CN101676290A - Levofloxacin salt, and preparation method thereof and medicament composition - Google Patents
Levofloxacin salt, and preparation method thereof and medicament composition Download PDFInfo
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- CN101676290A CN101676290A CN200810013207A CN200810013207A CN101676290A CN 101676290 A CN101676290 A CN 101676290A CN 200810013207 A CN200810013207 A CN 200810013207A CN 200810013207 A CN200810013207 A CN 200810013207A CN 101676290 A CN101676290 A CN 101676290A
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- levofloxacin
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- acetylcysteine
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Abstract
The invention relates to a levofloxacin salt, especially relates to a levofloxacin acetylcysteine salt, also relates to a preparation method for the salts and a medicament composition using them as active components. The preparation method for the salts is characterized by mixing the levofloxacin and the acetylcysteine with equal molar ratio in solution. The levofloxacin acetylcysteine salt of thepresent invention can overcome optical instability of the levofloxacin, thereby reducing the medicament degradation.
Description
Technical field
The present invention relates to the salt of levofloxacin, more particularly, especially relate to the levofloxacin acetyl-cysteine salt.The invention still further relates to the preparation method of its this salt and be the pharmaceutical composition of activeconstituents with it.
Background technology
The structural formula of levofloxacin is as follows:
Its English levofloxacin by name, chemistry (S)-(-) by name-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de]-[1,4]-benzoxazines-6-carboxylic acid, belong to Comprecin, the levo form for Ofloxacine USP 23 has broad-spectrum antibacterial action, anti-microbial effect is strong, and gram positive organisms such as streptococcus aureus, streptococcus pneumoniae, micrococcus scarlatinae and mycoplasma pneumoniae, Chlamydia pneumoniae are had anti-microbial effect.
Levofloxacin has commodity, and the aqueous solution formulation listing of multiple levofloxacin is arranged, and having gone on the market in the U.S. such as towering (Santen) company of Japan, (commodity are by name: Iquix), be used for the treatment of bacterila corneal ulcer for 1.5% levofloxacin eye drop; Domestic levofloxacin content is also arranged is the listing of 0.5% and 0.3% eye drop, is used for outer eye infections such as bacterial conjunctivitis, keratitis, keratohelcosis, dacryocystitis, postoperative infection.Also have the levofloxacin hydrochloride sodium chloride injection (0.1g/100ml, 0.2g/100ml, 0.3g/100ml), levofloxacin Lactate injection liquid (0.2g/100ml), (0.1g/2ml 0.2g/2ml) waits the aqueous solution commodity to the Levofloxacin M. S. A injection liquid.
Medicine is being produced, and transportation all might be degraded in the storage process, shows as that related substance increases except that activeconstituents, and colour-change etc. affect the treatment even may cause the toxic side effect increase, thus medicine to have satisfactory stability be very important.Illumination is an important factor that influences compound stability.
The structural formula of acetylcysteine is as follows:
English by name: Acetylcysteine, the sulfydryl in its chemical structure can make mucinous cystine linkage fracture, reduce phlegm viscosity, make the easy expectoration of phlegm, have had commodity to buy.
The inventor is surprised to find that the acetyl-cysteine salt of levofloxacin has good light stability.
Summary of the invention
One of purpose of the present invention provides a kind of salt of levofloxacin, and the levofloxacin acetyl-cysteine salt of saying so more specifically can overcome the photo-labile of levofloxacin.The present invention also provides the preparation method of this salt and is the pharmaceutical composition of activeconstituents with this salt.
Levofloxacin acetyl-cysteine salt of the present invention is represented with following structural formula:
The salt that becomes with the acetylcysteine of a part for the levofloxacin of a part.
The preparation method of levofloxacin acetyl-cysteine salt of the present invention be with levofloxacin and acetylcysteine in solvent with etc. the proportioning of amount of substance (etc. mol ratio) mix salify.Generally, except the reaction that feeds intake with the amount of substance such as grade, one of reactant can excessively feed intake, and any one reactant all is fine with interior such as excessive 10%, common excessive 20%.
Solvent can be selected the alcohol solvent for use, water, acetone, common solvent such as dimethyl formamide, the perhaps mixture of these solvents.Ethanol, water, acetone are very suitable.
In the strong illumination test, one embodiment of the present of invention are found: the levofloxacin alkali and the levofloxacin hydrochloride that compare, levofloxacin acetyl-cysteine salt of the present invention has better photochemical stability in the aqueous solution.Can predict thus: levofloxacin acetyl-cysteine salt of the present invention with situation that water contacts under, have better light stability.
Compound levofloxacin acetyl-cysteine salt of the present invention has the pharmacological action of levofloxacin, be applicable to be fit to use that usage quantity quite gets final product by active ingredient levofloxacin conversion back and existing various folk prescription or the compounds that contain the levofloxacin activeconstituents that use with the disease occasion of levofloxacin as active ingredient.
