CN102028684A - Pharmaceutical composition containing tosufloxacin or salt thereof - Google Patents
Pharmaceutical composition containing tosufloxacin or salt thereof Download PDFInfo
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- CN102028684A CN102028684A CN2010102928064A CN201010292806A CN102028684A CN 102028684 A CN102028684 A CN 102028684A CN 2010102928064 A CN2010102928064 A CN 2010102928064A CN 201010292806 A CN201010292806 A CN 201010292806A CN 102028684 A CN102028684 A CN 102028684A
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- pharmaceutical composition
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- tosufloxacin
- antiseptic
- aluminum
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Abstract
The present invention provides a pharmaceutical composition which contains tosufloxacin or a salt thereof. The pharmaceutical composition has excellent stability, excellent anti-corrosion effect and excellent anti-pollution effect. The pharmaceutical composition which comprises tosufloxacin or salt thereof, a metal composition with aluminum as one component, borax, alkali metal chloride and preservative has excellent stability, excellent preservative effect and excellent anti-pollution effect, and is particularly useful as eye drops, nose drops and ear drops.
Description
Technical field
The present invention contains the tosufloxacin (7-(3-amino-1-pyrrolidinyl)-1-(2 that brings into play antibacterial action, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid) or its salt, with the medicine compositions of aluminum as metallic compound, Borax, alkali metal chloride and the antiseptic of constituent, this pharmaceutical composition has excellent stability and safety.
Background technology
As everyone knows, tosufloxacin is for gram positive bacteria and the very excellent antibacterial of gram negative bacteria.In addition, as the stabilization method of its solution, known have interpolation with the method [patent documentation 1] of aluminum as metallic compound, Borax and the alkali metal chloride of constituent.
Yet, be applicable to eye drip with, collunarium with and drip aqueous liquor less amount of each use in long-time that ear is used etc.Therefore, the aqueous liquor probably can be contaminated.
Up to now, also find to contain tosufloxacin or its salt, with the pharmaceutical composition of aluminum as metallic compound, Borax, alkali metal chloride and the antiseptic of constituent.
The prior art document
Patent documentation
Patent documentation 1: No. the 3346586th, Japan Patent
Summary of the invention
The problem that invention will solve
Expect to contain tosufloxacin or its salt and have antiseptic effect and the pharmaceutical composition of preventing polluting effect.
The scheme that is used to deal with problems
Under such situation, the inventor furthers investigate, found that, contain tosufloxacin or its salt, have excellent stability and antiseptic effect, preventing polluting effect as the pharmaceutical composition of metallic compound, Borax, alkali metal chloride and the antiseptic of constituent, thereby finished the present invention with aluminum.
The effect of invention
Of the present inventionly containing tosufloxacin or its salt, have excellent stability and antiseptic effect, preventing polluting effect with aluminum as the pharmaceutical composition of metallic compound, Borax, alkali metal chloride and the antiseptic of constituent, is useful as eye drop, nasal drop and [especially.
The specific embodiment
Below, describe the present invention in detail.
Pharmaceutical composition of the present invention can followingly be made: add in the suspension of tosufloxacin or its salt with behind the metallic compound and dissolving of aluminum as constituent, add Borax and regulate pH value, in this solution, add imbibitions such as alkali metal chloride carries out, and then add antiseptic and dissolving.
As the salt of the tosufloxacin that uses in the pharmaceutical composition of the present invention, for example can list salt with mineral acids such as hydrochloric acid, sulphuric acid and phosphoric acid; With organic acid salt such as acetic acid, lactic acid, succinic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acids; With amino acid whose salt such as aspartic acid and glutamic acid; Sodium salt and potassium salt etc. are preferably with the salt of p-methyl benzenesulfonic acid.
In addition, under the situation that tosufloxacin or its salt exist with the crystal of solvate, hydrate and different shape, they are all in the present invention available, preferably use tosufloxacin p-methyl benzenesulfonic acid salt hydrate.
The consumption of tosufloxacin or its salt is 0.1～3% with respect to pharmaceutical composition, is preferably 0.3%.
As the alkali metal chloride that uses in the pharmaceutical composition of the present invention, for example can list sodium chloride and potassium chloride etc., preferred sodium chloride.
The consumption of alkali metal chloride be solution etc. the required amount of imbibition.
As use in the pharmaceutical composition of the present invention with the metallic compound of aluminum as constituent, for example can list aluminium potassium sulfate, aluminum chloride and aluminum sulfate and their hydrate etc., preferably sulfuric acid aluminum potassium dodecahydrate.
Be generally 0.1～30 times of mole of tosufloxacin or its salt, preferred 0.1～10 times of mole with aluminum as the consumption of the metallic compound of constituent.
