CN104083355A - Composition for preparing anti-fungal keratitis eye drop - Google Patents
Composition for preparing anti-fungal keratitis eye drop Download PDFInfo
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- CN104083355A CN104083355A CN201410318881.1A CN201410318881A CN104083355A CN 104083355 A CN104083355 A CN 104083355A CN 201410318881 A CN201410318881 A CN 201410318881A CN 104083355 A CN104083355 A CN 104083355A
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- cinnamic aldehyde
- ethyl hydroxybenzoate
- eye drop
- composition
- fungal keratitis
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- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 208000014260 Fungal keratitis Diseases 0.000 title claims abstract description 23
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 15
- 239000003889 eye drop Substances 0.000 title claims abstract description 15
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229940117916 cinnamic aldehyde Drugs 0.000 claims abstract description 56
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims abstract description 55
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims abstract description 54
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims abstract description 54
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- 241000228212 Aspergillus Species 0.000 claims abstract description 5
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- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 50
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 25
- 229920000053 polysorbate 80 Polymers 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 12
- 241000233866 Fungi Species 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
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- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 abstract description 4
- 206010023332 keratitis Diseases 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 abstract 1
- 230000003014 reinforcing effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 22
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- 238000012360 testing method Methods 0.000 description 10
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- 241000233732 Fusarium verticillioides Species 0.000 description 8
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- 230000000694 effects Effects 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 239000001888 Peptone Substances 0.000 description 7
- 108010080698 Peptones Proteins 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000000890 drug combination Substances 0.000 description 7
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- 235000019319 peptone Nutrition 0.000 description 7
- 238000004321 preservation Methods 0.000 description 6
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- 210000004087 cornea Anatomy 0.000 description 4
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 3
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- 229930016911 cinnamic acid Natural products 0.000 description 1
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a composition for preparing an anti-fungal keratitis eye drop. The composition comprises the following components in parts by weight: 1-10 parts of cinnamaldehyde and 0.2-20 parts of ethylparaben, wherein the weight ratio of the cinnamaldehyde to the ethylparaben is 1:(0.2-5). The composition for preparing the anti-fungal keratitis eye drop can be used for treating keratitis and keratohelcosis caused by fusarium, aspergillus, penicillium, saccharomyces and the like, and has strong applicability. According to the composition for preparing the anti-fungal keratitis eye drop, the cinnamaldehyde and the ethylparaben are screened and compatibly used by virtue of compatibility experiments; compared with respective application of the two components, the composition can be used for remarkably reinforcing the antibacterial activity of monomers, and is superior to an existing nipagin oil agent, and has a remarkable synergetic effect.
Description
Technical field
The present invention relates to a kind of compositions of medicine, it can be used for the eye drop of preparation treatment cornea fungal infection.
Background technology
Fungal keratitis is a kind of ophthalmology infectious disease thorny, blind rate is high that is in a bad way, treats.Most of patients is because failing to obtain early stage diagnosis and treatment or treatment causes perforation of cornea, blind not in time, and severe patient will row eyeball excise.Since 20th century, along with increasing year by year of sickness rate, danger is also more and more paid attention to.External report, 44% central cornea ulcer is by fungus-caused, and in China, sickness rate has significantly and increases closely during the last ten years, and plant trauma is the main cause that causes fungalkeratitis, has certain seasonality and provincialism, and the infected mostly is peasant.
At present, the pathogen of fungi known keratitis has kind more than 70, to China some areas Ru China Guangdong, Henan, Hebei, etc. the Epidemiological study carried out of ground show, pathogenic bacterium be take Fusarium, Eurotium as main, most areas Fusarium spp. is the first pathogenic bacterium, with fusarium moniliforme and Fusarinm solani, accounting for strong position, is secondly that aspergillosis, penicillium sp, candidiasis, curved spore are mould etc.
Due to less to this sick basic research at present, clinical early diagnosis and Drug therapy lack effective means, cause this sick poor prognosis, and treat thorny.Early stage diagnosis accurately and effectively Drug therapy are to improve the key that cure rate reduces blind rate.
Ethyl hydroxybenzoate (chemical name: ethylparaben): anticorrosion for food, cosmetics, has the antibacterial action of wide spectrum, to G
-, G
+, yeast, mycete all have good bacteriostasis.The routine clinical observation > of < < nipalgin eye drop treatment fungal corneal ulcer 94 > mono-literary composition that is published in Chinese general family medicine for 1999 discloses the nipalgin eye drop of preparing with 1% ethyl hydroxybenzoate, treats that fungal keratitis, ulcer are clinical obtains good curative effect.
