CN101129386A - Partial suspended eye drop containing ciprofloxacin and dexamethasone - Google Patents
Partial suspended eye drop containing ciprofloxacin and dexamethasone Download PDFInfo
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- CN101129386A CN101129386A CNA2007100623445A CN200710062344A CN101129386A CN 101129386 A CN101129386 A CN 101129386A CN A2007100623445 A CNA2007100623445 A CN A2007100623445A CN 200710062344 A CN200710062344 A CN 200710062344A CN 101129386 A CN101129386 A CN 101129386A
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Abstract
The invention discloses a suspension eye drops with ciprofloxacin and anaflogistico to give drug locally, which comprises the following parts: anaflogistico, ciprofloxacin, sodium chloride, hydroxypropylmethylcellulose, polysorbate 80 and acetic acid/sodium acetate buffer, wherein the density of hydroxypropylmethylcellulose is 1. 0-5. 0%. The invention has fitful viscosity to lengthen the retaining time of the drug and improve the biological utility of the drug, which reduces the stimulation for eyes effectively and improves the survivability for the patient.
Description
Technical field
But the present invention relates to a kind of ophthalmic preparation of topical, but particularly relate to a kind of suspended eye drop that contains the topical of ciprofloxacin and dexamethasone.Specifically, the present invention is to use the additive combination design with suitable viscosity to be applicable to the ophthalmic preparation prescription of ciprofloxacin and dexamethasone, with the bioavailability that improves eye drop with lower zest.
Background technology
But the eye that EP2065846A1 discloses topical with and ear with antibiotic/steroid class combination product, embodiment 1～3 has been described and has been contained some and the suspension formulation of using of the medicine of the excipient composition that comprises non-ionic polymers and non-ionic surface active agent.Embodiment 1 is the preparation of Clobetasone and lomefloxacin, contains nonionic reinforcing agent (glycerol); Embodiment 2 is preparations of flurandrenolide and norfloxacin, contains ionic reinforcing agent (sodium chloride); Embodiment 3 is preparations of ciprofloxacin and dexamethasone, contains nonionic reinforcing agent (mannitol).
But US5540930 and US5747061 disclose the steroid class suspension formulation of topical, and it contains non-ionic polymers, non-ionic surface active agent and nonionic reinforcing agent.These patents relate to " stable suspension of the water-insoluble steroid class medicine of granularity≤15 micron still can directly suspend when needed even it keeps this state " after long-term settlement.US5747061 thinks, should use non-ionic polymers, non-ionic surface active agent and nonionic reinforcing agent preparation corticosteroid aqueous suspension as far as possible, stable and do not have agglomeration with the aqueous suspension that guarantees preparation, be the main cause that causes the water slurry caking because have now found that ionic existence.Therefore, US5747061 has determined that nonionic glycol such as glycerol or mannitol rather than sodium chloride commonly used are preferred reinforcing agent.
Yet, Granted publication number is CN1158994C, denomination of invention but finds uncannily for the patent of " the partial suspended preparation that contains ciprofloxacin and dexamethasone ", do not produce agglomeration based on the moisture suspension formulation of corticosteroid (dexamethasone) of ionic reinforcing agent.The aqueous suspension preparation of this patent also includes antibiotic (ciprofloxacin) as second active agent except corticosteroid, though this aqueous suspension preparation contains ionic reinforcing agent, enough stable with when needed can be immediately and resuspending easily.
But the non-ionic polymers such as the preferred hydroxyethyl-cellulose concentration that are used for thickening among the CN1158994C are 0.1～0.5%, and this concentration is inappropriate.The effect of non-ionic polymers such as hydroxyethyl-cellulose is to adjust the viscosity of eye drop.Suitable viscosity can prolong drug the time of staying, improve bioavailability of medicament to greatest extent, can lower the zest of eye drop simultaneously again, make the patient that good tolerability be arranged.And this two aspect can both improve curative effect.The 4th edition pharmaceutics that the People's Health Publisher publishes pointed out: the viscosity that eye drop is suitable is 4.0～5.0cPas, and concentration to be 0.1～0.5% hydroxyethyl-cellulose obviously can not reach this purpose.
Summary of the invention
The objective of the invention is the existing partial suspended formulation components that contains ciprofloxacin and dexamethasone is improved, a kind of new eye drop prescription that is applicable to ciprofloxacin and dexamethasone is provided, this eye drop has suitable viscosity, can improve bioavailability of medicament, lower the zest of eye drop.
Simultaneously, the partial suspended eye drop that contains ciprofloxacin and dexamethasone of the present invention has excellent physical stability and easy and quick resuspending equally.
The present invention finds that the eye drop that contains 1.0～5.0% hydroxypropyl emthylcelluloses can be realized purpose of the present invention well.
Therefore, in the partial suspended eye drop that contains ciprofloxacin and dexamethasone provided by the invention, include 1.0～5.0% hydroxypropyl emthylcellulose.
Particularly, the partial suspended eye drop that contains ciprofloxacin and dexamethasone of the present invention includes:
A) 0.01～0.5% dexamethasone;
B) 0.1～0.4% ciprofloxacin;
C) 0.1～0.9% sodium chloride;
D) 1.0～5.0% hydroxypropyl emthylcelluloses;
E) 0.01～0.2% polyoxyethylene sorbitan monoleate; With
F) acetic acid/sodium acetate buffer
And the pH value of this suspended eye drop is 4.5 ± 0.5.
Active component in the suspended eye drop of the present invention includes corticosteroid medicine dexamethasone and antibiotics ciprofloxacin.Dexamethasone can have can existing with form by eye of poorly water soluble with any, so that prepared preparation is a suspending agent, wherein suitable form is a dexamethasone alcohol.Ciprofloxacin can exist with any form that can eye usefulness, so that the ciprofloxacin composition is being the solution form in final preparation, its preferred form is a hydration ciprofloxacin.
It is about 0.01～0.5% that the dexamethasone composition accounts in eye drop of the present invention, and the ciprofloxacin composition accounts for about 0.1～0.4%.Further, dexamethasone and the ciprofloxacin preferred amounts in eye drop of the present invention is respectively 0.1% and 0.3%.
Except active component, also contain sodium chloride in the suspended eye drop of the present invention as ionic reinforcing agent.Amount of sodium chloride generally should be enough to make eye drop to have the weight mole osmotic pressure of about 250～350mOsm.In the suspended eye drop of the present invention, the suitable consumption of sodium chloride is 0.1～0.9%.
