CN105884715A - Bendazac lysine pharmaceutical composition and medical application thereof - Google Patents
Bendazac lysine pharmaceutical composition and medical application thereof Download PDFInfo
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- CN105884715A CN105884715A CN201610260273.9A CN201610260273A CN105884715A CN 105884715 A CN105884715 A CN 105884715A CN 201610260273 A CN201610260273 A CN 201610260273A CN 105884715 A CN105884715 A CN 105884715A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
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Abstract
The invention discloses bendazac lysine pharmaceutical composition and medical application thereof. The bendazac lysine pharmaceutical composition comprises bendazac lysine and a novel-structured natural product compound (I) separated from the dried tubers of rhizoma corydalis. The bendazac lysine and the compound (I) can increase the GSH content in the liver tissue of a mouse, lower MDA content and inhibit TG accumulation and has a certain liver protecting effect when being used alone, and the liver protecting effect can be increased when the bendazac lysine and the compound (I) are used together. The bendazac lysine pharmaceutical composition can be developed into liver-protecting medicine and has outstanding substantial characteristics and evident progress as compared with the prior art.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of bendazac lysine, be specifically related to the drug regimen of bendazac lysine
Thing and the application in the liver protecting thereof.
Background technology
Bendazac lysine chemical name is 1B (1-benzyl-1H-indole azoles-3-epoxide) acetate, is a kind of ophthalmic remedy,
It is applicable to early-stage senile cataract.
How the metabolism of ethanol and decomposition complete in liver, and therefore heavy drinking can bring the biggest burden to liver.Simultaneously at ethanol
Metabolic process can produce many metabolites, such as acetaldehyde, radical ion etc..The injury to body of these metabolites is all
More than ethanol itself, inflammation can be caused, cause hepatocyte injury, reduce immunologic function, cause death.Body takes in second in a large number
After alcohol, under the catalysis of ethanol dehydrogenase (ADH), mainly it is oxidized to acetaldehyde, and is oxidized to Acetates thing by aldehyde dehydrogenase
Matter.It is taken as that ADH is the important enzyme of one during alcohol metabolism, keep its activity can speed up internal ethanol point
Solve metabolism, reduce the accumulation of internal ethanol.Ethanol aoxidizes in a large number so that tricarboxylic acid cycle obstacle and fatty acid oxidation weaken and affect
Lipid metabolism, causes fat to deposit in hepatocyte.Ethanol energy excited oxygen molecule simultaneously, produces oxygen-derived free radicals and causes liver plasma membrane
Lipid peroxidation and internal reduced glutathion (GSH) consume, malonaldehyde (MDA) raise, triglyceride (TG)
Metabolism also can be significantly affected.
Up to now, there is not yet bendazac lysine and pharmaceutical composition thereof to report with liver-protective dependency.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of bendazac lysine, containing bendazac lysine in this pharmaceutical composition
With a kind of natural product, bendazac lysine and this natural product can be with coordinating protection livers.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
A kind of pharmaceutical composition of bendazac lysine, including bendazac lysine, compound as claimed in claim 1 (I) and
Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses
Solve agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: the dry tuber of Rhizoma Corydalis is pulverized by (a), uses
80~90% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturated successively
N-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract;In (b) step (a)
N-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 30% ethanol elution, then with 12 cylinders of 85% ethanol elution
Long-pending, collect 85% eluent, concentrating under reduced pressure obtains 85% ethanol elution concentrate;C in () step (b), 85% ethanol elution is dense
Contracting thing purification on normal-phase silica gel separates, successively with the methylene chloride-methanol gradient elution that volume ratio is 100:1,50:1,25:1 and 12:1
Obtain 4 components;D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1,12:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 2:1;Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collects 13~16 column volumes and washes
De-liquid, eluent is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 85% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in preparing liver-protective medicine.
The application in preparing liver-protective medicine of the pharmaceutical composition of above-mentioned bendazac lysine.
