CN105837422A - Pharmaceutical composition of buprenorphine hydrochloride and application thereof in biomedicine - Google Patents
Pharmaceutical composition of buprenorphine hydrochloride and application thereof in biomedicine Download PDFInfo
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- CN105837422A CN105837422A CN201610249948.XA CN201610249948A CN105837422A CN 105837422 A CN105837422 A CN 105837422A CN 201610249948 A CN201610249948 A CN 201610249948A CN 105837422 A CN105837422 A CN 105837422A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
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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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/535—Perilla (beefsteak plant)
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Abstract
The invention discloses a pharmaceutical composition of buprenorphine hydrochloride and application thereof in biomedicine. The pharmaceutical composition of buprenorphine hydrochloride contains buprenorphine hydrochloride and a novel-structure natural product compound (I) separated from dried perilla leaves. The buprenorphine hydrochloride and the natural product have certain treatment effects on leukaemia when being independently used. The combination of the buprenorphine hydrochloride and the natural product has more obvious treatment effects on leukaemia, so that the pharmaceutical composition can be developed into drugs for treating leukaemia. Compared with the prior art, the pharmaceutical composition disclosed by the invention has outstanding substantial characteristics and marked progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of buprenorphin hydrochloride, be specifically related to a kind of buprenorphin hydrochloride
Pharmaceutical composition and the application in biological medicine thereof.
Background technology
Buprenorphin hydrochloride is mixed type opium agonistic-antagonistic, is to be widely used in analgesia clinic and one America and Europe the eighties
A little countries try out maintenance and replacement therapy medicine in Opioid Dependence patient it is considered to be up-and-coming new type analgesic and ring
Poison.Buprenorphin hydrochloride is in China's listing at the beginning of the nineties.It is applied to moderate clinically to the analgesia therapy of severe pain and opium
The detoxification treatment of dependent patient has preferable curative effect, is just paid close attention to by people.It is clinically used for all kinds of postoperative pain, chronic
Acroesthesia that cancer pain, burnt degree pain, vasculitis cause and angina pectoris and other Encelialgia.
Leukemia is a class hematopoietic stem cell malignant clone disease.Clonal leukaemia because proliferation out of control, dysdifferentiation,
The mechanism such as apoptosis is obstructed breed accumulation in bone marrow and other hemopoietic tissue in a large number, and infiltrate its hetero-organization and organ, the most normal
Hemopoietic is suppressed.Anemia, hemorrhage, infectious fever and liver in various degree, spleen, lymphadenectasis and skeleton pain seen from clinic
Bitterly.It is reported, the leukemic sickness rate in China each department accounts for the 6th in various tumors.Wherein, chronic myelocytic leukemia
Being a kind of malignant tumor affecting blood and bone marrow, its feature is to produce a large amount of jejune leukocyte, and these leukocyte are at bone
Assemble in marrow, the normal hematopoiesis of suppression bone marrow;And can be spread at whole body by blood, cause patient that anemia, easily occurs
Hemorrhage, infect and organ infiltration etc..
Treatment for chronic myelocytic leukemia depend on disease by stages, age and health status etc..One, chronic phase.The mesh for the treatment of
Be to control progression of disease and maintain hemocyte in normal range, it is possible to use hydroxyl urine, interferon or imatinib mesylate etc..Some year
Hypopathia people can consider that stem cell transplantation is to obtain the chance cured.Therapeutic scheme: (1) tyrosine kinase inhibitor (most preferably pushes away
Recommend);(2) imatinib 400mg is administered orally 1/;(3) nilotinib 300mg is administered orally 2/;(4) Dasatinib 100mg
Oral 1/ day;(5) relevant or Allogeneic Hematopoietic Stem Cell Transplantation (the HSCT) (tyrosine-kinase of unrelated donor that distribution type is harmonious
Consider when enzyme inhibitor cannot tolerate).Two, accelerated period and acute transformation phase.Progression of disease is accelerated, and needs stronger scheme,
The purpose for the treatment of is to remove leukaemia, recovers hemopoietic function of bone marrow or returns to chronic phase.Therapeutic scheme: (1) tyrosine-kinase
Enzyme inhibitor: nilotinib or Dasatinib;(2) allogeneic hematopoietic stem cell of the relevant or unrelated donor that distribution type is harmonious moves
Plant (HSCT) (considering when tyrosine kinase inhibitor cannot tolerate);(3) Clinical Trials can be used.Some patients
During diagnosis, there is substantial amounts of leukocyte in peripheral blood, causes blood circulation resistance to increase and blood vessel blockage, causes bleeding or anticoagulant
Deng, need to reduce leukaemia's quantity by leukapheresis or chemotherapy.Simultaneously need to a large amount of fluid infusion, by necrocytosis
The toxicant discharged is got rid of external.