The present invention selects for use hydroxypropyl emthylcellulose as the non-ionic polymers of regulating the suspended eye drop viscosity, and its consumption accounts for 1.0～5.0% of eye drop total amount.Preferred hydroxypropyl emthylcellulose concentration is 2.0%, and this concentration can guarantee that the viscosity of suspended eye drop reaches about 5.0cPas, so that suspended eye drop reaches better therapeutic.
Also should contain non-ionic surface active agent in the suspended eye drop, specifically be to select polysorbate 80 for use in the eye drop of the present invention, and its consumption is about 0.01～0.2%, preferred 0.1%.
In suspended eye drop of the present invention, can also include antiseptic, described antiseptic can be benzalkonium chloride, benzalkonium bromide or b diammonium disodium edta, b diammonium edta calcium sodium, or other ophthalmic preparation antiseptic, and the combination of above-mentioned various antiseptic.For example, selecting benzalkonium bromide is 0.005～0.3% as the suitable concentration of antiseptic, and further preferred concentration is 0.01%.
When having b diammonium edta calcium sodium or b diammonium disodium edta in the eye drop, it is except can be used as antiseptic, or the chelating agen in the suspension formulation.The preferred b diammonium edta calcium of the present invention sodium is as the chelating agen of preparation, and its concentration range should be 0.001～0.1%, and preferred 0.01%.
In most of the cases, also contain 0.1～1.5% boric acid in the suspension formulation of the present invention.
The pH value of the suspended eye drop of the present invention's preparation should be 3～5, and the best is 4.5.PH value can be regulated by NaOH/HCl, and cushions with buffer solution.Be used for the preferred acetic acid of the buffer solution system/sodium acetate buffer combination of suspended eye drop of the present invention.Usually, the concentration of acetic acid is 0.02～0.08%, and the concentration of sodium acetate is 0.015～0.06%.
Dexamethasone may cause the stimulation or the discomfort of eye as water insoluble active ingredient unique in the preparation of the present invention for avoiding its excessive granularity, and the particle mean size that should control it is lower than 10 μ m.Can use technology such as known technology such as ball milling, Micro Fluid and sonication classification to pulverize the dexamethasone granule so that it meets the requirements of particle size range.
In the suspended eye drop of the present invention, except that the active component and auxiliary agent of above-mentioned included content, remainder supplies 100% with sterile pure water.
Except as otherwise noted, all the components content that provides with percent among the present invention all is meant mass percentage content.
The preparation process that contains the partial suspended eye drop of ciprofloxacin and dexamethasone of the present invention can be carried out according to following usual manner.
1). get ciprofloxacin, sodium chloride, calcio-disodium edetate, benzalkonium bromide, acetic acid, sodium acetate, the boric acid of proportional quantity, add sterile pure water and dissolve in right amount.
2). get the hydroxypropyl emthylcellulose of proportional quantity, it is an amount of to add sterile pure water, heating for dissolving.
3). get proportional quantity and the dexamethasone and the polysorbate 80 mixing of sterilize (180 ° are following 2 hours), add an amount of sterile pure water, make suspension.
4). with 1), 2) behind the mixing, 100 ° of sterilizations are again with 3) mixing, add sterile pure water to needing 90% of volume.
5). detect the pH value of suspension, as required, the pH value of regulating suspension with aseptic NaOH or HCl solution is 4.5 ± 0.5, is diluted to sterile pure water and formulates volume promptly.
The present invention be directed to the improvement of CN1158994C " the partial suspended preparation that contains ciprofloxacin and dexamethasone " patent.The present invention is by moderately changing the original prescription in the CN1158994C patent and the additive amount of using reasonably being adjusted, make the partial suspended eye drop that contains ciprofloxacin and dexamethasone for preparing in the physical stability that continues to have kept original pharmaceutical composition excellence, in the time of easy and quick resuspending, the viscosity of preparation has more met the instructions for use of eye drop.Therefore, compare with the CN1158994C patent drug, suspended eye drop of the present invention is the time of staying of prolong drug effectively, has improved the bioavailability of active medicine to greatest extent.Simultaneously, also effectively reduce the zest of medicine, improved patient's toleration eyes based on the suspended eye drop under the viscosity of the present invention.And the improvement of above-mentioned two aspects has all improved the curative effect of medication of suspended eye drop of the present invention, makes that the effect of medicine of the present invention is excellent more.
Ciprofloxacin dexamethasone suspension eye drop is sold abroad with trade name " Ciplox-D ", according to " medicine registration management way " (trying) pertinent regulations, this medicine belongs to chemical drugs registration classification 3 classes the 2nd group---the compound preparation of list marketing abroad.Its pharmacology and toxicologic study data are as follows:
One, pharmacodynamic study
1. the antibacterial action of ciprofloxacin
Ciprofloxacin has broad-spectrum antibacterial action, especially to the antibacterial activity height of aerobic gram negative bacilli, following antibacterial is had a good antibacterial action external: most of antibacterial of enterobacteriaceae comprises Enterobacters such as bacillus citrate genus, cloaca, clostridium perfringen, escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, vibrio, yersinia etc.Often multi-drug resistant bacteria also had antibacterial activity.The drug-fast Diplococcus gonorrhoeae of penicillin, product enzyme hemophilus influenza and Moraxella all had the height antibacterial activity.Most of bacterial strains to Rhodopseudomonass such as Pseudomonas aeruginosas have antibacterial action.Ciprofloxacin has antibacterial activity to the methicillin-sensitivity staphylococcus, and streptococcus pneumoniae, Hemolytic streptococcus and enterococcus faecalis are only had medium antibacterial activity.Chlamydia trachomatis, mycoplasma, legionella are had good anti-microbial effect, tubercule bacillus and anonymous mycobacteria are also had antibacterial activity.Antibacterial activity to anaerobe is poor.Ciprofloxacin is an antibacterial, by acting on the A subunit of DNA of bacteria helicase, suppresses the synthetic of DNA and duplicates and cause antibacterial death.
Xiao Yonghong etc. have done ciprofloxacin pharmacokinetics and antibacterial activity in vitro research, the proof ciprofloxacin is tried pathogenic bacterium the strong antibiotic activity is all arranged various, especially more outstanding with golden Portugal bacterium and Gram-negative enterobacteriaceae lactobacteriaceae, bacteriostasis rate 90～100%, and MIC
90≤ 0.03～1 μ g/mL also reaches 87% to the bacillus pyocyaneus bacteriostasis rate, sees table 1 for details.
