CN1263452C - Powder injection of lactatelevo-ofloxacin and its preparation - Google Patents
Powder injection of lactatelevo-ofloxacin and its preparation Download PDFInfo
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- CN1263452C CN1263452C CN 200310108462 CN200310108462A CN1263452C CN 1263452 C CN1263452 C CN 1263452C CN 200310108462 CN200310108462 CN 200310108462 CN 200310108462 A CN200310108462 A CN 200310108462A CN 1263452 C CN1263452 C CN 1263452C
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Abstract
The present invention relates to a lactatelevo-ofloxacin powder injection and a preparation method thereof. The lactatelevo-ofloxacin powder injection is a sterile powder preparation obtained by the way that after a lactatelevo-ofloxacin water solution is decolorized, sterilized and filtered, the lactatelevo-ofloxacin water solution is crystallized by ethanol or propanone in a flushing mode and is filled in bottles. High-pressure liquid phase detection is adopted to discover that the content of dextroisomer in sterile powder is lower than 0.5%. Compared with the existing water injection, the lactatelevo-ofloxacin powder injection has the advantages of high purity, stable quality and small side effect, and is convenient for storage and transportation.
Description
Technical field
The present invention relates to field of medicine preparing technology.Be specifically related to levofloxacin lactate injectable powder and preparation method.
Background technology
Ofloxacin is a third generation Comprecin.Comprecin has has a broad antifungal spectrum, and antibacterial activity is strong, and convenient drug administration does not have cross resistance with antibacterials commonly used, and producing does not need grain, and price is cheaper than the antibiotic of therapeutic equivalence, to light, in, heavy all kinds of infection all have characteristics such as good efficacy.Ofloxacin has the characteristic of third generation carbostyril family antibacterial drugs, the antibacterial of most enterobacteriaceaes such as bacillus canalis capsulatus, Proteus, Salmonella typhimurium Pseudomonas, bacillus dysenteriae, part bacillus pyocyaneus, gonococcus, escherichia coli etc. are had stronger antibacterial activity, part staphylococcus, streptococcus pneumoniae, chlamydia etc. are also had good antibacterial action.As the renewal product levofloxacin of ofloxacin, its mechanism of action is the same with other quinolones, is to work by the DNA helicase that suppresses antibacterial.Its antibacterial activity in vitro is 2 times of raceme ofloxacin, for the 8-128 of d-isomer doubly, and this medicine has obvious selectivity to antibacterial and mammal isomerase II inhibitory action, both differences reach 1400 times, thereby obviously improved clinical application safety, especially central nervous system's toxicity is lower than ofloxacin.Gram negative bacteria, gram positive bacteria and part anaerobe there is bigger antibacterial action.Antibacterial activity in vivo shows, is 15 times of ofloxacin to the escherichia coli effectiveness, the effectiveness of golden Portugal bacterium and bacillus pyocyaneus is respectively 3 times and 1 times of ciprofloxacin.This medicine in vitro tests shows, its has a broad antifungal spectrum, and clinical use drug resistance is good.Levofloxacin has good pharmacokinetic properties, and this medicine oral absorption is fast, and bioavailability is 100%, and oral or 2 kinds of replaceable uses of route of administration of intravenous injection provide good foundation for clinical along passing through therapy.This medicine mainly excretes through urine with the medicine original shape, the few and non-activity of metabolite, and the half-life is long to be 6-8 hour, widely distributed in the body, penetrance is strong, and is higher with the drug level in the body fluid at tissue, the high several times of more antibiotic required MIC value.
Though the oral absorption of levofloxacin is very fast, critically ill patient still needs to come the quick control state of an illness with injection.The water solublity of levofloxacin is relatively poor, levofloxacin is made lactate after, water solublity changes to some extent, this lays a good foundation for injection.Levofloxacin lactate injection determined curative effect, toxic and side effects is lower, is subjected to the favorable comment in market, but injection is unfavorable for storage and transportation, stability is difficult to guarantee.
Summary of the invention
Technical problem to be solved by this invention is to improve the dosage form of existing levofloxacin lactate, provide a kind of prepare easy, purity is high, steady quality, side effect are low, the injectable powder of being convenient to store transportation.
Levofloxacin lactate injectable powder disclosed by the invention is through decolouring, the aseptic powdery preparation that obtains after precipitation and crystallization, the fill with ethanol or acetone after the aseptic filtration with the levofloxacin lactate aqueous solution.The employing high-pressure liquid phase detects, and dextroisomer content is lower than 0.5% in the sterilized powder.
Levofloxacin lactate injectable powder of the present invention specifically makes by following step:
1. levofloxacin lactate aseptic powder preparation
The levofloxacin lactate adding is had in the reactor of 3～4.5 times of distilled water, and stirring and dissolving adds active carbon, decolorization filtering, with 50% ethanol or acetone soln washing carbon cake, filtrate is through coarse filtration, fine straining, be evacuated in the aseptic crystallization pot, stir and add 25～35 times of dehydrated alcohol or acetone down, first crystallizing at room temperature, postcooling filtration, with an amount of absolute ethanol washing crystal, 100 ℃ of dryings get the levofloxacin lactate aseptic powder, and yield is 65～75%;
2. levofloxacin lactate packing
In 100 grades of clean zones, take by weighing the levofloxacin lactate aseptic powder, under laminar flow hood, be encapsulated into respectively in the molded antibiotic bottle of 10ml, press anhydride and calculate, every bottle contains levofloxacin 0.1g.
