CN102091078A - Maslinic acid anti-hepatocarcinoma effect and maslinic acid medicinal preparation - Google Patents
Maslinic acid anti-hepatocarcinoma effect and maslinic acid medicinal preparation Download PDFInfo
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- CN102091078A CN102091078A CN2010102926533A CN201010292653A CN102091078A CN 102091078 A CN102091078 A CN 102091078A CN 2010102926533 A CN2010102926533 A CN 2010102926533A CN 201010292653 A CN201010292653 A CN 201010292653A CN 102091078 A CN102091078 A CN 102091078A
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- crataegolic acid
- maslinic acid
- maslinic
- hepatocarcinoma
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Abstract
The invention discloses new medical application of a Maslinic acid on an anti-hepatocarcinoma aspect and a clinically acceptable medicinal preparation such as tablets, capsules, pills, injections, and the like prepared by taking the maslinic acid as a pharmaceutical raw material. The maslinic acid medicinal preparation comprises the following components in percentage by weight: 1%-99% of maslinic acids and 99%-1% medicinal excipients (including other medicaments for compatibility). The maslinic acids and the maslinic acid medicinal preparation have very good anti-hepatocarcinoma effect and have obvious activity inhibition effect on in-vitro human hepatocarcinoma cells and outstanding antitumor activity on nude mouse transplanted tumor of the tumor cells; and besides, the maslinic acid medicinal preparation takes traditional Chinese medicine extractives as active components, thereby having relatively little toxic side effect compared to chemotherapeutic drugs.
Description
Technical field
The present invention relates to application and the pharmaceutical preparation thereof of Crataegolic acid (Maslinic acid) aspect medicines resistant to liver cancer, belongs to the field of Chinese medicines.
Background technology
Crataegolic acid (Maslinic acid) is a pentacyclic triterpenoid.Main source Fructus Jujubae, Fructus Canarii albi, Fructus Crataegi, Punica granatum L. and the Salvia japonica Thunb. etc. of extracting.
Malignant tumor is the commonly encountered diseases and the frequently-occurring disease of serious threat human health, and the exploitation of cancer therapy drug has become the key subjects of new drug research in this century.At present, from plant, seek the antitumor drug of high-efficiency low-toxicity, become the emphasis of domestic and international antitumor drug research.We find that in screening antitumor drug process Crataegolic acid has the effect of very strong inhibition hepatoma carcinoma cell and solid tumor growth.
Before the present invention, do not find with the Crataegolic acid to be feedstock production pharmaceutical dosage form and the report that is used to prevent and treat liver cancer diseases.Crataegolic acid is almost non-toxic, and natural resources of Chinese medicinal materials is very abundant, is a kind of very promising antitumor drug.
The Crataegolic acid another name: (2alpha, 3beta)-2,3-dihydroxy olive-12-alkene-28-acid; Maslinic acid; 2a-hydroxyl oleanolic acid.Molecular weight: 472.7; Molecular formula: C
30H
48O
4
Chemical structural formula:
Summary of the invention
One of purpose of the present invention has provided the pharmaceutical preparation of Crataegolic acid;
Two of purpose of the present invention has provided the antineoplastic new usage of Crataegolic acid.
The objective of the invention is to be achieved through the following technical solutions:
Pharmaceutical preparation of the present invention contains the Crataegolic acid of 1%-99% and the excipient of 99%-1% (medicine that comprises other adapted), preferably contain the Crataegolic acid of 20%-80% and the excipient of 80%-20% (medicine that comprises other adapted), preferably contain the Crataegolic acid of 60%-70% and the excipient of 40%-30% (medicine that comprises other adapted).
Press practice of pharmacy, Crataegolic acid of the present invention can be prepared into the various clinical pharmaceutical dosage form as medicines resistant to liver cancer, comprise the dosage form of oral formulations or parenterai administration.Said oral formulations selects any in tablet, capsule, pill, granule, microcapsule tablet, suspensoid, drop pill, oral liquid; Said parenterai administration dosage form is selected from a kind of in the middle of injection, aerosol, suppository or the subcutaneous administration dosage form.
Adjuvant in the medicines resistant to liver cancer of the present invention is meant conventional excipient, as solvent, disintegrating agent, correctives, antiseptic, coloring agent, binding agent etc.The medicine that other compatibility in the antitumor drug of the present invention is used, the Crataegolic acid that refers to effective dose is certain medicine material, again compatibility other allowed the Chinese medicine or the chemical drugs that share.
Crataegolic acid pharmaceutical preparation of the present invention has antihepatocarcinoma effect, is to be confirmed by following pharmacodynamics test.
Test example 1 has been investigated the inhibitory action of Crataegolic acid to external hepatoma carcinoma cell
Cell: human liver cancer cell (BEL-7402).For ocean institute of Chinese Academy of Sciences marine drug laboratory provides.
Medicine and reagent: ocean institute of Crataegolic acid (Maslinic acid) Chinese Academy of Sciences marine drug laboratory provides white powder; 5-fluorouracil (5-FU) Nantong elite pharmaceutical Co. Ltd product, lot number is 100402; MTT(SIGMA, USA); DMSO(SIGMA, USA); Trypsin SIGMA, USA); RPMI1640(GIBCO, Invitragen Co., USA); DMEM(GIBCO, Invitragen Co., USA); The top grade hyclone (GIBCO, Invitragen Co., USA); Superfine hyclone Fetal Bovine Serum(Hyclone).
