CN105801590A - Alprazolam pharmaceutical composition and anti-inflammatory and analgesic effects thereof - Google Patents
Alprazolam pharmaceutical composition and anti-inflammatory and analgesic effects thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- 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
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
The invention discloses an alprazolam pharmaceutical composition and anti-inflammatory and analgesic effects thereof. The alprazolam pharmaceutical composition contains alprazolam and a natural product compound (I) which is separated and obtained from dry rhizomes of cyathula officinalis kuan and is novel in structure; when alprazolam and the natural product act separately, the anti-inflammatory and analgesic effects are common; when alprazolam and the natural product act jointly, the anti-inflammatory and analgesic effects are significantly improved, and alprazolam and the natural product can be developed into a drug capable of achieving the anti-inflammatory and analgesic effects. Compared with the prior art, the alprazolam pharmaceutical composition has the prominent substantive advantage and significant progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of alprazolam, be specifically related to pharmaceutical composition and the anti-inflammatory and analgesic effect thereof of a kind of alprazolam.
Background technology
Alprazolam is new BDZ class medicine, has the pharmacological action that same diazepam is similar, has anxiety, antidepressant, calmness, hypnosis, convulsion and the effect such as of flaccid muscles.Its angst resistance effect is stronger 10 times than diazepam, and mechanism of action is likely to relevant with receptor,β in brain.Rapidly and completely, within 1～2 hour, namely up to blood peak concentration of drug, plasma half-life is 12～18 hours to this product oral absorption, and within 2～3 days, blood drug level reaches stable state.Plasma protein binding rate is about 80%.It is distributed in whole body permeable placental barrier after absorption, milk also has medicine.Through liver CYP3A enzyme system, metabolism is active substance α-hydroxyl ALprazolanic, but concentration is too low without clinical meaning.Finally excreting from kidney, body accumulation amount is few, removes fast after drug withdrawal.
At present, there is not yet the relevant report of alprazolam and pharmaceutical composition thereof and anti-inflammatory and antalgic.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of alprazolam, this pharmaceutical composition can work in coordination with anti-inflammatory and antalgic containing alprazolam and a kind of natural product separating the novel structure obtained from Radix Cyathulae, alprazolam and this natural product.
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 alprazolam, including alprazolam, compound as above (I) and pharmaceutically acceptable carrier.
The preparation method of compound as above (I), comprise following operating procedure: the dry rhizome of Radix Cyathulae is pulverized by (a), extract with 75% 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 10 column volumes of 8% ethanol elution, then with 12 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 40:1,20:1,10:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 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 75%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, described macroporous resin is AB-8 type macroporous adsorbent resin.
The compound as above (I) application in the medicine preparing anti-inflammatory and antalgic.
The application in the medicine preparing anti-inflammatory and antalgic of the pharmaceutical composition of alprazolam as above.
Advantages of the present invention:
Containing alprazolam and a kind of natural product separating the novel structure obtained from Radix Cyathulae in the pharmaceutical composition of alprazolam provided by the invention, when alprazolam and this natural product independent role, anti-inflammatory pain-stopping effect is general；During the two synergy, anti-inflammatory pain-stopping effect significantly improves, it is possible to develop into the medicine of anti-inflammatory and antalgic.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: the dry rhizome (5kg) of Radix Cyathulae 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 AB-8 type macroporous resin remove impurity in () step (a), first with 10 column volumes of 8% ethanol elution, then with 12 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 40:1 (8 column volumes), 20:1 (8 column volumes), 10:1 (8 column volumes) and 5:1 (10 column volumes) successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 8:1 (8 column volumes), 5:1 (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 75%, collect 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (288mg, HPLC normalization purity is more than 98%).
