CN101309692A - Application of curbitacin or curbitacin combination in leucocyte increasing medicament preparation - Google Patents
Application of curbitacin or curbitacin combination in leucocyte increasing medicament preparation Download PDFInfo
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Abstract
The use of cucurbitacins or cucurbitacin compositions in preparation of medicaments for raising l
Description
Sprout the applied technical field of Lu Su or curbitacin combination in the medicine for improving leucocyte is prepared
The present invention relates to a kind of new pharmacologic application of known substance, and in particular to the application of a kind of cucurbitacin or curbitacin combination in the medicine for improving leucocyte is prepared.
Background technology
Cucurbitacin (Cupurbitacins) belongs to 19- methyl and appears in a class tetracyclic triterpenoids compound on C-9 positions, it is distributed mainly in cucurbitaceous plant, is also found in the higher plants such as Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae and some macro fungis（Including cucurbitacin A, B, C, D, E, I, Q etc.）.Kunming plant institute of Chinese Academy of Sciences researcher Qiu Minghua leads scientific and technical personnel on the basis of a series of new cucurbitacin of discovery, it have studied 229 almost all of cucurbitane compounds, propose new textural classification pattern, thus 5 preceding class formation types are divided into 12 classes again, have obtained the accreditation of international academic community.At present, the cucurbitacin of China's approval production is called Cucurbitacine, is Chinese medicine muskmelon pedicel（Alias：Calyx meto）Extract, mainly containing compositions such as Cucurbitacin B, E, Cucurbitacin B content is more than 60% in existing extract, and Cucurbitacin B content is up to more than 90% after purification.Cucurbit plain piece is used to treat chronic hepatitis (1986,21 (6) of cucurbit plain piece pharmacy circular:357), through 13, the ground such as Shanghai, Beijing, Chongqing hospital clinical, its effective percentage is 75.2%, and obvious effective rate is 44.6%.Clinically it was observed that cucurbit plain piece can more fully improve chronic hepatitis common sympton and main physical signs, and there is obvious drop enzyme（S-GPT), drop turbid（TTT, ZnTT) and the red matter effect of drop courage, S-GPT is not caused to bounce after drug withdrawal, albumen is inverted and hyperglobulinemia also has obvious role of correcting, moreover it is possible to the Nonspecific immunity ability of chronic hepatitis patient, no obvious toxic-side effects is improved.With the exception of this, cucurbit plain piece can be used for treating primary carcinoma of liver, be observed through six, the ground such as Shanghai, Beijing, Guangxi hospital clinical, count 169, effective percentage 69%, obvious effective rate 39%.Clinical observation shows, the medicine and 5-fluor-uracil (5 FU 5 fluorouracil, 5-Fluorouracil, 5-FU) compare, it improves symptom, eliminates hepatodynia, reduce knurl body, extension life cycle, regain one's strength, control group is superior to, and without the toxic side effect of general chemotherapeutics（" treatment hepatitis, liver cancer new drug cucurbit plain piece "《Chinese herbal medicine》 1987, 18(10):21, " 50 clinical observations of cucurbit extract for treating primary carcinoma of liver "《New drug and clinic》 1984,3(2):21-22, " pharmacology of cucurbitacin and clinical practice "《Chinese herbal medicine》 1992,23(11): 605 ~ 608 ).There is author to join cucurbit plain piece and chemotherapeutic recently, control ^ mid and late liver cancers, median survival interval was brought up to 12.5 ± 7.54 months by 6.1 ± 7.12 months of single chemotherapeutic（" calabash ' reed plain piece add the clinical observation on the therapeutic effect of Chemotherapeutic treatments advanced primary liver cancer "《Cancer》 1989, 8(6): 434-436)；It is another to there is text to find Cucurbitacin B, the g/ml of E (II) 20 are 82.6% to the killing rate of cancer cell, when concentration is improved to 80 g/ml, and its killing rate is up to 94.1%, and the influence to normal person's lymphocyte transformation rate then divides Do to be 90.6% and 89.5%, show（Π) there is stronger lethal effect to nasopharyngeal carcinoma cell, it can promote the transformation function of normal lymphocytes simultaneously；Found when carrying out cucurbit plain piece with existing medicine-Mieaoling treatment chronic hepatitis B comparitive study, calabash takes in treatment group