The main chemical compositions of Cortex cinnamomi japonici (Ramulus Cinnamomi) is volatile oil, i.e. Oleum Cinnamomi, and it is a kind of volatile oil of complicated.The composition more complicated of Oleum Cinnamomi, take cinnamic aldehyde as main, and content is more than 80%, and other also have Cortex cinnamomi japonici (Ramulus Cinnamomi) ester, eugenol, cinnamic acid etc.Its main active part is cinnamic aldehyde.The cinnamic aldehyde clinical practice spasmolytic, antipyretic of can easing pain, strengthens blood circulation, reduces the effects such as blood glucose, antibacterial, antitumor.Its activity has bacteriostasis to various bacteria, fungus, but there is no the research report that it acts on fungal keratitis.
Summary of the invention
The object of the present invention is to provide a kind of formula simple, there is synergistic function, fungal keratitis (Fusarium, aspergillus, Penicillium, Saccharomyces and various mycete) be can effectively prevent and treat and caused fungal keratitis and corneal ulcer infected, and safety is good, the pharmaceutical composition for the preparation of anti-fungal keratitis eye drop having no side effect.
In order to reach the object of foregoing invention, the technical solution adopted in the present invention is:
Compositions of the present invention comprises the component of following weight parts: cinnamic aldehyde 1 ~ 10 weight portion, and ethyl hydroxybenzoate 0.2 ~ 20 weight portion, wherein the weight ratio of cinnamic aldehyde and ethyl hydroxybenzoate is 1: (0.2 ~ 5).
Further, compositions of the present invention also comprises the Tween 80 of 0.1 ~ 10 weight portion.
Further, compositions of the present invention is prepared by following method: the Tween 80 of 0.1 ~ 10 weight portion is joined in the normal saline of 900 ~ 1000 weight portions of 60 ~ 80 ℃, add again until completely dissolved the ethyl hydroxybenzoate of 0.2 ~ 20 weight portion, and then add the cinnamic aldehyde of 1 ~ 10 weight portion, after mix homogeneously, standing to room temperature both.
Further, fungus of the present invention comprises the fungus of Fusarium, aspergillus, Penicillium or Saccharomyces.
Beneficial effect of the present invention is:
Compositions for the preparation of anti-fungal keratitis eye drop provided by the invention, can be used for treating keratitis and corneal ulcer due to Fusarium, Eurotium, Penicillium, Saccharomyces etc., and the suitability is strong.
Compositions for the preparation of anti-fungal keratitis eye drop provided by the invention, pass through Experiment of Compatibility, filtering out cinnamic aldehyde and ethyl hydroxybenzoate compatibility uses, compared to the two, use respectively the bacteriostatic activity that can significantly strengthen monomer, be better than existing nipalgin oil preparation, there is the effect of obvious Synergistic.
The Chinese medicine composition of anti-aspergillosis medicine provided by the invention, Tween 80 is wherein used as solubilizing agent, but the consumption of Tween 80 only has 0.01% ~ 1%(w/v), consumption well below 1 ~ 10% in Chinese Pharmacopoeia, the minimizing of supplementary product consumption can reduce medicine preparation cost, increases drug effect and reduces the discomfort that adjuvant causes.In prescription, the consumption of Tween 80 is 0.01% ~ 1%, and its pharmacodynamics, safety are all better than 1 ~ 10% consumption.
The specific embodiment
Embodiment 1:
Cinnamic aldehyde: 1 gram,
Ethyl hydroxybenzoate: 1 gram.
Embodiment 2:
Cinnamic aldehyde: 1 gram,
Ethyl hydroxybenzoate: 1 gram,
Tween 80: 1 gram.
Experimental example 1
Detect the activity of cinnamic aldehyde, ethyl hydroxybenzoate and the anti-fungal keratitis of Tween 80 compositions, to the anti-fungal keratitis activity of monomer cinnamic aldehyde, ethyl hydroxybenzoate and the synergistic mensuration of the anti-fungal keratitis of assembly cinnamic aldehyde, ethyl hydroxybenzoate and Tween 80, with fluconazol, contrast respectively.
Test specimen: cinnamic aldehyde >=98%, by Wuhan, Hubei, long-range Science and Technology Ltd. provides, and ethyl hydroxybenzoate is provided by Tianjin Tian Tai fine chemicals company limited, and Tween 80 is provided by Tianjin red rock chemical reagent factory, and fluconazol is provided by French Pfizer.
