CN102133219A - Anti-cervical cancer effect of oleanolic acid and pharmaceutical preparation thereof - Google Patents
Anti-cervical cancer effect of oleanolic acid and pharmaceutical preparation thereof Download PDFInfo
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- CN102133219A CN102133219A CN2010102926552A CN201010292655A CN102133219A CN 102133219 A CN102133219 A CN 102133219A CN 2010102926552 A CN2010102926552 A CN 2010102926552A CN 201010292655 A CN201010292655 A CN 201010292655A CN 102133219 A CN102133219 A CN 102133219A
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Abstract
The invention discloses a new medical application of oleanolic acid in cervical cancer resistance, and also discloses clinically acceptable pharmaceutical preparations such as tables, capsules, pills, injections and the like which are prepared by using oleanolic acid as a pharmaceutical raw material. The oleanolic acid pharmaceutical preparation of the present invention comprises 1%-99% of oleanolic acids and 99%-1% medicinal excipients (including other compatible drugs). The oleanolic acid and the pharmaceutical preparations thereof provided by the invention have an excellent anti-cervical cancer effect which is represented by significant inhibitory activity against in vitro human cervical cancer cells and significant tumor inhibitory activity against a transplanted tumor in nude mice of the cancer cell. In addition, the active components of the pharmaceutical preparation are traditional Chinese medicine extracts, so the preparation has the advantage of less toxic and side effect than chemotherapeutic drugs.
Description
Technical field
The present invention relates to application and the pharmaceutical preparation thereof of oleanolic acid (Oleanolic acid) aspect anti-cervical cancer, belongs to the field of Chinese medicines.
Background technology
Oleanolic acid (Oleanolic acid) is a pentacyclic triterpenoid, is present in the various plants with the form of episome and glycocide.The main leaf that extracts source Oleaceae plant olive, the Fructus Ligustri Lucidi fruit; Gentianaceae plant Herba Swertiae Mileensis herb, Swertia mussotii Franch.; Leaf, the root of the big star celery of samphire; Wu adds the root bark and the peel of stem of the Zhi Wu of section Cortex araliae chinensis; The big seed Radix Hemsleyae Macrospermae of cucurbitaceous plant, lovely Radix Hemsleyae Macrospermae, the tuber of Chinese Radix Hemsleyae Macrospermae.
The pharmacologic action that oleanolic acid has been reported mainly contains hepatoprotective and falls enzyme, promotes liver cell regeneration, antiinflammatory, heart tonifying, diuresis also have effects such as blood sugar lowering, blood fat reducing, calmness, is the effective ingredient of medicines such as exploitation treatment hepatopathy and blood sugar lowering.We find that in screening antitumor drug process oleanolic acid has the effect of stronger inhibition cervical cancer cell and solid tumor growth thereof.
Before the present invention, do not see with the oleanolic acid to be raw material research pharmaceutical dosage form and the report that is used to prevent and treat the cervical cancer disease.Oleanolic acid is a pentacyclic triterpenoid, and is almost non-toxic, and natural resources of Chinese medicinal materials is very abundant, is a kind of very promising antitumor drug.
The chemical name of oleanolic acid (Oleanolic acid): 3 β-hydroxy-olea-12-en-28-oic acid; Molecular formula C
30H
48O
3Molecular weight: 456.71.
Chemical structural formula:
Summary of the invention
One of purpose of the present invention has provided the pharmaceutical preparation of oleanolic acid;
Two of purpose of the present invention has provided the antineoplastic new usage of oleanolic acid.
The objective of the invention is to be achieved through the following technical solutions:
Pharmaceutical preparation of the present invention contains the oleanolic acid of 1%-99% and the excipient of 99%-1% (medicine that comprises other adapted), preferably contain the oleanolic acid of 20%-80% and the excipient of 80%-20% (medicine that comprises other adapted), preferably contain the oleanolic acid of 60%-70% and the excipient of 40%-30% (medicine that comprises other adapted).
