CN102342910B - Levofloxacin hydrochloride injection pharmaceutical composition and preparation method thereof - Google Patents
Levofloxacin hydrochloride injection pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN102342910B CN102342910B CN201110292309A CN201110292309A CN102342910B CN 102342910 B CN102342910 B CN 102342910B CN 201110292309 A CN201110292309 A CN 201110292309A CN 201110292309 A CN201110292309 A CN 201110292309A CN 102342910 B CN102342910 B CN 102342910B
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Abstract
The invention discloses a levofloxacin hydrochloride injection pharmaceutical composition and a preparation method thereof. The preparation method comprises the following steps of: dissolving levofloxacin hydrochloride with a proper amount of water for injection, adding a prescription amount of vitamin B6, lipoic acid and 2.3 g of activated carbon, then adding water for injection to 1000 ml, decarbonizing and filtering, detecting the intermediate, filling, performing moist heat sterilization at the temperature of 121 DEG C for 20 minutes, carrying out leakage detection and lamp inspection, and packaging a finished product. The levofloxacin hydrochloride injection pharmaceutical composition and the preparation method thereof have the advantages that: the characteristic that vitamin B6 is easy to damage under illumination is utilized to cover up the damage caused by illumination on levofloxacin hydrochloride in the production process; lipoic acid is used as an antioxidant and metal chelating agent, thereby reducing the oxidation loss of levofloxacin hydrochloride and reducing the generation of insoluble complex due to complexing of levofloxacin hydrochloride and multivalent metal introduced in the production process; and because the damage caused by metal element, illumination and high-temperature sterilization on the product are reduced, the total amount of insoluble microparticles in the finished product of a new combined formula drug is reduced, the color of the product is lightened, and the ratio of related substances is reduced.
Description
Technical field
The present invention discloses a kind of levofloxacin hydrochloride injection pharmaceutical composition, and this preparation of drug combination method also is provided simultaneously, belongs to field of medicine preparing technology.
Background technology
In medical technical field, the levofloxacin injection belongs to Comprecin, is the levo form of ofloxacin, and its antibacterial activity is about 2 times of ofloxacin, and its main mechanism is active for suppressing the DNA of bacteria gyrase, suppresses duplicating of DNA of bacteria.Levofloxacin has a broad antifungal spectrum, antibacterial action are strong, and side effect is little, and is cheap; Being classified as national essential drugs, is one of domestic the most salable several antibiotic kinds, but simultaneously; The levofloxacin injection also is one of more kind of domestic anti-infectives untoward reaction case; 5ml product 10 μ m and the above particle number of 10 μ m will reach 3000 ~ 4500 during " particulate matter " project indicator was produced in the quality standard, and " color " OD value reaches about 0.006, and " related substance " accounts for the main peak area and reach about 0.4; Improving the quality of products, is one of important means that reduces untoward reaction.
Summary of the invention
The present invention discloses a kind of levofloxacin hydrochloride injection pharmaceutical composition, and all more former technologies of index such as product " particulate matter ", " color ", " related substance " improve a lot.
The present invention also provides the method for preparing of this medicine, and it is simple to have technology, is applicable to characteristics such as suitability for industrialized production.
Levofloxacin hydrochloride injecta composition provided by the invention, process by following raw material:
Levofloxacin hydrochloride 15 ~ 30g, vitamin B6 3 ~ 5g, thioctic acid 2 ~ 4g, water for injection add to 1000ml and process.
Levofloxacin hydrochloride injecta composition provided by the invention, its preparation method is following:
Dissolve levofloxacin hydrochloride with proper amount of water for injection, add vitamin B6, thioctic acid, the active carbon 2.3g of recipe quantity, add the injection water again to 1000ml, decarbonization filtering; Detect intermediate, fill, 121 ℃, 20 minutes moist heat sterilizations; Leak detection, lamp inspection, finished product packing.
Below experiment shows that all more former technologies of index such as medicine body of the present invention " particulate matter ", " color ", " related substance " improve a lot:
Experiment one: particulate matter(light blockage method)
1. experimental enviroment and detection
The test operation environment should be introduced external microgranule, and the operation before measuring should be carried out in laminar flow station.Glass apparatus all should clean, no microgranule with other required articles for use.Test used microgranule inspection water (or other suitable solvent), must filter through the microporous filter membrane that is not more than 1.0 μ m before using.Get microgranule inspection water (or other suitable solvent) 50ml, measure by this method, the particulate matter that requires to contain among every 10ml more than 10 μ m and the 10 μ m should be below 10, and containing the above particulate matter of 25 μ m and 25 μ m should be below 2.
Test principle
When the microgranule in the liquid during through a narrow detection zone; With the vertical incident illumination of flow direction; Weaken owing to being stopped by microgranule; Therefore the signal by pick off output reduces, and it is relevant with the sectional area size of microgranule that sort signal changes, and particulate matter is promptly according to this principle in the light blockage method inspection injection.
General requirement to instrument
Instrument generally includes sampler, pick off and number, according to processor three parts.Measuring particle size range is 2～100 μ m, and detection of particles concentration is 0～10000/ml.