Reed plain piece, oral meal, 3 times on the 1st, 2 tablets once, with 3 ~ 6 months for a course for the treatment of.Control group takes Mieaoling Tablets.As a result Zhi Liao Group total effective rates are 67.4%, and control group total effective rate is 35.9%, Ρ<0.01 (" 89 observation of curative effect of cucurbit plain piece treatment chronic hepatitis B "《Zhejiang College Of Traditional Chinese Medicine journal》 1994, 18(4): 18-19 ) ；There is document to point out, long-term therapy medication（6 weeks）Gan Xian Wei Group can substantially be suppressed and knit hyperplasia, fatty degeneration of liver and the formation and development of cirrhosis is prevented.Existing formulation is tablet etc., for oral solid formulation, and due to the poorly water-soluble of cucurbitacin, the In Vitro Dissolution fluctuation of tablet is larger, and dissolution is slow, is so unfavorable for clinical treatment.For problems, someone has applied for the patent of nano medicine ' Hulusu ' and preparation method thereof, application number：01103658.3, in the disclosure in this patent, disclose the nano medicine ' Hulusu ' that the steps such as a kind of use microwave abstracting, Minus pressures concentration, the spray drying of supersonic jet technology are made, its grain fineness reaches 1200-1500 mesh, particle diameter is 0.1 200nm, wherein most particle diameters are less than 100nm.The drug bioavailability is high, and therapeutic effect is notable.In addition, still there is the following patent：" cucurbitacin cyclodextrin inclusion compound and its preparation " number of patent application： 02153647.3 ;" cucurbitacin liposome prescription and its preparation " number of patent application： 02144633.4;" drop pills of cucurbitacine and preparation method thereof " is applied（Patent）Number： 200310100943.3.Also there is document that cucurbitacin is prepared into emulsion, and investigated preparation technology（《Central-South pharmacy》 2004, 2(2): 73~76 ).In the publication, author prepares fat emulsion using soybean oil, and the concentration of its oil phase is 20%, and phospholipid concentration is 1.2%, and glycerol concentration is 2.1%, and drug dose is 0.01% (O.lmg/ml), and gained emulsion is in 115.C sterilizes 30 minutes, and granularity is 390nm.Author has also investigated stability influence of the pH value to medicine, and pH value is adjusted into 8.50,9.50 before finding sterilizing, and the pH value after sterilizing is 6.96,7.30, and the content of medicine is greatly reduced, particularly the latter, and content declines about 10%.In order to solve this problem, there is patent application to may filter that degerming emulsion.
Recently, it is beautiful！Researcher's report, the mechanism of action of cucurbitacin anticancer is suppresses STAT3 activity, and Bolleddula Jayaprakasam etc. compare cucurbitacin ^ D, E, I and adriamycin（Doxorubicin, DXR) to people's carcinoma of the rectum
(HCT-116), breast cancer（MCF-7), lung cancer（) and central nervous system cancer NCI-H460（SF-268) active anticancer of cell, as a result shows, in selected four kinds of oncocytes, and Cucurbitacin B is in 0.4 μ Μ, and the inhibiting rate to people's carcinoma of the rectum is 81.5%, human breast carcinoma 87%;Inhibiting rate in 0.1 μ Μ to human lung cancer is 96%;0.05 μ Μ are 92% to the inhibiting rate of people's CNS cancers, are above the inhibiting rate of adriamycin（Respectively 64%, 47%, 45%, 71%, 3 μ Μ), i.e. cucurbitacin Β corresponding oncocyte toxicity is at least adriamycin 7.5,30,60 times（ Bolleddula Jayaprakasam et al. Anticancer and antiinflammatoru activity of cucurbitacins from Cucurbita andreana Cancer Letters 2003, 189:11-16 X are in same piece document, and author also found, cucurbitacin Β selects COX-2 N to give birth to inhibitory action.Another sunset is foretold, the report Cucurbitacin B anti-liver cancer and anti-cell such as Judit Bartalis（HepG2 IC)50For 27.7 μM, cucurbitacin Ε is 15.3 μ Μ (Judit Bartalis et al Relationship between cucurbitacins reversed-phase high-performance liquid chromatography hydrophobicity index
and basal cytotoxicity on HepG2 cells Journal of Chromatography B , 818 ( 2005 ) 159-166 ).The content of the invention
It is an object of the invention to provide a kind of cucurbitacin or the new pharmacologic application of curbitacin combination, i.e. cucurbitacin or calabash Lu Su Group compounds are preparing the application in improving leucocyte medicine, to reach the therapeutic effect for improving leucocyte, quantity of leucocyte is particularly improved during cancer chemotherapy, strengthens the therapeutic effect to cancer.
Completing the scheme of foregoing invention task is, a kind of application process of cucurbitacin or curbitacin combination：The application of cucurbitacin or curbitacin combination in the medicine for improving leucocyte is prepared.
Cucurbitacin described in such scheme is the class tetracyclic triterpenoids compound extracted in cucurbitaceous plant, Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae plant and some macro fungis.
Described cucurbitacin or calabash Lu Su Group compounds includes：The exclusive use of the cucurbitacin of single component, and cucurbitacin A,
The curbitacin combination of two or more composition composition in B, C, D, E, I, Q, or the composition that cucurbitacin is constituted with other antineoplastics；Especially cucurbitacin constitutes the use in conjunction of composition with other antineoplastics.
Such scheme ^ is further limited：When cucurbitacin is used to prepare raising leucocyte medicine, Cucurbitacin B content is 50% ~ 100% in described cucurbitacin or curbitacin combination；Its remaining Group point includes cucurbitacin, cucurbitacin C, cucurbitacin 1), cucurbatacin E, cucurbitacin I, one or more kinds of compositions in cucurbitacin Q；Or antineoplastic.
The application recommends：Except the antineoplastic beyond the region of objective existence in composition, the cucurbitacin or curbitacin combination that preferentially use are the Cucurbitacines as Chinese medicine muskmelon pedicel extract, mainly containing compositions such as Cucurbitacin B, E.
