CN104434948B - The pharmaceutical composition of a kind of anti-pancreatic cancer and application thereof - Google Patents
The pharmaceutical composition of a kind of anti-pancreatic cancer and application thereof Download PDFInfo
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- CN104434948B CN104434948B CN201410632638.7A CN201410632638A CN104434948B CN 104434948 B CN104434948 B CN 104434948B CN 201410632638 A CN201410632638 A CN 201410632638A CN 104434948 B CN104434948 B CN 104434948B
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- Prior art keywords
- capecitabine
- pharmaceutical composition
- pancreatic cancer
- riboflavin tetrabutyrate
- active component
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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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses pharmaceutical composition and the application thereof of a kind of anti-pancreatic cancer, this pharmaceutical composition comprises active component and pharmaceutically acceptable adjuvant, and described active component includes capecitabine and Riboflavin Tetrabutyrate.Owing to Riboflavin Tetrabutyrate can strengthen the pancreatic cancer cell sensitivity to capecitabine, both create synergism by drug combination, thus reduce the Clinical practice dosage of capecitabine, reduce heavy dose and use toxic and side effects produced by capecitabine, improve safety clinical treatment index, there is preferable potential applicability in clinical practice.
Description
Technical field
The present invention relates to a kind of antitumor drug, particularly relate to pharmaceutical composition and the application thereof of a kind of anti-pancreatic cancer, belong to
Pharmaceutical technology field.
Background technology
Cancer is one of disease maximum to human life's health hazard.Substantial amounts of people is had to die from cancer every year.Cancer of pancreas
Being the cancer of pancreas appearance, its malignant tumor can grow at the pancreas of patient.It is reported, cancer of pancreas has become global range
Interior common cancer, due to its early diagnosis difficulty, poor prognosis, case fatality rate is high, is known as in the industry " king in cancer ".
Currently, the sickness rate of China's cancer of pancreas the most persistently rises；Show according to Shanghai City Center for Disease Control (CDC) data,
Shanghai City cancer of pancreas sickness rate relatively added 4 times before 20 years, and annual the most still with 2% speed increment.Cancer of pancreas onset is hidden
Hide, the most directly invade to pancreas week, or shift to far and near organ-tissue through lymphatic vessel and/or blood vessel, the pancreas more than 80%
It is late period when adenocarcinoma patients makes a definite diagnosis, and has lost radical surgery excision and radiocurable chance.At present, clinical
Although treatment has the combination chemotherapy scheme based on gemcitabine, but drug resistance of tumor to ultimately result in cancer of pancreas pre-
The most very poor, median survival interval is only 3-6 month, and within 5 years, survival rate is less than 5%；Therefore, inquire into cancer of pancreas to develop
Molecular mechanism, look for new targeted therapy molecule, contribute to researching and developing the more effective treatment of pancreatic cancer scheme of renewal
With early diagnosis instrument；And find an auxiliary and probe into that to improve the effectively research of cancer of pancreas early diagnosis and therapy level flat
Platform, has become as the task of top priority.
Capecitabine (capecitabine) is a kind of new oral fluorouracil mephenesin Carbamate series antineoplastic medicament, warp after being administered orally
Enzymatic reaction, is degraded to 5-fluorouracil in tumor cell, plays the antitumor action of high selectivity, to multiple
Entity tumor has stronger activity, is mainly used in clinically treating advanced breast cancer knot/rectal cancer and other solid tumors (peace
Fu Rong, Ge Shengrong, Zhu Deqiu.The pharmacology of capecitabine and Clinical advances [J]. China's new drug is miscellaneous with clinic
Will, 2002,21 (8): 503-507).Recent studies indicate that, gemcitabine associating capecitabine treatment late period cannot
The Pancreas cancer patients of operation has preferable short term effect (Wang Yue, gemcitabine associating capecitabine treatment advanced pancreatic cancer
Clinical observation, middle national health medical science, 2011/16).But, gemcitabine needs intravenous drip to be administered, long-term note
Penetrate medication and bring great misery to patient, be unfavorable for maintaining the interdependence of patient medication；And capecitabine oral administration
Good absorbing, clinic widespread adoption.Riboflavin Tetrabutyrate (RTB) is the derivant of vitamin B2, always by with
Make blood lipid-lowering medicine (Riboflavin Tetrabutyrate), there is suppression platelet aggregation and increase the effect of fibrinolytic activity, for height
The treatment of blood fat, coronary heart disease and thrombotic disease.