The pH value of pharmaceutical composition of the present invention is 3.5～7.0 when dissolving, is preferably 4.0～6.5, and this pH value can be regulated by the consumption of Borax.As required, also can in pharmaceutical composition of the present invention, add other alkali or acid.As alkali, can list for example sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate etc.As acid, for example can list hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, p-methyl benzenesulfonic acid and methanesulfonic acid etc.
As the antiseptic that uses in the pharmaceutical composition of the present invention, can list benzethonium chloride, methyl parahydroxybenzoate, ethylparaben, methaform, sodium dehydroacetate and sodium benzoate etc., preferred ethylparaben.
The consumption of antiseptic is preferably 0.001～0.1% of pharmaceutical composition, and more preferably 0.03～0.05%.
A preferred example of pharmaceutical composition of the present invention is: tosufloxacin p-methyl benzenesulfonic acid salt hydrate is suspended in water, after adding aluminum potassium sulfate 12 hydrate and dissolving, add Borax and regulate pH value, in this solution, add imbibitions such as sodium chloride carries out, and then add antiseptic and the liquor that obtains.
Pharmaceutical composition of the present invention mainly can be applied to injection (solution or time spent lysotype), eye drip with, collunarium with, drip ear with, oral cavity with or preparation for oral use.During the modulation preparation, also can further add pharmaceutically permissible auxiliary agent.As auxiliary agent, can list excipient, stabilizing agent, buffer agent, antioxidant, correctives, thickening agent and painlessization agent etc.
Throwing and method, throwing and amount and throwing and number of times can suitably be selected according to patient's age, body weight and symptom.About pharmaceutical composition of the present invention, usually to the adult adopt oral throwing AOI oral (for example injection and to the throwing at rectum position with etc.) throw with, the amount of counting 0.1～50mg/kg/ days with tosufloxacin can be divided into 1 time～throw for several times with.Pharmaceutical composition of the present invention with eye drip, drip that ear and collunarium etc. are thrown and the time, the amount of counting 1～100 μ g/kg/ days with tosufloxacin can be divided into 1 time～throw for several times with.
Embodiment
Then, list embodiment, comparative example and test example the present invention is described, but the present invention is not limited thereto.
As compd A, use tosufloxacin p-methyl benzenesulfonic acid salt hydrate.
The eye drop of comparative formulations in the test example 2 for not adding antiseptic and making by method similarly to Example 1.
Embodiment 1
0.3g compd A and 0.12g aluminum potassium sulfate 12 hydrate are added in the 90mL purified water, under 55 ℃, make its dissolving.Add 0.1g Borax and 0.1g ethylparaben and make its dissolving.After this solution is cooled to room temperature, with imbibitions such as sodium chloride carry out.With sodium hydroxide solution pH value is adjusted to 5.2, adding purified water, to make total amount be 100mL.After this solution carried out filtration sterilization with membrane filter (0.22 μ m), be filled in the polyethylene system eye drop bottle, make eye drop.
Embodiment 2
Use the 0.05g ethylparaben, make eye drop by method similarly to Example 1.
Embodiment 3
Use the 0.03g ethylparaben, make eye drop by method similarly to Example 1.
Embodiment 4
Use the 0.02g ethylparaben, make eye drop by method similarly to Example 1.
Comparative example 1
0.3g compd A and 0.12g aluminum potassium sulfate 12 hydrate are suspended in the 90mL purified water, under 55 ℃, make its dissolving.Dissolving 0.1g Borax and 0.82g sodium chloride in this solution.And then, in this solution, add 7mL purified water and 1mg/mL benzalkonium chloride aqueous solution 3mL.
Confirm insoluble matter after adding benzalkonium chloride.
Test example 1 (influence that antiseptic causes stability of formulation)
The preparation of embodiment 2 is preserved under room temperature and cold preservation, after 6 weeks, measured the concentration of compd A.
Obtain the survival rate of the compd A after 6 weeks.
Survival rate (%)=(concentration of the compd A the during concentration of the compd A after 6 weeks/beginning) * 100
The results are shown in the table 1.
[table 1]
The preparation of embodiment 2 is stable.
Test example 2 (antiseptic effect)
Antiseptic effect adopts following method to measure: based on Clinical andLaboratory Standards Institute (Association for Standardization of U.S. clinical laboratory, CLSI) the trace liquid diluting method of the sensitivity testing standard method M38-A2 of zymic sensitivity testing standard method M27-A3 of Tui Jianing and filamentous fungi.The 0.67%Difco yeast nitrogen that is added with 0.5% glucose-no aminoacid culture medium after the sensitivity testing culture medium use filtration sterilization (Yeast Nitrogen Base without AminoAcids, YNB).
The following modulation of inoculation bacterium liquid of Candida albicans TIMM1623 (Candida albicans TIMM1623):, make it reach final inoculation bacterium and measure (1 * 10 with the YNB dilution of the bacterium liquid of freezing preservation with 10 times of concentration
3CFU/mL) 10 times of concentration.