Up to now, there is not yet buprenorphin hydrochloride and pharmaceutical composition thereof to report with leukemic dependency.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of buprenorphin hydrochloride, containing hydrochloric acid fourth third in this pharmaceutical composition
Promise coffee and a kind of natural product of the novel structure of isolated from Folium Perillae, buprenorphin hydrochloride and this natural product can be assisted
Treat leukemic effect with playing, develop into the leukemic medicine for the treatment of.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of buprenorphin hydrochloride, including buprenorphin hydrochloride, compound as above (I) and pharmacy
Upper acceptable carrier.
The preparation method of compound (I) as above, comprises following operating procedure: the dried leaves of Folium Perillae is pulverized by (a),
With 70~80% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturation successively
N-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract;(b) step (a)
Middle n-butyl alcohol extract macroporous resin remove impurity, first with 6 column volumes of 15% ethanol elution, then with 70% ethanol elution 10
Column volume, collects 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate;C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, and washes by the methylene chloride-methanol gradient that volume ratio is 80:1,30:1,15:1 and 5:1 successively
Take off and 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,
The methylene chloride-methanol gradient elution of 15:1 and 2:1 obtains 3 components;Component 2 octadecyl silicon in (e) step (d)
The reverse phase silica gel of alkane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects 8~14 column volumes
Eluent, eluent is concentrated under reduced pressure to give pure compound (I).
Further, step (a) is extracted with 75% alcohol heat reflux, united extraction liquid.
Further, described macroporous resin is D101 type macroporous adsorbent resin.
The compound (I) as above application in leukemic medicine is treated in preparation.
The application in leukemic medicine is treated in preparation of the pharmaceutical composition of buprenorphin hydrochloride as above.
Advantages of the present invention:
The pharmaceutical composition of the buprenorphin hydrochloride that the present invention provides separates from Folium Perillae containing buprenorphin hydrochloride and one
When the natural product of the novel structure arrived, buprenorphin hydrochloride and this natural product independent role, leukemia is had certain controlling
Treatment effect;During the two synergy, the most notable to leukemic therapeutic effect, the leukemic medicine for the treatment of can be developed into.
The present invention compared with prior art 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
Separation method: the dried leaves (2kg) of Folium Perillae is pulverized by (a), extracts (20L × 3 time) with 75% alcohol heat reflux,
United extraction liquid, is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and
Water saturated n-butyl alcohol (4L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butanol extraction
Thing;B n-butyl alcohol extract D101 type macroporous resin remove impurity in () step (a), first with 6 cylinders of 15% ethanol elution
Long-pending, then with 10 column volumes of 70% ethanol elution, collect 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 (8 column volumes),
The methylene chloride-methanol gradient elution of 30:1 (8 column volumes), 15:1 (8 column volumes) and 5:1 (10 column volumes) obtains
To 4 components;D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 25:1 (8 by volume ratio successively
Column volume), the methylene chloride-methanol gradient elution of 15:1 (10 column volumes) and 2:1 (5 column volumes) obtain 3 components;
E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and is the first of 72% by concentration expressed in percentage by volume
Alcohol-water solution isocratic elution, collects 8~14 column volume eluents, eluent be concentrated under reduced pressure to give compound (I) (360mg,
HPLC normalization purity is more than 98%).