At present, still do not have Riboflavin Tetrabutyrate to report for antineoplastic document, more it is not joined with other anticarcinogens
Report with the document of rear anti-pancreatic cancer.
Summary of the invention
In view of the most most of tumor Drugs are drug administration by injection, the treatment adding patient is painful, the therefore present invention
Purpose be by research provide a kind of for anticancer oral drugs.
Capecitabine, as oral antitumor drug, is mainly used in treating advanced breast cancer knot/rectal cancer clinically, and because of mouth
Taking dosage causes greatly toxic and side effects bigger.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, has been surprisingly found that the two
Although to other malignant tumor such as breast carcinoma, colon cancer without preferably coordinating therapeutical effect after medication, but cancer of pancreas being had
There is the anti-proliferative effect of Synergistic.Study based on this, it is an object of the invention to provide the medicine group of a kind of anti-pancreatic cancer
Compound and application thereof.
The object of the present invention is achieved like this: the pharmaceutical composition of a kind of anti-pancreatic cancer, and this pharmaceutical composition comprises activity
Composition and pharmaceutically acceptable adjuvant, described active component includes capecitabine and Riboflavin Tetrabutyrate.At this
In bright preferably technical scheme, the active component in this pharmaceutical composition is by capecitabine and Riboflavin Tetrabutyrate group
Become.
The pharmaceutical composition of the present invention relies on Riboflavin Tetrabutyrate and capecitabine to play anti-pancreatic cancer as active component
Synergism, the amount ratio of both components is screened by inventor by lot of experiments, and result is capecitabine
During with the quality amount ratio of Riboflavin Tetrabutyrate in the range of 2-40:1, the effect of its anti-pancreatic cancer cell proliferation is more
Good；Further, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is preferably 4-20:1.
It is true that for the toxic and side effects reducing capecitabine, the present invention is more likely to reduce the consumption of this active component,
Especially reduce the consumption of capecitabine, therefore in the most preferred external embodiment of the present invention, capecitabine and riboflavin
The quality amount ratio of four butyrates is 4-10:1.
Clearly as capecitabine and Riboflavin Tetrabutyrate all can be absorbed with speed faster by gastrointestinal tract and be played
Biological activity, therefore the pharmaceutical composition of the present invention is preferably oral formulations.Pharmaceutical units preparation can be conventional preparation
Technique makes pharmaceutics acceptable any conventional peroral dosage form, such as tablet, granule, capsule, dry suspension,
Drop pill.For making above-mentioned dosage form be capable of, pharmaceutically acceptable adjuvant need to be added when preparing these dosage forms, such as: fill out
Fill agent, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives etc..Filler includes: starch, pre-
Gelling starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.；Disintegrating agent includes: starch, pregelatinated
Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, crosslinking carboxylic
Sodium carboxymethylcellulose pyce etc.；Lubricant includes: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.；Help
Suspension includes: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.；Binding agent
Including, starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.；Sweeting agent includes: saccharin sodium, aspa
Smooth, sucrose, cyclamate, enoxolone etc.；Correctives includes sweeting agent and various essence.
It is it should be noted that though capecitabine combines other chemotherapeutics can improve the response rate for the treatment of tumor, but little
Show synergism, and add drug toxicity.The present inventor is in transplanted tumor in nude mice Research of Animal Model for Study, and core is yellow
Element four butyrates show certain tumor-inhibiting action, but tumor killing effect is not notable, and when Riboflavin Tetrabutyrate combines card training
During his shore medication together, its tumour inhibiting rate significantly rises, and more simple capecitabine chemotherapy group is high, and statistically significant.