The correction of instrument and calibratingUsed instrument should be proofreaied and correct once in per at least 6 months.
(1) after sample volume is treated instrument stabilizer, get more than the microgranule of sample volume inspection water and place sampling cup, claim decide weight, through sampler by the microgranule inspection water of measuring certain volume in the sampling cup after, weight decided in title once more.Difference with the fixed weight of twice title is calculated sample volume.METHOD FOR CONTINUOUS DETERMINATION 3 times, record volume should be in ± 5% with the difference of measuring the indicating value of volume at every turn.Volumetric meansigma methods should be in ± 3% with the difference of measuring the indicating value of volume.Also can adopt other suitable methods to proofread and correct, the result should meet afore mentioned rules.
(2) counting micro particles is got relative standard deviation and is not more than 5%, and mean diameter is the standard particle of 10 μ m, processes the suspension that contains 1000～1500 particle numbers among every 1ml; Leave standstill the degassing in 2 minutes, turn on agitator slowly stirs and makes its even (avoiding bubble to produce); Measure 3 times in accordance with the law; Write down the stored count of 5 μ m passages, data are disregarded for the first time, and back twice mensuration result's the meansigma methods and the difference of known population should be in ± 20%.
(3) sensor resolution is got relative standard deviation and is not more than 5%; Mean diameter is the standard particle (standard deviation of average particle diameter should be not more than 1 μ m) of 10 μ m; Process the suspension that contains 1000～1500 particle numbers among every 1ml, leave standstill the degassing in 2 minutes, turn on agitator; Slowly stir and make it evenly (avoid bubble to produce); Measure the population of 8 μ m, 10 μ m and three passages of 12 μ m in accordance with the law, calculate the difference counting of 8 μ m and two passages of 10 μ m and the difference counting of 10 μ m and two passages of 12 μ m, above-mentioned two differences counting all must not be less than 68% with the ratio of the stored count of 10 μ m passages.If correcting result is against regulation, proofread and correct once more behind the adjusting instrument again, can use after up to specification.With self check software, can carry out self check like institute's use instrument.
Inspection technique
Get test sample, water is cleaned container outer wall, carefully overturns 20 times; Make the solution mix homogeneously, left standstill 2 minutes or the appropriate time degassing careful openable container; Directly the test sample container is placed on the sampler, open and stir or slowly rotate, make solution mixing (avoiding producing bubble) with hands; Directly extract an amount of solution (exceeding) by instrument, measure and record data not suck bubble; Other is taken to few 3 test samples, measures with method.The data of first test sample are disregarded, and get subsequent measurements result's mean value calculation.
Levofloxacin hydrochloride injection particulate matter assay
| The name of an article | Levofloxacin hydrochloride concentration | Be distributed into 10 μ m and the above particle number of 10 μ m behind the 5ml preparation | Be distributed into 25 μ m and the above particle number of 25 μ m behind the 5ml preparation |
| Original formulation | 1ml:0.02g | 3650 | 456 |
| Embodiment 1 | 1ml:0.02g | 1976 | 234 |
| Embodiment 2 | 1ml:0.015g | 1951 | 251 |
| Embodiment 3 | 1ml:0.03g | 1966 | 245 |
| Embodiment is average | ? | 1964 | 243 |
Conclusion: new combination formula medicine levofloxacin hydrochloride injection particulate matter total amount greatly reduces.
Experiment two: color(spectrophotography)
Get test sample, add the solution that water is processed hydrochloric levofloxacin 1mg among every 1ml, use spectrophotography, measure trap in the wavelength of 450nm.
Levofloxacin hydrochloride injection color assay
| The name of an article | Levofloxacin hydrochloride concentration | The OD value |
| Original formulation | 1ml:0.02g | 0.006 |
| Embodiment 1 | 1ml:0.02g | 0.004 |
| Embodiment 2 | 1ml:0.015g | 0.003 |
| Embodiment 3 | 1ml:0.03g | 0.003 |
| Embodiment is average | ? | 0.003 |
Conclusion: new combination formula medicine levofloxacin hydrochloride injection color shoals.
Experiment three: related substance(HPLC)
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler; With copper sulfate D-phenylalanine solution (get D-phenylalanine 1.32g and copper sulfate 1g, add water 1000ml dissolving after, regulate pH value to 3.5 with sodium hydroxide test solution)-methanol (82:18) is mobile phase; 40 ℃ of column temperatures; Flow velocity 1ml/min; The detection wavelength is 293nm.It is an amount of to get the ofloxacin reference substance; Add the mobile phase dissolving and be diluted to the solution that contains 0.2mg among every 1ml approximately; Get 20 μ l and inject chromatograph of liquid; Right ofloxacin, levofloxacin flow out successively, and number of theoretical plate calculates by the levofloxacin peak should be not less than 2500, and be right, the peak-to-peak separating degree of laevoisomer should be up to specification.