The present invention also provides and has contained the levofloxacin acetyl-cysteine salt pharmaceutical composition for the treatment of significant quantity.It makes preparation can be conventional solid preparation such as tablet, capsule, pulvis, granula; The injection that powder injection, aqueous injection, transfusion etc. are conventional; Other solution such as eye drop, oral liquid.
The various formulations of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then.
Embodiment
Mode below by embodiment further specifies the present invention, does not therefore limit the present invention among the described scope of embodiments.
The preparation of embodiment 1 levofloxacin acetyl-cysteine salt
With the 5.00g levofloxacin, place reaction flask, add 200mL acetone, be heated to 40 ℃, be stirred to molten entirely, splash into the acetylcysteine of 2.258g and the solution that 30mL acetone is configured to, drip and finish, stirred 5 minutes, cooling crystallization, filter, filter cake washs with small amount of acetone, gets the white solid powder promptly to be.
1H-NMR (300MHz, methanol solvate) chemical shift (ppm): 8.82 (s, 1H), 7.63 (d, 1H), 4.76 (multi, 1H), 4.43-4.59 (multi, 3H), 3.57 (broad, 4H), 3.16 (broad, 4H), 2.91 (multi, 1H), 2.77 (s, 3H), 2.01 (s, 3H), 2.56 (d, 3H).
Embodiment 2, light stability test
1) experiment purpose: test light stability.
2) experimental technique: according to 2005 editions two appendix VD high effective liquid chromatography for measuring of Chinese Pharmacopoeia
Chromatographic condition: with octadecylsilane chemically bonded silica is weighting agent, and (precision is measured phosphatase 11 0ml respectively, and triethylamine 10ml puts in the 1000ml measuring bottle with phosphoric acid triethylamine solution, the thin up constant volume is to scale, shake up, get final product)-methyl alcohol-acetonitrile (120: 5: 15, volume ratio) is a moving phase; Column temperature 40 degree; Detect wavelength 291nm; The resolution of main peak and other impurity peaks should meet the requirements.
3) assay method
Precision takes by weighing sample an amount of (being equivalent to levofloxacin 40mg approximately) and puts in the 100ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, and is need testing solution.Precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, and thin up shakes up to scale, in contrast solution.Get contrast solution 20ul and inject liquid chromatograph, regulate instrumental sensitivity, make the peak height at principal constituent peak be about the 20%-25% of registering instrument full range, precision is measured need testing solution and each 20ul of contrast solution again, inject liquid chromatograph respectively, the record color atlas calculates total impurities to 2 times of main composition peak retention time with external standard method.
4) strong illumination test:
By method 3) prepare the need testing solution and the contrast solution of levofloxacin, levofloxacin hydrochloride, levofloxacin acetyl-cysteine salt respectively.Need testing solution is placed under the medicine exposure experiments to light instrument, to place 6 days under about 4500LX illuminance.Respectively at 0,1,2,3,4,5,6 samplings on time, to measure according to test method respectively, its test-results sees Table 1.
Table 1 strong illumination test-results
This shows that levofloxacin hydrochloride that the levofloxacin acetyl-cysteine salt compares and levofloxacin alkali have better light stability.
Embodiment 3, levofloxacin acetyl-cysteine salt injection prescription of freeze-drying powder and preparation technology
Specification: 0.2g/ props up (in levofloxacin)
1, prescription
Levofloxacin acetyl-cysteine salt 290g
N.F,USP MANNITOL 600g
Needle-use activated carbon 3g
Water for injection 3L
Make 1000
2, technology
Get recipe quantity levofloxacin acetyl-cysteine salt, N.F,USP MANNITOL is dissolved in the full dose water for injection, be warming up to 40 ℃ behind the clear and bright solution to be formed, stir and add the recipe quantity needle-use activated carbon down, insulated and stirred 30min, takes off charcoal at coarse filtration, filtrate with the smart filter of 0.22 μ m millipore filtration to hundred grades of clean areas, just filtrate discards, subsequent filtrate is done packing after the intermediate check conversion loading amount, and about 3ml/ bottle is more than freezing, the dry 30h.Jump a queue, roll lid, full inspection, packing are promptly.
Embodiment 4, levofloxacin acetyl-cysteine salt injection formula and preparation technology
Specification: 0.2g/ props up (in levofloxacin)
1, prescription
Levofloxacin acetyl-cysteine salt 290g
Sodium-chlor 900g
Needle-use activated carbon 50g
Water for injection 100L
Make 1000
2, technology
Get recipe quantity levofloxacin acetyl-cysteine salt, sodium-chlor, add about 80% the amount water for injection, be stirred to dissolving after, be warming up to 40 ℃, add the recipe quantity needle-use activated carbon, insulated and stirred 30min, coarse filtration is taken off charcoal, filtrate is filtered with 0.22 μ m millipore filtration is smart, filtrate adds to the full amount of water for injection, and after stirring, intermediate is surveyed in sampling, lid is jumped a queue, is rolled in packing after the conversion loading amount.100 ℃ of flowing steam sterilization 30min, cooling immediately.Unacceptable product is rejected in the inspection of cooling back light, and all the other are examined entirely, pack promptly.
