CN103565816A - Tobramycin-dexamethasone eye drops - Google Patents
Tobramycin-dexamethasone eye drops Download PDFInfo
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- CN103565816A CN103565816A CN201210259747.XA CN201210259747A CN103565816A CN 103565816 A CN103565816 A CN 103565816A CN 201210259747 A CN201210259747 A CN 201210259747A CN 103565816 A CN103565816 A CN 103565816A
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Abstract
The invention discloses tobramycin-dexamethasone eye drops. The tobramycin-dexamethasone eye drops contain tobramycin micro-powder and dexamethasone as active components, and also contain one or more accessory materials for eye drops. The tobramycin-dexamethasone eye drops are characterized in that the used dexamethasone micro-powder meets the grain size conditions that D50 is in a range of 3.0-4.0 microns, the maximum grain size is less than 30 microns, a ratio of micro-powder grains having sizes of 1-5 microns is in a range of 60-66%, a ratio of the micro-powder grains having sizes of 5-10 microns is in a range of 21-26%, and a ratio of the micro-powder grains having sizes less than or equal to 10 microns is in a range of 92-98%.
Description
Technical field:
The present invention relates to the compound eye drops of a kind of glucocorticoid and macrolide antibiotics.
Background technology:
Tobramycin dexamethasone eye drop, be widely used in the treatment of eye inflammation, China document " development of compound tobramycin eye drop " (Yu Qingzhen, Shanghai medicine the 20th volume o. 11th in 1999,36-37), disclose a kind of formula of tobramycin dexamethasone eye drop, and disclose particle size range and distribution as the dexamethasone drug powder of active component.Wherein approach the micropowder that 99% drug particles is 1-5 μ m, we find, the suspensoid of preparing according to this diameter of aspirin particle scope, no doubt can meet national standard, but due to adding of the adjuvants such as suspending agent, liquid viscosity is increased, make to obtain suspension after drug particles precipitates completely, need the jolting of long period can realize good redispersion, in Chinese Pharmacopoeia, eye is not made stipulations by the redispersibility of suspensoid, China's document " the suspending agent screening of acyclovir ophthalmic suspension " (Liu Jie etc., food and pharmaceutical the 10th volume o. 11th in 2008, a kind of detection method of redispersibility is disclosed 21-23), by adopting the nessler colorimetric tube upset of 25ml to mix, detect the redispersibility that average upset number of times characterizes suspensoid, but in fact, after unpacking, place and pollute for a long time, the packing specification of eye drop is generally no more than 5ml, and different from the glass material of color comparison tube, eye-drop liquid bottle is generally the plastic materials such as PET/PE/PP, the tension force of its inner surface and imbibition characteristic and glass material also exist obvious difference, in fact through us, test discovery, adopt suspension and conventional 25ml or the glass material color comparison tube of 50ml of conventional plastic bottle fractional pack, when redispersibility is tested, show characteristic inconsistent.Performance bad when some suspension of doing well in conventional redispersibility test adopts fractional pack to test again.In addition, a lot of user, when using eye drop, often adopt jolting form to carry out redispersion, and jolting or upset number of times are generally all less, also different with the upset in common test, and, a lot of user are when drug development, and development person often ignores this point.Therefore we find to adopt suspendible eye drop prepared by the micropowder of existing particle size distribution, in a lot of actual situations about using, all cannot realize good redispersion, thereby cause and splash into dosage and nominal standard dose is not inconsistent, especially along with the use of medicine, to the later stage, drug level and labelled amount produce larger difference, thereby will directly affect therapeutic effect.
Summary of the invention:
We find, when the dexamethasone micropowder for the preparation of tobramycin dexamethasone eye drop is selected special particle size distribution, resulting eye drop is when meeting suspensoid quality standard, and jolting or upset through fairly simple, just can realize full and uniform redispersion.The redispersion characteristic of the eye drop having improved significantly.
The percentage ratio that relates to grain size of micropowder scope in description of the present invention and embodiment is particulate percentages, and the micro powder granule number in certain particle size range accounts for the percentage ratio of total particle number.Generally take laser particle analyzer to detect.