Table 1 ciprofloxacin antibacterial activity in vitro
| The bacterium name | The strain number | MIC scope (μ g/mL) | MIC 90(μg/mL) | Bacteriostasis rate (%) |
| The inferior Salmonella of the gold coccus streptococcus faecalis escherichia coli proteus pneumonia bacillary dysentery bacillus Bacillus typhi citrobacter Serratieae bacillus cloacae aerobacteria acinetobacter calcoaceticus bacillus pyocyaneus Hough Buddhist nun of bacterium tetracoccus table Portugal of Portugal | 131 11 8 6 130 37 79 76 101 10 39 19 12 46 141 2 | ＜0.03～1 ＜0.03～0.06 ＜0.03～0.25 0.25～1 ＜0.03～4 ＜0.03～4 ＜0.03～＞182 ＜0.03～32 ＜0.03～＞128 ＜0.03 ＜0.03～8 ＜0.03～4 ＜0.03～4 ＜0.03～4 ＜0.03～＞128 ＜0.03 | 0.125 0.06 0.5 1 0.06 ＜0.03 0.25 ＜0.03 1 0.5 2 4 2 | 100 100 93 95 94 99 93 100 90 90 67 87 87 |
Zhang Jianhao etc. have done the comparative study of ciprofloxacin eye drop antibacterial activity, and strain is bacillus pyocyaneus, staphylococcus aureus, staphylococcus epidermidis, gonorrhea diplococcus.Ciprofloxacin eye drop, tarivid eye drop (Japanese Santen Pharmaceutical Co. Ltd.), norfloxacin eye drop (Jiang Fu pharmaceutical factory, Nanjing) have been compared, the antibacterial activity of compound recipe polymyxin B eye drop, gentamycin eye drop.From the inhibition zone size, three kinds of quinolione class eye drops are identical to the effect of bacillus pyocyaneus, staphylococcus epidermidis, effect size to gold-coloured staphylococci is ciprofloxacin eye drop＞norfloxacin eye drop＞tarivid eye drop, to gonococcal effect size is ciprofloxacin eye drop＞tarivid eye drop＞norfloxacin eye drop, illustrate that the antibacterial activity of ciprofloxacin eye drop is the strongest in these three kinds of quinolione class antibacterials.
Zhang Jingwen etc. have done the drug sensitive test analysis of ocular infection separation of bacterial to eye drop commonly used, and the result shows ciprofloxacin as the New-type wide-spectrum antibiotic, and positive bacteria and negative bacterium are all had strong activity, are better than other kinds (table 2).The foreign scholar reports simultaneously, and ciprofloxacin obviously is better than vancomycin, cefazolin sodium and tobramycin in the curative effect of treatment golden Portugal bacterium property keratitis or Pseudomonas Aeruginosa Keratitis keratitis.
Six kinds of eye drop of table 2 compare Grain-positive and negative bacterium drug sensitivity tests
| The medicine name | Gram positive bacteria | Gram-negative bacteria | ||||
| The strain number | Sensitive strain | Responsive rate (%) | The strain number | Sensitive strain | Responsive rate (%) | |
| Ofloxacin gentamycin norfloxacin rifampicin ciprofloxacin chloromycetin | 75 75 75 75 75 75 | 33 48 38 29 48 31 | 44.0 64.0 50.7 38.7 64.0 41.3 | 98 98 98 98 98 98 | 62 54 62 13 83 29 | 63.3 55.1 63.3 13.3 84.7 29.6 |
2. the pharmacodynamic study of dexamethasone
Glucocorticoid has effect widely to immune system.Heavy dose of glucocorticoid can reduce antibody and generate, and suppresses cellular immunization.Glucocorticoid also suppresses digestion and the sterilizing function in the macrophage.
1) dexamethasone suppresses macrophage generation oxygen-derived free radicals and nitric oxide
Wang Guangqing etc. have made dexamethasone and have suppressed macrophage generation oxygen-derived free radicals and nitric oxide production research, and peritoneal macrophage obtains from mouse peritoneal, has proved:
A) dexamethasone stimulates with endotoxin to the influence of macrophage sterilizing rate that its sterilizing rate is 0.326 ± 0.86 (n=6) behind the macrophage, if add dexamethasone, then its sterilizing rate is 0.136 ± 0.108 (n=6), P＜0.01.Show that dexamethasone can significantly reduce the sterilizing rate of macrophage.
B) dexamethasone directly stimulates macrophage to the influence of macrophage reduction NBT with zymosan, then the A value of reproducibility NBT is 0.097 ± 0.022 (n=6), when having dexamethasone to exist, the A value of reproducibility NBT is 0.067 ± 0.011 (n=6), and the two is P＜0.01 relatively.Show that dexamethasone suppresses zymosan and stimulates the huge carefully full oxidative metabolism ability of biting, thereby suppress the generation of reproducibility NBT.
C) dexamethasone produces nitric oxide production influence to macrophage and produces nitric oxide with the endotaxin induction macrophage, and metabolism generates stable nitroso-group then.Behind Mixed culture 7h, observe nitroso existence, nitroso-group stable content behind the cultivation 24h is observed so choose this moment.Show that dexamethasone obviously suppresses macrophage and produces nitroso-group.
2) dexamethasone is to the influence of the early stage neutrophilic granulocyte correlation function of rabbit acute lung injury
Wang Shuo etc. have done the research of dexamethasone to the early stage neutrophilic granulocyte correlation function influence of rabbit acute lung injury, copy the animal model that the infection toxic shock causes acute lung injury with the escherichia coli endotoxin lipopolysaccharide, final result shows, behind the laboratory animal injection escherichia coli endotoxin lipopolysaccharide, the expression that can make PMN surface C D11B is met the imagination of making according to relevant theory by quick active and rise.Dexamethasone is as clinical glucocorticoid commonly used, can be by the activity of inhibition nuclear factor κ B (NF-κ B) and the degraded of κ B Profilin (I κ B), thereby suppress transcribing of the various kinds of cell factor, make inflammatory cytokine in SIRS, discharge minimizing, inflammatory reaction is had the inhibitory action of strong row.This research is divided into two groups of E, P with animal, to observe at the therapeutic effect of different time administration to acute lung injury, attempts to find out the best administration time that the acute lung injury high-risk patient takes place clinically.The result shows, no matter be pretreated group or early intervention group, glucocorticoid has all shown curative effect preferably, has not only obviously suppressed the PMN surface C D11B expression intensity with acute lung injury order of severity height correlation, and has significantly alleviated the order of severity of lungs pathology damage under the light microscopic.Can think that dexamethasone is attributed to the damage of its excessive activation that has suppressed PMN to tissue to the therapeutic effect of acute lung injury, thereby cause the improvement of a series of physical signs.Statistical result shows; after using dexamethasone; on blood pressure and two indexs of blood PMN counting; there are significant difference in E, P for two groups; the pretreatment of this explanation hormone causes that for the escherichia coli endotoxin lipopolysaccharide order of severity of toxic shock has some improvement, and has the better protection effect to laboratory animal.Experiment and theory point out that all the escherichia coli endotoxin lipopolysaccharide causes that the activation of PMN is rapid and lasting, therefore, as not using effective inhibitors as early as possible, in case the waterfall type reaction takes place, will be difficult to again with its reverse.