Structural identification: colorless oil, HR-ESI-MS shows [M+H]+For m/z435.2245, can obtain molecular formula in conjunction with nuclear-magnetism feature is C26H30N2O4, degree of unsaturation is 13.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3null，500MHz): H-3 (3.98，t，J=3.2Hz)，H-5(3.48，d，J=7.3Hz)，H-6a(3.32，dd，J=16.3，7.3Hz)，H-6b(2.61，br，d，J=16.3Hz)，H-9(7.49，d，J=8.2Hz)，H-10(7.11，td，J=8.2，1.3Hz)，H-11(7.22，td，J=8.2，1.3Hz)，H-12(7.30，d，J=8.2Hz)，H-14a(2.74，d，J=13.0Hz)，H-14b(1.88，d，J=13.0Hz)，H-17a(4.33，d，J=12.1Hz)，H-17b(4.16，d，J=12.1Hz)，H-18(1.57，s)，H-20(2.89，dd，J=12.3，8.4Hz)，H-21(1.88，m)，H-21(2.41，m)，H-23(6.22，d，J=10.4Hz)，H-24(6.05，dd，J=10.4，3.2Hz)，H-25(4.92，m)，H-26(3.41，dd，J=12.1，3.2Hz)，H-26(3.81，dd，J=12.1，2.0Hz)，N1-Me (3.64, s), N4-Me (2.34, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 132.4 (C, 2-C), 53.5 (CH, 3-C), 61.4 (CH, 5-C), 23.7 (CH2, 6-C), 107.3 (C, 7-C), 126.8 (C, 8-C), (118.4 CH, 9-C), 119.2 (CH, 10-C), 121.2 (CH, 11-C), (109.5 CH, 12-C), 136.7 (C, 13-C), 33.3 (CH2, 14-C), 126.2 (C, 15-C), 130.0 (C, 16-C), 59.6 (CH2, 17-C), 24.3 (CH3, 18-C), 116.2 (C, 19-C), 40.1 (CH, 20-C), 32.2 (CH2, 21-C), 101.2 (C, 22-C), 139.2 (CH, 23-C), 132.7 (CH, 24-C), 89.4 (CH, 25-C), 64.5 (CH2, 26-C), 30.2 (CH3, N1-Me), 41.3 (CH3, N4-Me).At 3415cm in infrared spectrum-1Absworption peak is to be produced by the hydroxyl in this compound；And UV spectrogram shows there is uv absorption at 233nm and 284nm, show that this compound contains indole chromophoric group.13C-NMR, DEPT and hsqc spectrum show 26 carbon signals, including three methyl δC24.3,30.2,41.3；One methylol δC64.5；Four methylene (company's Oxymethylene) δC23.7,33.3,59.6,32.2；Ten methine (company's oxygen methine) δC53.5,61.4,118.4,119.2,121.2,109.5,40.1,139.2,132.7,89.4；And eight quaternary carbon (two two connect oxygen quaternary carbon) δC132.4,107.3,126.8,136.7,126.2,130.0,116.2,101.2；In conjunction with insatiable hunger sum, function above structure shows that this compound is seven ring structures.1H-NMR spectrum one group of proton signal δ without substituted indole fragment of displayH-97.49 (1H, d, J=8.2Hz), δH-107.11 (1H, td, J=8.2,1.3Hz), δH-117.22 (1H, td, J=8.2,1.3Hz) and δH-127.30 (1H, d, J=8.2Hz)；A pair methylol proton signal δH-263.41 (1H, dd, J=12.1,3.2Hz) and 3.81 (1H, dd, J=12.1,2.0Hz)；One methyl proton signal δH-181.57 (3H, s, Me)；Two N-CH3Proton signal δH3.64 (3H, s, N1-Me) and 2.34 (3H, s, N4-Me)；One group of company Oxymethylene proton signal δ shifting to low fieldH-17a4.33 (1H, d, J=12.1Hz) and δH-17b4.16 (1H, d, J=12.1Hz)；Three groups of methene proton signal δH-6a3.32 (1H, dd, J=16.3,7.3Hz) and δH-6b2.61 (1H, d, J=16.3Hz), δH-14a2.74 (1H, d, J=13.0Hz) and δH-14b1.88 (1H, d, J=13.0Hz) and δH-211.88 (1H, m) and δH-212.41 (1H, m)；One group of olefinic proton signals δH-236.22 (1H, dd, J=10.4Hz) and δH-246.05 (1H, d, J=10.4,3.2Hz)；One company oxygen methine proton signal δH-254.92 (1H, m).13C-NMR spectrum, DEPT