Advantages of the present invention:
Containing bendazac lysine and a kind of from the dry tuber of Rhizoma Corydalis in the pharmaceutical composition of the bendazac lysine that the present invention provides
When the natural product of the novel structure of isolated, bendazac lysine and this natural product independent role, there is liver effect;Two
During person's synergy, the protective effect to liver improves further, can develop into liver-protective medicine.The present invention is with existing
Technology is compared has prominent substantive distinguishing features and significantly progress.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.To the greatest extent
The present invention is explained in detail by pipe with reference to preferred embodiment, it will be understood by those within the art that, can be to the present invention
Technical scheme modify or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, purchased from Shanghai Ling Feng chemistry
Reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: the dry tuber (2kg) of Rhizoma Corydalis is pulverized by (a), extracts (15L × 3 time) with 85% alcohol heat reflux,
United extraction liquid, is concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and
Water saturated n-butyl alcohol (3L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butanol extraction
Thing;B acetic acid ethyl ester extract D101 type macroporous resin remove impurity in () step (a), first with 6 posts of 30% ethanol elution
Volume, then with 12 column volumes of 85% ethanol elution, collect 85% eluent, concentrating under reduced pressure obtains 85% ethanol elution concentrate;
C in () step (b), 85% ethanol elution concentrate purification on normal-phase silica gel separates, be 100:1 (12 cylinders by volume ratio successively
Long-pending), the methylene chloride-methanol of 50:1 (10 column volumes), 25:1 (8 column volumes) and 12:1 (8 column volumes) terraced
Degree affords 4 components;D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (6 column volumes), 12:1 (8 column volumes) and 2:1 (6 column volumes) obtains 3
Individual component;E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and by concentration expressed in percentage by volume is
The methanol aqueous solution isocratic elution of 88%, collects 13~16 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I)
(270mg, HPLC normalization purity is more than 98%).
Structural identification: white solid;The quasi-molecular ion peak m/z 219.1715 [M+H] that HRAPCIMS is given+, show chemical combination
Thing molecular formula is C15H22O2, degree of unsaturation is 5.1H-NMR composes (CDCl3, 600MHz) in, H-1 (2.56, d, J=4.3Hz),
H-2 (3.17, dd, J=6.2,4.3Hz), H-3 (5.39, d, J=6.2Hz), H-5 (2.04, br, d, J=13.2Hz),
H-6a (1.45, m), H-6b (1.84, m), H-7 (2.11, tt, J=13.5,4.4Hz), H-8a (1.57, m),
H-8b (1.79, m), H-9a (1.37, dt, J=12.6,3.5Hz), H-9b (2.03, dt, J=12.6,4.0Hz),
H-12 (4.83, br, s, 2H), H-13 (1.84, s), H-14 (0.99, s), H-15 (1.83, br, s);13C-NMR
Spectrum (CDCl3, 150MHz) in, show 15 carbon signals, C-1 (80.3, CH), C-2 (52.7, CH), C-3
(121.7, CH), C-4 (136.1, C), C-5 (47.2, CH), C-6 (26.1, CH2), C-7 (43.9, CH),
C-8 (26.5, CH2), C-9 (36.2, CH2), C-10 (40.2, C), C-11 (149.2, C), C-12 (112.8,
CH2), C-13 (21.1, CH3), C-14 (19.2, CH3), C-15 (20.3, CH3)。1H-NMR composes display one
Individual olefinic proton signals δ H5.39 (1H, d, J=6.2Hz, H-3);Two methyl proton signals δ H0.99 (3H, s, H-14)
With 1.83 (3H, br, s, H-15);One group of isopropenyl proton signal δ H1.84 (1H, s, H-13), 4.83 (2H,
Br, s, H-12);Two methine proton signal δ H2.04 (1H, br, d, J=13.2Hz, H-5), 2.11 (1H, tt,
J=13.5,4.4Hz, H-7);One group of glycidyl proton signal δ H2.56 (1H, d, J=4.3Hz, H-1), 3.17 (1H,
Dd, J=6.2,4.3Hz, H-2).13C-NMR spectrum combines three methyl carbon signals in DEPT stave this structure bright, four
Mesomethylene carbon signal (three saturated carbon and an alkene carbon), five methine carbon signals (two saturated carbon, two company's oxygen carbon
With an alkene carbon), three quaternary carbon signals (saturated carbon and two alkene carbon).By HMBC analysis of spectrum,
H-7 and C-6, C-8 and C-11, and H2With the coherent signal of C-7 and C-13 ,-12 show that isopropenyl is connected with C-7 position.