3) dexamethasone to adult rat persistence focal cerebral ischemia after the influence of apoptosis and Bcl2 protein expression
Feng Tao etc. done dexamethasone to adult rat persistence focal cerebral ischemia after the influence research of apoptosis and Bcl2 protein expression, set up the focal cerebral ischemic model of persistence (sham operated rats is omitted this step) with Mus.Postoperative 1h begins, normal saline group tail vein injection 0.9%NaCl injection (0.5mL/d), Dexamethasone group tail vein injection dexamethasone (0.5mgkg
-1D
-1).
The infarction kitchen range is limited to white matter under the cortex in middle cerebral artery blood supply district, right side and the cortex.Sham operated rats is not seen the TUNEL positive apoptotic cells.The normal saline group 48,72, the visible TUNEL positive apoptotic cells of 120h time point infarction range edge, the TUNEL positive cell is based on neurocyte.Dexamethasone group TUNEL positive apoptotic cells occurs that time point is 24,48,72,120h.Density of apoptotic cells significantly increases (P＜0.01) than normal saline group when ischemia 48,120h; 72h and normal saline group there was no significant difference (P＞0.05).
The Bcl2 immunohistochemical staining: normal saline group ischemia 3h, at ischemic region edge visible minority Bcl2 immunohistochemical staining positive cell, cellular morphology is complete; 6, the 12h positive cell number increases gradually; 24h positive cell number and signal intensity reach maximum; 48,72h positive cell number quantity still is in high level, positive signal moderate strength; Level when the 120h positive cell number reduces to 3h.Bcl2 immune group chemistry stained positive cell mainly is positioned at the edge of ischemic infarction kitchen range, infarction kitchen range center and do not see positive cell away from the zone of infarction kitchen range.The Bcl2 positive cell mainly is a neurocyte, and immune group chemistry stained positive signal mainly is positioned at endochylema.Compare with the normal saline group, Dexamethasone group is when ischemia 6,12,48,72,120h, and Bcl2 immunohistochemical staining positive cell density reduces, and significant difference (P＜0.05) is arranged; 3,24h time point Dexamethasone group is similar to normal saline group positive cell density.
4) influence that the topical application dexamethasone changes rabbit encephalopathy reason behind the cerebral trauma
Yang Bo etc. have done the influence that the topical application dexamethasone is managed change to the rabbit encephalopathy behind the cerebral trauma and have studied, and health is divided into A, B2 group at random from rabbit, 10 of A groups, and B organizes 5.The A group is one-sided cortex damage group, and the B group is bilateral cortex damage group.The A1 group is physiology saline control group, and the A2 group is local dexamethasone treatment group.After the B treated animal is anaesthetized successfully, cut scalp as stated above and expose parietal bone.With the boring of left and right sides parietal bone, as above method is finished 2 bone windows respectively, after the shaping rabbit is fixed on the fixed station of beating device, implements bilateral volume top corresponding site cortex and hits, and causes the model of cortex contusion equally.If the left side is a physiology saline control side (B1), the right side is a dexamethasone treatment side (B2).
(1) normal electroencephalogram was that the α ripple of 9 weeks/s is main before electroencephalogram dynamic change A group rabbit was caused injury, accidental β fast wave.The irregular δ ripple of paroxysmal short distance 40～60 μ V appears in the back 1min that causes injury.Dynamic observe the 5min electroencephalogram and still do not have change.The more preceding no significant change of EEG behind the A1 group 90min.1minEEG no change after the A2 group local application, but 90min rear backdrop electrograph serves as that the master has fast wave concurrently with the α ripple then, the more preceding obvious attenuating of left side slow wave, slow wave is the theta rhythm than the 7 weeks/s of rule.A1 group pathologic EEG improves not obviously behind the 48h, but A2 group background electrograph has on a small quantity fast wave by a narrow margin concurrently based on α ripple by a narrow margin, slow wave complete obiteration, as seen respiration difference more by a small margin.Have part β fast wave concurrently on the background electrograph of normal EEG based on the α ripple of bilateral cortex before B group rabbit is caused injury, the α ripple is rule.5min after bilateral is caused injury, alpha index obviously reduce and wave amplitude is low than hindering preceding, and both sides are dispersed in volume θ ripple, δ ripple and irregular slow wave.5minEEG no change after the cortex local application of right side (B2 side), left and right visible wave amplitude of (B1, B2) bilateral and time limit slow wave about equally.40min after the medication of B2 side, EEG show before the bilateral slow wave is than medication and reduce that wave amplitude lowers, but B2 side slow wave obviously reduces, and wave amplitude obviously reduces.48h rear backdrop electrograph is based on the α ripple, and it is low θ slow wave that still visible more irregular, the wave amplitude of B1 side is hindered the back.B2 side EEG is basic near normal.
(2) cerebral vasodilators hyperemia after cerebral morphology variation A1 group and B1 side rabbit are caused injury, the damage kitchen range is had a few, lamellar is hemorrhage, is contusion and shows, and peripheral edema is obvious, can reach the white matter deep layer, the outer and ECS expansion of blood vessel.After the local application, A2 group and B2 side cortex edema degree alleviate, and damage kitchen range scope is dwindled, and alleviate more obviously with cortex shallow-layer edema, and cellular morphology is complete, and blood vessel and cell peripheral gap are less, and the interior little congestion of blood vessel of brain also reduces.
Two, general pharmacology is learned research
1. the general pharmacology of ciprofloxacin is learned research
1) experimental animal
(1) healthy Kunming kind white mice, body weight 18～21g, male and female have concurrently.
(2) mongrel, body weight 12～20Kg, male and female have concurrently.