In the levofloxacin lactate raw material, contain the lactic acid dextrorotation ofloxacin of trace, in the raw materials quality standard, must control lactic acid dextrorotation ofloxacin less than 1.0%.Although dextroisomer content is lower, the dosage that injection itself uses is less, and making the medicine effective dose deficiency influences therapeutic effect, and may increase side effect.In aqueous injection, do not see the report that the control dextroisomer is arranged.The present invention utilizes levofloxacin lactate and the dextroisomer dissolubility difference in solvent, the higher levofloxacin lactate sterilized powder of acquisition purity by increasing with solvent towards precipitation and crystallization in the injectable powder preparation process.Table 1 is and adopts the inventive method left handed crystal powder that obtains and the dextroisomer content made from extra care preceding raw material relatively, and the result shows that dextroisomer content obviously reduces after the crystallization.
The left and right component content that revolves compares before and after table 1 solvent crystal
| Sequence number | Before the solvent crystal | Behind the solvent crystal (the inventive method) | ||
| Lactic acid left side oxygen (%) | The right oxygen (%) of lactic acid | Lactic acid left side oxygen (%) | The right oxygen (%) of lactic acid | |
| 1 | 98.77 | 0.63 | 99.98 | 0.39 |
| 2 | 98.45 | 0.66 | 99.97 | 0.38 |
| 3 | 98.54 | 0.65 | 99.99 | 0.39 |
| 4 | 98.36 | 0.68 | 99.98 | 0.40 |
| 5 | 98.75 | 0.62 | 100.01 | 0.36 |
| 6 | 98.44 | 0.67 | 99.98 | 0.39 |
Injectable powder and levofloxacin lactate water injection that the inventive method is obtained carry out stable controlled trial, the amount of dextroisomer and related substance all is starkly lower than water injection in 24 months examinations discovery preparation of the present invention, and the increment of dextroisomer and related substance also obviously is less than water injection, sees Table 2.
Table 2 injection levofloxacin lactate and levofloxacin lactate injection stability is (unit: %) relatively
| Time | The injection levofloxacin lactate | The levofloxacin lactate injection | ||||||
| Content | Related substance | D-isomer | The outward appearance color | Content | Related substance | D-isomer | The solution color | |
| 0 month | 100.6 | 0.015 | 0.401 | Off-white color | 100.10 | 0.023 | 0.421 | Faint yellow |
| March | 100.3 | 0.023 | 0.451 | Off-white color | 99.78 | 0.053 | 0.551 | Faint yellow |
| June | 100.1 | 0.048 | 0.446 | Off-white color | 98.67 | 0.102 | 0.587 | Faint yellow |
| December | 99.99 | 0.050 | 0.462 | Off-white color | 98.10 | 0.178 | 0.665 | Yellow |
| 24 months | 99.86 | 0.061 | 0.495 | Off-white color | 98.01 | 0.276 | 0.785 | Yellow |
The injectable powder that obtains with the inventive method is carried out the test of ethanol residual quantity, hemolytic test, hypersensitive test and blood vessel irritation test, all do not detect any side reaction, prove preparation safety of the present invention.
The existing aqueous injection of levofloxacin lactate injectable powder of the present invention has following remarkable advantage:
(1) the present invention adopts solvent crystallization, helps improving the purity of its active component, makes the unhelpful dextrorotation component content of human body is reduced;
(2) make pressed powder, its stability is improved;
(3) be beneficial to the storage and transportation in ensure the quality of products;
(4) easy and simple to handle, the process conditions gentleness, with low cost, be fit to suitability for industrialized production;
(5) be beneficial to the allotment of clinical dosage;
(6) this product side effect is low, is generally accepted by patient easily;
(7) this product water solublity is better, and the injection energy quick control critically ill patient state of an illness can satisfy the needs that clinical critically ill patient is treated.
The invention will be further described below in conjunction with embodiment.
Description of drawings
The empty sample introduction of Fig. 1 mobile phase
Fig. 2 one thousandth detectability
Fig. 3 acid destroys (dextroisomer)
Fig. 4 alkali destroys (dextroisomer)
Fig. 5 oxidation destroys (dextroisomer)
Fig. 6 prerun solution (dextroisomer)
Fig. 7 dextroisomer is checked
The specific embodiment
Embodiment 1
Levofloxacin lactate 170g adding is had in the 2L reactor of 595ml distilled water, and stirring and dissolving 15min adds the 3.6g active carbon, stir 30min and filter, and wash the charcoal cake with 2 * 85m150% ethanol water, filtrate is through coarse filtration, fine straining is evacuated in the sterilizing room crystallizing pan, stirs to add the 5.1L dehydrated alcohol down, elder generation's crystallizing at room temperature, postcooling filters, with an amount of absolute ethanol washing crystal 2,100 ℃ of dryings, get the about 120g of levofloxacin lactate aseptic powder, yield 71%.D-isomer content 0.39%, its related substances 0.06%.