These results suggest that Riboflavin Tetrabutyrate has after being combined with capecitabine in terms of suppression Cell Proliferation of Pancreatic Cancer Cell certain
Synergism.It is otherwise noted that in drug combination group, the dosage of capecitabine or Riboflavin Tetrabutyrate is all
It is the half of independent medication group, but tumor killing effect becomes apparent from, illustrate that therapeutic alliance is more more effective than single therapy, Er Qiehe
Flavin four butyrate associating capecitabine curative effect in the case of reducing capecitabine dosage increases considerably on the contrary, so that
The impact of nude mice toxic and side effects is alleviated by gemcitabine.Based on the studies above achievement and combine the common of those skilled in the art
Technological know-how, the present invention also provides for a kind of pharmaceutical applications, it may be assumed that Riboflavin Tetrabutyrate and the compositions of capecitabine composition
Application in the medicine of preparation anti-pancreatic cancer.
Compared with prior art, the pharmaceutical composition that the present invention relates to has the advantage that and significantly improves:
(1) anticancer therapeutic is good.Riboflavin Tetrabutyrate adds the biological activity of capecitabine suppression growth of xenografted,
The two combination has the synergism of antitumor propagation, and the increment suppression ratio of pancreatic cancer cell especially can be made to reach 67.14%,
Thirst for developing into a line medication of anti-pancreatic cancer clinically.
(2) toxic and side effects is low.Owing to Riboflavin Tetrabutyrate can strengthen the pancreatic cancer cell sensitivity to capecitabine,
Both create synergism by drug combination, thus reduce the Clinical practice dosage of capecitabine, reduce heavy dose and use
Toxic and side effects produced by capecitabine, improves safety clinical treatment index, has preferable potential applicability in clinical practice.
Detailed description of the invention
The following is the effect test example of the present invention, technical scheme and technique effect are done to be laid down a definition further and saying
Bright, but protection scope of the present invention is not limited to following example.Every change without departing substantially from present inventive concept or equivalent
Within replacement is included in protection scope of the present invention.
Human pancreatic carcinoma PANC-1 cell line, after taking out cryopreservation tube, puts in 37 DEG C of water-baths, shakes defrosting 2min, wine
The outer rear flank of essence sterilization tube wall, is proceeded in super-clean bench, is transferred in centrifuge tube by pipe inner cell, added 5ml 37 DEG C pre-
The DMEM culture medium containing 10% hyclone of heat, and clean cryopreservation tube once, centrifuge tube is centrifuged (1000rpm,
5min), abandoning supernatant, add the DMEM culture medium containing 10% hyclone of 2ml 37 DEG C preheating, proceed to
In culture bottle, it is positioned over 37 DEG C, 50mL/L CO2The incubator of saturated humidity is cultivated, and disappears with 0.5% trypsin
Change and routine passage.
SPF level BALB/c-nu nude mouse 32,6 week old, male, body weight 18～20g.Take and be in exponential phase
Human pancreatic cancer cell PANC-1, be inoculated in the right oxter of nude mice, every Mus about injects 2 × 106Individual cell, continuous passage
After 3 generations, when the 4th generation growth of xenografted was to 3 weeks, puts to death tumor bearing nude mice, take fresh tumor tissue, be cut into volume about 8mm3
Tumor mass, is inoculated in oxter on the right side of experiment nude mice, and above operation is all carried out under aseptic condition in super-clean bench.After transplanting
Within 8 days, tumor survives in local and grows to diameter about 0.5cm, is divided by successful for modeling Transplanted tumor model mice stochastic averagina
It is four groups, often group 8, each group is carried out treating 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 1% hydroxymethyl cellulose
Gavage after sodium solution suspendible, every day 1 time；
Cap group: every nude mice presses the capecitabine of weight gavage 750mg/kg, with 1% Carboxymethyl cellulose sodium solution
Gavage after suspendible, every day 1 time；
RTB+Cap group: every nude mice presses the Riboflavin Tetrabutyrate of weight gavage 60mg/kg and 375mg/kg
Capecitabine, with gavage, every day 1 time after 1% Carboxymethyl cellulose sodium solution suspendible.
