CN104434948A - Anti-pancreatic-cancer medicine composition and application thereof - Google Patents
Anti-pancreatic-cancer medicine composition and application thereof Download PDFInfo
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- CN104434948A CN104434948A CN201410632638.7A CN201410632638A CN104434948A CN 104434948 A CN104434948 A CN 104434948A CN 201410632638 A CN201410632638 A CN 201410632638A CN 104434948 A CN104434948 A CN 104434948A
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- capecitabine
- cancer
- riboflavin tetrabutyrate
- pancreas
- pharmaceutical composition
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
Abstract
The invention discloses an anti-pancreatic-cancer medicine composition and an application thereof. The medicine composition comprises active components and pharmaceutically-acceptable auxiliary materials, wherein the active components comprise capecitabine and riboflavin tetrabutyrate. Because riboflavin tetrabutyrate can be used for enhancing the sensitivity of pancreatic cancer cells to capecitabine, and synergistic effects can be achieved by virtue of the combined medication of riboflavin tetrabutyrate and capecitabine, the clinical dosage of capecitabine can be reduced, the toxic or side effects caused by using a large dosage of capecitabine can be reduced, the security index of clinical treatment can be improved, and relatively good clinical application prospects can be achieved.
Description
Technical field
The present invention relates to a kind of antitumor drug, particularly relate to a kind of pharmaceutical composition and application thereof of anti-cancer of pancreas, belong to medical art.
Background technology
Cancer is to one of maximum disease of human life's health hazard.A large amount of people is had to die from cancer every year.Cancer of pancreas is the cancer that pancreas occurs, its malignant tumor can grow at the pancreas of patient.It is reported, cancer of pancreas has become common cancer in global range, and due to its early diagnosis difficulty, poor prognosis, case fatality rate is high, is known as in the industry " king in cancer ".Current, the sickness rate of China's cancer of pancreas continues to rise just with surprising rapidity; According to the display of Shanghai City Center for Disease Control (CDC) data, Shanghai City cancer of pancreas sickness rate comparatively added 4 times before 20 years, and annual still with 2% speed increment.Cancer of pancreas onset is hidden, and invades in early days, or shift to far and near organ-tissue through lymphatic vessel and/or blood vessel directly to pancreas week, has been late period, and loses radical surgery excision and radiocurable chance when the Pancreas cancer patients more than 80% is made a definite diagnosis.At present, although there is the combination chemotherapy scheme based on gemcitabine in clinical treatment, drug resistance of tumor finally causes cancer of pancreas prognosis very poor, and median survival interval is only 3-6 month, and within 5 years, survival rate is less than 5%; Therefore, inquire into the molecular mechanism that development occurs cancer of pancreas, look for new targeted therapy molecule, contribute to researching and developing the more effective treatment of pancreatic cancer scheme of renewal and early diagnosis instrument; And find an auxiliary effective research platform improving cancer of pancreas early diagnosis and therapy level of probing into, become the task of top priority.
Capecitabine (capecitabine) is a kind of new oral fluorouracil mephenesin Carbamate series antineoplastic medicament, through enzymatic reaction after oral, 5-fluorouracil is degraded in tumor cell, play the antitumor action of high selectivity, stronger activity is had to multiple entity tumor, be mainly used in treatment advanced breast cancer knot/rectal cancer and other solid tumors (An Furong, Ge Shengrong, Zhu Deqiu clinically.The pharmacology of capecitabine and Clinical advances [J]. Chinese Journal of New Drugs and Clinical Remedies, 2002,21 (8): 503-507).Research in recent years shows, gemcitabine associating capecitabine is treated the Pancreas cancer patients cannot performed the operation late period and is had good short term effect (Wang Yue, the clinical observation of gemcitabine associating capecitabine treatment advanced pancreatic cancer, middle national health medical science, 2011/16).But gemcitabine needs intravenous drip administration, long-term injecting drug use brings great misery to patient, is unfavorable for the interdependence maintaining patient medication; And capecitabine oral administration good absorbing, clinic widespread adoption.Riboflavin Tetrabutyrate (RTB) is the derivant of vitamin B2, be used as blood lipid-lowering medicine (Riboflavin Tetrabutyrate) always, there is the effect of anticoagulant and increase fibrinolytic activity, for the treatment of hyperlipidemia, coronary heart disease and thrombotic disease.
At present, still there is no Riboflavin Tetrabutyrate for antineoplastic bibliographical information, more not by the bibliographical information of anti-cancer of pancreas after itself and other anticarcinogen coupling.