Above animal provides by plant of Institute of Experimental Animals, Chinese Academy of Medical Sciences, observes week back use in animal housing.
2) experimental technique
(1) to neural influence
A influences the mice random packet to the mice autonomic activities, and 10 every group, male and female half and half, oral ciprofloxacin 25mg/kg and 100mg/kg respectively, other establishes matched group (normal saline).Behind the administration 50min, by only putting into mice autonomic activities monitor, adapt to 2～3 minutes, the number of times of mice autonomic activities in the record 10min is made significance analysis with the t check.
B is the same with medication to the synergism grouping of pentobarbital sodium sub-threshold lull dosage, and behind the oral 50min, intraperitoneal injection pentobarbital sodium 30mg/kg observes the above number of animals of righting reflex loss 1min in the 15min, uses X
2The administration group is measured in check and matched group has there was no significant difference.
(2) to breathing and the influence of cardiovascular system
Get healthy dog, anaesthetize by forelimb intravenous injection pentobarbital sodium (30mg/kg), be fixed in operating-table, cut the left side skin of groin, separate the ligation tremulous pulse, cut an osculum, insert arterial cannula, and link, as the usefulness of measuring blood pressure with pressure transducer, connect extremity electrocardio lead and respiration pickup simultaneously, to measure electrocardiogram and respiratory variations.
After treating that blood pressure, breathing, electrocardiogram are steadily, the result slowly injects ciprofloxacin 1mg/kg and 10mg/kg by vein in contrast then before the record administration, the variation of blood pressure, heart rate, electrocardiogram and the breathing of record 1,5,10,30,60min, be contrast with the administration previous crops, analyze the gained result.
3) experimental result
(1) to neural influence
The result shows that oral ciprofloxacin 25mg/kg and 100mg/kg do not have obvious influence to the mice autonomic activities, does not also see synergism with pentobarbital sodium sub-threshold lull dosage, and prompting this product may obviously not influence nervous system.
(2) to Sanguis Canitis pressure, heart rate and Electrocardiographic influence
Experimental result shows, 3 Canis familiaris L. intravenous injection ciprofloxacin 1mg/kg, and 1～60min does not all have obvious influence to blood pressure, heart rate and electrocardiogram, does not see significant difference with comparing before the administration.Behind the quiet notes 10mg/kg, have of short duration blood pressure drops fast a little with heart rate, 5min recovers normally gradually, and wherein the Q ripple and the R-S ripple that lead of 1 Canis familiaris L. has the phenomenon of increasing, and electrocardiogram recovers normal substantially during 30min.
(3) influence that Canis familiaris L. is breathed
Experimental result shows, 3 Canis familiaris L. intravenous injection ciprofloxacin 1mg/kg and 10mg/kg do not have obvious influence to frequency of respiration and respiratory depth.
2. the general pharmacology of dexamethasone is learned research
Do not find the general pharmacology test data of dexamethasone.
Three, acute toxicity test
1. the acute toxicity test of ciprofloxacin
1) mice
Ciprofloxacin shows that to the toxicity test result of mice single administration mice is lower to this product toleration, and is especially oral bigger to mouse toxicity, its LD
50Be 2991.5mg/kg, the toxicity (LD of other approach single administrations
50) similar to other fluoroquinolones antibacterial, see table 3 for details.
Table 3 ciprofloxacin is to the chmice acute toxicity data
| Route of administration | LD 50(mg/kg) | 90% puts between letter |
| Oral intravenous injection intramuscular injection subcutaneous injection | 2991.52 223.88 831.08 1133.42 | 2763.13～3249.63 208.36～240.55 735.21～939.46 981.56～1308.74 |
The toxicity of this product drug administration by injection occurs very fast, and the dead animal great majority concentrate in the 10h, and the quiet notes administration animal dead of especially heavy dose of group is fast.In the injection process,, after the part animal twitches, show as unablely, recover normal activity in the rapid breathing, 10min even slowly injection can cause that also the animal paroxysmal back of twitching is dead.It is slower that intramuscular injection and skin are annotated animal dead, and the tic symptom similar to quiet notes appears in 10min after the general administration.The toxicity of oral administration occurs later, general oral back 20min have a convulsion symptom and death, and the appearance toxic reaction of part animal is more late.
This product shows through observation the acute toxicity of each approach single administration of mice, does not see to delay toxicity, and each administration is not seen animal dead, and all than increasing before the administration, animal activity and gait are normal for its body weight, also do not see the signs of toxicity that delays of other system.
Dead animal is not dissected inspection after a week observes, and removing the part that intramuscular injection and skin annotate has the obvious irritation (muscle and subcutaneous tissue have downright bad and fester), and obvious pathological changes is not seen in other detector palaces.
2) rat
Ciprofloxacin shows that to each approach toxicity of rat single administration rat has good tolerability, the oral LD of rat
50＞6000mg/kg, its acute toxicity are low than mice obviously, and the toxicity of other administrations (except that intravenously administrable) is low than mouse toxicity also, sees table 4 for details.
Table 4 ciprofloxacin is to the rat acute toxicity data
| Route of administration | LD 50(mg/kg) |
| Oral intravenous injection intramuscular injection subcutaneous injection | ＞5000 ＞200 ＞1000 ＞1200 |
2. the acute toxicity test of dexamethasone
Dexamethasone sees Table 5 to the acute toxicity test data of animal.
Table 5 dexamethasone is to the animal acute toxicity data
| Animal | Administering mode | LD 50(mg/kg) |
| Mus (mouse) Mus (rat) rabbit | Lumbar injection lumbar injection subcutaneous injection | 410 54 7200 |
Four, long term toxicity test
1. the long term toxicity test of ciprofloxacin
1) laboratory animal
Wistar kind rat, the male 214 ± 16g of body weight, female 149 ± 9g.Provide by plant of Institute of Experimental Animals, Chinese Academy of Medical Sciences, observe week back use in animal housing.
2) experimental technique
It is some to get healthy rat, random packet, and 20 every group, male and female half and half, 0.25% sodium carboxymethyl cellulose suspension of difference oral ciprofloxacin 500,250,100mg/kg and equivalent, offer medicine once every day, oral weekly 6 days, schedules to last February.