Embodiment 5, levofloxacin acetylcysteine tablet formulation and preparation technology
Specification: 0.1g (in left oxygen)
1, prescription
Levofloxacin acetyl-cysteine salt 145g
Microcrystalline Cellulose 75g
Pregelatinized Starch 50g
2% hypromellose solution 50ml
Talcum powder 10g
Magnesium Stearate 5g
Carboxymethylstach sodium 15g
Make 1000
2, technology
1) getting the levofloxacin acetyl-cysteine salt, to pulverize 80 mesh sieves standby.
2) it is standby that all the other auxiliary materials are all crossed 80 mesh sieves.
3) get recipe quantity levofloxacin acetyl-cysteine salt, Microcrystalline Cellulose, pregelatinized Starch and mix, add 2% hypromellose solution system softwood.
4) 18 mesh sieves are granulated, and particle is in 50 ℃ of dry 3h, and stir frequently.
5) dried particle is with the whole grain of 16 mesh sieves.
6) above-mentioned particle adding recipe quantity talcum powder, Magnesium Stearate, carboxymethylstach sodium mix the back and survey intermediate content.
7) conversion weight after with 10
#Shallow round stamping.
8) full inspection, packing are promptly.
Embodiment 6, levofloxacin acetylcysteine capsule prescription and preparation technology
1, prescription
Levofloxacin acetyl-cysteine salt 145g
Pregelatinized Starch 100g
2% hypromellose solution 30ml
Talcum powder 10g
Carboxymethylstach sodium 5g
Make 1000
2, technology
1) getting the levofloxacin acetyl-cysteine salt, to cross 80 mesh sieves standby.
2) it is standby that all the other auxiliary materials are all crossed 80 mesh sieves.
3) get recipe quantity levofloxacin acetyl-cysteine salt, pregelatinized Starch, adding 2% hypromellose solution system softwood.
4) 18 mesh sieves are granulated, and 50 ℃ of dry 3h stir frequently.
5) dried particle is with the whole grain of 16 mesh sieves.
6) above-mentioned particle adds talcum powder, carboxymethylstach sodium mixes the back and surveys intermediate content.
7) irritate in 1 after the conversion weight
#In the Capsules promptly.
8) full inspection, packing.
Claims (9)
1, a kind of levofloxacin salt is a part levofloxacin and the salt that a part acetylcysteine is become, and has following structure:
2, the preparation method of the described levofloxacin salt of claim 1 is characterized in that comprising following step: levofloxacin and acetylcysteine are mixed in solution.
3, the preparation method of the described levofloxacin salt of claim 2 is characterized in that comprising following step: with levofloxacin and acetylcysteine with etc. amount of substance than in solution, mixing.
4, a kind of pharmaceutical composition is characterized in that containing described compound of the claim 1 for the treatment of significant quantity and pharmaceutically acceptable carrier.
5, pharmaceutical composition according to claim 4 is characterized in that: preparation of drug combination or storage process contact with water.
6, pharmaceutical composition according to claim 4, it is characterized in that: pharmaceutical composition is made transfusion.
7, pharmaceutical composition according to claim 4, it is characterized in that: pharmaceutical composition is made sterile injection powder.
8, pharmaceutical composition according to claim 4, it is characterized in that: pharmaceutical composition is made tablet.
9, pharmaceutical composition according to claim 4, it is characterized in that: pharmaceutical composition is made capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN200810013207A CN101676290A (en) | 2008-09-16 | 2008-09-16 | Levofloxacin salt, and preparation method thereof and medicament composition |
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| CN200810013207A CN101676290A (en) | 2008-09-16 | 2008-09-16 | Levofloxacin salt, and preparation method thereof and medicament composition |
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| CN101676290A true CN101676290A (en) | 2010-03-24 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843625A (en) * | 2010-03-30 | 2010-09-29 | 重庆巴仕迪动物药业有限公司 | Compound ofloxacin injection for livestock and preparation method thereof |
-
2008
- 2008-09-16 CN CN200810013207A patent/CN101676290A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843625A (en) * | 2010-03-30 | 2010-09-29 | 重庆巴仕迪动物药业有限公司 | Compound ofloxacin injection for livestock and preparation method thereof |
| CN101843625B (en) * | 2010-03-30 | 2012-02-08 | 重庆巴仕迪动物药业有限公司 | Compound ofloxacin injection for livestock and preparation method thereof |
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Open date: 20100324 |