CN105663138A - Clonazepam medicinal composition and medicinal application thereof - Google Patents
Clonazepam medicinal composition and medicinal application thereof Download PDFInfo
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- CN105663138A CN105663138A CN201610259547.2A CN201610259547A CN105663138A CN 105663138 A CN105663138 A CN 105663138A CN 201610259547 A CN201610259547 A CN 201610259547A CN 105663138 A CN105663138 A CN 105663138A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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Abstract
The invention discloses a clonazepam medicinal composition and medicinal application thereof. The clonazepam medicinal composition provided by the invention contains clonazepam and a natural product compound (I) with a novel structure; the composition of the clonazepam and the compound (I) has an obvious anti-inflammatory cough relieving effect which is superior to an independent anti-inflammatory cough relieving effect of the clonazepam or the compound (I), can be developed into an anti-inflammatory cough relieving medicament, and has prominent substantive features and remarkable progress as compared with the prior art.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of clonazepam, be specifically related to the pharmaceutical composition of clonazepam and the application in antiinflammatory cough-relieving thereof.
Background technology
The similar diazepam of clonazepam effect and nitrazepam. But anticonvulsant action is stronger 5 times than the former two, and effect is rapidly. Similar with the central inhibitory action of other BDZ class medicines, due to the Chlorion influx of accelerator nerve cell, make cell hyperpolarization, make neural cell excitability reduce. Glutamate decarboxylase is also had certain effect by it simultaneously, thus has wide spectrum antiepileptic action. This product still has anxiety, hypnosis and central myorelaxant effects.
Up to now, there is not yet the dependency of clonazepam and pharmaceutical composition thereof and antiinflammatory cough-relieving report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of clonazepam, containing clonazepam and a kind of natural product in this pharmaceutical composition, clonazepam and this natural product can work in coordination with antiinflammatory cough-relieving.
The above-mentioned purpose of the present invention is achieved by the techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of clonazepam, including clonazepam, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepares into the dosage form of needs.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form includes tablet, capsule, oral liquid, sucks 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), comprise following operating procedure: Herba Centellae is pulverized by (a), extract with 70～80% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract; B n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate; In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 80:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components; D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1,15:1 and 2:1 methylene chloride-methanol gradient elution obtain 3 components; E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains pure compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 75% 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) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
The above-claimed cpd (I) application in the medicine preparing antiinflammatory cough-relieving.
The application in the medicine preparing antiinflammatory cough-relieving of the pharmaceutical composition of above-mentioned clonazepam.
Advantages of the present invention:
The pharmaceutical composition of clonazepam provided by the invention contains the natural product of clonazepam and a kind of novel structure, when clonazepam and this natural product independent role, there is antiinflammatory antitussive action; During the two synergy, antiinflammatory cough suppressing effect is better, it is possible to develop into the medicine of antiinflammatory cough-relieving. The present invention compared with prior art has prominent substantive distinguishing features and significant progressive.
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. Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, 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 chemical reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Herba Centellae (2kg) is pulverized by (a), (20L × 3 time) are extracted with 75% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (4L), extract with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol (4L × 3 time) successively, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract; B n-butyl alcohol extract D101 type macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate; C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 80:1 (8 column volumes), 30:1 (8 column volumes), 15:1 (8 column volumes) and 5:1 (10 column volumes) successively; D in () step (c), component 3 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 25:1 (8 column volumes), 15:1 (10 column volumes) and 2:1 (5 column volumes) successively; E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+Na]+For m/z397.1988, can obtain molecular formula in conjunction with nuclear-magnetism feature is C22H30O5, degree of unsaturation is 8. Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1a (1.27, m), H-1b (1.43, m), and H-2a (1.82, m), H-2b (1.99, m), and H-3 (4.88, s), H-6a (2.56, d, J=12.2Hz), H-6b (2.71, d, J=12.2Hz), H-9 (2.26, m, 2H), and H-12 (1.83, s), H-13 (2.03, s), H-14 (0.95, s), and H-15 (1.12, s), H-4 ' (1.26, s), H-5 ' (1.32, s), and 3 '-AcO (1.95, s); Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 32.4 (CH2, 1-C), 27.6 (CH2, 2-C), 77.3 (CH, 3-C), 137.8 (C, 4-C), 137.3 (C, 5-C), 22.3 (CH2, 6-C), 130.2 (C, 7-C), 201.1 (C, 8-C), 58.5 (CH2, 9-C), 36.7 (C, 10-C), 136.3 (C, 11-C), 22.3 (CH3, 12-C), 23.1 (CH3, 13-C), 18.4 (CH3, 14-C), 15.3 (CH3, 15-C), 167.3 (C, 1 '-C), 104.6 (C, 2 '-C), 155.8 (C, 3 '-C), 16.8 (CH3, 4 '-C), 10.7 (CH3, 5 '-C), 169.6 (C, 3 '-AcO), 21.3 (CH3, 3 '-AcO). 1715cm in infrared spectrum-1With 1680cm-1Absorption band shows there is carbonyl and double bond fragment in structure.13C-NMR, DEPT and hsqc spectrum show 22 carbon signals, including seven methyl, four methylene, company's oxygen methine, and ten quaternary carbons (three carbonyl carbon and six alkene carbon). In conjunction with insatiable hunger sum, function above structure shows that this compound is twin nuclei.1H-NMR spectrum shows six methyl proton signal δ in conjunction with hsqc spectrumH1.83 (3H, s), 2.03 (3H, s), 0.95 (3H, s), H-15 (1.12, s), 1.26 (3H, s), 1.32 (3H, s), an acetylmethyl proton signal δH1.95 (3H, s), a company oxygen methine proton signal δH4.88 (1H, s); Above NMR data can confirm that this compound is fetid marsh fleabane ketone derivatives. H in HMBC spectrum3-12 and C-11, H3-13 and C-11, H3-14 and C-10, H3-15 can be attributed to the methyl fragment on fetid marsh fleabane ketone with the coherent signal of C-4, and C-3 position proton signal is shifted to low field and illustrated that C-3 hydroxyl is esterified, and in being composed by HMBC, the coherent signal of H-3 and C-1 ' is further confirmed that. H in being composed by HMBC3-4 ' and C-3 ', H3-5 ' and C-2 ' and C-1 ', and the coherent signal of acetyl methyl proton signals and C-3 ' can confirm that existence 3 '-acetyl group-2 in structure '-methyl-2 '-crotonyl oxygen base side chain structure, and proton signal δH1.26 (3H, s) and 1.32 (3H s) can be attributed to the methyl signals of H-4 ' and the methyl signals of H-5 '. H in NOESY spectrumβ-1/H3-14, HβThe coherent signal of-1/H-3 shows H-3 and H3-14 is beta comfiguration. Additionally, the relative configuration of this compound is confirmed by X-single crystal diffraction further, the absolute configuration of C-3 position be can confirm that as R configuration by acidolysis reaction and Mosher method. Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value. This compound chemistry formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 medicines and reagent
Clonazepam is purchased from Nat'l Pharmaceutical & Biological Products Control Institute. Compound (I) is made by oneself, and preparation method is shown in embodiment 1. Glacial acetic acid, Nanning chemical reagent factory produces; Dimethylbenzene, Solution on Chemical Reagents in Shanghai company of Chinese Medicine group produces; Evans blue, Solution on Chemical Reagents in Shanghai purchasing and supply station subpackage factory produces. Aspirin tablet (100mg/ sheet), Baeyer drugmaker produces; GUILONG KECHUANNING JIAONANG, Guilong Medicine Co., Ltd., Shanxi produces; Exocarpium Citri Rubrum electuary, Nanchang Kang Zhengde pharmaceutical Co. Ltd produces.
1.2 laboratory animals
Kun Ming mice 90, weight (20 ± 2) g, male and female half and half; Wistar rat 60, weight (200 ± 20) g, male and female half and half, provide by Hubei Province's Experimental Animal Center.
1.3 equipment
1.80-2 type centrifuge, Shanghai Surgical Operation Equipment Factory produces; 721 type spectrophotometers, Shanghai the 3rd analytical tool factory produces; AEU-210 type electronic balance, Japan's Shimadzu produces.
1.4 antiinflammatory experiments
1.4.1 xylol causes the impact of mice auricle swelling degree
Take mice 50, it is randomly divided into 5 groups, often group 10, it is respectively as follows: normal saline group, aspirin group (300mg/kg), clonazepam group (80mg/kg), compound (I) group (80mg/kg), clonazepam and compound (I) compositions group [40mg/kg clonazepam+40mg/kg compound (I)] respectively group is by corresponding dosage administration, and normal saline group gavages normal saline. The equal gastric infusion of each group, every day 1 time, continuous 5d. After last administration 1h, each group mouse right ear is only coated with dimethylbenzene 0.05ml/, and left ear is not coated with does self-blank comparison. After smearing dimethylbenzene 30min, mice dislocation of cervical vertebra is put to death, lays the disk of left and right ears same area with the card punch of internal diameter 6mm, claim quality respectively, of poor quality for swelling with auris dextra quality and left ear, the swelling of relatively more each group.