Embodiment 2
Levofloxacin lactate 100g adding is had in the 1L reactor of 300ml distilled water, and stirring and dissolving 15min adds the 3.0g active carbon, stir 30min and filter, and wash the charcoal cake with 2 * 60ml, 30% aqueous acetone solution, filtrate is through coarse filtration, fine straining is evacuated in the sterilizing room crystallizing pan, stirs to add 2.8L acetone down, elder generation's crystallizing at room temperature, postcooling filters, with proper amount of acetone washing crystal 2 times, 100 ℃ of dryings get the about 75g of levofloxacin lactate aseptic powder, yield 75%.D-isomer content 0.1%, its related substances 0.03%.
The mensuration of ethanol residual quantity in the embodiment 3 injection levofloxacin lactate
1) chromatographic condition
Instrument: Tianjin, island GC-14B
Detector: fid detector
Chromatographic column: glass packed column (2m * 4mm, filler: Porapak QS 80/100 order)
Column temperature: 130 ℃
Injector temperature: 160 ℃
Detector temperature: 260 ℃
Sample size: 1 μ l
2) algoscopy
It is an amount of that precision takes by weighing ethanol, adds the quantitative dilution of water and make the solution that contains ethanol 0.5mg among every 1ml, product liquid in contrast; Other gets the about 0.5g of this product, accurate claim fixed, with water dissolution and be diluted to 5ml, as need testing solution.Above-mentioned two kinds of solution, the 1 μ l of accurate absorption, according to Determination of Residual Organic Solvents algoscopy (two appendix VIII of Chinese Pharmacopoeia version in 2000 P, first method), under above-mentioned chromatographic condition, measure in accordance with the law, theoretical cam curve must not be lower than 1000 by alcohol meter, the record chromatogram is pressed external standard method with calculated by peak area, promptly.
3) linear test
It is an amount of that precision takes by weighing ethanol, add the quantitative dilution of water and make the solution that contains ethanol 2mg among every 1ml approximately, as linear storing solution, accurate this storing solution 1.0ml, 2.0ml, 4.0ml, 6.0ml and the 8.0ml of drawing places respectively in the 10ml measuring bottle, and thin up is to scale, shake up, add that storing solution (totally 6 concentration point) as measuring solution, shines the said determination method and measures in accordance with the law, the record chromatogram.With sample introduction concentration is abscissa, is that vertical coordinate carries out linear regression analysis with the ethanol peak area that records, and the result is as follows:
Ethanol: A=601727C-37421 r=0.9997
4) precision test
Following No. 3 solution of line taking test item are as test solution, and continuous sample introduction is 6 times in accordance with the law, calculate the relative standard deviation (RSD) of the average correction factor, the results are shown in following table 3.
| The sample introduction number of times | The ethanol peak area |
| 1 | 979531 |
| 2 | 966536 |
| 3 | 983104 |
| 4 | 971564 |
| 5 | 982588 |
| 6 | 968852 |
| Average | 975362 |
| RSD | 0.74％ |
5) recovery test
Test sample lot number: 020101 (not detecting)
Test method:
Get the about 0.1g of this product, the accurate title, decide, and uses water dissolution, the linear stock solution 2ml of accurate adding, and 4ml, 6ml is diluted with water to 10ml, shakes up, as need testing solution.Measure according to the said determination method.The results are shown in Table 4.
| Numbering | Amount of alcohol in the sample (mg/ml) | Addition (mg/ml) | The amount of recording (mg/ml) | Average recovery (%) | Average recovery rate (%) |
| 1 | 0 | 0.404 | 0.39 | 96.53 | 100.66 |
| 2 | 0 | 0.404 | 0.41 | 101.48 | |
| 3 | 0 | 0.404 | 0.42 | 103.96 | |
| 4 | 0 | 0.808 | 0.83 | 102.72 | 100.66 |
| 5 | 0 | 0.808 | 0.82 | 101.48 | |
| 6 | 0 | 0.808 | 0.79 | 97.77 | |
| 7 | 0 | 1.212 | 1.19 | 98.18 | 98.18 |
| 8 | 0 | 1.212 | 1.18 | 97.36 |
| 9 | 0 | 1.212 | 1.20 | 99.01 |
6) lowest detectable limit
Get least concentration under the linear term as storing solution, water dilutes the back in varing proportions to be measured, and is that 3: 1 o'clock concentration is lowest detectable limit with signal to noise ratio, specific as follows:
Ethanol: 2.1ng
7) sample determination
Requirement by the algoscopy item is measured in accordance with the law, and it the results are shown in Table 5:
| Lot number | Sample weighting amount (g) | Ethanol (%) |
| 020101 | 0.4753 | Do not detect |
| 020102 | 0.4955 | Do not detect |
| 020103 | 0.4864 | Do not detect |
Embodiment 4 dextroisomer high-efficient liquid phase determining methods are determined
1) high performance liquid chromatograph---Tianjin, island LC-10ATvp pump, Tianjin, island SPD-10Avp UV-detector, chromatographic column are Luna 5 μ C18 (2) 250 * 4.6mm (DM), and methanol is chromatographically pure, and other reagent is analytical pure.
2) selection of wavelength
Sample thief is mixed with mobile phase and contains 5 μ g solution among every 1ml approximately, and levofloxacin lactate has absorption maximum near the 293nm wavelength in the 200-400nm wave-length coverage, so the detection wavelength of selecting the 293nm wavelength to check as dextroisomer.