Medicine monomer: cinnamic aldehyde is dissolved in 95% ethanol, be mixed with 10%(w/v) mother liquid medicine, after 0.2um filter filters, be dissolved in respectively and in culture medium, make the pharmaceutical culture medium containing cinnamic aldehyde 1mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml, 0.0625mg/ml, 0.3125mg/ml, 0.0156mg/ml, 0.0078mg/ml, 0.0039mg/ml, each test tube subpackage 5ml places inclined-plane, solidifies rear cold preservation standby.Wherein culture medium is the proof agar base (4% glucose, 1% peptone, 2% agar) after autoclaving.
Ethyl hydroxybenzoate is dissolved in 95% ethanol, be mixed with 10%(w/v) mother liquid medicine, after 0.2um filter filters, be dissolved in respectively and in culture medium, make the pharmaceutical culture medium containing ethyl hydroxybenzoate 1mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml, 0.0625mg/ml, 0.3125mg/ml, 0.0156mg/ml, 0.0078mg/ml, 0.0039mg/ml, each test tube subpackage 5ml places inclined-plane, solidifies rear cold preservation standby.Wherein culture medium is the proof agar base (4% glucose, 1% peptone, 2% agar) after autoclaving.
Tween 80 is dissolved in 95% ethanol, be mixed with 10%(w/v) mother liquid medicine, after 0.2um filter filters, be dissolved in respectively the pharmaceutical culture medium of making tween 80 1mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml, 0.0625mg/ml, 0.3125mg/ml, 0.0156mg/ml, 0.0078mg/ml, 0.0039mg/ml in culture medium, each test tube subpackage 5ml places inclined-plane, solidifies rear cold preservation standby.Wherein culture medium is the proof agar base (4% glucose, 1% peptone, 2% agar) after autoclaving.
The pharmaceutical composition of pharmaceutical composition: embodiment 1, be dissolved in respectively in 95% ethanol, be mixed with 10% mother liquid medicine, after 0.2um filter filters, be dissolved in respectively and in culture medium, make A(cinnamic aldehyde 1mg/ml, ethyl hydroxybenzoate 1mg/ml), B(cinnamic aldehyde 0.5mg/ml, ethyl hydroxybenzoate 0.5mg/ml), C(cinnamic aldehyde 0.25mg/ml, ethyl hydroxybenzoate 0.25mg/ml), D(cinnamic aldehyde 0.125mg/ml, ethyl hydroxybenzoate 0.125mg/ml), E(cinnamic aldehyde 0.0625mg/ml, ethyl hydroxybenzoate 0.0625mg/ml), F(cinnamic aldehyde 0.03125mg/ml, ethyl hydroxybenzoate 0.03125mg/ml), G(cinnamic aldehyde 0.0156mg/ml, ethyl hydroxybenzoate 0.0156mg/ml), H(cinnamic aldehyde 0.0781mg/ml, ethyl hydroxybenzoate 0.0781mg/ml), I (cinnamic aldehyde 0.0039mg/ml, ethyl hydroxybenzoate 0.0039mg/ml) pharmaceutical culture medium, each test tube subpackage 5ml places inclined-plane, solidify rear cold preservation standby.Wherein culture medium is the proof agar base (4% glucose, 1% peptone, 2% agar) after autoclaving.
The pharmaceutical composition of embodiment 2, is dissolved in respectively in 95% ethanol, is mixed with 10% mother liquid medicine, after 0.2um filter filters, is dissolved in respectively and in culture medium, makes A(cinnamic aldehyde 1mg/ml, ethyl hydroxybenzoate 1mg/ml, Tween 80 1mg/ml), B(cinnamic aldehyde 0.5mg/ml, ethyl hydroxybenzoate 0.5mg/ml, Tween 80 0.5mg/ml), C(cinnamic aldehyde 0.25mg/ml, ethyl hydroxybenzoate 0.25mg/ml, Tween 80 0.25mg/ml), D(cinnamic aldehyde 0.125mg/ml, ethyl hydroxybenzoate 0.125mg/ml Tween 80 0.125mg/ml), E(cinnamic aldehyde 0.0625mg/ml, ethyl hydroxybenzoate 0.0625mg/ml, Tween 80 0.0625mg/ml), F(cinnamic aldehyde 0.03125mg/ml, ethyl hydroxybenzoate 0.03125mg/ml, Tween 80 0.03125mg/ml), G(cinnamic aldehyde 0.0156mg/ml, ethyl hydroxybenzoate 0.0156mg/ml, Tween 80 0.0156mg/ml), H(cinnamic aldehyde 0.00781mg/ml, ethyl hydroxybenzoate 0.00781mg/ml, Tween 80 0.0078mg/ml), I (cinnamic aldehyde 0.0039mg/ml, ethyl hydroxybenzoate 0.0039mg/ml, Tween 80 0.0039mg/ml) pharmaceutical culture medium, each test tube subpackage 5ml places inclined-plane, solidifies rear cold preservation standby.Wherein culture medium is the proof agar base (4% glucose, 1% peptone, 2% agar) after autoclaving.
