CN109481688A - Pharmaceutical composition containing chemotherapeutics and Berbamine hydrochloride - Google Patents

Pharmaceutical composition containing chemotherapeutics and Berbamine hydrochloride Download PDF

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Publication number
CN109481688A
CN109481688A CN201811436483.4A CN201811436483A CN109481688A CN 109481688 A CN109481688 A CN 109481688A CN 201811436483 A CN201811436483 A CN 201811436483A CN 109481688 A CN109481688 A CN 109481688A
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China
Prior art keywords
active constituent
pharmaceutical composition
chemotherapeutics
berbamine hydrochloride
berbamine
Prior art date
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Pending
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CN201811436483.4A
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Chinese (zh)
Inventor
肖建勇
王坤
陈博南
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Guangzhou University Of Chinese Medicine (guangzhou Institute Of Traditional Chinese Medicine)
Guangzhou University of Chinese Medicine
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Guangzhou University Of Chinese Medicine (guangzhou Institute Of Traditional Chinese Medicine)
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Priority to CN201811436483.4A priority Critical patent/CN109481688A/en
Publication of CN109481688A publication Critical patent/CN109481688A/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a kind of pharmaceutical compositions, it is characterised in that: the pharmaceutical composition species contain active constituent (a) chemotherapeutics, active constituent (b) Berbamine hydrochloride and its pharmaceutically acceptable salt;And (c) pharmaceutically acceptable carrier.Berbamine hydrochloride and chemotherapy drugs in combination medication are improved into chemotherapeutics to the therapeutic effect of cancer patient in the present invention, and the side effect of chemotherapeutics can be reduced.

