CN102351881B - Stable levofloxacin hydrochloride compound - Google Patents
Stable levofloxacin hydrochloride compound Download PDFInfo
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- CN102351881B CN102351881B CN201110227345.7A CN201110227345A CN102351881B CN 102351881 B CN102351881 B CN 102351881B CN 201110227345 A CN201110227345 A CN 201110227345A CN 102351881 B CN102351881 B CN 102351881B
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Abstract
The invention belongs to the technical field of medicines and particularly relates to amorphous levofloxacin hydrochloride and a preparation method thereof. The amorphous levofloxacin hydrochloride has high purity and stability.
Description
Technical field
The invention belongs to medical technical field, be specifically related to unformed form of levofloxacin hydrochloride and preparation method thereof, the invention still further relates to and use this unformed form preparation quality stable composition.
Background technology
Fluorine promise ketone antibiotic is the class novel anti-infection medicine growing up early 1970s.At present, the world market scale of Fluorquinolones has reached annual 5000000000 dollars of left and right, is only second to cephalosporins and penicillin medicine in antibacterials market, suitable with Macrocyclolactone lactone kind medicine.Global best-selling drugs 400 persistent erections in 2003,73 anti-infective brand medicine total sales volumes have accounted for 12.7%, reach 321.94 hundred million dollars. and wherein, fluorine promise ketone brand medicine has 7, and sales volume amounts to 41.89 hundred million dollars, accounts for 13.01% of anti-infective total sales volume.
Antibacterials are that global drug market maximum, while are also one of the classifications that can get a profit.This market
Scale by 27,000,000,000 dollars of 32,000,000,000 dollars of being increased to 2010 from calendar year 2001.Expect 2010, Fluorquinolones will become a fastest-rising class medicine in antibacterials market, and it increases and will surpass the best Cephalosporins of current market.According to estimates, during this period by 21 novel antibacterial medicament production that come into the market, have 1/3 for fluorine promise ketone.In Fluorquinolones, best-selling product is Ciprofloxacin and levofloxacin, and the two has occupied 65% (being about 3,300,000,000 dollars) of such medicine world market.The features such as levofloxacin has efficiently, wide spectrum, safety, be to have one of Fluorquinolones of development prospect most at present, 1999 are only sales volume in Japan just reaches 25,200,000,000 yen, occupies the 4th of prescription drug, first of anti-infectives, is widely used in the whole world.
First levofloxacin is succeeded in developing and goes on the market in Japan in 1994 by Japanese Daiichi Pharmaceutical Co., Ltd. the earliest.Levofloxacin bulk drug and the tablet of nineteen ninety-five Japan the first pharmaceutical manufacturing get permission to enter Chinese market.After this, 5,000 ten thousand dollars of the said firm's investments and Beijing medication economics technological development zone center are set up joint venture, by day wood the first pharmacy, provide levofloxacin bulk drug, tablet is produced in the packing of Pekinese joint venture You Erte pharmaceutcal corporation, Ltd, packing product was in listing in 1996, commodity are called Cravit, 100 of retail prices were 699 yuans at that time, due to Cravit good effect, side effect is little, only need every day to take 1 one 2 times, easy to use, therefore in China big city hospital, to promote and come rapidly. sales volume also straight line rises.
Fluorine promise ketone antimicrobial drug is the third generation product of such medicine. the first-generation was succeeded in developing in 1962.Take Nalidixic Acid as representative, within 1964, be applied to clinical urinary system infection, but oneself is eliminated because narrow antimicrobial spectrum easily produces resistance; The s-generation in 1973 synthetic take adjoin croak acid, oxolinic acid is representative, within 1979, be applied to clinical, although increase than first-generation anti-microbial activity, but Plasma Concentration is low, the untoward reaction of neuropsychic symptom is more, and oneself seldom applies now: chemists in 1978 add fluorine atom on 6, the skeleton of promise ketone, 7 upper croak piperazine ring or other derivatives introduced, form the fluorine-containing promise ketone medicine of a new generation. due to the improvement of structure, its proterties is better than front two generations, and curative effect is suitable with a full rhzomorph of new generation.It is reported, it is to gram negative bacillus effect compared with strong 4-64 of first, second generation times, and the strong 8-64 of effect of resisting gram-positive bacteria doubly.