Observe ordinary circumstance before the administration, get tail vein fluid inspection hemoglobin, RBC number, total white blood cells and classification.Uroscopy comprises urine pH, albumen, sugar and sediment microscopic inspection.Observe ordinary circumstance in the administration process, gait, reaction to external world, behavioral activity, the cosmetic variation in eyes and limb joint, front and back, results of regular determination food and moisture content consumption are observed the body weight gain situation.Except that checking above-mentioned blood and routine urinalysis, and get that liver function is looked in blood examination and renal function comprises glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT, albumin, total protein, creatinine, blood urea nitrogen and alkali phosphatase etc. during drug withdrawal.24h after the last administration, put to death the half animal of each dosage group and matched group, dissect and check that organ and tissue do not have not change substantially, and core, lung, thymus, liver, spleen, pancreas, kidney, adrenal gland, stomach, small intestinal, large intestine, caecum, bladder, testis or piece of tissue such as ovary, lymph node, muscle, eyeball, joint, brain and cerebellum, be fixed in Bouin ' the s liquid, paraffin embedding, the pathology histological observation is made in HE dyeing.Do not put to death and put to death after the animal drug withdrawal continues to observe January, carry out above-mentioned dissection inspection and histopathology and observe.
3) experimental result
(1) to the influence of ordinary circumstance
Oral ciprofloxacin 100,250,500mg/kg, administration early, in and the later stage, rat reaction to external world, gait, behavior, activity and hair color etc. are similar to matched group, do not see significant difference, eyeball and extremities joint also show no obvious abnormalities.
(2) to the influence of body weight gain
In the experimentation, male Mus of administration group and matched group and the fluctuation of female Mus body weight gain are all in normal range.The 500mg/kg group is slightly faster than matched group in the early stage body weight gain speed of administration, but compares not statistically significant (P＞0.05) with matched group; Mid-term and later stage, the weight of animals of each dosage group increased similar to matched group.
(3) influence that food and moisture content are consumed
Early stage in administration, the moisture content consumption of 500mg/kg and 250mg/kg group slightly increases than matched group; The moisture content consumption in administration mid-term is similar to matched group; The consumption in later stage then reduces relatively, but not statistically significant (P＞0.05).
(4) to the influence of hemopoietic function
Oral ciprofloxacin, rat erythrocyte, leukocyte and hemoglobin are not seen obvious minimizing or increase, and compare with matched group before the administration, fluctuation is not all in normal range, see obvious influence to leukocyte differential count yet; Compare with matched group before the lymphocyte of each dosage group, neutrophilic granulocyte, eosinophilic granulocyte and monokaryon granulocyte etc. and the administration and there is no significant change.
(5) to the influence of rats'liver function
The result shows, the SGPT of each dosage group, SGOT, albumin and total protein are compared with matched group, except that active higher the comparing with matched group variant (P＜0.01) of the ALP of 500mg/kg group, other do not see notable difference (P＞0.05), and prompting this product does not have obvious influence to liver function.One month SGPT of drug withdrawal, SGOT, AP and AT be no abnormality seen also, and ALP returned in normal range.
(6) to the influence of renal function
Administration is early stage, the urine in mid-term and later stage is often seen and checked and show no obvious abnormalities, and urinary sediment microscopy is not found epithelial cell and cast, does not see this product crystallization yet.The renal function biochemical analysis shows during drug withdrawal, and 500mg/kg group BUN slightly raises, and does not have notable difference (P＞0.05) but compare with matched group.The BUN value of 250mg/kg and 100mg/kg group is similar to matched group with creatinine (Cr) value, and all in normal model, drug withdrawal is observed and also do not seen changing function in one month, and the prompting ciprofloxacin does not have obvious damage to renal function.
(7) to the influence of caecum
Ciprofloxacin can make rat caecum weight increase, and caecum weight and dosage are linear.Wherein 500mg/kg and 250mg/kg organize weight ratio matched group weight significance (P＜0.05); 100mg/kg group caecum weight is also than matched group heavy (P＜0.05).After the drug withdrawal one month, 500mg/kg organizes the caecum weight of male Mus and does not recover normally (P＜0.05) yet, female Mus caecum weight then similar to matched group (P＞0.05); 100mg/kg and 250mg/kg group caecum weight recover normal, do not have significant difference (P＞0.05) with matched group.
(8) to the influence of Rats Organs and Tissues coefficient
Branches such as the heart, liver, lung, kidney, spleen, brain and testis another name to each dosage group execution animal during drug withdrawal is heavy, the result shows that the organ coefficient (internal organs g weight/100g weight ratio) of above-mentioned organ and tissue is similar to matched group, learns by statistics and handles nonsignificance (P＞0.05).
(9) histopathologic examination
The heart of control animals, lung, thymus, liver,spleen,kidney, bladder, adrenal gland, stomach, small intestinal, large intestine, caecum, pancreas, testis, epididymis or ovary, lymph node, knee joint, muscle, eyeball, brain and cerebellum etc. there is no obvious pathological change through the gross anatomy inspection during drug withdrawal, and the tissue pathological slice microscopy confirms that also above-mentioned organ or tissue do not see obvious Histological change.Drug withdrawal one month, 5 animals have one-sided or 1 leaf pulmonary consolidation in 10 animals, and lung tissue section also turns out to be pneumonia, and other 5 induced lung show no obvious abnormalities, and other organs are not seen pathological change.
Except that caecum weight ratio matched group obviously increased, other organ and tissue showed no obvious abnormalities during the drug withdrawal of administration group, and obvious pathological changes is not seen by histopathologic slide yet.Above-mentioned inspection organ and tissue that animal was put to death in drug withdrawal in one month there is no obvious pathological change.
2. the long term toxicity test of dexamethasone
Do not find the long term toxicity test data of dexamethasone.
Five, mutagenicity test
1. ciprofloxacin mutagenicity test
1) Salmonella reversion test is under the Mlc of ciprofloxacin, and selecting 5 various dose is that 1.2,0.6,0.3,0.24,0.12 μ g/ ware there is no positive findings to TA97, TA98, TA100.When dosage is 0.6,0.3,0.12 μ g/ ware, no matter whether add S9mix, returning of TA102 become the bacterium colony number average return more than 2 times of change, and tangible dose-effect relationship is arranged above nature; When dosage strengthened again, antibacterial or bactericidal action appearred.The like products of West Germany Bayerco and Shanghai Medicine plant No. 2 is carried out controlled trial, and its dosage and intensity that produces sudden change is all close, and visible ciprofloxacin has mutagenic action to TA102 in Salmonella reversion test.
2) micronucleus test is once irritated stomach with the dosage per os of ciprofloxacin 3000,1500,750mg/kg and is given Kunming mouse, put to death behind the administration 24h, the micronucleus number relatively in the bone marrow polychromatic erythrocyte of sample sets and blank group, its difference nonsignificance (P＞0.05), and positive controls ring phosphorus phthalein amine and blank group relatively have the difference (P＜0.01) of highly significant.