Matched group: fluconazol is dissolved in 95% ethanol, be mixed with 10%(w/v) mother liquid medicine, after 0.2um filter filters, be dissolved in respectively and in culture medium, make the pharmaceutical culture medium containing cinnamic aldehyde 1mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml, 0.0625mg/ml, 0.3125mg/ml, 0.0156mg/ml, 0.0078mg/ml, 0.0039mg/ml, each test tube subpackage 5ml places inclined-plane, solidifies rear cold preservation standby.Wherein culture medium is the proof agar base (4% glucose, 1% peptone, 2% agar) after autoclaving.
Tested strain:
All from No.2 Hospital, Hebei Medical Univ. Mycology Lab, preserve bacterial strain, be pathogenic strain (being directly from patient's corneal ulcer surface scraping secretions, the direct visible branched mycelia of microscopy, then obtain tested strain through culture identification).
Strain inoculation:
The bacterial strain that picking has been transferred and activated, adds in 0.85% sodium chloride solution, with blood cell counting plate, by bacteria suspension concentration adjustment, is 1 * 10
5 ~ 6cFU/ml.Inoculation 100ul bacteria suspension in each test tube medicine base, each concentration inoculation 2 pipe compares with proof agar base simultaneously, puts in 36 ℃ of calorstats, observes growing state every day, and record, 7 days sentence read result.
The interpretation of MIC value: the situation of every pipe growth is compared with the positive and negative control pipe, and the medicine base tube that the lowest drug concentration of take is grown without culture is MIC terminal.
MFC measures: get glucose peptone liquid base 2ml, add respectively 2h in the test tube of bacteriostatic test asepsis growth, after concussion, take out 100ul and be inoculated in sabouraud culture medium 36 ℃ and hatch 7 days, with least concentration without being grown to MFC terminal.
Determining FIC(mark Mlc): when during for drug combination, the MIC value of each medicine is respectively divided by medication separately the business of MIC value with.That is:
Wherein A is cinnamic aldehyde, and B is ethyl hydroxybenzoate, combines for cinnamic aldehyde and ethyl hydroxybenzoate drug combination.
Interaction is: FIC<1 has synergism, FIC >=1 but <2 has summation action, and there is antagonism FIC >=2.
Quality Control: set up respectively the positive and negative control, repeat once with program as stated above.
Statistical procedures: data acquisition SPSS13.0 software analysis.
Experimental result is in Table 1-2.
Table 1 medicine monomer corneal fungus MIC distribution situation (MIC/mgml
-1)
Table 2 pharmaceutical composition corneal fungus MFC distribution situation (MFC/mgml
-1)
From as above experimental result: the independent medication of cinnamic aldehyde is 0.0625 mg/ml to the MIC value of Fusarium spp. (fusarium moniliforme, Fusarinm solani or Fusarlum poae), MIC value during with ethyl hydroxybenzoate drug combination, fusarium moniliforme is 0.0156 mg/ml, and Fusarinm solani and Fusarlum poae are 0.03125 mg/ml.
The medication of cinnamic aldehyde associating ethyl hydroxybenzoate is 0.3744 to the FIC of fusarium moniliforme, to Fusarinm solani, the FIC of Fusarlum poae is 0.75, to the FIC of Aspergillus flavus, be 0.625, to the FIC of Aspergillus fumigatus, be 0.624, to the FIC of Candida albicans, being 0.624, is 1 every the FIC of bacterium to chain mutually, and to pure green cyan, mould FIC is 0.3744.
Cinnamic aldehyde and ethyl hydroxybenzoate drug combination are described, for the fungus of antagonism Fusarium, aspergillus, Penicillium or Saccharomyces, have the effect of significant Synergistic.Cinnamic aldehyde associating ethyl hydroxybenzoate corneal fungus synergism is followed successively by: fusarium moniliforme, penicillium viridicatum, Aspergillus fumigatus, white thought, Aspergillus flavus, Fusarlum poae, Fusarinm solani, has summation action every bacterium mutually to chain.