Instrument: ultra cold storage freezer (Nature, USA), cell culture incubator (SANYO, Japan), inverted microscope (NIKON, Japan), microplate reader (Bio-Tek Instruments, Inooski, VT, USA), PH counts (Thermo orion, USA), superclean bench (FLC-Harbin Dong Lian instrument plant).
Experimental technique mtt assay: tumor cell line is gone down to posterity according to the conventional method cultivation, collect the exponential phase cell, regulate concentration of cell suspension 5 * 10
4About individual/ml.Cell suspension is added in 96 well culture plates, and each hole adds 180 μ l.After placing 37 ℃ of constant incubators to cultivate 24 h, experimental group adds each concentration Crataegolic acid (with 5-FU as positive controls) 20 μ l/ holes, establishes 4 parallel holes for every group, and establishes blank well (only adding the medicinal solvent of dissolving) with zeroing.37 ℃ of incubators, cultivate 48 h after, with liquid-transfering gun liquid in 96 orifice plates is cleaned every hole, back and adds MTT(1 mg/ml) 30 μ l, put CO
2Incubator is cultivated 4 h for 37 ℃, supernatant discarded, and every hole adds DMSO 150 μ l, puts shaking table and shakes up 30 min, detects under 492 nm with microplate reader, utilizes the SPSS statistical software, calculates cell mortality, asks for IC
50
Result of the test shows, through the SPSS software statistics, the Crataegolic acid of variable concentrations has in various degree inhibitory action to the human liver cancer cell (BEL-7402) that is used to test, and is certain dose-dependence, and the Crataegolic acid of variable concentrations is to suppression ratio, the IC of hepatoma carcinoma cell
50Value sees table 1 for details.
The Crataegolic acid of table 1 variable concentrations is to the suppression ratio of hepatoma carcinoma cell
Test example 2 Crataegolic acids are to the tumor-inhibiting action of hepatoma carcinoma cell transplanted tumor in nude mice
Laboratory animal: the BALB/c nude mice is available from Shanghai Slac Experimental Animal Co., Ltd., and animal licence numbering: SYXK (Shanghai) 2010-0047, totally 20, in 7 ~ 9 ages in week, body weight 20 ~ 22g is male Mus.Animal feeding and experiment are raised in the Affiliated Hospital of Qingdao University Experimental Animal Center for no special pathogen level barrier system.
Tumor cell inoculation: the human liver cancer cell of the trophophase of taking the logarithm (BEL-7402) is made tumor cell suspension (1 * 10
7Individual/as ml), to implant BALB/c male nude mouse armpit subcutaneous (about 0.3ml/ only), situations such as inoculation back routine observation mice spirit, diet and defecation.After going down to posterity once, with the aseptic taking-up of tumor tissues and be cut into big or small identical 2mm
3Fritter, it is subcutaneous to be seeded in the nude mice armpit with the trocar.
Test grouping and method: the major diameter of vernier caliper measurement tumor nodule (a), minor axis (b), by formula V=a * b
2* 0.52 calculates gross tumor volume, when subcutaneous transplantation tumor length to 100 mm
3After, selecting tumor nude mice of the same size, nude mice is weighed is divided into 3 groups with the table of random number method, is respectively negative control group, positive controls, Crataegolic acid group, every group of 5 nude mices.Drug level reaches and specifically is grouped as follows: (1) negative control group: lumbar injection 0.2ml normal saline; (2) positive drug matched group: the 5-FU of lumbar injection 30mg/kg; (3) Crataegolic acid group: 8mg/kg lumbar injection.Injection in per 3 days is once injected 10 times continuously, behind last administration 24 h, takes out the tumor piece, and it is heavy to measure tumor, calculates the average tumor suppression ratio at last.Adopt the SPSS software statistics, test data is with (average ± standard deviation) expression, and P is a significant difference significance criterion of meaning less than 0.01.Result of the test sees Table 2.
Table 2 Crataegolic acid is to the inhibitory action result of the test of BEL-7402 transplanted tumor in nude mice (`X ± SD)
Annotate: compare * * P＜0.01 * P＜0.05 with matched group
By table 2 as seen, the transplanted tumor in nude mice of Crataegolic acid treatment group and 5-FU treatment group all has been subjected to inhibition in various degree than matched group, and the Crataegolic acid group to the influence of nude mice body weight all less than 1.0%, show that Crataegolic acid does not have obvious toxic-side effects.
Above-mentioned isolated test and bulk testing show that Crataegolic acid all has the obvious suppression effect to stripped and whole man's hepatoma carcinoma cell, and does not have obvious toxic-side effects, and the prompting Crataegolic acid is a kind of very promising medicines resistant to liver cancer.
The specific embodiment
The preparation of embodiment 1 tablet
Crataegolic acid 1000g, medical starch 100g, mix homogeneously is granulated as binding agent with an amount of ethanol, drying, through the pelletizing machine granulate, tabletting, every 0.30g, oral, each 1-2 sheet, twice of every day.