spectrum show in this compound there is indole structure fragment δC-2132.4(C)、δC-7107.3(C)、δC-8126.8(C)、δC-9118.4(CH)、δC-10119.2(CH)、δC-11121.2(CH)、δC-12109.5 (CH) and δC-13136.7 (C), a methylol signal δC-2664.5(CH2OH), a methyl signals δC-1824.3(CH3), two N-methyl signals δC30.2(CH3, N1-Me) and 41.3 (CH3, N4-Me).COSY and HSQC spectral data discloses in this compound containing-NCHCH2-structure fragment (-N4-C5-C6-and-N4-C3-C14-).Analyze HMBC spectrum, H further2-14 with C-15 and C-20, H2-17 exist coherent signal with C-15 and C-19, H-20 and C-14 and C-19, in conjunction with13Even oxygen hexatomic ring fragment, H in addition is there is in C-NMR spectrum in associated carbon signal hint structure3With the coherent signal of C-19 ,-18 show that C-19 position is connected with a methyl.In COSY spectrum, there is also a complex set of1H-1H coherent signal, can analyze structure fragment-CHCH that may be present in this compound by this group signal2-and-CHCHCHCH2O-, in conjunction with HMBC analysis of spectrum, it is possible to infer that in the structure of this compound, E/F ring is double; two five yuan of spirane structures.Separately in HMBC composes, also there is H-5 and C-3, C-7 and C-17, H in display2-14 and C-13, N1The coherent signal of-Me and C-2 and C-13, can build the relevant hydrocarbon connected mode of this compound.In NOESY spectrum, H3-18 to determine the connected mode of E/F ring with the coherent signal of H-17a, H-20 be H3-18 connect into α configuration with H-20 cis.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 chemical structure formula and carbon atoms numbered are as follows:
Embodiment 2: anti-inflammatory and analgesic effect
1, materials and methods
1.1 medicines and reagent
Alprazolam is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Aspirin Enteric-coated Tablets (Yongning, Jinan Pharmacy stock Co., Ltd), Tween 80 (Tianjin Guang Cheng chemical reagent company limited)；Dimethylbenzene (Tianjin Chemical Co., Ltd. of Botong)；AZO-blue (Chemical Reagent Co., Ltd., Sinopharm Group).
1.2 animals
Kunming mouse, body weight 18～22g, male and female half and half, cleaning grade, Taishan Hospital's Experimental Animal Center provide.
1.3 analgesic experiments: mouse writhing method
Take mice 50, male and female half and half, body weight 18～22g, be randomly divided into alprazolam group (0.2g kg-1), compound (I) group (0.2g kg-1), alprazolam and compound (I) compositions group (0.1g kg-1+0.1g·kg-1), aspirin group (0.2g kg-1) and saline control group.Often group 10, gastric infusion.Administration volume 20mL kg-1.After normal saline group and aspirin group administration 30min, after administration group administration 60min, lumbar injection 0.6% glacial acetic acid 10mL kg-1, in observed and recorded 15min, there is writhing response Mus number and writhing number of times in mice, calculates writhing number of times average and suppresses writhing response rate.