3) the Chinese hamster ovary celI chromosomal aberration test with Chinese hamster ovary celI at 5%CO
237 ℃ of cultivations in the incubator, culture fluid is RPMI1640, and adds 10～15% calf serum.Chromosomal aberration test dosage is 90,45,22.5 μ g/mL, no matter whether add S9mix, the sample sets chromosome aberrations rate is all less than 2%, belong to the normal variation scope, and positive control ametycin (0.2 μ g/mL) and ring phosphorus phthalein amine (60 μ g/mL) chromosome aberrations rate are respectively 64% and 30%, with solvent control group comparing difference highly significant (P＜0.01).
Positive findings appears in ciprofloxacin in Salmonella reversion test, with the positive findings that other in vitro method obtains that is applied to of Bredberg etc. (1989) and Charlene A (1987) report certain dependency is arranged, the prompting ciprofloxacin has obvious damaging action to DNA of bacteria under conditions in vitro, even also shows tangible mutagenesis under Mlc.Because this medicine, comprises that the influence of topoisomerase enzyme is little to mammiferous DNA enzymatic activity, mouse microkernel test, CHO chromosomal aberration test are not seen positive findings, and visible ciprofloxacin is to mammiferous genetoxic and not obvious.
2. dexamethasone mutagenicity test
External, the reaction that is negative is analyzed in Ai Musishi salmonella counter-rotating, but dexamethasone causes the exchange of lymphocyte sister chromatid and the chromosome of artificial culture not normal; In vivo, the mouse micronucleus test is positive, and dexamethasone still causes the exchange of mouse medullary cell sister chromatid.
Six, reproductive toxicity test
1. the reproductive toxicity test of ciprofloxacin
Mouse oral administration every day ciprofloxacin 100mg/kg is not to there being relevant infringement fertility.Female Mus oral administration 100mg/kg or the above ciprofloxacin of IV administration 30mg/kg do not have teratogenesis or fetus to poison.Produce gastrointestinal dysfunction during female rabbit oral administration 〉=30mg/kg, thereby take place that body weight reduces and the abortion ratio increase, but be not teratogenecity.Female rabbit IV administration 20mg/kg or following does not observe toxicity, and does not observe fetus and poison and teratogenecity in the offspring.More than the phenomenon that from the experiment of rabbit, obtains be that a lot of antibacterials institute is ubiquitous.
2. the reproductive toxicity test of dexamethasone
Public Corium Mus skin administration 1.8mg/kg 26 weeks of dexamethasone, the variation that male reproductive organs such as proof epididymis, deferent duct, prostate, seminal vesicle, Cowper gland and accessory body of gland exert an influence to fertility, unlikely ear epidermis by short-term uses dexamethasone and causes.
Publication has been described the research of being treated with adrenocortical hormone every day by eye about conceived New Zealand white rabbit during organ generates.Each treatment group has 10 rabbits, and half was die in 29 days trimester of pregnancy, and second half had given birth to the offspring before dying.Studies show that dexamethasone (0.1%) and abnormal rate rising (mainly being intraperitoneal) is relevant, these have comprised renal hypoplasia, intestinal disappearance and abdominal viscera hernia.Treatment is not lower than 1% with the fetal anomaly rate of normal saline treatment matched group, and the average weight of mother and fetus is higher than medication therapy groups; The fetal anomaly rate of 2 dexamethasone treatment groups is respectively 32.3% (term) and 15.6% (29 days).Although the eye that these data have been used to contain dexamethasone is with in the description of product, pharmacologist can not be sure of that these data have enough value.
Seven, carcinogenic test
Rodent oral ciprofloxacin 750mg/kg every day (mice) and more than the 250mg/kg (rat) carries out the biological study in 2 years, the sign of no carcinogenesis.
There is not research about the dexamethasone carcinogenecity.
The specific embodiment
Embodiment 1
One hydration ciprofloxacin 30.0g (in ciprofloxacin)
Dexamethasone 10.0g
Sodium chloride 43g
Acetic acid 4g
Sodium acetate 3.9g
Hydroxypropyl emthylcellulose 200g
Polyoxyethylene sorbitan monoleate 10g
Calcio-disodium edetate 1g
Boric acid 60g
Benzalkonium bromide 1g
Water for injection 10000mL
Make 1000 bottles
1). a hydration ciprofloxacin, sodium chloride, acetic acid, sodium acetate, calcio-disodium edetate, boric acid, the benzalkonium bromide of getting proportional quantity mix, with the dissolving of 3500mL sterile pure water.
2). get the hydroxypropyl emthylcellulose of proportional quantity, add in the 4000mL sterile pure water heating for dissolving.
3). get proportional quantity and sterilize the dexamethasone of (180 ° following 2 hours) and polysorbate 80 elder brother even, add the 800mL sterile pure water and make suspension.
4). with 1), 2) behind the mixing, in 100 ° of sterilizations, again with 3) behind the mixing, be diluted to 9000mL with sterile pure water.
5). as required, after the pH value of regulating suspension with aseptic NaOH or HCl solution is 4.5 ± 0.5, be diluted to 10000mL with sterile pure water at last, divide to install in 1000 bottles, obtain product.
Embodiment 2
One hydration ciprofloxacin 30.0g (in ciprofloxacin)
Dexamethasone 10.0g
Sodium chloride 43g
Acetic acid 2g
Sodium acetate 1.9g
Hydroxypropyl emthylcellulose 200g
Polyoxyethylene sorbitan monoleate 5g
Calcio-disodium edetate 1g
Boric acid 60g
Benzalkonium bromide 1g
Water for injection 10000mL
Make 1000 bottles
Preparation method is with embodiment 1.
Comparative example 1
The eye drop product and the CN1158994C product of the embodiment of the invention are compared test, and the result is as follows:
Table 6 embodiment of the invention product and CN1158994C properties of product are relatively
| Viscosity (cPas) | Osmotic pressure (mOsm) | The counter-rotating number of times of complete resuspending | |
| Embodiment 1 | 5.84 | 302 | 11 |
| Embodiment 2 | 5.56 | 289 | 12 |
| CN1158994C | 1.91 | 298 | 12 |
As can be seen from the above table, the eye drop viscosity that the present invention makes has reached the viscosity requirement of eye drop apparently higher than CN1158994C, and better therapeutic can be provided.Other performance indications then with the CN1158994C product quite or slightly high.