1.4.2 Dichlorodiphenyl Acetate causes the effect that mouse peritoneal capillary permeability increases
Take mice 50, be grouped and be administered same 1.4.1. Each group gives medicine every day 1 time, continuous 3d. After last administration 1h, after the normal saline 0.1ml/10g of mouse tail vein injection 0.5% Evans blue, only 0.6% acetic acid 0.2ml/ is injected immediately in mouse peritoneal, after 20min, broken end sacrificed by exsanguination mice, with 5ml normal saline flushing abdominal cavity 3 times, collects cleaning mixture, centrifugal (1000rpm) 5min, measures trap (OD value) at 721 type spectrophotometer 590nm places.
1.5 cough-relieving experiments
1.5.1 SO2 is caused the impact coughing mice
Take mice 50, it is randomly divided into 5 groups, often group 10, i.e. normal saline group, clonazepam group (80mg/kg), compound (I) group (80mg/kg), clonazepam and compound (I) compositions group [40mg/kg clonazepam+40mg/kg compound (I)], GUILONG KECHUANNING group (5g/kg). Each group is by corresponding dosage administration, and normal saline group gavages normal saline, every day 1 time, altogether 7d. 1h after last administration, puts into mice in the wide mouthed bottle of 500ml, passes into SO26ml draws and coughs, and occurs significantly dehiscing to pant for cough index with mice, observes and records mice and put into the incubation period occurred to cough in bottle and 3min cough number of times.
1.5.2 the impact on rat expectoration amount
Take Wistar rat 50, it is randomly divided into 5 groups, often group 10, i.e. normal saline group, clonazepam group (80mg/kg), compound (I) group (80mg/kg), clonazepam and compound (I) compositions group [40mg/kg clonazepam+40mg/kg compound (I)], Exocarpium Citri Rubrum electuary group (5g/kg). Each group is by corresponding dosage administration, and normal saline group gavages normal saline, every day 1 time, altogether 7d. Before experiment, water 12h is can't help in fasting, after last administration 30min, anaesthetize with pentobarbital sodium 30mg/kg, dorsal position is fixed, and cuts off neck center skin, separates trachea, hit exactly among two cartilaginous rings at thyroid cartilage lower edge, prick an aperture with injection needle, be inserted into one, the capillary tube of the known quality (G1) of diameter 0.5ml, long 10cm. Capillary glass-tube is made just to contact surface, trachea portion, to draw the sputum in trachea, if a glass-tube is filled, change a glass-tube at once, collect the expectoration amount of rat 60min, then collect the weight (G2) of the glass-tube having sputum with electronic scale weighing, G2-G1 is the expectoration amount of rat 60min, calculates the drain mg number of 60min/100g as index of eliminating the phlegm.
1.6 statistical methods
Application SPSS11.5 software kit carries out data process. Measurement data represents with x ± s, compares employing t inspection between group. P < 0.05 is that difference is statistically significant.
2, experimental result
2.1 xylol cause mice auricle swelling and Dichlorodiphenyl Acetate causes the impact of the effect that mouse peritoneal capillary permeability increases
Compare with normal saline group, swelling and the OD value of clonazepam and compound (I) compositions group and aspirin group all substantially reduce, difference statistically significant (P < 0.01), clonazepam group, compound (I) group also can significantly reduce swelling and OD value (P < 0.05), illustrate that clonazepam is more apparent with the antiinflammation of compound (I) compositions, and OD value can be significantly reduced, more apparent suppression acetic acid causes mouse peritoneal capillary permeability to be increased. In Table 1.
Table 1 anti-inflammation test result (x ± s, n=10)
| Group | Swelling | Trap (OD value) |
| Normal saline group | 1.95±0.35 | 0.566±0.112 |
| Positive controls | 1.45±0.23 | 0.411±0.079 |
| Clonazepam group | 1.65±0.31 | 0.432±0.045 |
| Compound (I) group | 1.58±0.42 | 0.438±0.072 |
| Clonazepam and compound (I) compositions group | 1.35±0.36 | 0.414±0.068 |
2.3 couples of mice SO2Cause the antitussive action coughed
Comparing with normal saline group, clonazepam all can reduce mice SO with compound (I) compositions group and GUILONG KECHUANNING group2Causing the cough number of times coughed, extend cough latent period, difference statistically significant (P < 0.01), clonazepam group, compound (I) group also can reduce cough number of times, extends cough latent period (P < 0.05). In Table 2.