Structural identification: white powder, HR-ESI-MS shows [M+Na]+For m/z 333.1471, molecule can be obtained in conjunction with nuclear-magnetism feature
Formula is C20H22O3, degree of unsaturation is 10.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-2 (2.48,
Dd, J=13.9,6.6Hz), H-3a (3.05, dd, J=18.3,6.7Hz), H-3b (1.91, dd, J=18.3,2.1Hz),
H-8 (1.96, dd, J=10.3,4.8Hz), H-9 (3.09, d, J=4.8Hz), H-12 (6.17, d, J=10.5Hz),
H-13 (6.74, dd, J=10.5,6.6Hz), H-14 (2.64, dd, J=10.3,6.6Hz), H-16a (4.85, s),
H-16b (4.87, s), H-17 (1.66, s), H-18a (4.83, s) H-18b (4.37, s), H-19 (1.25, d,
J=7.8Hz), and H-20 (2.33, s);Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 209.8 (C,
1-C), 40.5 (CH, 2-C), 34.2 (CH2, 3-C), 162.3 (C, 4-C), 187.5 (C, 5-C), 108.8
(C, 6-C), 202.5 (C, 7-C), 42.4 (CH, 8-C), 33.6 (CH, 9-C), 149.4 (C, 10-C),
148.9 (C, 11-C), 129.9 (CH, 12-C), 137.8 (CH, 13-C), 48.9 (CH, 14-C), 144.3
(C, 15-C), 114.3 (CH2, 16-C), 19.8 (CH3, 17-C), 112.4 (CH2, 18-C), 18.7 (CH3,
19-C), 10.2 (CH3, 20-C).Infrared spectrum shows that this compound contains hydroxyl (3352cm-1), carbonyl (1742cm-1
With 1677cm-1) and alkene (1628cm-1) group;And it has uv absorption at 242nm, show containing α, β-unsaturation carbonyl
Base unit.13C-NMR, DEPT and hsqc spectrum show 20 carbon signals, including three methyl, three methylene (two
Individual alkene carbon), six methines (two alkene carbon), and eight quaternary carbons (two carbonyl carbon, one even oxygen alkene carbon and
Five alkene carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is tricyclic structure.1H-NMR spectrum combines HSQC
Spectrum three methyl proton signal δ of displayH1.66 (3H, s), 1.25 (3H, d, J=7.8Hz), 2.33 (3H, s), one
Group methene proton signal δH3.05 (1H, dd, J=18.3,6.7Hz) and 1.91 (1H, dd, J=18.3,2.1Hz),
Two groups of terminal olefine proton signal δH4.85 (1H, s) with 4.87 (1H, s), 4.83 (1H, s) with 4.37 (1H, s),
A pair olefinic proton signals δH6.17 (1H, d, J=10.5Hz) and 6.74 (1H, dd, J=10.5,6.6Hz), four times
Methyl proton signal δH2.48 (1H, dd, J=13.9,6.6Hz) 1.96 (1H, dd, J=10.3,4.8Hz), 3.09 (1H,
D, J=4.8Hz), 2.64 (1H, dd, J=10.3,6.6Hz).1H-1H COSY spectrum in exist H-12/H-13/H-14/H-8,
H-8/H-9 and H2-3/H-2/H3-19 coherent signals, show H in HMBC spectrum simultaneously2-3 with C-1, C-4 and C-10,
H-8 Yu C-6, C-7, C-9 and C-14, H-13 Yu C-8, C-12, C-14 and C-15, H2-16 with C-14, C-15 and
C-17, H2-18 with C-9, C-11 and C-12, H3-19 with C-1, C-2 and C-3, H3-20 with C-5, C-6 and C-7 phase
OFF signal, can be built the connected mode of this compound, and may determine that this change by the relevant information in above-mentioned H NMR spectroscopy
Compound is rhamnofolane type diterpene-kind compound.-OH absorption band 3352cm in IR spectrum-1With13C-7 in C-NMR spectrum
Chemical shift shows that C-7 position is connected with a hydroxyl.C-12 can be confirmed by H-12 Yu H-13 chemical shift and coupling constant
And be double bond between C-13.Additionally, understanding Me-19 by consulting literatures contrast is α configuration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC
Spectrum and ROESY compose, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, three-dimensional structure
Type is determined by ECD test further, and theoretical value is basically identical with experiment value.Chemical constitution and carbon atoms numbered are as follows:
Embodiment 2: treatment leukemia effect
One, material and instrument
K562 cell is provided by Chinese Academy of Sciences's Shanghai biological cell.Buprenorphin hydrochloride is purchased from China's pharmaceutical biological product calibrating research
Institute.Compound (I) is to make by oneself by embodiment 1 method, and HPLC normalization purity is more than 98%.RPMI-1640 dry powder is trained
Foster base is purchased from Gibco company.Calf serum is purchased from Sijiqing Bioengineering Material Inst., Hangzhou City.Penicillin, streptomycin are purchased from
North China Pharmaceutical Factory.Glutamine, MTT, DMSO are purchased from AMRESCO.Annexinv-FITC apoptosis test regent
Box is purchased from Nanjing KaiJi Biology Science Development Co., Ltd.MOPS, Rnasin, agarose, smell second ingot, the magnificent biology of bromjophenol blue
Huamei Bio-Engrg Co., of engineering company.