The present invention is described with reference to some embodiment preferred, but should be appreciated that, the present invention can change enforcement with other particular forms or its under the situation that does not deviate from its main idea or basic feature.Therefore, above-mentioned embodiment of the present invention be illustrative and nonrestrictive, scope of the present invention is shown by appended claims rather than above stated specification.
Claims (10)
1. partial suspended eye drop that contains ciprofloxacin and dexamethasone includes:
A) 0.01～0.5% dexamethasone;
B) 0.1～0.4% ciprofloxacin;
C) 0.1～0.9% sodium chloride;
D) hydroxypropyl emthylcellulose;
E) 0.01～0.2% polyoxyethylene sorbitan monoleate; With
F) acetic acid/sodium acetate buffer;
And the pH value of this suspended eye drop is 4.5 ± 0.5,
It is characterized in that the concentration of described hydroxypropyl emthylcellulose is 1.0～5.0%.
2. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1 is characterized in that described hydroxypropyl emthylcellulose concentration is 2.0%.
3. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1 is characterized in that described dexamethasone is a dexamethasone alcohol, and ciprofloxacin is a hydration ciprofloxacin.
4. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1 is characterized in that dexamethasone concentration is 0.1%, and ciprofloxacin concentration is 0.3%.
5. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1, the concentration that it is characterized in that polyoxyethylene sorbitan monoleate is 0.1%.
6. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1 is characterized in that also including 0.005～0.3% benzalkonium bromide.
7. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 6, the concentration that it is characterized in that benzalkonium bromide is 0.01%.
8. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1 is characterized in that also including 0.1～1.5% boric acid.
9. the partial suspended eye drop that contains ciprofloxacin and dexamethasone according to claim 1 is characterized in that also including 0.001～0.1% calcio-disodium edetate.
10. partial suspended eye drop that contains ciprofloxacin and dexamethasone, form by following composition:
A) 0.1% dexamethasone alcohol;
B) 0.35% 1 hydration ciprofloxacin;
C) 0.1～0.9% sodium chloride;
D) 2.0% hydroxypropyl emthylcellulose;
E) 0.1% polyoxyethylene sorbitan monoleate;
F) acetic acid/sodium acetate buffer;
G) 0.01% benzalkonium bromide;
H) 0.01% b diammonium edta calcium sodium; With
I) 0.6% boric acid;
And the pH value of said composition is 4.5 ± 0.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100623445A CN101129386A (en) | 2007-07-17 | 2007-07-17 | Partial suspended eye drop containing ciprofloxacin and dexamethasone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100623445A CN101129386A (en) | 2007-07-17 | 2007-07-17 | Partial suspended eye drop containing ciprofloxacin and dexamethasone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101129386A true CN101129386A (en) | 2008-02-27 |
Family
ID=39126896
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100623445A Pending CN101129386A (en) | 2007-07-17 | 2007-07-17 | Partial suspended eye drop containing ciprofloxacin and dexamethasone |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012068998A2 (en) * | 2010-11-24 | 2012-05-31 | Wu Zhinan | Triamcinolone acetonide ophthalmic preparation and preparation method thereof |
| WO2013084194A1 (en) * | 2011-12-09 | 2013-06-13 | Lupin Limited | Topical pharmaceutical compositions of anti-microbial agents and anti-inflammatory agents |
| GB2516137A (en) * | 2013-04-09 | 2015-01-14 | Cresset Biomolecular Discovery Ltd | The local treatment of inflammatory ophthalmic diseases |
| CN105342990A (en) * | 2015-10-30 | 2016-02-24 | 上海昊海生物科技股份有限公司 | Eye drops containing moxifloxacin hydrochloride and hexadecadrol and preparation method of eye drops |
| CN105997866A (en) * | 2016-07-13 | 2016-10-12 | 成都明慈医药科技有限公司 | Suspension containing dexamethasone and preparation method of suspension |
| CN107970244A (en) * | 2016-10-21 | 2018-05-01 | 武汉武药科技有限公司 | A kind of composition containing Ciprofloxacin and dexamethasone and preparation method thereof |
| EP3322482A4 (en) * | 2015-07-14 | 2019-01-09 | Parikh, Nilesh | Topical ciprofloxacin compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012068998A2 (en) * | 2010-11-24 | 2012-05-31 | Wu Zhinan | Triamcinolone acetonide ophthalmic preparation and preparation method thereof |
| WO2012068998A3 (en) * | 2010-11-24 | 2012-07-19 | 金健亚洲集团有限公司 | Triamcinolone acetonide ophthalmic preparation and preparation method thereof |
| WO2013084194A1 (en) * | 2011-12-09 | 2013-06-13 | Lupin Limited | Topical pharmaceutical compositions of anti-microbial agents and anti-inflammatory agents |
| GB2516137A (en) * | 2013-04-09 | 2015-01-14 | Cresset Biomolecular Discovery Ltd | The local treatment of inflammatory ophthalmic diseases |
| GB2516137B (en) * | 2013-04-09 | 2016-02-17 | Cresset Biomolecular Discovery Ltd | The local treatment of inflammatory ophthalmic diseases |
| EP3322482A4 (en) * | 2015-07-14 | 2019-01-09 | Parikh, Nilesh | Topical ciprofloxacin compositions |
| CN105342990A (en) * | 2015-10-30 | 2016-02-24 | 上海昊海生物科技股份有限公司 | Eye drops containing moxifloxacin hydrochloride and hexadecadrol and preparation method of eye drops |
| CN105342990B (en) * | 2015-10-30 | 2020-05-19 | 上海昊海生物科技股份有限公司 | Eye drops containing moxifloxacin hydrochloride and dexamethasone and preparation method thereof |
| CN105997866A (en) * | 2016-07-13 | 2016-10-12 | 成都明慈医药科技有限公司 | Suspension containing dexamethasone and preparation method of suspension |
| CN105997866B (en) * | 2016-07-13 | 2019-08-20 | 成都明慈医药科技有限公司 | A kind of suspension and preparation method thereof containing dexamethasone |
| CN107970244A (en) * | 2016-10-21 | 2018-05-01 | 武汉武药科技有限公司 | A kind of composition containing Ciprofloxacin and dexamethasone and preparation method thereof |
| CN107970244B (en) * | 2016-10-21 | 2020-07-14 | 武汉武药科技有限公司 | Composition containing ciprofloxacin and dexamethasone and preparation method thereof |
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