Table 2 is to mice SO2Cause the antitussive action (x ± s, n=10) coughed
| Group | Cough number of times (secondary) | Incubation period (s) |
| Normal saline group | 59.7±6.3 | 41.97±7.76 |
| Positive controls | 38.8±5.9 | 69.66±8.67 |
| Clonazepam group | 46.3±4.5 | 51.57±7.25 |
| Compound (I) group | 44.2±7.5 | 52.92±7.13 |
| Clonazepam and compound (I) compositions group | 32.2±2.4 | 70.34±8.42 |
2.4 impacts on rat expectoration amount
Clonazepam group, compound (I) group and the mg number of Exocarpium Citri Rubrum electuary group 60min/100g drain are 3.21 ± 0.57,3.25 ± 0.37 and 3.28 ± 0.42 be above normal saline group (2.24 ± 0.43), difference statistically significant (P < 0.05), clonazepam and compound (I) compositions group are 3.54 ± 0.68, are significantly higher than normal saline group (P < 0.01).
In sum, clonazepam provided by the invention and compound (I) compositions have an obvious antiinflammatory antitussive action, and are better than clonazepam or the independent antiinflammatory antitussive action of compound (I).
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, it is possible to technical scheme is modified or equivalent replacement, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a clonazepam, it is characterised in that: include clonazepam, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of clonazepam according to claim 2, it is characterised in that: pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
4. the pharmaceutical composition of clonazepam according to claim 2, it is characterised in that: described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: Herba Centellae is pulverized by (a), extract with 70～80% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract; B n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate; In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 80:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components; D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1,15:1 and 2:1 methylene chloride-methanol gradient elution obtain 3 components; E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains pure compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 75% alcohol heat reflux, united extraction liquid.
7. the preparation method of compound according to claim 5 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
8. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
9. the application in the medicine preparing antiinflammatory cough-relieving of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described clonazepam of claim 2～4 application in the medicine preparing antiinflammatory cough-relieving.
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| CN105837449A (en) * | 2016-04-18 | 2016-08-10 | 镇江高海生物药业有限公司 | Pharmaceutical composition for L-tert-leucine and application thereof in biological medicine |
| CN105884741A (en) * | 2016-04-23 | 2016-08-24 | 徐挺 | Drug composition of bisoprolol fumarate and pharmaceutical application thereof |
| CN106146601A (en) * | 2016-06-23 | 2016-11-23 | 崔坤峰 | The pharmaceutical composition of azithromycin and the medical usage of cough-relieving thereof |
| CN110420190A (en) * | 2019-08-29 | 2019-11-08 | 湖南洞庭药业股份有限公司 | Clonazepam tablet and preparation method thereof |
| CN112898203A (en) * | 2021-03-23 | 2021-06-04 | 济南同路医药科技发展有限公司 | Preparation method for continuous flow synthesis of clonazepam |
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2016
- 2016-04-23 CN CN201610259547.2A patent/CN105663138A/en not_active Withdrawn
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837449A (en) * | 2016-04-18 | 2016-08-10 | 镇江高海生物药业有限公司 | Pharmaceutical composition for L-tert-leucine and application thereof in biological medicine |
| CN105884741A (en) * | 2016-04-23 | 2016-08-24 | 徐挺 | Drug composition of bisoprolol fumarate and pharmaceutical application thereof |
| CN106146601A (en) * | 2016-06-23 | 2016-11-23 | 崔坤峰 | The pharmaceutical composition of azithromycin and the medical usage of cough-relieving thereof |
| WO2017220050A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Azithromycin pharmaceutical composition and medical use thereof for cough relief |
| CN110420190A (en) * | 2019-08-29 | 2019-11-08 | 湖南洞庭药业股份有限公司 | Clonazepam tablet and preparation method thereof |
| CN110420190B (en) * | 2019-08-29 | 2021-07-09 | 湖南洞庭药业股份有限公司 | Clonazepam tablets and preparation method thereof |
| CN112898203A (en) * | 2021-03-23 | 2021-06-04 | 济南同路医药科技发展有限公司 | Preparation method for continuous flow synthesis of clonazepam |
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Application publication date: 20160615 |