CO2Incubator (Thermo company of the U.S.), superclean bench (Suzhou Decontamination Equipment Plant), magnetic stirring apparatus (upper Hainan
Remittance Telecommunication Apparatus Factory), inverted microscope (OLYMPUS company of Japan), horizontal type centrifuger (Town in Shanghai booth scientific instrument
Factory), electronic analytical balance (Sartorius company of Germany), automatic microplate reader (Humareader company of Germany), U-3010
Type ultraviolet spectrophotometer (HITACHI company of Japan), flow cytometer (BECKMAN company of the U.S.), Eppendorf
Centrifuge 5417R centrifuge (Eppendorf company of Germany).
Two, test method
1, the cultivation of K562 cell
By the culture bottle surface of newly purchased cell strain 75% alcohol wipe 3 times.Cell suspension is sucked centrifuge tube, 1000rpm
Centrifugal 10min.Supernatant discarded, dropping is containing the RPMI-1640 complete medium of 10%NBS, and piping and druming is prepared as cell and hangs gently
Liquid.It is inoculated in culture bottle, is placed in 37 DEG C, 5%CO2Incubator is cultivated, changes liquid and pass on every day.
2, experiment packet
The RPMI-1640 of Normal group: 10%NBS;
The buprenorphin hydrochloride of the RPMI-1640+ final concentration 80mg/L of buprenorphin hydrochloride group: 10%NBS;
RPMI-1640+ final concentration 80mg/L compound (I) of compound (I) group: 10%NBS;
The hydrochloric acid of the RPMI-1640+ final concentration 40mg/L of buprenorphin hydrochloride and compound (I) compositions group: 10%NBS
Buprenorphine+final concentration 40mg/L compound (I).
3, the mtt assay detection impact on K562 cell proliferation
Take the cell that growth conditions is good, with the RPMI-1640 culture fluid containing 10%NBS, cell is configured to cell suspension, with
5×103Cells/well is inoculated in aseptic 96 well culture plates.(2) according to experiment packet, often group adds the medicine 50 μ L of variable concentrations,
If acellular hole is blank group, often group sets 8 multiple holes, and 96 well culture plates are put into CO2Incubator is cultivated;(3)
24, taking out 96 well culture plates after 48 and 72h, every hole adds 20 μ L MTT (5mg/mL), puts into CO2Incubator is hatched
4h, i.e. has hyacinthine crystal to generate, and the growing amount of crystal is directly proportional to cell number.(4) every hole adds the SDS 100 μ L of acidifying
Put into CO2Incubator is overnight.(5) measure OD by microplate reader, return to zero with blank well during colorimetric.
4, statistical procedures
Experimental group and matched group operate the most in triplicate, and result is with (x ± s represents, P < 0.05 is shown with significant difference.Compare between group
Relatively use one factor analysis of variance.All data SPSS 18.0 statistical softwares carry out statistical analysis.