The particle diameter of indication of the present invention is D50 particle diameter, corresponding particle diameter when the cumulative particle sizes distribution number of a sample reaches 50%.Its physical significance be particle diameter be less than it granule number account for 50% of total amount.
The invention provides a kind of tobramycin dexamethasone eye drop, contain dexamethasone micropowder and tobramycin as active component, water is applicable to the adjuvant of eye drop with one or more, it is characterized in that, described dexamethasone micropowder, its particle size distribution meets the following conditions simultaneously:
D50 is 3.0-4.0 μ m, and maximum particle diameter is less than 30 μ m
Particle diameter is in the micropowder amount of 1-5 μ m, and particulate percentages is 60%-66%, wherein
Particle diameter is at the micropowder of 5-10 μ m, and particulate percentages is 21%-26%;
Particle diameter is less than or equal to the micropowder total amount of 10 μ m, and particulate percentages is 92-98%.
Described eye drop, the bulking value percentage composition of dexamethasone is 0.05%-0.2%.Preferably 0.1%.
Described eye drop, the bulking value percentage composition that it is characterized in that tobramycin is 0.2%-0.4%, preferably 0.3%
Described eye drop, the described adjuvant that is applicable to eye drop is selected from one or more in pH adjusting agent, osmotic pressure regulator, suspending agent, antioxidant, chelating agen, surfactant.
Described pH adjusting agent is selected from one or more in phosphoric acid and salt, boric acid and salt thereof, citric acid and salt thereof, acetic acid and salt thereof, tartaric acid and salt thereof, sulphuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethane, one or more in preferably sulfuric acid, hydrochloric acid, sodium hydroxide.
Described osmotic pressure regulator is selected from glycerol, propylene glycol, sodium sulfate, sodium chloride, potassium chloride, Sorbitol, mannitol.One or more in preferred sodium chloride, sodium sulfate, glycerol.
Described antibacterial is selected from one or more in benzalkonium chloride, benzethonium chloride, sorbic acid, potassium sorbate, benzyl alcohol, methyl parahydroxybenzoate (methyl hydroxybenzoate), propyl p-hydroxybenzoate (propylparaben), chlorobutanol.
Described suspending agent is selected from one or more in sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, polyvinyl alcohol, carboxy vinyl polymer, polyvinyl pyrrolidone, carbomer.One or more in preferred hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose.
Described surfactant is selected from tween 80, polyoxyethylene castor oil 60, HCO60, polyglycol distearate, Polyethylene Glycol, lecithin, sucrose ester, polyoxyethylene aliphatic alcohol ether, one or more in poloxamer, tyloxapol (Tyloxapol), preferably one or more in tween 80, HCO60, polyoxyethylene castor oil 60.
Described chelating agen is selected from disodium edetate or calcium disodium edetate.
Described antioxidant can be selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite.
Dexamethasone Eye Drops preferably, is characterized in that the component that the described adjuvant that is applicable to eye drop contains following percent weight in volume:
Sodium chloride, 0.01%-0.05%,
Tween 80,0.01%-0.1%,
Hydroxypropyl emthylcellulose, 4%-6%.
Sodium sulfate 0.5-2%
Preferably also contain
Disodium edetate or calcium disodium edetate, 0.01%-0.1%,
Antibacterial, 0.01%-0.1%.
Described percent weight in volume is the percentage ratio of composition weight and eye drop volume.
The preparation method that a kind of dexamethasone micropowder is provided of the present invention, is characterized in that, dexamethasone is dissolved in the organic solvent dissolving each other with water, separately getting water for injection stirs, stir on limit, and limit slowly splashes into the organic solvent solution of dexamethasone, all splashes into rear lasting stirring 20-30min.Filtration obtains dexamethasone micropowder.
The preparation method of described dexamethasone micropowder, one or more in the preferred lower alcohol of organic solvent, acetone, oxolane, described lower alcohol is the monohydric alcohol of C1-C4, the envelope-bulk to weight ratio of described organic solvent and dexamethasone is preferably 1:10-20, preferably by the organic solvent that has dissolved dexamethasone filtering with microporous membrane degerming.The volume ratio of described water for injection and organic solvent is preferably 10-20:1.