The preparation of embodiment 2 capsules
Crataegolic acid 1000g, medical starch 100g, mix homogeneously is granulated as binding agent with an amount of ethanol, and drying is crossed 120 mesh sieve granulate, dress 0# capsule, every 0.300g, each oral 1-2 grain, twice of every day.
The preparation of embodiment 3 drop pills
Polyethylene Glycol
4000400g, in water-bath, melt, add Crataegolic acid raw material 250g, stir, in the impouring insulating tube, regulate thermostat, make medicinal liquid under 80-90 ℃, splash in the liquid paraffin that cooled off (temperature ± 4 ℃), after dripping off, to blot paraffin oil on the pill impouring filter paper, add a small amount of Pulvis Talci again, mixing gets 10000 of Crataegolic acid drop pill.Oral, one time four, three times on the one, one after each meal.
The preparation of embodiment 4 granules
Crataegolic acid raw material 100g, starch 1000g, Icing Sugar 500g, mix homogeneously is used an amount of alcohol granulation, and drying, granulate, packing are promptly.Oral, a 5g, twice on the one.
The preparation of embodiment 5 microencapsule tablets
Take by weighing stearic acid 12g and 18ml Herba Origani oil respectively as compound recipe capsule material, take by weighing Crataegolic acid 80g as capsule core material, by the spray congealing encystation, capsule directly is 10-100 μ m with compressed air.Then with microcapsule and microcrystalline Cellulose mixing, add the mixed encystation material of 12% ethyl cellulose alcoholic solution, make granule by 18 order nylon mesh,, placed exsiccator interior 24 hours in oven dry below 50 ℃, add 1%-3% magnesium stearate tabletting, get the Crataegolic acid microencapsule tablet, sheet heavily is 0.4g, and is oral, a 1-2 sheet, twice on the one.
The preparation of embodiment 6 injections
Crataegolic acid 40g, propylene glycol 50ml, PEG400 100ml, water for injection 600ml mixes heating in water bath 30 minutes, add benzyl alcohol 90ml, reuse water for injection adds to 1800ml, handles 10 minutes in ultrasound wave, heats 30 minutes in water-bath again, adjust pH is 5.5-6.5, filter, embedding, sterilization is promptly.Every 3ml, intramuscular injection, a 3ml, twice on the one.
Claims (9)
1. pharmaceutical preparation that is used for the treatment of hepatocarcinoma is characterized in that containing the Crataegolic acid for the treatment of effective dose and one or more pharmaceutically acceptable pharmaceutical excipients, or can with the other medicines of Crataegolic acid prescription.
2. pharmaceutical preparation according to claim 1, but it is characterized in that containing Crataegolic acid and the pharmaceutical excipient of 99%-1% or the medicine of other prescription of 1%-99%.
3. pharmaceutical preparation according to claim 2, but it is characterized in that containing Crataegolic acid and the pharmaceutical excipient of 80%-20% or the medicine of other prescription of 20%-80%.
4. pharmaceutical preparation according to claim 3, but it is characterized in that containing Crataegolic acid and the pharmaceutical excipient of 40%-30% or the medicine of other prescription of 60%-70%.
5. pharmaceutical preparation according to claim 1 is characterized in that said medicine is the dosage form of oral formulations or parenterai administration.
6. pharmaceutical preparation according to claim 5 is characterized in that said oral formulations is selected from any in tablet, pill, capsule, granule, microcapsule tablet, suspensoid, drop pill, the oral liquid.
7. pharmaceutical preparation according to claim 5 is characterized in that said parenterai administration dosage form is selected from any in the middle of injection, aerosol, suppository or the subcutaneous administration dosage form.
8. the application of Crataegolic acid in the preparation medicines resistant to liver cancer.
9. purposes according to Claim 8 is characterized in that said anti-hepatocarcinoma is meant the growth that suppresses human liver cancer cell (BEL-7402) and nude mice transplanted tumor thereof.
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| CN2010102926533A CN102091078A (en) | 2010-09-27 | 2010-09-27 | Maslinic acid anti-hepatocarcinoma effect and maslinic acid medicinal preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670621A (en) * | 2012-06-12 | 2012-09-19 | 昆明理工大学 | Application of maslinic acid in preparation of anti-tumor-angiogenesis medicament |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1450900A (en) * | 2000-07-31 | 2003-10-22 | 日清奥利友株式会社 | Antitumor agents |
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2010
- 2010-09-27 CN CN2010102926533A patent/CN102091078A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1450900A (en) * | 2000-07-31 | 2003-10-22 | 日清奥利友株式会社 | Antitumor agents |
Non-Patent Citations (1)
| Title |
|---|
| 王博等: "山楂酸的研究进展", 《生命科学》, vol. 21, no. 2, 30 April 2009 (2009-04-30), pages 264 - 269 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670621A (en) * | 2012-06-12 | 2012-09-19 | 昆明理工大学 | Application of maslinic acid in preparation of anti-tumor-angiogenesis medicament |
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Application publication date: 20110615 |