Description

Pharmaceutical composition containing chemotherapeutics and Berbamine hydrochloride
Technical field
The present invention relates to biomedicine field, in particular to a kind of pharmaceutical composition containing chemotherapeutics and Berbamine hydrochloride Object.
Background technique
Malignant tumour is always a global public health problem, greatly endangers the health of the mankind, and Through the main reason for becoming new century human death.And the cure rate of cancer and the time-to-live of cancer patient are improved, it is existing In the key points and difficulties of scientific research person's research.Most patients find to already belong to middle and advanced stage when malignant tumour, lose The Best Times of surgical intervention, even if some patientss have carried out Operation in early stage, but recurrence rate is still high, changes at this time Treatment becomes for its main therapeutic modality.Although common chemotherapy has obtained certain achievement, in practical applications still There are anticancer drug poor biocompatibility, the absorption of patient's body cell is low, and the ill-effect that but will generate drug resistance is used for a long time, Cause the actual medical function effect of anticancer drug unsatisfactory, in addition ordinary anticancer drugs are also different to human normal function The side effect of degree, it is therefore desirable to the improvement of very big volume.
Researcher improves its anticancer effect, has conducted extensive research, taken at present to overcome the defect of chemotherapeutics Obtain many achievements.
CN108191995A discloses a kind of amphiphilic polysaccharide derivative and its preparation method and application that reduction is sensitive, this Kind amphiphilic polysaccharide derivative is a kind of excellent pharmaceutical carrier, unique excellent especially for having in insoluble anti-tumor medicament Gesture.This reduction sensitivity characteristic can reach fast depolymerization derivative carrier in tumour cell, thus quick release vitamin E Succinate and altogether carrying anti-tumor drug, enhance tumor locus drug accumulation, are conducive to promote curative effect, reduce side effect and reduce Drug resistant generation.
CN108467439A discloses a kind of preparation method of water-soluble paclitaxel chemotherapeutics, is repaired in the invention with acid anhydrides Hyaluronic acid is adornd, then is connected to taxol, which shows good injection safety, self aggregation characteristic and Drug loading capacity.
CN103043635A discloses a kind of preparation method of the cis-platinum mineralized liquid of anti-drug resistance, comprising the following steps: (1) Cis-platinum is added in follow-on DMEM culture medium, reacts the midbody solution replaced under similar physiological condition;(2) Calcic inorganic salts are added into obtained substituted midbody solution, under similar physiological condition reaction obtain nanometer it is cured in Mesosome system;(3) fetal calf serum albumen is added into the obtained cured intermediate system of nanometer, obtains the cis-platinum mineralising Liquid.The invention also discloses cis-platinum mineralized liquid and its application made from the preparation method, which has tumour cell There is stronger lethality, and the tumour with obvious drug resistance difficult to treat for cis-platinum has apparent therapeutic effect.
CN104784700A discloses the preparation method that a kind of drug carries compound, micella and micella altogether, and drug carries multiple altogether Object is closed to be combined by cis-platinum, adriamycin and multi-arm copolymer.The drug carries compound altogether and forms micella in an aqueous medium, more PEG block is in the outer core of micella in arm copolymer, and polyglutamic acid block or aspartic acid block are in glue in multi-arm copolymer The kernel of beam, cis-platinum and adriamycin are among this two parts and are protected, and keep its stability preferable, will not occur to discharge suddenly Phenomenon.In addition, the carboxyl of cis-platinum and multi-arm copolymer is coordinated, there is crosslinked action, increase the stability of micella;Swollen Tumor tissue or near tumor cells, adriamycin and Platinol cisplatin with quick release and can play drug effect, to improve curative effect of medication, reduce Toxic side effect.
It is temporarily had not seen in the prior art by Berbamine hydrochloride and chemotherapeutic drugs to improve chemotherapeutics chemotherapy effect, Reduce the report of its ill effect.
Summary of the invention
The purpose of the present invention is to provide a kind of purposes of Berbamine hydrochloride, i.e., for improving chemotherapeutics to cancer patient Therapeutic effect, or the side effect for reducing chemotherapeutics.
Another object of the present invention is to provide the pharmaceutical compositions and its application of a kind of chemotherapeutics and Berbamine hydrochloride.
The technical solution used in the present invention is:
A kind of pharmaceutical composition, it is characterised in that: the pharmaceutical composition species contain
Active constituent (a) chemotherapeutics,
Active constituent (b) Berbamine hydrochloride and its pharmaceutically acceptable salt;And
(c) pharmaceutically acceptable carrier.
Further, the total content of active constituent (a) and active constituent (b) is 1~99wt% of pharmaceutical composition.
Further, active constituent (a) is cis-platinum or derivatives thereof.
Further, the mass ratio of active constituent (a) and active constituent (b) is (0~2): (10~300), and activity at The amount for dividing (a) is not 0.
Further, the mass ratio of active constituent (a) and active constituent (b) is (0.1~1): (100~300).
Further, active constituent (a) is taxol or derivatives thereof.
Further, active constituent (a), active constituent (b) mass ratio be (0~2): (10~300), and active constituent (a) amount is not 0.
Further, active constituent (a), active constituent (b) mass ratio be (1~2): (80~300).
Further, pharmaceutical composition is at least one of injection, tablet, capsule.
A kind of purposes of Berbamine hydrochloride is used to prepare a kind of preparation or a kind of medicine box, and the preparation or medicine box are for mentioning High chemotherapeutics is to the therapeutic effect of cancer patient, or the side effect for reducing chemotherapeutics.
The beneficial effects of the present invention are:
Berbamine hydrochloride and chemotherapy drugs in combination are used in the present invention, compared to independent medication, lung carcinoma cell is killed Power is stronger, more promotion Increase Apoptosis of Lung Cancer Cells, has stronger inhibiting effect to the growth of knurl.
Berbamine hydrochloride and chemotherapy drugs in combination are used in the present invention, enhance cancer cell to the sensitivity of chemotherapeutics Property, the drug resistance of chemotherapeutics is greatly reduced, makes it possible that it is clinically widely used.