Institute of the present invention defined particle size scope is for adopting laser particle analyzer to detect the data that obtain.
Tobramycin dexamethasone eye drop provided by the invention, compare with eye drop of the prior art, in standing storage a period of time, in situation at the bottom of drug powder has been deposited to bottle completely, more approach actual service condition jolting several times on a small quantity or upset after can realize very soon redispersion, and eye drop prepared by the micropowder that adopts existing particle size range, although its settling ratio and the redispersibility test result and the eye drop provided by the invention that adopt 25ml glass color comparison tube to carry out do not have significant difference, but when eye drop being distributed into after plastic bottle fractional pack, in the upset experiment 2 and jolting experiment that are more similar to actual service condition, eye drop provided by the invention, show better redispersion characteristic, the upset of number of times still less and and jolting under can realize uniform redispersion, the eye drop that redispersion Temin is aobvious is better than adopting the drug powder of existing particle size range to be prepared, illustrate that the present invention is by the particle size range of preferred dexamethasone micropowder, obtain a kind of which kind of mode that no matter adopts and can realize very soon redispersion, and with the better eye drop of the eye-drop liquid bottle suitability of plastic bottle material, by the later stage uniformity, test simultaneously, more show, the eye drop Dexamethasone Eye Drops provided by the invention of preparing with existing particle size range drug powder is because its redispersibility is better, between the whole operating period, can keep higher uniformity of dosage units, effective ingredient concentration is substantially with using the consumption of eye drop to change.
The specific embodiment
Adopt Hydro 2000MU type laser particle analyzer.
Following embodiment calculates inventory according to every 1000ml suspension, and all eyes are as follows with the accessory formula of aqueous suspension,
The dexamethasone micropowder preparation method formula of embodiment 1 ~ embodiment 15 sees the following form, wherein
Solvent A is oxolane; Solvent B is ethanol; Solvent C is methanol; Solvent D is acetone
Ratio 1 represents the envelope-bulk to weight ratio of organic solvent and dexamethasone
Ratio 2 is the volume ratio of solvent and water
Described dexamethasone micropowder preparation method is: medicine material is dissolved into (heating if desired) in organic solvent, cross 0.45 μ m microporous filter membrane, getting water for injection stirs, maintaining under stirring condition, speed with 0.5-1ml/s slowly drips the organic solvent that has dissolved medicine in water, after finishing, stop stirring, within standing 1 hour, filtration drying obtains drug powder.Described drug powder particle size distribution meets following condition simultaneously:
D50 is 3.0-4.0 μ m, and maximum particle diameter is less than 30 μ m
Particle diameter is in the micropowder amount of 1-5 μ m, and particulate percentages is 60%-66%, wherein
Particle diameter is at the micropowder of 5-10 μ m, and particulate percentages is 21%-26%;
Particle diameter is less than or equal to the micropowder total amount of 10 μ m, and particulate percentages is 92-98%.
Compound method:
The adjuvant of recipe quantity and water-soluble medicine (only limiting to embodiment 2,6,10) are dissolved in the water of recipe quantity 90%, after fully dissolving, cross 0.22 μ m microporous filter membrane and obtain liquid <1>, when preparation to after adding tobramycin in liquid <1> with sulfur acid for adjusting pH to 5-6.Take out 10% of liquid <1>, drug powder is added wherein and stirs and make dense thick suspension, again dense thick suspension is added in raffinate <1>, stir and supply water for injection to recipe quantity, obtain target suspension, specification described in table on suspension is distributed into 2ml or the bottled eye drop of 5ml.Standby.