Summary of the invention
In view of most of tumor Drugs is drug administration by injection clinically, the treatment adding patient is painful, therefore the object of the invention is to provide a kind of for anticancer oral drugs by research.
Capecitabine, as oral antitumor drug, is mainly used in treatment advanced breast cancer knot/rectal cancer clinically, and causes greatly toxic and side effects larger because of oral dose.In order to play the antitumor efficacy of capecitabine, reduce its toxic and side effects simultaneously, the present inventor is by reducing the consumption of capecitabine, and by itself and Riboflavin Tetrabutyrate use in conjunction, after medication both finding although unexpected to other malignant tumor such as breast carcinoma, colon cancer without better coordinating therapeutical effect, cancer of pancreas is had to the anti-proliferative effect of Synergistic.Based on this research, the object of the present invention is to provide a kind of pharmaceutical composition and application thereof of anti-cancer of pancreas.
The object of the present invention is achieved like this: a kind of pharmaceutical composition of anti-cancer of pancreas, and this pharmaceutical composition comprises active component and pharmaceutically acceptable adjuvant, and described active component comprises capecitabine and Riboflavin Tetrabutyrate.In technical scheme preferred for this invention, the active component in this pharmaceutical composition is made up of capecitabine and Riboflavin Tetrabutyrate.
Pharmaceutical composition of the present invention relies on Riboflavin Tetrabutyrate and capecitabine as the synergism of the anti-cancer of pancreas of active ingredient exerts, inventor is screened by the amount ratio of lot of experiments to these two kinds of components, result be the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate in the scope of 2-40:1 time, the better effects if of its anti-Cell Proliferation of Pancreatic Cancer Cell; Further, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate can be preferably 4-20:1.
In fact, in order to reduce the toxic and side effects of capecitabine, the present invention is more prone to the consumption reducing this active component, especially reduces the consumption of capecitabine, therefore, in the most preferred external embodiment of the present invention, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 4-10:1.
Obviously, because capecitabine and Riboflavin Tetrabutyrate all can be absorbed with speed faster and play biological activity by gastrointestinal tract, therefore pharmaceutical composition of the present invention is preferably oral formulations.Pharmaceutical units preparation can be that conventional preparation process makes the acceptable any conventional peroral dosage form of pharmaceutics, such as tablet, granule, capsule, dry suspension, drop pill.For enabling above-mentioned dosage form realize, the acceptable adjuvant of pharmacy need be added when preparing these dosage forms, such as: filler, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives etc.Filler comprises: starch, pregelatinized Starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.; Disintegrating agent comprises: starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.; Lubricant comprises: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.; Suspending agent comprises: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar, hydroxypropyl emthylcellulose etc.; Binding agent comprises, starch slurry, polyvinylpyrrolidone, hydroxypropyl emthylcellulose etc.; Sweeting agent comprises: saccharin sodium, Aspartane, sucrose, cyclamate, enoxolone etc.; Correctives comprises sweeting agent and various essence.
It should be noted that, though capecitabine combines the response rate that other chemotherapeutics can improve treatment tumor, seldom show synergism, and add drug toxicity.The present inventor is in transplanted tumor in nude mice Research of Animal Model for Study, Riboflavin Tetrabutyrate shows certain tumor-inhibiting action, but tumor killing effect is not remarkable, and when Riboflavin Tetrabutyrate associating capecitabine together medication, its tumour inhibiting rate significantly rises, more simple capecitabine chemotherapy group is high, and has statistical significance.Suppressing, in Cell Proliferation of Pancreatic Cancer Cell, there is certain synergism after these results suggest that Riboflavin Tetrabutyrate and capecitabine coupling.It should be noted that in addition, in drug combination group, the dosage of capecitabine or Riboflavin Tetrabutyrate is all the half of independent medication group, but tumor killing effect is more obvious, illustrate that therapeutic alliance is more effective than single therapy, and Riboflavin Tetrabutyrate associating capecitabine curative effect when reducing capecitabine dosage increases considerably on the contrary, thus the impact of gemcitabine on nude mice toxic and side effects is alleviated.Based on above-mentioned achievement in research and in conjunction with the ordinary technical knowledge of those skilled in the art, the present invention also provides a kind of pharmaceutical applications, that is: the application of the compositions of Riboflavin Tetrabutyrate and capecitabine composition in the medicine of the anti-cancer of pancreas of preparation.