It is an amount of that precision is measured test sample, processes the solution that contains 0.5mg among every 1ml approximately with mobile phase dissolving and dilution, as need testing solution.It is an amount of that precision is measured need testing solution, is diluted to the solution that contains 5 μ g among every 1ml with mobile phase, as contrast solution.Get contrast solution 10 μ l and inject chromatograph of liquid; Regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 20%～25% of a full scale, and precision is measured need testing solution and each 10 μ l of contrast solution again; Inject chromatograph of liquid respectively; 2 times of record chromatogram to main constituent chromatographic peak retention time, in the need testing solution chromatogram if any impurity peaks, calculate each impurity peak area and with the ratio of contrast solution main peak area.
Levofloxacin hydrochloride injection related substance assay
| The name of an article | Levofloxacin hydrochloride concentration | Test sample impurity peak area/contrast solution main peak area |
| Original formulation | 1ml:0.02g | 0.39 |
| Embodiment 1 | 1ml:0.02g | 0.24 |
| Embodiment 2 | 1ml:0.015g | 0.23 |
| Embodiment 3 | 1ml:0.03g | 0.26 |
| Embodiment is average | ? | 0.24 |
Conclusion: new combination formula medicine levofloxacin hydrochloride injection related substances reduces.
The present invention compares with existing levofloxacin hydrochloride injection has following good effect:
In the levofloxacin hydrochloride injection formulation production process, the polyvalent metal element in the various containers, illumination, high temperature sterilize have all produced destruction to levofloxacin.Utilize vitamin B6 to meet the characteristic of light destructible, to cover and to have reduced the destruction of the illumination in the production process to levofloxacin; Thioctic acid is as antioxidant and metal-chelator, not only reduced the oxidational losses of levofloxacin hydrochloride but also reduced the insoluble complex that the polyvalent metal complexation introduced in levofloxacin hydrochloride and the production process produces.Because reduced " metallic element ", " illumination " and " high temperature sterilize " destruction to product, new combination formula medicine finished product particulate matter total amount reduces, color shoals, the reduction of related substance ratio.
Embodiment 1
With proper amount of water for injection dissolving 20g levofloxacin hydrochloride, add 3g vitamin B6,3g thioctic acid, active carbon 2.3g, add the injection water again to 1000ml, decarbonization filtering; Detect intermediate, fill, 121 ℃, 20 minutes moist heat sterilizations; Leak detection, lamp inspection, finished product packing.
Embodiment 2
With proper amount of water for injection dissolving 15g levofloxacin hydrochloride, add 4g vitamin B6,2g thioctic acid, active carbon 2.3g, add the injection water again to 1000ml, decarbonization filtering; Detect intermediate, fill, 121 ℃, 20 minutes moist heat sterilizations; Leak detection, lamp inspection, finished product packing.
Embodiment 3
Levofloxacin hydrochloride 30g, vitamin B6 5g, thioctic acid 4g, water for injection are added to 1000ml and processes.
Its preparation method is following: dissolve levofloxacin hydrochloride with proper amount of water for injection, add vitamin B6, thioctic acid, the active carbon 2.3g of recipe quantity, add the injection water again to 1000ml; Decarbonization filtering detects intermediate, fill; 121 ℃, 20 minutes moist heat sterilizations, leak detection; Lamp inspection, finished product packing.
Claims (2)
1. levofloxacin hydrochloride injection pharmaceutical composition is characterized in that being processed by following raw material:
Levofloxacin hydrochloride 15 ~ 30g, vitamin B6 3 ~ 5g, thioctic acid 2 ~ 4g, water for injection add to 1000ml.
2. the said levofloxacin hydrochloride injection of claim 1 preparation of drug combination method may further comprise the steps:
Dissolve levofloxacin hydrochloride with proper amount of water for injection, add vitamin B6, thioctic acid, the active carbon 2.3g of recipe quantity, add the injection water again to 1000ml, decarbonization filtering; Detect intermediate, fill, 121 ℃, 20 minutes moist heat sterilizations; Leak detection, lamp inspection, finished product packing.
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| CN103479522B (en) * | 2013-09-25 | 2015-09-16 | 海南华拓天涯制药有限公司 | A kind of preparation method of levofloxacin hydrochloride and sodium chloride injection |
| CN103550144B (en) * | 2013-10-25 | 2015-10-14 | 深圳朗欧医药集团有限公司 | levofloxacin hydrochloride composition injection and preparation method thereof |
| CN109528637A (en) * | 2018-12-20 | 2019-03-29 | 江西润泽药业有限公司 | Levofloxacin Hydrochloride Injection and preparation method thereof |
| CN109580837A (en) * | 2018-12-31 | 2019-04-05 | 辰欣药业股份有限公司 | A kind of detection method of Levofloxacin Hydrochloride Injection |
| CN113640416A (en) * | 2021-08-12 | 2021-11-12 | 海南海神同洲制药有限公司 | Content determination method of levofloxacin hydrochloride tablets |
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Address after: 130011 No. 358 Innovation Road, Changchun High-tech Zone, Jilin Province Patentee after: Changchun Bethune Pharmaceutical Co., Ltd. Address before: 130012 No. 358 Innovation Road, Changchun High-tech Zone, Jilin Province Patentee before: Pharmaceutical Factory, Bethune Medical Univ. |