In NOESY spectrum, there is dependency in Me-14 Yu H-1, Me-14 Yu H-2, H-1 Yu H-2, H-5 Yu H-7, meanwhile,
There is also dependency between Me-14 and H-8a, additionally H-5 Yu H-7 coupling constant is respectively J=13.2Hz and J=13.5Hz,
The configuration direction that can confirm H-5 with H-7 is consistent, for α configuration, does not shows that Me-14 with H-5 deposits in NOESY spectrum simultaneously
At dependency, therefore Me-14, H-1 and H-2 are beta comfiguration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, with
And document is about correlation type nuclear magnetic data, can substantially determine that this compound is shown below, spatial configuration passes through ECD further
Test determines, theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 materials and instrument
Bendazac lysine is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.ICR
Female white mice body weight (25 ± 5) g, Shanghai Si Laike laboratory animal responsibility company limited;Coomassie brilliant G-250, glycerol three
Biology is built up in fat test kit, malonaldehyde testing cassete, glutathione peroxidase test kit, alcohol dehydrogenase enzymatic determination test kit Nanjing
Graduate School of Engineering;Hai Wangjin cup, ShenZhen,GuangDong Hai Wang pharmaceutcal corporation, Ltd;56 ° of Red Star strong, colourless liquor distilled from sorghum Chinese liquor, Beijing Red Star winery.
Christ company of Alpha-D2 freeze dryer Germany;Electronic balance, Shanghai balance equipment factory;UV752N UV, visible light spectrophotometric
Meter, Shanghai INESA Analytical Instrument Co., Ltd..
1.2 animal packets
By 72 ICR mices in (22 ± 1) DEG C, humidity 40%~60%, 12h alternation of day and night, ad lib, the bar of water inlet
After adaptability feeds one week under part, it is randomly divided into six groups.Blank group 12: be left intact in experimentation, freely
Feed;The normal saline of model group 12: 0.9%;Bendazac lysine group 12: concentration is 100mg/mL;Compound (I)
Organize 12: concentration is 100mg/mL;Bendazac lysine and compound (I) compositions group 12: concentration is 50mg/mL
Bendazac lysine+50mg/mL compound (I);Positive controls 12: concentration is extra large Wang Jin cup solution of 25mg/mL.
1.3 be administered
Every day, per os gavage gave 20mL/kg BW given the test agent.Blank group does not do any gavage, ad lib, water inlet;
Model control group gives normal saline, successive administration 30d by body weight.Weigh weekly once, adjust dosage according to body weight.Give
At the end of giving given the test agent, giving Chinese liquor 5mL/kg BW by model control group and gavage of each sample group, blank group is given
Distilled water.
Prepared by 1.4 liver specimens
After last is administered, water 12h is can't help in fasting, is put to death by mice cervical dislocation, dissects and takes out complete liver, pre-cooling physiology salt
Water clean to washing liquid without color after, blot liver surface moisture.Clip 0.1g liver organization is placed in small beaker (in frozen water),
Prepare 9 times (0.9mL) in the normal saline of the 0.9% of liver organization weight, the normal saline of transfer total amount 2/3 in beaker,
Shred piece of tissue as early as possible, pour glass homogenizer into, more remaining 1/3 normal saline flushing is remained in the broken piece of tissue in beaker,
Pour homogenate tube together into be homogenized, after being fully ground, make the tissue homogenate of 10%, be centrifuged with 2000r/min in centrifuge
15min, takes supernatant standby.
1.5 Testing index
Mouse Weight: weigh weekly a Mouse Weight, until experiment terminates, to investigate given the test agent to each group of Mouse Weight
Impact.Hepatic tissue index determining: GSH, MDA and TG content in each group hepatic tissue, ADH determination of activity is according to each reagent
Box description operating procedure is carried out.
1.3 data statistics
Data all represent with (meansigma methods ± standard deviation), and group difference uses SPSS16.0 to carry out single factor analysis (ANOVA),
Determine that difference is the most statistically significant with P < 0.05 or P < 0.01.
2, experimental result
2.1 on glutathion, the impact of mda content
The total content of liver glutathion (GSH) is the important indicator evaluating medicine facilitating alcohol metabolism and protecting liver function.As shown in Table 1,
Comparing with blank group, model group mice is after Chinese liquor gavage, and liver gsh content pole significantly reduces (P < 0.01), and this mould is described
Type modeling success.Positive controls and bendazac lysine and GSH content and mould in compound (I) compositions group mouse liver even slurry
Type group compares significantly rising (P < 0.01), and in bendazac lysine group, compound (I) group mouse liver even slurry, GSH content is also
Significantly raised (P < 0.05).Compositions is able to maintain that liver gsh content, the liver GSH that Anti-ethanol damage causes are exhausted,
Improve body and remove the ability of free radical, thus mouse liver is played a protective role.Owing to GSH can stop to a certain extent
Lipid peroxidation in hepatic tissue, and malonaldehyde (MDA) is one of product of lipid peroxidation, therefore GSH is dense
The reduction of degree can cause the increase of liver MDA content indirectly.As shown in Table 1, compare with blank group, model group mouse stomach
After, liver MDA content significantly raises (P < 0.01), and this model modeling success is described.Positive controls and benzyl Dalai's ammonia
Acid is remarkably decreased P (< 0.01), benzyl compared with model group with MDA content in compound (I) compositions group mouse liver even slurry
Dalai's propylhomoserin group, compound (I) group also shows MDA content and is decreased obviously, significance level (P < 0.05).