Compared with prior art, the pharmaceutical composition tool that the present invention relates to has the following advantages and progress significantly:
(1) anticancer therapeutic is good.Riboflavin Tetrabutyrate adds the biological activity that capecitabine suppresses growth of xenografted, the two coupling has the synergism of antitumor propagation, especially the increment suppression ratio of pancreatic cancer cell can be made to reach 67.14%, thirst for the line medication being developed to anti-cancer of pancreas clinically.
(2) toxic and side effects is low.Because Riboflavin Tetrabutyrate can strengthen the sensitivity of pancreatic cancer cell to capecitabine, both create synergism by drug combination, thus reduce the Clinical practice dosage of capecitabine, reduce heavy dose of toxic and side effects using capecitabine to produce, improve safety clinical treatment index, there is good potential applicability in clinical practice.
Detailed description of the invention
Be below effect test of the present invention example, technical scheme of the present invention and technique effect are done and lays down a definition further and illustrate, but protection scope of the present invention be not limited to following examples.Every do not deviate from the present invention's design change or equivalent substituting include within protection scope of the present invention.
Human pancreatic carcinoma PANC-1 cell line, after taking out cryopreservation tube, drop in 37 DEG C of water-baths, shake the 2min that thaws, the outer rear flank of alcohol disinfecting tube wall, proceeded in super-clean bench, pipe inner cell is transferred in centrifuge tube, adds the DMEM culture medium containing 10% hyclone of 5ml 37 DEG C of preheatings, and clean cryopreservation tube once, by centrifugal for centrifuge tube (1000rpm, 5min), abandoning supernatant, then the DMEM culture medium containing 10% hyclone adding 2ml 37 DEG C of preheatings, proceed in culture bottle, be positioned over 37 DEG C, 50mL/L CO
2cultivate in the incubator of saturated humidity, and with 0.5% trypsinization and routine passage.
SPF level BALB/c-nu nude mouse 32,6 week age, male, body weight 18 ~ 20g.Get the human pancreatic cancer cell PANC-1 being in exponential phase, be inoculated in the right oxter of nude mice, every Mus about injects 2 × 10
6individual cell, after continuous passage 3 generation, when the 4th growth of xenografted to 3 week in generation, puts to death tumor bearing nude mice, gets fresh tumor tissue, be cut into volume and be about 8mm
3tumor block, be inoculated in oxter on the right side of experiment nude mice, above operation is all carried out under aseptic condition in super-clean bench.After transplanting, the 8th day tumor survives in local and grows to diameter and be about 0.5cm, successful for modeling Transplanted tumor model mice stochastic averagina is divided into four groups, often organizes 8, and each group carries out treatment 3 weeks by the tested material of following dosage respectively:
Blank group: every nude mice gavage 1% Carboxymethyl cellulose sodium solution 0.1ml/10g, every day 1 time;
RTB group: every nude mice presses the Riboflavin Tetrabutyrate of weight gavage 120mg/kg, with gavage after 1% Carboxymethyl cellulose sodium solution suspendible, every day 1 time;
Cap group: every nude mice presses the capecitabine of weight gavage 750mg/kg, with gavage after 1% Carboxymethyl cellulose sodium solution suspendible, every day 1 time;
RTB+Cap group: every nude mice presses the Riboflavin Tetrabutyrate of weight gavage 60mg/kg and the capecitabine of 375mg/kg, with gavage after 1% Carboxymethyl cellulose sodium solution suspendible, every day 1 time.
Administration terminates latter 2nd day, puts to death each treated animal, is separated transplanted tumor, claims tumor weight, tumour inhibiting rate=(matched group tumor weight-treatment group tumor weight)/matched group tumor heavy × 100%.Heavy and the tumour inhibiting rate of each group of average tumor refers to table 1.Can be found out by the test statistics result of table 1, the average tumor of Cap group is heavily starkly lower than matched group (P<0.05), although the average tumor of RTB group is heavy lower than matched group, there is no significant difference solid (P>0.05); The average tumor of RTB+Cap group is heavily compared with each single medicine group with blank group all obvious decline, and difference has statistical significance (P<0.05 or P<0.01).This shows that Riboflavin Tetrabutyrate adds the biological activity of capecitabine suppression growth of xenografted, and the two coupling has the synergism of antitumor propagation.
Table 1 respectively group nude mice tumor weighs the comparison of tumour inhibiting rate
Compare with blank group,
*p < 0.05,
*p < 0.01; Compare with RTB group,
$p < 0.05,
$$p < 0.01; Compare with Cap group,
#p < 0.05,
##p < 0.01.