Berbamine hydrochloride and chemotherapy drugs in combination are used in the present invention, reduce the side effect of chemotherapeutics, improves and suffers from The life quality of person.Cisplatin chemotherapy people digest road side effect is serious, and Berbamine hydrochloride can improve people digest road function.And And cisplatin chemotherapy patient will appear bone marrow suppression, the quantity of leucocyte and blood platelet can continue to decline, when reducing to a certain extent Shi Bixu is discontinued, and also will affect the treatment of tumour.And Berbamine hydrochloride plays the role of increasing leukocyte, can alleviate to a certain extent The generation of the side effect.Therefore, Berbamine hydrochloride and Cisplatin can effectively improve the life quality of patient.
Berbamine hydrochloride is a kind of Common drugs, and by it, easy to use and economic benefit is extremely good with chemotherapy drugs in combination It is good.
Detailed description of the invention
Fig. 1 is inhibiting rate of the various concentration Berbamine hydrochloride to H1299;
Fig. 2 is cell experiment figure;
Fig. 3 is zoopery figure.
Specific embodiment
Below in conjunction with specific experiment, the present invention is further explained, it should be appreciated that following experiment be merely to illustrate the present invention and It is not used in and limits the scope of the invention.
It is whether statistically significant using t inspection statistics analysis group difference, hydrochloric acid barberry is evaluated using the equal q value method of Nintaus The concertedness of amine and cis-platinum drug effect, specific formula are as follows: Q=RA+B/ (RA+RB-RA × RB).Q < 0.85 is antagonism, 0.85≤Q < 1.15 is to be added, and Q >=1.15 are concertedness synergistic effect.Wherein, RA+B is the tumor control rate of drug combination group, and RA is salt The tumor control rate of sour berbamine, RB are the tumor control rate of cis-platinum.
(1) cell experiment
A) MTT experiment:
Drug is detected to the inhibiting rate of tumour cell H1299 by MTT experiment, setting drug concentration gradient is respectively 0 μM, It is thin to tumour to detect drug under various concentration for 1.5 μM, 3.125 μM, 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100 μM, 200 μM The inhibiting rate of born of the same parents H1299, as a result as shown in Figure 1, the toxicity of display Berbamine hydrochloride is very low.
B) CCK8 is tested:
The effect that detection Berbamine hydrochloride enhanced sensitivity cis-platinum kills lung carcinoma cell is tested by CCK8.CCK8 experiment can be accurate Drug is detected to the inhibiting rate of tumour cell, H1299 lung cancer cell line is selected in this experiment, and it is small that grouping is set as control group, hydrochloric acid Bark of a cork tree amine independent role group, cis-platinum independent role group, Berbamine hydrochloride and cisplatin combined medication group, wherein Berbamine hydrochloride concentration is set It is set to 5 μM;Cis-platin concentrations are respectively set to 12.5 μM, 25 μM, 50 μM.That is the mixed proportion of cis-platinum and Berbamine hydrochloride are as follows: 5: 2;5:1;10:1.Determine whether Berbamine hydrochloride kills lung carcinoma cell tool to cis-platinum by detecting the survival condition of group of cells There is sensitization.Wherein Fig. 2A is that the cell state with Cisplatin Berbamine hydrochloride is applied alone in microscopically observation cis-platinum, is found Obviously there is apoptosis in drug combination group cell.Fig. 2 B is that CCK8 detects different cis-platin concentrations combination Berbamine hydrochlorides to cell inhibition Effect, joint group apoptosis rate is higher than cis-platinum list medicine group (P < 0.01) as the result is shown, and enhanced sensitivity Q value > 1.15, it is seen that hydrochloric acid barberry Amine has sensitization to cis-platinum and taxol killing lung carcinoma cell.
C) streaming apoptosis is tested:
The effect that detection Berbamine hydrochloride enhanced sensitivity cis-platinum kills lung carcinoma cell is tested by streaming apoptosis.Cultivate H1299 lung Cancer cell line, according to control group, Berbamine hydrochloride independent role group, cis-platinum independent role group, Berbamine hydrochloride and cisplatin combined Four medication group, Berbamine hydrochloride and paclitaxel plus medication group groupings carry out bed board and feeding operations, wherein Berbamine hydrochloride It is 5 μM that concentration, which is arranged, and it is 25 μM that concentration, which is arranged, in cis-platinum, and it is 1 μM that concentration, which is arranged, in taxol.According to Annexin-V-PI apoptosis reagent Box is using step process sample and carries out machine testing in streaming, the apoptosis rate of group of cells is obtained, so that it is determined that Berbamine hydrochloride Whether there is effect of enhanced sensitivity to cis-platinum killing lung carcinoma cell.Fig. 2 C is that Flow cytometry experiments detect Apoptosis: Berbamine hydrochloride Combination group apoptosis rate, which is apparently higher than, is applied alone a group apoptosis rate, with statistically significant (the P < of cis-platinum list medicine group comparing difference 0.01), the enhanced sensitivity Q value > 1.15 of Berbamine hydrochloride and Cisplatin, Berbamine hydrochloride and Cisplatin have synergistic effect (left Figure);Berbamine hydrochloride combination group apoptosis rate, which is apparently higher than, is applied alone a group apoptosis rate, has system with taxol list medicine group comparing difference Meter learns meaning (P < 0.01), enhanced sensitivity Q value > 1.15 associated with berbamine and taxol, and Berbamine hydrochloride and taxol combination have It acts synergistically (right figure).Berbamine hydrochloride has sensitization to cis-platinum and taxol killing lung carcinoma cell as the result is shown.
(2) nude mice lotus knurl is tested
The nude mice of 5-8 week old, weight 18-22g is bought, is inoculated with first with H1299 cell strain, subcutaneous transplantation knurl model is carried out Building, proposed adoption lung cancer cell line H1299 is inoculated with, every 5,000,000 cells of inoculation, carries out drug to nude mice after tumor formation Abdominal cavity drug injection, 1 time/d of frequency of injection, grouping are set as control group, Berbamine hydrochloride independent role group (30mg/kg), suitable Platinum independent role group (0.5mg/kg), Berbamine hydrochloride and Combined with Cisplatin for The Treatment group, the i.e. mixing ratio of cis-platinum and Berbamine hydrochloride Example is 1:60.The volume that tumor is measured while administration, puts to death mouse after tumor reaches certain volume, takes pictures, remove tumour, claims Taking tumor weight, wherein Fig. 3 A takes pictures for the grouping of tumor bearing nude mice and subcutaneous knurl;Fig. 3 B is gross tumor volume grouped comparison, Fig. 3 C For tumor weight grouped comparison.The knurl inhibiting effect of joint group is significantly stronger than single medicine group, and Berbamine hydrochloride and Cisplatin Enhanced sensitivity Q value > 1.15, Berbamine hydrochloride and Cisplatin have synergistic effect.The tumor control rate of drug combination group as the result is shown Maximum, and Berbamine hydrochloride and cis-platinum have synergistic effect to inhibition tumour.

