 5001x light cupboard.
3. test method: sample was placed experimental condition following ten days, investigate, its result comparison during with 0 day in sampling in 5,10 days.
4. result of the test the results are shown in Table 1.
Table 1 stability test result
The sample title Freezing-dried powder injection Little pin Infusion solutions
0 day Character indicates content (%) related substance (%) Off-white color, block 101.1 0.09 Yellow green clear liquid 101.6 0.13 Yellow green clear liquid 102.2 0.11
5 days Outward appearance indicates content (%) related substance (%) Off-white color, block 99.83 0.31 Yellow clear liquid 99.20 0.51 Yellow green clear liquid 101.0 0.45
10 days Outward appearance indicates content (%) related substance (%) Off-white color, block 99.47 0.35 Yellow clear liquid 99.85 0.83 Yellow clear liquid 100.9 0.81
Lyophilized powder injection of levofloxacin mesylate, little pin, infusion solutions under the 45001x condition 10 days, content there is no significant change, but related substance all increases, and the lyophilized powder injection of levofloxacin mesylate related substance increases less than Levofloxacin M. S. A infusion solutions and the little pin of Levofloxacin M. S. A.
5. conclusion
Lyophilized powder injection of levofloxacin mesylate has better stability than its little pin and infusion solutions.

Claims (7)

1. lyophilized powder injection of levofloxacin mesylate is made up of active component Levofloxacin M. S. A and pharmaceutically-acceptable excipients.
2. according to the described freezing-dried powder injection of claim 1, it is characterized in that: described excipient is a glucose; In levofloxacin, the weight ratio between Levofloxacin M. S. A and the excipient is 1: 1-20: 1.
3. according to the described freezing-dried powder injection of claim 2, it is characterized in that: in levofloxacin, the weight ratio 1 between Levofloxacin M. S. A and the glucose: 1-10: 1.
4. according to the described freezing-dried powder injection of claim 2, it is characterized in that: in levofloxacin, the weight ratio between Levofloxacin M. S. A and the glucose 5: 1.
5. the preparation method of claim 1 or 2 described lyophilized powder injection of levofloxacin mesylate, it is characterized in that: get excipient earlier and be dissolved in the water for injection, make into the excipient solution of 50～70wt%, regulate pH to 3.8～4.0, add 0.3～1.0g needle-use activated carbon by the 100ml excipient solution, Steam Heating was boiled 30～120 minutes, cooling, and filtering decarbonization gets excipient filtrate; The Levofloxacin M. S. A raw material is added in the above-mentioned excipient filtrate, regulate pH to 3.0～4.5, adding the injection water is the Levofloxacin M. S. A solution of 10～20wt% to forming in levofloxacin concentration; Active carbon depyrogenation, membrane filtration degerming, absolute ethanol washing, vacuum drying, lyophilizing promptly get lyophilized powder injection of levofloxacin mesylate.
6. preparation method according to claim 5 is characterized in that: the used water for injection of preparation excipient solution is 30 ℃～100 ℃ water for injection.
7. the preparation method of claim 1 or 2 described lyophilized powder injection of levofloxacin mesylate, it is characterized in that: excipient, Levofloxacin M. S. A are added the dissolving of injection water, regulate pH to 3.0～4.5, adding the injection water is the Levofloxacin M. S. A solution of 10～20wt% to forming in levofloxacin concentration; Active carbon depyrogenation, membrane filtration degerming, absolute ethanol washing, vacuum drying, lyophilizing promptly get lyophilized powder injection of levofloxacin mesylate.
CN 200610019305 2006-06-09 2006-06-09 Lyophilized powder injection of levofloxacin mesylate and preparation method thereof Pending CN1864666A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102018678A (en) * 2010-12-20 2011-04-20 蚌埠丰原涂山制药有限公司 Preparation method of antofloxacin hydrochloride powder injection
CN101991546B (en) * 2009-08-21 2012-02-22 华北制药集团制剂有限公司 Methanesulfonic acid levofloxacin freeze-dried powder injection and preparation method thereof
CN105232480A (en) * 2015-11-27 2016-01-13 湖南科伦制药有限公司 Preparation method of ofloxacin freeze-dried powder injection
CN106491529A (en) * 2016-12-08 2017-03-15 广东彼迪药业有限公司 A kind of levofloxacin hydrochloride sodium chloride injection and preparation method thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101991546B (en) * 2009-08-21 2012-02-22 华北制药集团制剂有限公司 Methanesulfonic acid levofloxacin freeze-dried powder injection and preparation method thereof
CN102018678A (en) * 2010-12-20 2011-04-20 蚌埠丰原涂山制药有限公司 Preparation method of antofloxacin hydrochloride powder injection
CN105232480A (en) * 2015-11-27 2016-01-13 湖南科伦制药有限公司 Preparation method of ofloxacin freeze-dried powder injection
CN105232480B (en) * 2015-11-27 2019-02-19 湖南科伦制药有限公司 A kind of preparation method of Ofloxacin freeze drying powder injection
CN106491529A (en) * 2016-12-08 2017-03-15 广东彼迪药业有限公司 A kind of levofloxacin hydrochloride sodium chloride injection and preparation method thereof

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