Suppression ratio=(matched group writhing number-administration group writhing number)/matched group writhing number × 100%
1.4 analgesic experiments: mice tail-flick method is tested
Taking Kunming mouse 50, male and female half and half, body weight 18～22g, before experiment, water is can't help in 12h fasting.Mice is loaded in the fixing cylinder of mice, outside afterbody is exposed to, when surveying pain, makes mouse tail tip 1/3 place overlap with spotlight lamp hole, measurement after animal peace and quiet, whipping is occurred as pain reaction index using rat-tail by thermostimulation.Record mice is irradiated to the incubation period (TFLs) of whipping reaction as the threshold of pain from starting light.Packet and administration are with 1.3.After normal saline group and aspirin group administration 30min, after administration group administration 60min, measure its whipping time.Calculate threshold of pain average and threshold of pain increase rate.
Threshold of pain increase rate=(after administration the threshold of pain-Basic Pain Threshold)/Basic Pain Threshold × 100%
1.5 antiinflammatory experiments: xylol causes the impact of mice auricle swelling
Weigh 18～22g healthy mice 40 respectively, be divided into 5 groups, often group 8, male and female half and half.Every mice presses 20mL kg-1Gastric infusion, dosage is arranged with 1.3.Successive administration 7d.After 7th day administration 0.5h, each group mice is coated dimethylbenzene 50 μ L in auris dextra positive and negative and causes inflammation, is put to death by de-for mice cervical vertebra after 1h, two ears are cut along auricle baseline, lay round auricle at same position respectively with 8mm diameter card punch, weigh immediately and record its quality, calculating swelling and swelling rate.
Swelling=auris dextra quality-left ear quality；Swelling rate=[(auris dextra quality-left ear quality)/left ear quality] × 100%
1.6 antiinflammatory experiments: glacial acetic acid is caused the impact of mice blood vessel permeability changes
Packet administration is with 1.3.After 7th day administration 0.5h, the AZO-blue normal saline solution 10mL kg of tail vein injection 1%-1, lumbar injection 0.6% acetic acid normal saline solution 10mL kg immediately-1, after 30min, de-cervical vertebra puts to death mice, after gently rubbing mouse web portion 1min, opens abdominal cavity, collects peritoneal fluid, waits that collecting complete 4mL normal saline mark time rinses abdominal cavity, with syringe sucking-off cleaning mixture, adds normal saline to 5mL, with 1000r min after merging-1Centrifugal 5min, takes supernatant 721 type spectrophotometers and surveys absorbance (A) in 680nm place, calculate and ooze out suppression ratio.
Ooze out suppression ratio=(negative control group A-administration group A)/negative control group A × 100%
1.7 statistical method
Adopting SPSS19.0 software, data represent with x ± s, compare and check with t, and P < 0.05 is for there being statistical significance.
2, experimental result
2.1 analgesic activities
With matched group ratio, alprazolam all significantly reduces (P < 0.01) with compound (I) compositions group mouse writhing reaction times and writhing response Mus number, Dichlorodiphenyl Acetate causes the inhibition of mouse writhing reaction times and is better than positive drug aspirin, and when being better than alprazolam or compound (I) independent role, Dichlorodiphenyl Acetate causes the inhibition of mouse writhing reaction times.Result is in Table 1.
With matched group ratio, alprazolam and compound (I) compositions group mice optical heat radiation cause the threshold of pain of pain reaction and significantly improve (P < 0.01), threshold of pain increase rate is basically identical with positive drug aspirin, and mice optical heat radiation causes when being better than alprazolam or compound (I) independent role the threshold of pain increase rate of pain reaction.Result is in Table 2.