Embodiment 1-4 eye-drop liquid bottle adopts PET(polyethylene terephthalate) material, embodiment 5-8 eye-drop liquid bottle adopts PP(polypropylene) material, and embodiment 9-13 eye-drop liquid bottle adopts PE(polyethylene) material
Embodiment 1
Accessory formula is hydroxypropyl emthylcellulose 10g
Tween 80 1g
Glycerol 20g
Propylparaben 0.5g
Methyl hydroxybenzoate 0.5g
Calcium disodium edetate 1g
Sodium chloride 0.5g
Water for injection is to 1000ml
Embodiment 2
Accessory formula is hydroxyethylmethyl-cellulose 10g
Tween 80 0.5g
Glycerol 30g
Hyaluronate sodium 1g
HCO60 0.5g
Benzalkonium chloride
Calcium disodium edetate 1g
Water for injection is to 1000ml
Embodiment 3
Accessory formula is methylcellulose 10g
Tween 80 3g
Glycerol 20g
Propylparaben 0.5g
Methyl hydroxybenzoate 0.5g
Disodium edetate 1g
Sodium chloride 7g
Water for injection is to 1000ml
Embodiment 4
Accessory formula is hydroxypropyl emthylcellulose 40g
Tween 80 0.1g
Benzalkonium chloride 0.1g
Calcium disodium edetate 1g
Sodium chloride 0.1g
Sodium sulfate 20g
Water for injection is to 1000ml
Embodiment 5
Accessory formula is hydroxypropyl emthylcellulose 60g
Tween 80 0.6g
Propylparaben 0.05g
Methyl hydroxybenzoate 0.05g
Disodium edetate 1g
Sodium chloride 0.5g
Sodium sulfate 10g
Water for injection is to 1000ml
Embodiment 6
Accessory formula is hydroxypropyl emthylcellulose 40g
Tween 80 1g
Propyl p-hydroxybenzoate (propylparaben) 0.05g
Methyl parahydroxybenzoate (methyl hydroxybenzoate) 0.05g
Disodium edetate 1g
Sodium chloride 0.5g
Sodium sulfate 5g
Water for injection is to 1000ml
Embodiment 7
Accessory formula is hydroxypropyl emthylcellulose 50g
Tween 80 0.1g
Benzyl alcohol 1g
Calcium disodium edetate 1g
Sodium chloride 0.3g
Sodium sulfate 10g
Water for injection is to 1000ml
Embodiment 8-13 accessory formula see the following form (in 1000ml suspension)
Reference examples 1-1-reference examples 13-1
According to the formula of embodiment 1-embodiment 10, adopt fluid energy mill to pulverize respectively and obtain dexamethasone micropowder, gained drug powder mean diameter is 10 μ m, and maximum particle diameter is less than 30 μ m, and the eye drop that packing obtains is routine 1-1 ~ reference examples 10-1 in contrast.
Reference examples 1-2-reference examples 13-2
According to the formula of embodiment 1-embodiment 10, adopt fluid energy mill to pulverize respectively and obtain dexamethasone micropowder, gained drug powder maximum particle diameter is less than 20 μ m, and between 99% drug powder particle diameter 1-5 μ m, the eye drop that packing obtains is routine 1-1 ~ reference examples 10-2 in contrast.
EXPERIMENTAL EXAMPLE again distributes
Settling volume is than detecting
According to the detection method of disclosed suspension type eye drop in 2010 editions appendix 10 of Chinese Pharmacopoeia, detect embodiment 1-embodiment 13, reference examples 1-1 ~ reference examples 13-1, and reference examples 1-2 ~ reference examples 10-2 makes the settling ratio H of suspensoid.Through detecting the settling ratio of all samples, be all greater than 0.90, meet the requirement in Chinese Pharmacopoeia 2010 editions.
Upset experiment 1 turns at vertical plane internal rotation around its center of gravity
To test drugs packaging in 25 mL nessler colorimetric tubes, after the static placement of room temperature 2d, spin upside down color comparison tube to bottom without precipitation, in suspension without grumeleuse.In experiment, every upset once refers to and will test medicine be housed, and original state is that mouth of pipe color comparison tube straight up planar carries out dextrorotation turnback to the opposite direction of the mouth of pipe towards original sensing at major axis, and reversal rate is upset per second 2 times.The results are shown in following table, n=5
When upset experiment 1 shows to adopt 25ml nessler colorimetric tube as experimental facilities, the sample redispersion characteristic of all embodiment and reference examples is basically identical without significant difference.