3) selection of mobile phase
Selecting L-phenylalanine and copper sulfate in the dextroisomer inspection is chirality mobile phase additive, and wherein, the L-phenylalanine is a compounding ingredient, and copper sulfate is for cooperating ion.Test shows that the L-phenylalanine can make the left and right isomer acquisition good separation of revolving.Select methanol with reference to the version standard WS-576 of levofloxacin lactate office (X-508)-99: chirality solution (get L-phenylalanine 0.33g, copper sulfate 0.25g, add water 1000ml dissolving after, shake up, promptly) (13: 87) are mobile phase.
4) the mobile phase sample introduction is seen Fig. 1.
5) one thousandth detectability
It is an amount of to get this product, adds mobile phase and is mixed with the solution that every 1ml contains levofloxacin 1 μ g, gets this solution 10 μ l injecting chromatographs, and the record colour circle is seen Fig. 2.Result of the test shows that sample can be detected under this concentration.
6) acid, alkali, oxidation failure test
1. sour failure test
Get this product 12mg and put in the 10ml volumetric flask, add 1mol/L hydrochloric acid 1ml, put in the boiling water bath heating 0.5 hour, take out, put coldly, add the mobile phase standardize solution and get this solution 10 μ l, inject chromatograph of liquid, the record chromatogram the results are shown in Figure 3.
2. alkali failure test
Get this product 12mg and put in the 10ml volumetric flask, add 1mol/L, sodium hydroxide 1ml puts in the boiling water bath heating 0.5 hour, takes out, and puts coldly, adds the mobile phase standardize solution, gets this solution 10 μ l, injects chromatograph of liquid, and the record chromatogram the results are shown in Figure 4.
3. oxidation failure test
Get this product 12mg and put in the 10ml volumetric flask, add 10% hydrogen peroxide 1ml, put in the boiling water bath heating 0.5 hour, take out, put coldly, add the mobile phase standardize solution, get this solution 10 μ l, inject chromatograph of liquid, the record chromatogram the results are shown in Figure 5.
4. conclusion (seeing Table 7)
| Failure condition | Adjacent impurity peaks appearance time (min) | Main peak appearance time (min) | Conclusion | |
| Acid destroys | 9.6 | 13.9 | 12.2 | Main peak can better separate with each impurity, and system's specificity is good |
| Alkali destroys | 5.3 | 15.4 | 12.9 | |
| Oxidation destroys | 10.9 | 14.9 | 12.4 | |
7) the dextroisomer inspection method determines
Get this product, add mobile phase and make the solution that contains levofloxacin 1mg among every 1ml, as need testing solution; Other gets the ofloxacin reference substance, make the solution that contains 0.02mg among every 1ml with mobile phase, as prerun solution, according to high efficiency chromatography method (two appendix VD of Chinese Pharmacopoeia version in 2000), with the octadecylsilane chemically bonded silica is filler, with methanol: chirality solution (get L-phenylalanine 0.33g, copper sulfate 0.25g, add water 1000ml dissolving after, shake up, promptly) (13: 87) are mobile phase, and the detection wavelength is 293nm, regulate flow velocity and make the laevoisomer retention time about 12 minutes.Get prerun solution 10 μ l and inject chromatograph of liquid (Fig. 6), each component peak sequence is followed successively by the laevoisomer and the dextroisomer of ofloxacin, regulate instrumental sensitivity, make the main peak height be about the 40-50% of full scale, theoretical cam curve is calculated by the levofloxacin peak should be not less than 2500, and left and right separating degree of revolving between the isomer should be greater than 1.5.Get need testing solution 10 μ l again, inject chromatograph of liquid, the record chromatogram is to 2 times of the main peak retention time, and the dextroisomer peak area must not be greater than 0.5% of total peak area in the chromatogram of need testing solution.
8) mensuration of the dextroisomer of three batch samples
Get three batches of this product, measure as stated above, the results are shown in Table 8 and Fig. 7.
The dextroisomer check result of table 8 three batch samples
| Lot number | 1# | 2# | 3# |
| Dextroisomer (%) | 0.419 (Fig. 7) | 0.395 | 0.387 |
Embodiment 5 stability tests
One, sample is adopted the source
1. test sample is originated: provided by Shanghai Xinya Pharmaceutical Industry Co. Ltd.
2. sample lot number: 010401,010402,010403
Two, investigation project:
1. test objective: the injection levofloxacin lactate is carried out influence factor's test (under the 45001x strong illumination, under 60 ℃ of high temperature and RH 92.5% high humidity), and accelerated test, long term test are investigated, to determine its production, packing, storage requirement and effect duration.
2. investigation project and method
(1) appearance color is observed judgment experiment front and back sample appearance change in color.
(2) clarity, solution colour, acidity, dextroisomer, related substance, moisture, content (percentage composition, sign content) are measured and are all investigated test with reference to the assay method in the declaration material.
Three, experimental technique
1. this product (lot number: 010402) is got in influence factor's test, place respectively under strong illumination (45001x), 60 ℃ of high temperature and RH92.5% high humidity (opening) condition and placed 10 days, difference sampling and measuring in the time of 5,10 days, and in 0 day with the batch sample data relatively, experimental result sees Table 9.