Claims (10)

1. a kind of pharmaceutical composition, it is characterised in that: the pharmaceutical composition species contain
Active constituent (a) chemotherapeutics,
Active constituent (b) Berbamine hydrochloride and its pharmaceutically acceptable salt;And
(c) pharmaceutically acceptable carrier.
2. pharmaceutical composition according to claim 1, it is characterised in that: active constituent (a) always contains with active constituent (b) Amount is 1~99wt% of pharmaceutical composition.
3. pharmaceutical composition according to claim 1 or 2, it is characterised in that: active constituent (a) is cis-platinum or its derivative Object.
4. pharmaceutical composition according to claim 3, it is characterised in that: the quality of active constituent (a) and active constituent (b) Than for (0~2): (10~300), and the amount of active constituent (a) is not 0.
5. pharmaceutical composition according to claim 4, it is characterised in that: the quality of active constituent (a) and active constituent (b) Than for (0.1~1): (100~300).
6. pharmaceutical composition according to claim 1 or 2, it is characterised in that: active constituent (a) is taxol or its derivative Object.
7. pharmaceutical composition according to claim 6, it is characterised in that: the quality of active constituent (a), active constituent (b) Than for (0~2): (10~300), and the amount of active constituent (a) is not 0.
8. pharmaceutical composition according to claim 7, it is characterised in that: the quality of active constituent (a), active constituent (b) Than for (1~2): (80~300).
9. pharmaceutical composition according to claim 1, it is characterised in that: pharmaceutical composition is injection, tablet, capsule At least one of.
10. a kind of purposes of Berbamine hydrochloride, it is characterised in that: be used to prepare a kind of preparation or a kind of medicine box, the preparation or Medicine box is for improving chemotherapeutics to the therapeutic effect of cancer patient, or for reducing the side effect of chemotherapeutics.
CN201811436483.4A 2018-11-28 2018-11-28 Pharmaceutical composition containing chemotherapeutics and Berbamine hydrochloride Pending CN109481688A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111265545A (en) * 2020-02-18 2020-06-12 广州中医药大学(广州中医药研究院) Composition for treating lung tumor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103181896A (en) * 2011-12-30 2013-07-03 沈阳药科大学 Liposome preparation comprising berbamine medicine, and preparation method thereof
CN106031726A (en) * 2016-03-17 2016-10-19 上海交通大学 Docetaxel and berbamine double-load drug chitosan nanoparticles and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103181896A (en) * 2011-12-30 2013-07-03 沈阳药科大学 Liposome preparation comprising berbamine medicine, and preparation method thereof
CN106031726A (en) * 2016-03-17 2016-10-19 上海交通大学 Docetaxel and berbamine double-load drug chitosan nanoparticles and preparation method thereof

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Title
JIA, FENG 等: "Synergistic Antitumor Effects of Berbamine and Paclitaxel through ROS/Akt Pathway in Glioma Cells.", 《EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE》 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111265545A (en) * 2020-02-18 2020-06-12 广州中医药大学(广州中医药研究院) Composition for treating lung tumor

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