Upset experiment 2
Adopt and divided the embodiment 1-embodiment 13 installing, reference examples 1-1 ~ reference examples 13-1, and reference examples 1-2 ~ reference examples 13-2, after standing 2d, every group samples 10 bottles, overturn after 6 times, bottleneck sampling at once, from upper strata sampling 0.1ml, surveys the wherein concentration of dexamethasone and the ratio of nominal value, and carry out experimental result and see the following form, the check of t in groups of Data Processing in Experiment employing SAS system (
)
Upset experiment 2 shows, tobramycin dexamethasone eye drop provided by the invention, and after being distributed into the packing of the following specification of 5ml, after the experiment of overturning, its dexamethasone content and nominal value recording from bottleneck sampling is basically identical.And eye drop prepared by the drug powder that adopts other particle size range, the dexamethasone content and the nominal value that from bottleneck sampling, record exist obvious gap (P < 0.05).Illustrate in fact, the redispersion characteristic of the eye drop that adopts larger packing and fractional pack when overturning experiment is also inconsistent, and the present invention is by the particle size range of preferred dexamethasone, the better tobramycin dexamethasone eye drop of redispersion characteristic when a kind of employing fractional pack is provided.
Jolting experiment 1
Eye drop after the packing that the employing embodiment of the present invention and reference examples provide, method of testing is: forearm stretches out parallel with horizontal plane, hand-held medicine bottle, bottleneck vertically upward, be take ancon as axle, and in vertical guide, 90 °, fast rotational forearm is extremely vertical with horizontal plane, now bottleneck direction is parallel with horizontal plane, then fast forearm is being rotated to original position, completing this process and be jolting once, each jolting activity should complete in 1s.
Adopt and divided the embodiment 1-embodiment 10 installing, reference examples 1-1 ~ reference examples 10-1, and reference examples 1-2 ~ reference examples 10-2, after standing 2d, every group samples 10 bottles, after jolting 5 times, bottleneck sampling, from upper strata sampling 0.1ml, surveys the wherein concentration of dexamethasone and the ratio of nominal value, and carry out experimental result and see the following form, the check of t in groups of Data Processing in Experiment employing SAS system (
)
Jolting experiment shows, tobramycin dexamethasone eye drop provided by the invention, and after being distributed into the packing of the following specification of 5ml, after carrying out jolting experiment, content and the nominal value of its dexamethasone medicine recording from bottleneck sampling are basically identical.And eye drop prepared by the drug powder that adopts other particle size range, content and the nominal value of the dexamethasone recording from bottleneck sampling exist obvious gap (P < 0.05), and with in upset experiment, record dexamethasone content and compare also on the low side, illustrate in fact, the redispersion characteristic of the suspensoid that adopts larger packing and fractional pack when carrying out jolting experiment is also inconsistent, compare with the redispersion form of employing upset, the eye drop providing in prior art, is not suitable for the redispersion mode that adopts jolting more.
Later stage uniformity testing
Get embodiment 1 ~ embodiment 13, reference examples 1-1 ~ reference examples 13-1, and reference examples 1-2 ~ reference examples 13-2 makes each 10 bottles of eye drops.Every day according to after method jolting in jolting experiment 12 times immediately according to method upset in upset experiment 22 times, ooze 10% of eye drop at once, all the other time eye drops are uprightly placed, within the 10th day, measure the concentration of dexamethasone and the ratio of nominal value of eye drop, described level concussion method of testing is once: forearm stretches out parallel with horizontal plane, hand-held eye drop medicine bottle, take ancon as axle, in horizontal plane, fast rotational forearm is 90 °, keep bottleneck vertically upward, and then fast forearm is rotated to original position, each jolting activity should complete in 1s.Experimental result sees the following form, the check of t in groups of Data Processing in Experiment employing SAS system (
)
Prove by experiment, adopt the eye drop of different-grain diameter dexamethasone micropowder, in continuing use procedure, using later stage dexamethasone content to have larger difference, the eye drop that the embodiment of the present invention provides, even adopt aforementioned number of times less, more inviolent concussion and flipped form are carried out redispersion, between the whole operating period, to the last also can also keep the homogeneity of content, embodied good redispersion characteristic, and eye drop in reference examples is when adopting same upset or concussion form, redispersibility is just poor, using the concentration of later stage medicinal liquid that significant variation has occurred.