Administration terminate after the 2nd day, put to death each treated animal, separate transplanted tumor, claim tumor weight, tumour inhibiting rate=(matched group tumor weight-
Treatment group tumor weight)/matched group tumor weight × 100%.The average tumor weight of each group and tumour inhibiting rate refer to table 1.Test by table 1
Statistical result is it can be seen that the average tumor of Cap group is heavily significantly lower than matched group (P < 0.05), although RTB group average tumor weight is low
In matched group, but do not have significant difference solid (P > 0.05)；The average tumor weight of RTB+Cap group and blank group and respectively
Single medicine group is compared and is all decreased obviously, and difference has statistical significance (P < 0.05 or P < 0.01).This shows riboflavin four
Butyrate adds the biological activity of capecitabine suppression growth of xenografted, and the two combination has the collaborative work of antitumor propagation
With.
The comparison of nude mice tumor weight tumour inhibiting rate respectively organized by table 1
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.
It addition, self administration of medication starts to treat on the 1st day, respectively organize with vernier caliper measurement before Per-Hop behavior transplanted tumor major diameter and
Minor axis, gross tumor volume V=0.5 × major diameter × minor axis × minor axis (mm3).Table 2 is asked for an interview in the change of each group volume.By table 2
Test statistics result it can be seen that transplanted tumor volume rapid development in matched group oxter after Jie Zhong, remaining respectively organizes transplanted tumor body
Long-pending growth all receives a certain degree of suppression, and especially RTB+Cap group transplanted tumor volume is significantly lower than blank group
With each single medicine group (P < 0.05 or P < 0.01), it is anti-swollen that this imply that Riboflavin Tetrabutyrate combination capecitabine has further
The synergism of tumor propagation.
Comparison (the mm of transplanted tumor in nude mice volume after treating respectively organized by table 23)
Compare with blank group,*P ＜ 0.05；Compare with RTB group,$P ＜ 0.05；Compare with Cap group,#P ＜ 0.05.
Claims (6)
1. the pharmaceutical composition of an anti-pancreatic cancer, this pharmaceutical composition comprises active component and pharmaceutically acceptable adjuvant, it is characterized in that, described active component is made up of capecitabine and Riboflavin Tetrabutyrate, and in described active component, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 2-40:1.
The pharmaceutical composition of anti-pancreatic cancer the most according to claim 1, it is characterised in that in described active component, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 4-20:1.
The pharmaceutical composition of anti-pancreatic cancer the most according to claim 2, it is characterised in that in described active component, the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 4-10:1.
The pharmaceutical composition of anti-pancreatic cancer the most according to claim 1, it is characterised in that described pharmaceutical composition is oral formulations.
The pharmaceutical composition of anti-pancreatic cancer the most according to claim 4, it is characterised in that described oral formulations includes tablet, granule, capsule, dry suspension and drop pill.
6. the compositions of Riboflavin Tetrabutyrate and capecitabine composition application in the medicine of preparation anti-pancreatic cancer, wherein the quality amount ratio of capecitabine and Riboflavin Tetrabutyrate is 2-40:1.
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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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| CN108210499B (en) * | 2018-01-29 | 2021-02-19 | 丽水学院 | Application of lutein in preparation of tumor chemoradiotherapy sensitizer and antitumor pharmaceutical composition |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06279445A (en) * | 1993-03-31 | 1994-10-04 | Nippon Zeon Co Ltd | Cancer metastasis suppressor |
| CN1522144A (en) * | 2002-01-31 | 2004-08-18 | 关西Tlo株式会社 | 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 |
-
2014
- 2014-11-11 CN CN201410632638.7A patent/CN104434948B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06279445A (en) * | 1993-03-31 | 1994-10-04 | Nippon Zeon Co Ltd | Cancer metastasis suppressor |
| CN1522144A (en) * | 2002-01-31 | 2004-08-18 | 关西Tlo株式会社 | 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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