Table 9 injection levofloxacin lactate influence factor tests and investigates result's (lot number: 010402)
| The placement condition | Time (my god) | Appearance luster | Clarity | Solution colour | Acidity | Dextroisomer (%) | Related substance (%) | Divide forever (%) | Percentage composition (%) | Labelled amount (%) |
| Off-white color or light yellow crystalline powder | Up to specification | A≤0.1 | 4.5-5.5 | ≤0.5 | ≤0.5 | ≤6.0 | ≥98.5 | 90.0-110.0 | ||
| 0 | The off-white color crystalline powder | Up to specification | 0.055 | 5.22 | 0.395 | 0.029 | 4.22 | 100.8 | 96.76 | |
| Illumination 45001x | 5 | The off-white color crystalline powder | Up to specification | 0.055 | 5.22 | 0.413 | 0.100 | 4.20 | 100.5 | 96.44 |
| 10 | The off-white color crystalline powder | Up to specification | 0.055 | 5.19 | 0.459 | 0.161 | 4.16 | 100.3 | 96.33 | |
| 60 ℃ of high temperature | 5 | The off-white color crystalline powder | Up to specification | 0.054 | 5.24 | 0.417 | 0.049 | 4.17 | 100.4 | 96.44 |
| 10 | The off-white color crystalline powder | Up to specification | 0.055 | 5.21 | 0.444 | 0.058 | 4.14 | 100.1 | 96.22 | |
| High humidity RH 92.5% | 5 | Light yellow crystalline powder | Up to specification | 0.055 | 5.20 | 0.390 | 0.092 | 6.33 | 101.0 | 97.59 |
| 10 | Light yellow crystalline powder | Up to specification | 0.057 | 5.17 | 0.428 | 0.259 | 6.73 | 98.65 | 95.11 |
Above result shows: the sample under each influence factor's condition, after placing 5,10 days, with 0 day result relatively, related substance increases to some extent under high humidity (RH 92.5%) condition, moisture transfinites, content (10 days) slightly descends and illumination (4500k) condition under related substance increase to some extent other no significant changes.
2. accelerated test three batch samples (lot number: 010401,010402,010403, the simulation commercially available back), be placed on exsiccator top, it is 75% solution that relative humidity is put in the bottom, and exsiccator is moved in the calorstat, adjusts the temperature to 40 ℃, placed 6 months, the sampling and measuring respectively in 0,1,2,3,6 month, and with 0 month with the batch sample data relatively, result of the test sees Table 10.
Table 10 injection levofloxacin accelerated test is investigated the result
| Lot number | Time (moon) | Appearance luster | Clarity | Solution colour | Acidity | Dextroisomer (%) | Related substance (%) | Moisture (%) | Percentage composition (%) | Labelled amount (%) |
| Off-white color or faint yellow acicular crystal powder | Up to specification | ≤YG-3 | 4.5-5.5 | ≤0.5 | ≤0.5 | ≤6.0 | ≥98.5 | 90.0- 110.0 | ||
| 010401 | 0 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.30 | 0.401 | 0.015 | 4.20 | 100.6 | 96.53 |
| 1 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.37 | 0.432 | 0.030 | 4.34 | 100.3 | 96.06 | |
| 2 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.39 | 0.444 | 0.058 | 4.45 | 100.1 | 95.81 | |
| 3 | Faint yellow acicular crystal powder | Up to specification | ＜YG-3 | 5.40 | 0.462 | 0.067 | 4.50 | 99.72 | 95.38 | |
| 6 | Faint yellow acicular crystal powder | Up to specification | ＜YG-3 | 5.43 | 0.495 | 0.104 | 4.62 | 99.36 | 94.92 | |
| 010402 | 0 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.22 | 0.395 | 0.029 | 4.22 | 100.8 | 96.76 |
| 1 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.30 | 0.428 | 0.036 | 4.35 | 100.5 | 96.36 | |
| 2 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.33 | 0.414 | 0.063 | 4.47 | 100.1 | 95.88 | |
| 3 | Faint yellow acicular crystal powder | Up to specification | ＜YG-3 | 5.35 | 0.466 | 0.073 | 4.52 | 99.77 | 95.49 | |
| 6 | Faint yellow acicular crystal powder | Up to specification | ＜YG-3 | 5.38 | 0.503 | 0.107 | 4.63 | 99.43 | 95.06 | |
| 010403 | 0 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.17 | 0.387 | 0.020 | 4.15 | 101.0 | 97.29 |
| 1 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.25 | 0.409 | 0.039 | 4.29 | 100.6 | 96.75 | |
| 2 | Off-white color acicular crystal powder | Up to specification | ＜YG-3 | 5.25 | 0.414 | 0.058 | 4.41 | 100.2 | 96.27 | |
| 3 | Faint yellow acicular crystal powder | Up to specification | ＜YG-3 | 5.28 | 0.462 | 0.061 | 4.46 | 99.92 | 95.92 | |
| 6 | Faint yellow acicular crystal powder | Up to specification | ＜YG-3 | 5.27 | 0.505 | 0.109 | 4.57 | 99.39 | 95.31 |
Above result shows: accelerated test compared with 0 month result after 6 months, except that related substance increases to some extent, and other no significant changes, this product steady quality.