During the independent medication of Tween 80 to above-mentioned 8 kinds of funguses all without antibiotic property, during drug combination, do not affect the antibacterial action of cinnamic aldehyde, ethyl hydroxybenzoate.Can be applicable to use with cinnamic aldehyde and ethyl hydroxybenzoate compatibility, increase the water solublity of the two.
Fluconazol is to Candida albicans, and chain has antibacterial action every bacterium mutually, to other 6 kinds of fungal keratitis without antibacterial action.
Conclusion: cinnamic aldehyde, the independent medication of ethyl hydroxybenzoate all have a stronger antibacterial action every bacterium, Pure Malachitum are mould mutually to Fusarium spp. (beading, eggplant are sick, pears spore), aspergillosis (Aspergillus flavus, Aspergillus fumigatus), Candida albicans, chain.When cinnamic aldehyde, ethyl hydroxybenzoate drug combination, produce synergism, further strengthen Fusarium spp. (beading, eggplant disease, pears spore), aspergillosis (Aspergillus flavus, Aspergillus fumigatus), Candida albicans, chain mutually every bacterium, the mould antibacterial action of pure green cyan.To provide a kind of effective Therapeutic Method for treatment cornea fungal infection.
Embodiment 3
Cinnamic aldehyde: 0.5 gram,
Ethyl hydroxybenzoate: 0.1 gram,
Tween 80: 0.1 gram,
0.9% normal saline adds to 100 milliliters,
Preparation: first 0.1 gram of Tween 80 is joined in 0.9% normal saline, add successively 0.1 gram of ethyl hydroxybenzoate, then add 0.5 gram of cinnamic aldehyde, enough 100 milliliters.Autoclaving, subpackage, 5 mls/branch, every day, eye drip was 4 ~ 6 times, and each 3 ~ 5, being used in conjunction 2 weeks is a course for the treatment of.
Embodiment 4 ~ 10 is that from the difference of embodiment 3 proportioning of each component is different, all uses 0.9% normal saline to be settled to 100 milliliters, specifically in Table 3.And detect the MIC value of each embodiment to fusarium moniliforme, to assess the effect of its inhibition fungal keratitis.
MIC the value (/mgml of 3 ~ 10 pairs of fusarium moniliformes of table 3 embodiment
-1)
As shown in the above results, cinnamic aldehyde and ethyl hydroxybenzoate drug combination all have significant inhibitory action to fusarium moniliforme, and MIC is all less than 0.02 mg/ml, are better than cinnamic aldehyde significantly or ethyl hydroxybenzoate is used separately.Wherein the weight ratio at cinnamic aldehyde and ethyl hydroxybenzoate is 1: when (0.2 ~ 5), the content of cinnamic aldehyde is higher, and biocidal property is more obvious.
Claims (4)
1. for the preparation of a compositions for anti-fungal keratitis eye drop, it is characterized in that the component that it comprises following weight parts:
Cinnamic aldehyde: 1 ~ 10 weight portion
Ethyl hydroxybenzoate: 0.2 ~ 20 weight portion
Wherein the weight ratio of cinnamic aldehyde and ethyl hydroxybenzoate is 1: (0.2 ~ 5).
2. a kind of compositions for the preparation of anti-fungal keratitis eye drop according to claim 1, is characterized in that the Tween 80 that it also comprises 0.1 ~ 10 weight portion.
3. a kind of compositions for the preparation of anti-fungal keratitis eye drop according to claim 2, it is characterized in that it prepares by following method: the Tween 80 of 0.1 ~ 10 weight portion is joined in the normal saline of 900 ~ 1000 weight portions of 60 ~ 80 ℃, add again until completely dissolved the ethyl hydroxybenzoate of 0.2 ~ 20 weight portion, and then add the cinnamic aldehyde of 1 ~ 10 weight portion, after mix homogeneously, standing to room temperature both.
4. a kind of compositions for the preparation of anti-fungal keratitis eye drop according to claim 3, is characterized in that described fungus comprises the fungus of Fusarium, aspergillus, Penicillium or Saccharomyces.
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| WO1995000110A1 (en) * | 1993-06-28 | 1995-01-05 | Lion Corporation | Composition for oral cavity |
| CN1126433A (en) * | 1993-06-28 | 1996-07-10 | 狮子株式会社 | Composition for oral cavity |
| CN101073552A (en) * | 2006-05-19 | 2007-11-21 | 上海医药工业研究院 | Double hydrochloride vertebral gel spray for purifying nose and its use |
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