Press practice of pharmacy, oleanolic acid of the present invention can be prepared into the various clinical pharmaceutical dosage form as medicament for resisting cervical 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 medicament for resisting cervical 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 oleanolic acid that refers to effective dose is certain medicine material, again compatibility other allowed the Chinese medicine or the chemical drugs that share.
Oleanolic acid pharmaceutical preparation of the present invention has the anti-cervical cancer effect, is to be confirmed by following pharmacodynamics test.
Test example 1 has been investigated the inhibitory action of oleanolic acid to external cervical cancer cell
Cell: human cervical carcinoma's epithelial cell (Hela).For ocean institute of Chinese Academy of Sciences marine drug laboratory provides.
Medicine and reagent: ocean institute of oleanolic acid (Oleanolic 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 oleanolic 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 oleanolic acid of variable concentrations has in various degree inhibitory action to the human cervical carcinoma's epithelial cell (Hela) that is used to test, and is certain dose-dependence, and the oleanolic acid of variable concentrations is to suppression ratio, the IC of cervical cancer cell
50Value sees table 1 for details.
The oleanolic acid of table 1 variable concentrations is to the suppression ratio of cervical cancer cell (Hela)
Test example 2 oleanolic acid are to the tumor-inhibiting action of cervical cancer 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: human cervical carcinoma's epithelial cell (Hela) of the trophophase of taking the logarithm 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, oleanolic 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) oleanolic acid group: 40mg/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 oleanolic acid is to the inhibitory action result of the test of Hela 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 oleanolic acid treatment group and 5-FU treatment group all has been subjected to inhibition in various degree than matched group, and the oleanolic acid group to the influence of nude mice body weight all less than 1.0%, show that oleanolic acid does not have obvious toxic-side effects.
Above-mentioned isolated test and bulk testing show that oleanolic acid all has the obvious suppression effect to stripped and whole man's cervical cancer cell, and does not have obvious toxic-side effects, and the prompting oleanolic acid is a kind of very promising medicament for resisting cervical cancer.
The specific embodiment
The preparation of embodiment 1 tablet
Oleanolic 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
Oleanolic 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 oleanolic 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 Olea acid dropping balls.Oral, one time four, three times on the one, one after each meal.
The preparation of embodiment 4 granules
Oleanolic 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 oleanolic 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 oleanolic 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
Oleanolic 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 cervical cancer is characterized in that containing the oleanolic acid for the treatment of effective dose and one or more pharmaceutically acceptable pharmaceutical excipients, or can with the other medicines of oleanolic acid prescription.
2. pharmaceutical preparation according to claim 1, but it is characterized in that containing oleanolic 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 oleanolic 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 oleanolic 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 oleanolic acid in the preparation medicament for resisting cervical cancer.
9. purposes according to Claim 8 is characterized in that said anti-cervical cancer is meant the growth that suppresses human cervical carcinoma's epithelial cell (Hela) and nude mice transplanted tumor thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013079024A1 (en) | 2011-12-01 | 2013-06-06 | 杭州本生药业有限公司 | Oleanolic acid amidate derivatives, preparation methods and uses thereof |
| WO2013079018A1 (en) | 2011-12-01 | 2013-06-06 | 杭州本生药业有限公司 | 2-substituted oleanolic acid derivative, method preparing for same, and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1704062A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Sustained release tablet of oleanolic acid and its preparation method |
-
2010
- 2010-09-27 CN CN2010102926552A patent/CN102133219A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1704062A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Sustained release tablet of oleanolic acid and its preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 耿传营等: "中药单体齐墩果酸、姜黄素和大蒜素增强宫颈癌Me180细胞放疗敏感性", 《中华放射医学与防护杂志》, vol. 29, no. 5, 31 October 2009 (2009-10-31), pages 472 - 475 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013079024A1 (en) | 2011-12-01 | 2013-06-06 | 杭州本生药业有限公司 | Oleanolic acid amidate derivatives, preparation methods and uses thereof |
| WO2013079018A1 (en) | 2011-12-01 | 2013-06-06 | 杭州本生药业有限公司 | 2-substituted oleanolic acid derivative, method preparing for same, and application thereof |
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Application publication date: 20110727 |