3. long term test is investigated three batch samples (lot number: 010401,010402,010403, the simulation commercially available back), in 25 ℃ of temperature, relative humidity RH 60% places, respectively at 3,6,9,12,18,24 grades are period sampling measuring in the time of individual month, and compares with the batch sample data with 0 month, and result of the test sees Table 11.
Table 11 injection levofloxacin accelerated test is investigated the result
| Lot number | Time (moon) | Appearance luster | Clarity | Solution colour | Acidity | Dextroisomer (%) | Related substance (%) | Divide forever (%) | Percentage composition (%) | Labelled amount (%) |
| Off-white color or light yellow crystalline powder | Up to specification | A≤0.1 | 4.5-5.5 | ≤0.5 | ≤0.5 | ≤6.0 | ≥98.5 | 90.0- 110.0 | ||
| 010401 | 0 | The off-white color crystalline powder | Up to specification | 0.056 | 5.30 | 0.401 | 0.015 | 4.20 | 100.6 | 96.53 |
| 3 | The off-white color crystalline powder | Up to specification | 0.056 | 5.35 | 0.451 | 0.023 | 4.32 | 100.3 | 96.13 | |
| 6 | Light yellow crystalline powder | Up to specification | 0.058 | 5.38 | 0.446 | 0.048 | 4.48 | 99.92 | 95.59 | |
| 9 | Light yellow crystalline powder | Up to specification | 0.057 | 5.38 | 0.462 | 0.085 | 4.54 | 99.56 | 95.19 | |
| 12 | Light yellow crystalline powder | Up to specification | 0.056 | 5.42 | 0.495 | 0.091 | 4.61 | 99.41 | 94.93 | |
| 010102 | 0 | The off-white color crystalline powder | Up to specification | 0055 | 5.22 | 0.395 | 0.029 | 4.22 | 100.8 | 96.76 |
| 3 | The off-white color crystalline powder | Up to specification | 0.056 | 5.28 | 0.416 | 0.109 | 4.33 | 100.5 | 96.41 | |
| 6 | Light yellow crystalline powder | Up to specification | 0.055 | 5.33 | 0.465 | 0.053 | 4.48 | 99.85 | 95.61 | |
| 9 | Light yellow crystalline powder | Up to specification | 0.057 | 5.34 | 0.487 | 0.090 | 4.56 | 99.61 | 95.30 | |
| 12 | Light yellow crystalline powder | Up to specification | 0.056 | 5.37 | 0.492 | 0.102 | 4.61 | 99.39 | 95.04 | |
| 010403 | 0 | The off-white color crystalline powder | Up to specification | 0.056 | 5.17 | 0.387 | 0.020 | 4.15 | 101.0 | 97.29 |
| 3 | The off-white color crystalline powder | Up to specification | 0.056 | 5.24 | 0.444 | 0.021 | 4.28 | 100.6 | 96.79 | |
| 6 | Light yellow crystalline powder | Up to specification | 0.054 | 5.25 | 0.473 | 0.048 | 4.46 | 100.0 | 96.00 | |
| 9 | Light yellow crystalline powder | Up to specification | 0.058 | 5.27 | 0.466 | 0.080 | 4.51 | 99.74 | 95.70 | |
| 12 | Light yellow crystalline powder | Up to specification | 0.055 | 5.32 | 0.493 | 0.103 | 4.56 | 99.48 | 95.40 |
Above result shows, after keeping sample 12 months for a long time, compares with 0 month data, and except that related substance increases to some extent, other no significant changes, this product steady quality.
Four, conclusion:
By influence factor test (remove that related substance increases to some extent under high humidity (RH 92.5%) condition, moisture transfinites, content (10 days) slightly descends and illumination (45001x) condition under related substance increase to some extent), accelerated test 6 months (removing related substance increases to some extent), long term tests investigated (except that related substance increases to some extent) in 12 months, sample has no significant change, the interpret sample steady quality.
2. investigated the result in 12 months by accelerated test 6 months, long term test and show that simulation commercially available back mold-formed bottle (10ml mold-formed bottle) does not have influence to sample.
Embodiment 6 hemolytic tests
One, test objective
Directly contact with blood by test sample, observe test sample and whether cause external haemolysis and cohesion.
Two, test material
1. test sample:
The name of an article: injection levofloxacin lactate
Specification: 0.19/ bottle
Lot number: (1) 02-01-01 (2) 02-01-02 (3) 02-01-03
Production unit: Shanghai Xinya Pharmaceutical Industry Co. Ltd.
2. test liquid preparation
Get 1 bottle (0.1g/ bottle) and add the 3.5ml sterilized water for injection, after the dissolving, add the chlorination sodium injection and be diluted to 50ml, supply test behind the mixing.
Three, test method
The preparation of 1.2% Sanguis Leporis seu oryctolagi red blood cell suspension
Get the rabbit cardiac blood, be equipped with in the container of bead, jolting number minute, remove Fibrinogen, make to become to take off fine blood, add normal saline, shake up, centrifugal, the supernatant that inclines, sedimentary erythrocyte reuse normal saline washing 3-4 time is till the apparent redness of centrifugal back supernatant, press the gained erythrocyte volume then, be diluted to 2% suspension with normal saline.Used the same day, and the time spent shakes up.