Popular name: levofloxacin hydrochloride
English name: Levofloxacin Hydrochloride
The Chinese phonetic alphabet: Yansuanzuoyangfushaxing
Chemical name is: (S)-(-)-9-is fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-fluoro-7H-pyridine benzene a pair of horses going side by side [1,2,3-de]-[Isosorbide-5-Nitrae] Ben Pian oxazine-6-carboxylic acid hydrochloride
Chemical structural formula:
Molecular formula: C
18h
20FN
3o
4hClH
2o
Molecular weight: 415.85
The development prospect of levofloxacin hydrochloride: levofloxacin hydrochloride has gone on the market for many years, is obtaining more data aspect drug safety and pharmacokinetics.Levofloxacin hydrochloride is soluble in water, and its injection be take water completely as solvent, has avoided the discomfort reaction of organic solvent.This medicine oral absorption is effective, and the transformation period is very short, transforms very soon in vivo.Although its mechanism of action and the mechanism of going deep into still need further to be studied, levofloxacin hydrochloride promise well, its clinical application may also will constantly be expanded.
Levofloxacin hydrochloride has multiple preparation method, because preparation method especially process for purification is different, obtains anhydride and hydrate.In research process, repeat the method for patent documentation prepared by above-mentioned anhydride, the levofloxacin hydrochloride obtaining has polymorphism.
The unformed levofloxacin hydrochloride that the present invention obtains, purity is high, and maximum contaminant is less than 1 ‰, and total impurities is less than 2 ‰; Good stability, even moisture absorption weightening finish is also not obvious under high humidity; There is good formability etc.; The injection visible foreign matters making is good.
Summary of the invention
One object of the present invention, discloses a kind of unformed levofloxacin hydrochloride.
Another object of the present invention, discloses the preparation method of unformed levofloxacin hydrochloride.
Another object of the present invention, discloses the pharmaceutical composition that comprises unformed levofloxacin hydrochloride.
The invention also discloses the application of unformed levofloxacin hydrochloride in manufacturing the medicines such as moderate and severe infection such as treatment respiratory system, urinary system, reproduction, skin soft tissue, enteron aisle.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
This unformed levofloxacin hydrochloride, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.There is obvious unformed characteristic peak in its powder x-ray diffraction collection of illustrative plates, there is no sharp-pointed absorption peak, is diffuse type, sees Fig. 1.
Another object of the present invention, discloses the preparation method of unformed levofloxacin hydrochloride, by levofloxacin hydrochloride is soluble in water, filters, and filtrate adds in isopropyl ether-methylene dichloride mixing solutions under stirring, then is incubated for some time and obtains.
It is characterized in that comprising the following steps: that levofloxacin hydrochloride adds in 3-4 water doubly, filter, filtrate adds in the mixed solution of 15-20 times of 0 ℃ of-10 ℃ of isopropyl ether-methylene dichloride=10:1 under stirring, then is incubated 1-2 hour, filters, and drying obtains.
Through the researchs of a plurality of batches, find, when filtrate adds 15-20 doubly in the mixed solution of 0 ℃ of-10 ℃ of isopropyl ether-methylene dichloride=10:1, stirring velocity reaches requirement at 240-300 revs/min.
Levofloxacin hydrochloride used, the method providing according to document is synthetic, and the chemical structure of synthetic levofloxacin hydrochloride is through proton nmr spectra, and ultimate analysis, proves that chemical structure is correct.
Another object of the present invention, provides the composition that comprises the levofloxacin hydrochloride that unformed levofloxacin hydrochloride and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.
The amount of the active ingredient containing in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, 1%～30%(weight that the weight range of active compound is composition).
The present invention also provides the application of unformed levofloxacin hydrochloride in manufacturing the medicines such as moderate and severe infection such as treatment respiratory system, urinary system, reproduction, skin soft tissue, enteron aisle.