In addition, self administration of medication starts to treat on the 1st day, respectively organizes major diameter and the minor axis of transplanted tumor, gross tumor volume V=0.5 × major diameter × minor axis × minor axis (mm before Per-Hop behavior with vernier caliper measurement
3).Table 2 is asked for an interview in the change of each group of volume.Can be found out by the test statistics result of table 2, matched group oxter transplanted tumor volume rapid development after inoculation, all the other are respectively organized transplanted tumor volume and increase the suppression all received to a certain degree, especially RTB+Cap group transplanted tumor volume is starkly lower than blank group and each single medicine group (P<0.05 or P<0.01), and this imply that Riboflavin Tetrabutyrate coupling capecitabine has the synergism of antitumor propagation further.
Comparison (the mm of rear transplanted tumor in nude mice volume treated by table 2 respectively group
3)
Compare with blank group,
*p < 0.05; Compare with RTB group,
$p < 0.05; Compare with Cap group,
#p < 0.05.
Claims (8)
1. a pharmaceutical composition for anti-cancer of pancreas, this pharmaceutical composition comprises active component and pharmaceutically acceptable adjuvant, it is characterized in that, described active component comprises capecitabine and Riboflavin Tetrabutyrate.
2. the pharmaceutical composition of anti-cancer of pancreas according to claim 1, it is characterized in that, described active component is made up of capecitabine and Riboflavin Tetrabutyrate.
3. the pharmaceutical composition of anti-cancer of pancreas according to claim 1 or 2, it is characterized in that, in described active component, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 2-40:1.
4. the pharmaceutical composition of anti-cancer of pancreas according to claim 3, it is characterized in that, in described active component, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 4-20:1.
5. the pharmaceutical composition of anti-cancer of pancreas according to claim 4, it is characterized in that, in described active component, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 4-10:1.
6. the pharmaceutical composition of anti-cancer of pancreas according to claim 1 or 2, it is characterized in that, described pharmaceutical composition is oral formulations.
7. the pharmaceutical composition of anti-cancer of pancreas according to claim 6, it is characterized in that, described oral formulations comprises tablet, granule, capsule, dry suspension and drop pill.
8. the application of the compositions of Riboflavin Tetrabutyrate and capecitabine composition in the medicine of the anti-cancer of pancreas of preparation.
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| CN201410632638.7A CN104434948B (en) | 2014-11-11 | 2014-11-11 | The pharmaceutical composition of a kind of anti-pancreatic cancer and application thereof |
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| CN201410632638.7A CN104434948B (en) | 2014-11-11 | 2014-11-11 | The pharmaceutical composition of a kind of anti-pancreatic cancer and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210499A (en) * | 2018-01-29 | 2018-06-29 | 丽水学院 | Application and antineoplastic pharmaceutical compositions of the lumiflavin in tumor chemoradiotherapy sensitizer is prepared |
| CN113164483A (en) * | 2018-11-28 | 2021-07-23 | 国立癌症中心 | Pharmaceutical composition for preventing or treating cancer comprising PLK1 activation inhibitor as active ingredient |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06279445A (en) * | 1993-03-31 | 1994-10-04 | Nippon Zeon Co Ltd | Cancer metastasis suppressor |
| WO2003063860A1 (en) * | 2002-01-31 | 2003-08-07 | Kansai Technology Licensing Organization Co., Ltd. | Compositions for preventing human cancer and method of preventing human cancer |
| CN101040865A (en) * | 2007-04-28 | 2007-09-26 | 济南帅华医药科技有限公司 | Sustained-released injection including antimetabolite medicine and alkylate agent |
| CN101185654A (en) * | 2007-12-11 | 2008-05-28 | 常州安孚立德药业技术有限公司 | Gemcitabine hydrochloride or gemcitabine composition |
| CN101584699A (en) * | 2008-05-20 | 2009-11-25 | 崔福贵 | Application of lactoflavin ester derivative for preparing medicine for treating diabetes mellitus and complication thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210499A (en) * | 2018-01-29 | 2018-06-29 | 丽水学院 | Application and antineoplastic pharmaceutical compositions of the lumiflavin in tumor chemoradiotherapy sensitizer is prepared |
| CN113164483A (en) * | 2018-11-28 | 2021-07-23 | 国立癌症中心 | Pharmaceutical composition for preventing or treating cancer comprising PLK1 activation inhibitor as active ingredient |
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| CN104434948B (en) | 2016-11-23 |
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