The following modulation of inoculation bacterium liquid of Aspergillus fumigatus TIMM0063 (Aspergillus fumigatus TIMM0063):, make it reach final inoculation bacterium amount (1 * 10 with of the YNB dilution of cryopreserved bacterium liquid with 10 times of concentration
4CFU/mL) 10 times of concentration.
Free cultivate with porous plate MS-8096R (Sumitomo ベ-Network ラ イ ト, 96 holes, flat) on, with embodiment 1～4 and the comparative formulations of 180 μ L, with distilled water with common ratio 2 stepwise dilutions 10 times.And then, will inoculate bacterium liquid and be seeded in each hole, every hole 20 μ L, (Microplate Mixer) makes its suspension with microwell plate mixing instrument.After cultivating 48 hours under 35 ℃, judge by visual.In addition, during for yeast, with microwell plate mixing instrument culture fluid is suspended before judging.
In order to obtain the index of antiseptic effect, with the naked eye determine to can be observed the extension rate of the maximum in transparent hole.The results are shown in the table 2.
[table 2]
Confirm the growth inhibited more than 50% in a stock solution
B does not confirm growth inhibited
The preparation that does not add the antiseptic ethylparaben does not confirm fungi growth to be suppressed.But the preparation that contains 0.03～0.1% ethylparaben has suppressed fungi growth fully.
Know by above result, contain tosufloxacin or its salt, have stability and antiseptic effect, preventing polluting effect as the pharmaceutical composition of the present invention of metallic compound, Borax, alkali metal chloride and the antiseptic of constituent with aluminum, especially very excellent as eye drop, nasal drop and [.
Claims (4)
1. pharmaceutical composition, it contains 7-(3-amino-1-pyrrolidinyl)-1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid or its salt, with metallic compound, Borax, alkali metal chloride and the antiseptic of aluminum as constituent.
2. pharmaceutical composition according to claim 1, wherein, antiseptic is an ethylparaben.
3. pharmaceutical composition according to claim 1 wherein, is aluminum potassium sulfate 12 hydrate with aluminum as the metallic compound of constituent, and alkali metal chloride is a sodium chloride, and antiseptic is an ethylparaben.
4. pharmaceutical composition according to claim 3, wherein, the content of ethylparaben is 0.001～0.1% with respect to pharmaceutical composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2009220574A JP2011068589A (en) | 2009-09-25 | 2009-09-25 | Pharmaceutical composition containing tosufloxacin or salt thereof |
| JP2009-220574 | 2009-09-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102028684A true CN102028684A (en) | 2011-04-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102928064A Pending CN102028684A (en) | 2009-09-25 | 2010-09-25 | Pharmaceutical composition containing tosufloxacin or salt thereof |
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| JP (1) | JP2011068589A (en) |
| CN (1) | CN102028684A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198093A (en) * | 2011-05-26 | 2011-09-28 | 浙江工业大学 | Tosufloxacin tosylate eye drop and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0558895A (en) * | 1991-08-29 | 1993-03-09 | Toyama Chem Co Ltd | Medicinal composition containing pyridone carboxylic acid or its salt and stabilization of solution of pyridone carboxylic acid or its salt |
| CN1191723A (en) * | 1998-03-30 | 1998-09-02 | 中国药品生物制品检定所 | Compound eye drops for preventing and treating eye infection and its preparation |
| CN1298706A (en) * | 1999-12-24 | 2001-06-13 | 国家药品监督管理局四川抗菌素工业研究所 | Kelarmycin eye drops and its preparing process |
| CN101690712A (en) * | 2009-08-25 | 2010-04-07 | 武汉武药科技有限公司 | Sitafloxacin eye drop and preparation method thereof |
-
2009
- 2009-09-25 JP JP2009220574A patent/JP2011068589A/en active Pending
-
2010
- 2010-09-25 CN CN2010102928064A patent/CN102028684A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0558895A (en) * | 1991-08-29 | 1993-03-09 | Toyama Chem Co Ltd | Medicinal composition containing pyridone carboxylic acid or its salt and stabilization of solution of pyridone carboxylic acid or its salt |
| CN1191723A (en) * | 1998-03-30 | 1998-09-02 | 中国药品生物制品检定所 | Compound eye drops for preventing and treating eye infection and its preparation |
| CN1298706A (en) * | 1999-12-24 | 2001-06-13 | 国家药品监督管理局四川抗菌素工业研究所 | Kelarmycin eye drops and its preparing process |
| CN101690712A (en) * | 2009-08-25 | 2010-04-07 | 武汉武药科技有限公司 | Sitafloxacin eye drop and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198093A (en) * | 2011-05-26 | 2011-09-28 | 浙江工业大学 | Tosufloxacin tosylate eye drop and preparation method thereof |
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| Publication number | Publication date |
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| JP2011068589A (en) | 2011-04-07 |
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Application publication date: 20110427 |