Table 1 given the test agent is on the impact of GSH, MDA content in murine liver tissue
Group | GSH(mmol/L) | MDA(nmol/mg prot) |
Blank group | 27 | 5.2 |
Model group | 17 | 11.7 |
Positive controls | 26 | 6.2 |
Bendazac lysine group | 23 | 8.7 |
Compound (I) group | 23 | 8.9 |
Bendazac lysine and compound (I) compositions group | 29 | 5.4 |
2.2 impacts on content of triglyceride
When body takes in a large amount of ethanol, ethanol aoxidizes under the effect of ethanol dehydrogenase in a large number so that tricarboxylic acid cycle and fat
Metabolism is obstructed so that triglyceride (TG) is constantly piled up in liver, not only can induce the most serious cardiovascular disease, also
Fatty liver can be caused.As shown in Table 2, comparing with blank group, model group mouse liver tissue T G content significantly raises
(P < 0.01), illustrates this model modeling success.Compare with model group, bendazac lysine and compound (I) compositions group and
In positive controls mouse liver even slurry, TG content pole significantly reduces (P < 0.01).In this experiment, each medicine group all shows fall
Low drunk mouse liver TG content, and compositions group all reaches pole significant level (P < 0.01), illustrates that this compositions can drop
Low drunk mouse liver tissue T G content, alleviates liver fat and piles up, play liver-protective effect.
Table 2 given the test agent is on the impact of TG content in murine liver tissue
Group | TG(mmol/L) |
Blank group | 0.6±0.02 |
Model group | 1.4±0.14 |
Positive controls | 0.7±0.01 |
Bendazac lysine group | 0.9±0.03 |
Compound (I) group | 0.9±0.02 |
Bendazac lysine and compound (I) compositions group | 0.7±0.02 |
Above-mentioned test shows, bendazac lysine, compound (I) can improve GSH content in murine liver tissue, reduces MDA
Content, the accumulation of suppression TG, there is certain hepatoprotective effect;When bendazac lysine and compound (I) are used in combination, control
Therapeutic effect is more preferable, can be developed into hepatic.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a bendazac lysine, it is characterised in that: include bendazac lysine, as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of bendazac lysine the most according to claim 2, it is characterised in that: pharmaceutically acceptable carries
Body includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, suction
Appendix body or lubricant.
The pharmaceutical composition of bendazac lysine the most according to claim 2, it is characterised in that: described dosage form include tablet,
Capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution
Agent, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry tuber of Rhizoma Corydalis is pulverized, with 80~90% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses successively
Petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and positive fourth
Alcohol extract;B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 30% ethanol elution,
Again with 12 column volumes of 85% ethanol elution, collecting 85% eluent, concentrating under reduced pressure obtains 85% ethanol elution concentrate;(c)
In step (b), 85% ethanol elution concentrate purification on normal-phase silica gel separates, and is 100:1,50:1,25:1 and 12:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components;D in () step (c), component 4 separates further by purification on normal-phase silica gel,
3 components are obtained successively with the methylene chloride-methanol gradient elution that volume ratio is 20:1,12:1 and 2:1;(e) step (d)
The reverse phase silica gel that middle component 2 is bonded by octadecylsilane separates, and washes with the methanol aqueous solution that concentration expressed in percentage by volume is 88% is isocratic
De-, collect 13~16 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) 85% second
Alcohol circumfluence distillation, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is D101
Type macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in preparing liver-protective medicine of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described bendazac lysine of claim 2~4 application in preparing liver-protective medicine.
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CN105801540A (en) * | 2016-04-23 | 2016-07-27 | 黄亦琼 | Carteolol hydrochloride medicine composition and medicine purpose thereof |
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CN109481434A (en) * | 2018-12-18 | 2019-03-19 | 湖北远大天天明制药有限公司 | Eye drops, and the preparation method and application thereof |
CN109481434B (en) * | 2018-12-18 | 2020-11-10 | 湖北远大天天明制药有限公司 | Eye drops, preparation method and application thereof |
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Application publication date: 20160824 |