Through animal (male rat, Wistar) test, the acute toxicity test of unformed levofloxacin hydrochloride of the present invention, the medium lethal dose (LD of intravenously and oral administration
50) be respectively 68.3mg/kg and 400.1mg/kg.Through animal (dog), test, give unformed levofloxacin hydrochloride 0.3mg/kg, the volume of blood flow in femoral artery increases by 64%, and in vertebral artery, has increased by 230%, have the pharmacologically active good compared with crystalline state levofloxacin hydrochloride, administering mode also can be identical with crystalline state levofloxacin hydrochloride.
stability test
Contriver is studied unformed chemical stability of the present invention, and investigation condition is high temperature (60 ℃ ± 2 ℃), strong illumination (4500Lx ± 500lx), and (92.5%, RH) investigate index is outward appearance to high humidity, content and related substance.
Result: under high light, high temperature, super-humid conditions from 0-10 days, outward appearance, related substance, content do not change, and illustrates that chemical stability is good, manufacture and the standing storage of applicable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in unformed levofloxacin hydrochloride:
Result: at 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in levofloxacin hydrochloride anhydride crystal:
Result: at 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), levofloxacin hydrochloride anhydride crystal has moisture absorption weightening finish, to moist lability.
tablet hardness test
Under 600kg and 800kg pressing pressure, the hardness (kg) of the sheet of 3 batches of unformed levofloxacin hydrochlorides that obtain respectively:
Result: there is good formability.
Clinical efficacy and the Plasma Concentration of medicine are closely related, and in medicine body Plasma Concentration and vitro Drug quality particularly dissolution rate is in close relations.
Result of study shows, unformed Levofloxacin Tablet has good dissolution rate compared with crystalline state Levofloxacin Tablet.
figure of description:
Fig. 1, the X-ray diffractogram of unformed levofloxacin hydrochloride;
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
In the present invention, levofloxacin hydrochloride chemical name used is (S)-(-)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-fluoro-7H-pyridine benzene a pair of horses going side by side [1,2,3-de]-[1,4] Ben Pian oxazine-6-carboxylic acid hydrochlorides, the method providing according to document is synthetic, purity 99.6% (HPLC normalization method), by the method for existing publication, refine 1-3 times purity approximately 98.7% (HPLC normalization method).Its chemical structure is through proton nmr spectra, ultimate analysis confirmation, and results of elemental analyses, proves that chemical structure is correct.The moisture recording by karl Fischer method is 0.31%.
embodiment 1
In the 5000ml reaction flask of stirring, thermometer, condenser is housed, add 100 grams of levofloxacin hydrochlorides and 300ml distilled water, stir 10 minutes, filter, under filtrate is stirred, 260 revs/min of rotating speeds, add in the 2800ml isopropyl ether-methylene dichloride=10:1 mixed solution that is chilled in advance 4 ℃-6 ℃, be incubated again 1 hour, filter, through indoor seasoning, obtain 92.4 grams of the white powders of highly purified above-mentioned unformed levofloxacin hydrochloride.The moisture recording by karl Fischer method is 0.18%.
The X-ray diffractogram of this powder is shown in Fig. 1.Instrument model and condition determination: Rigaku D/max 2500 type diffractometers; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°.
The infrared spectrogram of this crystallization, uses KBr compressing tablet during mensuration.
embodiment 2
The granule that contains unformed levofloxacin hydrochloride
Prescription: 100 grams of unformed levofloxacin hydrochlorides, 610 grams of lactose, 75 grams of polyvinylpolypyrrolidone, 78 grams of PEG-4000,130 grams of Vltra tearss, distilled water is appropriate, makes 1000 bags.
Technique: PEG-4000 and levofloxacin hydrochloride are pulverized jointly, cross 80 mesh sieves, mix rear with being packed as granule after distilled water softwood processed, granulation, cryodrying with other material.
embodiment 3
The capsule that contains unformed levofloxacin hydrochloride
Prescription: 200 grams of unformed levofloxacin hydrochlorides, propylene glycol 1.8ml, 145 grams of starch, make 1000.