Glacial acetic acid is caused the impact (x ± s, n=10) of mouse writhing number of times by table 1
| Group | Dosage/g kg-1 | Writhing number/only | Writhing number of times suppression ratio/% |
| Matched group | - | 10 | 0 |
| Aspirin group | 0.2 | 5 | 64.4 |
| Alprazolam group | 0.2 | 8 | 43.6 |
| Compound (I) group | 0.2 | 8 | 47.4 |
| Alprazolam and compound (I) compositions group | 0.1+0.1 | 6 | 69.5 |
Thermostimulation is caused the impact (x ± s, n=10) that the mice threshold of pain changes by table 2
| Group | Dosage/g kg-1 | Threshold of pain increase rate/% |
| Matched group | - | 0 |
| Aspirin group | 0.2 | 64.4 |
| Alprazolam group | 0.2 | 25.8 |
| Compound (I) group | 0.2 | 27.9 |
| Alprazolam and compound (I) compositions group | 0.1+0.1 | 66.3 |
2.2 antiinflammatory actions
After caused by dimethylbenzene xylene inflammation, alprazolam group, compound (I) group mice auricle swelling rate reduces notable (P < 0.01) lower than the mice auricle swelling rate of matched group (P < 0.05), alprazolam and compound (I) compositions group.Result is in Table 3.After glacial acetic acid causes inflammation, alprazolam group, compound (I) group mouse peritoneal liquid AZO-blue A significantly reduces (P < 0.01) lower than the mouse peritoneal liquid A of negative control group (P < 0.05), alprazolam and compound (I) compositions group.Result is in Table 4.
Table 3 xylol causes the impact (x ± s, n=8) of mice auricle swelling
| Group | Dosage/g kg-1 | Swelling rate/% |
| Matched group | - | 135.12±10.66 |
| Aspirin group | 0.2 | 22.15±5.17 |
| Alprazolam group | 0.2 | 40.21±10.02 |
| Compound (I) group | 0.2 | 39.08±6.96 |
| Alprazolam and compound (I) compositions group | 0.1+0.1 | 24.53±9.54 |
Glacial acetic acid is caused the impact (x ± s, n=8) of mice blood vessel permeability changes by table 4
| Group | Dosage/g kg-1 | Ooze out suppression ratio/% |
| Matched group | - | - |
| Aspirin group | 0.2 | 75.26 |
| Alprazolam group | 0.2 | 35.53 |
| Compound (I) group | 0.2 | 39.16 |
| Alprazolam and compound (I) compositions group | 0.1+0.1 | 55.27 |
Result above shows, alprazolam and compound (I) compositions have significant anti-inflammatory and analgesic effect, and it is better than alprazolam or the independent anti-inflammatory and analgesic effect of compound (I), illustrate, between alprazolam and compound (I), there is synergism, performance anti-inflammatory and analgesic effect can be worked in coordination with, it is possible to develop into anti-inflammation analgesia medicine.
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 (6)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of an alprazolam, it is characterised in that: include alprazolam, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: the dry rhizome of Radix Cyathulae is pulverized by (a), extract with 75% 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 10 column volumes of 8% ethanol elution, then with 12 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 40:1,20:1,10:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 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 75%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
4. the preparation method of compound according to claim 3 (I), it is characterised in that: described macroporous resin is AB-8 type macroporous adsorbent resin.
5. the application in the medicine preparing anti-inflammatory and antalgic of the compound (I) described in claim 1.
6. the pharmaceutical composition of the alprazolam described in claim 2 application in the medicine preparing anti-inflammatory and antalgic.
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Cited By (2)
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|---|---|---|---|---|
| CN105837589A (en) * | 2016-03-24 | 2016-08-10 | 薛君 | Bumetanide medicine composition and anti-inflammatory and abirritation effects thereof |
| CN106083771A (en) * | 2016-06-13 | 2016-11-09 | 崔坤峰 | The pharmaceutical composition of carbidopa and the medical usage for the treatment of liver cancer thereof |
-
2016
- 2016-03-22 CN CN201610164442.9A patent/CN105801590A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837589A (en) * | 2016-03-24 | 2016-08-10 | 薛君 | Bumetanide medicine composition and anti-inflammatory and abirritation effects thereof |
| CN106083771A (en) * | 2016-06-13 | 2016-11-09 | 崔坤峰 | The pharmaceutical composition of carbidopa and the medical usage for the treatment of liver cancer thereof |
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Application publication date: 20160727 |