Three, result and conclusion
The mtt assay detection inhibited proliferation to K562 cell
After medicine effect K562 cell 24h, 48h, 72h, detect OD by microplate reader490Display: with Normal group ratio, make
With buprenorphin hydrochloride group after 24h and compound (I) group inconspicuous to cell K562 cyto-inhibition (P > 0.05, P > 0.05),
Buprenorphin hydrochloride and compound (I) compositions group have inhibitory action (P < 0.05) to K562 cell;With Normal group ratio,
Effect 48h and 72h after, buprenorphin hydrochloride group and compound (I) group cell K562 cell is had inhibitory action (P < 0.05,
P < 0.05), buprenorphin hydrochloride and compound (I) compositions group can significantly inhibit K562 cell (P < 0.01).
MTT value after 1 each group of effect K562 cell of table
Conclusion: buprenorphin hydrochloride and compound (I) compositions can significantly inhibit the propagation of K562 cell, and inhibitory action is strong
K562 cell is acted solely in buprenorphin hydrochloride or compound (I).Between buprenorphin hydrochloride and compound (I)
There is synergism, the leukemic medicine for the treatment of can be developed into.
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 (7)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a buprenorphin hydrochloride, it is characterised in that: include buprenorphin hydrochloride, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dried leaves of Folium Perillae is pulverized, with 70~80% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses stone successively
Oil ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol
Extract;N-butyl alcohol extract macroporous resin remove impurity in (b) step (a), first with 6 column volumes of 15% ethanol elution,
Again with 10 column volumes of 70% ethanol elution, collecting 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, and is 80:1,30:1,15:1 and 5:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components;D in () step (c), component 3 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 25:1,15:1 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 72% is isocratic
De-, collect 8~14 column volume eluents, eluent is concentrated under reduced pressure to give pure compound (I).
The preparation method of compound the most according to claim 3 (I), it is characterised in that: with 75% in step (a)
Alcohol heat reflux extracts, united extraction liquid.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described macroporous resin is D101
Type macroporous adsorbent resin.
6. the application in leukemic medicine is treated in preparation of the compound (I) described in claim 1.
7. the pharmaceutical composition of the buprenorphin hydrochloride described in claim 2 application in leukemic medicine is treated in preparation.
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CN104945333A (en) * | 2014-03-27 | 2015-09-30 | 沈阳药科大学 | Perilla alcohol analogs, and preparation and application thereof |
CN105669621A (en) * | 2016-04-23 | 2016-06-15 | 吴珺 | Pharmaceutical composition of chlortetracycline hydrochloride and medical application of pharmaceutical composition |
CN105732628A (en) * | 2016-03-18 | 2016-07-06 | 温州聚宜创科技有限公司 | Pharmaceutical composition of amikacin sulfate and medical application of pharmaceutical composition |
CN105777684A (en) * | 2016-04-28 | 2016-07-20 | 周俭 | Pharmaceutical composition of fenofibrate and pharmaceutical application of pharmaceutical composition |
CN106074561A (en) * | 2016-06-13 | 2016-11-09 | 崔坤峰 | The pharmaceutical composition of carbocisteine and to leukemic therapeutical effect |
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2016
- 2016-04-20 CN CN201610249948.XA patent/CN105837422A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104945333A (en) * | 2014-03-27 | 2015-09-30 | 沈阳药科大学 | Perilla alcohol analogs, and preparation and application thereof |
CN105732628A (en) * | 2016-03-18 | 2016-07-06 | 温州聚宜创科技有限公司 | Pharmaceutical composition of amikacin sulfate and medical application of pharmaceutical composition |
CN105669621A (en) * | 2016-04-23 | 2016-06-15 | 吴珺 | Pharmaceutical composition of chlortetracycline hydrochloride and medical application of pharmaceutical composition |
CN105777684A (en) * | 2016-04-28 | 2016-07-20 | 周俭 | Pharmaceutical composition of fenofibrate and pharmaceutical application of pharmaceutical composition |
CN106074561A (en) * | 2016-06-13 | 2016-11-09 | 崔坤峰 | The pharmaceutical composition of carbocisteine and to leukemic therapeutical effect |
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