2. test procedure
It is some to get test tube, is divided into each one group of 3 groups of test samples, feminine gender and positive control, and every group 2 pipe pressed table 12 application of sample successively, after shaking up, puts in the water bath with thermostatic control rapidly.Keep 37 ℃, observe 4 hours (10:30-14:30).
Table 12
| Group | Test sample | ||||||
| 1 | 2 | 3 | 4 | 5 | Negative control | Positive control | |
| 2% red blood cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Normal saline (ml) | 2.0 | 2.1 | 2.2 | 2.3 | 2.4 | 2.5 | - |
| Distilled water (ml) | - | - | - | - | - | - | 2.5 |
| 37 ℃ of water bath heat preservations 30 minutes | |||||||
| Test liquid (ml) | 0.2 | 0.4 | 0.3 | 0.2 | 0.1 | - | - |
Four, conclusion: no haemolysis and coacervation.
Embodiment 7 hypersensitive tests
Test objective: observe the animal duplicate injection and tried the anaphylaxis situation that produced behind the thing.
Tried thing:
The name of an article: injection levofloxacin lactate; Specification: 0.1g/ bottle; Lot number: 02-01-03 production unit: Shanghai Xinya Pharmaceutical Industry Co. Ltd.
The solution preparation:
Sensitization liquid: get 1 bottle and add the 25ml sodium chloride injection, after the dissolving, for test.
Test liquid: get 1 bottle and add the 25ml sodium chloride injection, after the dissolving, for test.
Tester:
1. negative control thing:
The name of an article: sodium chloride injection; Specification: 250ml; Lot number: 9711112
Production unit: Changzheng Pharmaceutical Factory, Shanghai
The solution preparation:
Sensitization liquid: sodium chloride injection
Test liquid: sodium chloride injection
2. positive control:
The name of an article: bovine serum albumin
Specification: biochemical reagents
Lot number: 011205
Production unit: beautiful pearl east wind Bioisystech Co., Ltd
The solution preparation:
Sensitization liquid: it is an amount of to get bovine serum albumin, makes the solution that every 1ml contains 10mg with sodium chloride injection dissolving and dilution
Test liquid: it is an amount of to get bovine serum albumin, makes the solution that every 1ml contains 10mg with sodium chloride injection dissolving and dilution
Experimental animal:
Title: Cavia porcellus; Sex: ♂; Body weight: 250-300 ℃
Source: pine connection laboratory animal plant; The quality certification number: SCXK (Shanghai 2002-0012)
Test method:
Get 18 of healthy guinea pigs, be divided into and tried 3 groups of things, feminine gender, each 1 group of positive control, continuous 3 the every other day lumbar injection sensitization liquid 0.5ml/ of difference are only, then Cavia porcellus is divided into two parts, each 3, respectively at only injecting for the first time back 14 days and 21 days, observe the anaphylaxis situation of animal in back 15 minutes of the injection, and continue to observe 24 hours from intravenous injection test liquid 1.0ml/.
The result:
Table 13 negative control group
| Labelling | Body weight (g) before the injection | First after the injection | Symptom | |
| The 14th day | 21 days body weight (g) | |||
| Head | 298 | 310 | There is no anaphylaxis | |
| The back of the body | 298 | 317 | ||
| Tail | 272 | 305 | ||
| The head back of the body | 254 | 305 | ||
| End to end | 250 | 298 | ||
| From | 256 | 317 | ||
Table 14 positive controls
| Labelling | Body weight (g) before the injection | First after the injection | Symptom | |
| The 14th day | 21 days body weight (g) | |||
| Head | 250 | 283 | Perpendicular hair, dyspnea, hello sound | |
| The back of the body | 259 | 290 | Perpendicular hair, dyspnea, tic | |
| Tail | 251 | 287 | Collapse, paralysis | |
| The head back of the body | 250 | 301 | Hello sound, tic | |
| End to end | 250 | 315 | Hello sound, tic, perpendicular hair |
| In vain | 254 | 398 | Dead |
Table 15 is tried the thing group
| Labelling | Body weight (g) before the injection | First after the injection | Symptom | |
| The 14th day | 21 days body weight (g) | |||
| Head | 283 | 315 | There is no anaphylaxis | |
| The back of the body | 270 | 301 | ||
| Tail | 270 | 290 | ||
| The head back of the body | 260 | 308 | ||
| End to end | 250 | 319 | ||
| In vain | 255 | 295 | ||
Conclusion: this product was not met quick reaction through the Cavia porcellus hypersensitive test.
The test of embodiment 8 blood vessel irritations
Test objective:
Observe a certain amount of vascular stimulation response situation that produced behind the thing tried of animal intravenous injection.
Be subjected to the reagent thing:
The name of an article: injection levofloxacin lactate; Specification: 0.1g/ bottle
The unit of providing: Shanghai Xinya Pharmaceutical Industry Co. Ltd.; Lot number: 02-01-03
Preparation: get 1 bottle (0.1g/ bottle) and add the 20ml sodium chloride injection, after the dissolving, for test.