Technique: by unformed levofloxacin hydrochloride, starch, wetting with 15% aqueous solution of propylene glycol, the granulation of sieving after mixing, 60 ℃ are dry, whole grain, filled capsules.
embodiment 4
The tablet that contains unformed levofloxacin hydrochloride
Prescription: 300 grams of unformed levofloxacin hydrochlorides, 175 grams of lactose, 22 grams of PEG-4000,5 grams of Magnesium Stearates, 26 grams of PVP K30s, 40 grams of croscarmellose sodiums, distilled water is appropriate, makes 1000.
Technique: PEG-4000 and unformed levofloxacin hydrochloride are pulverized jointly, cross 80 mesh sieves, mix rear with distilled water softwood processed with other material, 16 mesh sieve particle processed, put in loft drier in 40-45 ℃ dry, the whole grain of 16 mesh sieves, Magnesium Stearate adds in dry particle and mixes, compressing tablet (pressing pressure 800kg, hardness 8.4).
Claims (1)
1. the preparation method of the unformed form of the levofloxacin hydrochloride shown in formula I,
（Ⅰ）
It is characterized in that comprising the following steps: that levofloxacin hydrochloride adds in 3-4 water doubly, filter, filtrate adds in the mixed solution of 15-20 times 0 ℃-10 ℃ of isopropyl ether-methylene dichloride=10:1 under stirring, be incubated again 1-2 hour, filter, drying obtains, and powder x-ray diffraction collection of illustrative plates of this unformed form exists obvious unformed characteristic peak, there is no sharp-pointed absorption peak, is diffuse type.
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| CN201110227345.7A CN102351881B (en) | 2011-08-10 | 2011-08-10 | Stable levofloxacin hydrochloride compound |
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| CN201110227345.7A CN102351881B (en) | 2011-08-10 | 2011-08-10 | Stable levofloxacin hydrochloride compound |
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| CN102351881B true CN102351881B (en) | 2014-04-09 |
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| CN102775424A (en) * | 2012-07-09 | 2012-11-14 | 浙江司太立制药股份有限公司 | Preparation method for levofloxacin impurity |
| CN106674250A (en) * | 2016-12-27 | 2017-05-17 | 河南康达制药有限公司 | Preparation method of levofloxacin hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634072A (en) * | 2003-12-28 | 2005-07-06 | 彭红 | Levofloxacin dripping pills and its preparing process |
| WO2006048889A1 (en) * | 2004-11-08 | 2006-05-11 | Neuland Laboratories Ltd. | An improved process for the preparation of levofloxacin hemihydrate |
| CN1813758A (en) * | 2005-12-07 | 2006-08-09 | 范敏华 | Levofloxacin hydrochloride micro-pill capsule and its preparing method |
| CN101863904A (en) * | 2010-07-08 | 2010-10-20 | 浙江东亚药业有限公司 | Preparation method of high-purity Levofloxacin semihydrate |
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2011
- 2011-08-10 CN CN201110227345.7A patent/CN102351881B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634072A (en) * | 2003-12-28 | 2005-07-06 | 彭红 | Levofloxacin dripping pills and its preparing process |
| WO2006048889A1 (en) * | 2004-11-08 | 2006-05-11 | Neuland Laboratories Ltd. | An improved process for the preparation of levofloxacin hemihydrate |
| CN1813758A (en) * | 2005-12-07 | 2006-08-09 | 范敏华 | Levofloxacin hydrochloride micro-pill capsule and its preparing method |
| CN101863904A (en) * | 2010-07-08 | 2010-10-20 | 浙江东亚药业有限公司 | Preparation method of high-purity Levofloxacin semihydrate |
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Effective date of registration: 20180926 Address after: 300409 88 Huashi Road, Beichen science and Technology Park, Tianjin Patentee after: TIANJIN HANRUI PHARMACEUTICAL CO., LTD. Address before: 300203 Tianjin Hexi District Dagu South Road 4, 3 Patentee before: Tianjin Hankang Pharmaceutical Biotechnology Co., Ltd. |