By above-mentioned experiment, can prove, the suspendible eye drop of conventional particle diameter can in use can cause initial eye drip medicament contg low, to using, later stage eye drip medicament contg is high, front and back gap is greatly about 10% left and right, the starting stage of especially using at eye drop needs most the stage of medicine often, and at this moment conventional suspendible eye drop often content is lower, cause the medicine deficiency that tells on, and the main cause that eye drop is used the higher untoward reaction often of the stage drug level in later stage to produce.In the present invention, by preferable particle size, the generation of the problems referred to above will better be avoided.
Claims (10)
1. a tobramycin dexamethasone eye drop, contain dexamethasone micropowder and tobramycin as active component, water is applicable to the adjuvant of eye drop with one or more, it is characterized in that, described dexamethasone micropowder, its particle size distribution meets the following conditions simultaneously:
D50 is 3.0-4.0 μ m, and maximum particle diameter is less than 30 μ m
Particle diameter is in the micropowder amount of 1-5 μ m, and particulate percentages is 60%-66%, wherein
Particle diameter is at the micropowder of 5-10 μ m, and particulate percentages is 21%-26%;
Particle diameter is less than or equal to the micropowder total amount of 10 μ m, and particulate percentages is 92-98%.
2. eye drop as claimed in claim 1, the bulking value percentage composition that it is characterized in that dexamethasone is 0.05%-0.2%.
3. eye drop as claimed in claim 1, the bulking value percentage composition that it is characterized in that tobramycin is 0.2%-0.4%.
4. the eye drop as described in as arbitrary in claim 1-3, is characterized in that the described adjuvant that is applicable to eye drop is selected from one or more in pH adjusting agent, osmotic pressure regulator, suspending agent, antioxidant, chelating agen, surfactant.
5. eye drop as claimed in claim 4, is characterized in that described pH adjusting agent is selected from one or more in phosphoric acid and salt, boric acid and salt thereof, citric acid and salt thereof, acetic acid and salt thereof, tartaric acid and salt thereof, sulphuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethane.
6. eye drop as claimed in claim 4, is characterized in that described osmotic pressure regulator is selected from glycerol, propylene glycol, sodium sulfate, sodium chloride, potassium chloride, Sorbitol, mannitol.
7. eye drop as claimed in claim 4, is characterized in that described antibacterial is selected from one or more in benzalkonium chloride, benzethonium chloride, sorbic acid, potassium sorbate, benzyl alcohol, methyl parahydroxybenzoate (methyl hydroxybenzoate), propyl p-hydroxybenzoate (propylparaben), chlorobutanol.
8. eye drop as claimed in claim 4, is characterized in that described suspending agent is selected from one or more in sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, polyvinyl alcohol, carboxy vinyl polymer, polyvinyl pyrrolidone, carbomer.
9. eye drop as claimed in claim 4, it is characterized in that described surfactant is selected from tween 80, polyoxyethylene castor oil 60, HCO60, polyglycol distearate, Polyethylene Glycol, lecithin, sucrose ester, polyoxyethylene aliphatic alcohol ether, one or more in poloxamer, tyloxapol (Tyloxapol).
10. eye drop as claimed in claim 1,, it is characterized in that the component that the described adjuvant that is applicable to eye drop contains following percent weight in volume:
Sodium chloride, 0.01%-0.05%,
Tween 80,0.01%-0.1%,
Hydroxypropyl emthylcellulose, 4%-6%,
Sodium sulfate 0.5-2%.
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| CN201210259747.XA CN103565816A (en) | 2012-07-25 | 2012-07-25 | Tobramycin-dexamethasone eye drops |
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| CN104083443A (en) * | 2014-07-15 | 2014-10-08 | 四川兴科蓉药业有限责任公司 | Compound tobramycin eye drop |
| CN105708844A (en) * | 2014-12-05 | 2016-06-29 | 成都青山利康药业有限公司 | Tobramycin and dexamethasone nanosuspension eye drop and preparation method thereof |
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Application publication date: 20140212 |