Tester:
The name of an article: sodium chloride injection; Specification: 250ml/ bottle;
Production unit: Changzheng Pharmaceutical Factory, Shanghai; Lot number: 9711112
Experimental animal:
Title: new zealand rabbit; Sex: female; Body weight: 2.0-2.5kg
Source: old capable warren; Credit number: the moving word of doctor 02-53-1 number
Test method:
Get 3 of above-mentioned healthy animal, every day, 1 auricular vein injection was tried thing and each 5.0ml/kg of tester, continuous 3 times respectively for left ear and auris dextra.24 hours perusal rabbit auricular veins after the last administration, put to death animal then, every ear by inserting needle light every 1.5 centimetres get one section totally 3 sections auricular veins (width of drawing materials is 0.5 centimetre) make the pathology sections observation, see significant stimulation such as having or not tissue degeneratiaon or necrosis reaction, carry out the result with the pathological section result of the 3rd section (proximal part) and judge.
Result of the test: (the 3rd section) table 16
| Group | Tried thing (right side ear) | Tester (left side ear) | |||||
| Rabbit number | 1 | 2 | 3 | 1 | 2 | 3 | |
| Pathologic finding | Hemorrhage | (-) | (-) | (-) | (-) | (-) | (-) |
| Cell infiltration | (-) | (-) | (-) | (-) | (-) | (-) | |
| Tissue degeneratiaon's necrosis | (-) | (-) | (-) | (-) | (-) | (-) | |
Perusal: the injection of rabbit auricular vein is tried to have there is no hyperemia, red and swollen phenomenon behind thing or the tester.
Conclusion: this product is through the test of rabbit blood vessel irritation, and not seeing has irritative response.
Claims (2)
1, levofloxacin lactate injectable powder, it is characterized in that this injectable powder be with the levofloxacin lactate aqueous solution through decolouring, after the aseptic filtration with ethanol or acetone towards precipitation and crystallization, the aseptic powdery preparation that obtains after the fill; The employing high-pressure liquid phase detects, and dextroisomer content is lower than 0.5% in the sterilized powder; Its preparation method comprises the following steps:
1) levofloxacin lactate aseptic powder preparation
The levofloxacin lactate adding is had in the reactor of 3～4.5 times of distilled water, stirring and dissolving, add active carbon, decolorization filtering, with 50% ethanol or acetone soln washing carbon cake, filtrate is through coarse filtration, fine straining, be evacuated in the aseptic crystallization pot, stir 25～35 times of dehydrated alcohol of adding or acetone down, first crystallizing at room temperature, postcooling filters, with an amount of absolute ethanol washing crystal, 100 ℃ of dryings, get the levofloxacin lactate aseptic powder, the employing high-pressure liquid phase detects, and dextroisomer content is lower than 0.5% in the sterilized powder;
2) levofloxacin lactate packing
In 100 grades of clean zones, take by weighing the levofloxacin lactate aseptic powder, under laminar flow hood, divide in the antibiotic bottle of packing into respectively.
2, levofloxacin lactate injectable powder according to claim 1 is characterized in that the method that dextroisomer content adopts high-pressure liquid phase to detect in the sterilized powder wherein is:
Chirality solution: get L-phenylalanine 0.33g, copper sulfate 0.25g, add water 1000ml dissolving after, shake up, promptly;
Mobile phase: methanol: chirality solution=13: 87
Detect wavelength: 293nm
Need testing solution: get sterilized powder, add mobile phase and make the solution that contains levofloxacin 1mg among every 1ml;
Prerun solution: get the ofloxacin reference substance, make the solution that contains 0.02mg among every 1ml with mobile phase;
Method: according to two appendix VD of Chinese Pharmacopoeia version in 2000 high efficiency chromatography method, be filler, regulate flow rate of mobile phase and make the laevoisomer retention time about 12 minutes with the octadecylsilane chemically bonded silica; Get prerun solution 10 μ l and inject chromatograph of liquid, each component peak sequence is followed successively by the laevoisomer and the dextroisomer of ofloxacin, regulate instrumental sensitivity, make the main peak height be about the 40-50% of full scale, theoretical cam curve is calculated by the levofloxacin peak should be not less than 2500, and left and right separating degree of revolving between the isomer should be greater than 1.5; Get need testing solution 10 μ l again, inject chromatograph of liquid, the record chromatogram is to 2 times of the main peak retention time, and the dextroisomer peak area must not be greater than 0.5% of total peak area in the chromatogram of need testing solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 200310108462 CN1263452C (en) | 2003-11-06 | 2003-11-06 | Powder injection of lactatelevo-ofloxacin and its preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310108462 CN1263452C (en) | 2003-11-06 | 2003-11-06 | Powder injection of lactatelevo-ofloxacin and its preparation |
Publications (2)
| Publication Number | Publication Date |
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| CN1613451A CN1613451A (en) | 2005-05-11 |
| CN1263452C true CN1263452C (en) | 2006-07-12 |
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| CN 200310108462 Expired - Lifetime CN1263452C (en) | 2003-11-06 | 2003-11-06 | Powder injection of lactatelevo-ofloxacin and its preparation |
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| CN109666034B (en) * | 2017-10-13 | 2021-01-26 | 浙江京新药业股份有限公司 | Lactic acid levofloxacin crystal form and preparation method and application thereof |
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