Method of administration includes external application, oral and drug administration by injection；Form of administration is tablet, powder, glue Nang agent, granule, supensoid agent, syrup, oral liquid, emulsion, nanoparticle, liposome, ointment, patch or injection.
When the clinical drug is used to improve leucocyte, cucurbitacin or the curbitacin combination dosage according to Cucurbitacin B content be more than 50%, total cucurbitacin that two or more composition in cucurbitacin A, B, C, D, E, I, Q is constituted calculates, mouse with O.OOl mg/kilogram ~ l mg/kg body weight are administered, health adult is 0.1mg 5mg/ days with dosage.
Described cucurbitacin or curbitacin combination is preparing the application in improving leucocyte medicine, can be the folk prescription of above-mentioned cucurbitacin；It can also be the prescription that the cucurbitacin or curbitacin combination are collectively formed with other drugs.
In folk prescription Huo Group square preparations, cucurbitacin accounts for 0.0001% ~ 99.9% weight.
For example, the prescription that the folk prescription of cucurbitacin, cucurbitacin and other drugs are collectively formed, can be selected from order side or prescription：
Cucurbit essence injecta folk prescription：
Cucurbitacin and lecithin mass ratio 1： 200〜 1 ： 10000;
Described lecithin includes yolk ovum crack fat or soybean lecithin.
Cucurbitacin and ethanol-HS15- water 0.1: 200-800 ： 50-500: 0~800.
The cucurbitacin Ru Ji Group sides especially emphasized, each component mass ratio composition：
Cucurbitacin 0.005 ~ 0.015g, HS15 l ~ 2g, the bony 0.5 ~ 1.5g of fat of soybean, midchain oil (pungent certain herbaceous plants with big flowers acid glyceride）0 ~ 20g, soybean oil 0 20g, 0 ~ 0.15g of vitamin E, 2 ~ 3g of glycerine;Midchain oil therein（Pungent certain herbaceous plants with big flowers acid glyceride）With in two components of soybean oil, the consumption of at least one be 0;
The following is when with antineoplastic use in conjunction, the reduction leucocyte of cucurbitacin reduction antineoplastic toxicity, i.e. cucurbitacin or calabash Lu Su Group compound antagonism antineoplastics is acted on：
Cucurbitacin and antineoplastic prescription
Endoxan (CTX) and cucurbitacin mass ratio 300/1-500/1；
Docetaxel and cucurbitacin mass ratio 500/2-500/4；
Adriamycin（DXR) with cucurbitacin mass ratio 100/1-30/1;
Taxol and 1000/1-100/5 of cucurbitacin mass ratio；
The further optimization of each above-mentioned prescription, its mass ratio is,
Cucurbitacin and egg yolk lecithin 1： 300 - 1 600;
Cucurbitacin and ethanol-HS15- water 0.1: 300-500 100-300: 50-500;
Ring upright stone tablet acid amides and cucurbitacin 400/1;
Docetaxel and cucurbitacin 500/3；
Adriamycin and cucurbit quality 100/2；
Taxol and cucurbitacin 400/1- 1000/3;
The newborn agent Group side of described cucurbitacin, each Group points of mass ratioes are：Cucurbitacin O.Olg, HS15 1.5g, soybean lecithin lg, pungent certain herbaceous plants with big flowers acid glyceride 4 ~ 6g, 4 ~ 6g of soybean oil, 0.05 ~ 0.15g of vitamin E, glycerine 2.5g;
In above-mentioned cucurbitacin emulsion prescription, pungent certain herbaceous plants with big flowers acid glyceride optimum quality ratio is 5g;Soybean oil optimum quality ratio is 5g;Vitamin E optimum quality ratio is O.lg.
The application recommends following prescription：
Cucurbitacin lipidosome injection：Cucurbitacin is 1 with egg yolk lecithin mass ratio: 300-1 : 500 ( 1 : 600 );Cucurbitacin and antineoplastic prescription：
Endoxan（CTX it is) 40 mg/0.1mg (400/1) with cucurbitacin mass ratio;
Docetaxel is 50mg/0.3mg (500/3) with cucurbitacin mass ratio;
Adriamycin（DXR) it is with cucurbitacin mass ratio, 10 mg/0.2mg (100/2)；
Taxol and cucurbitacin, mass ratio are 40 mg/0.1mg ~ 100mg/0.3mg (400/1-1000/3);
Cucurbitacin emulsion for injection：Cucurbitacin O.Olg, HS15 1.5g, soybean lecithin lg, pungent certain herbaceous plants with big flowers acid glyceride 5g, soybean oil 5g, vitamin E O.lg, glycerine 2.5g, remaining is water for injection, is added to 100g.
In addition, other formulations can be used, such as following prescription：
This Group of Ji of powder into（Calculated according to 1000 single doses）It is as follows：Cucurbitacin B 0.1g, xylitol 1000g, hydroxypropyl Yue base celluloses（HPMC) lg, micro mist baby's glue lg, essence, appropriate sweetener.
Glue Nang basic composition（Calculated according to 1000 single doses) it is as follows：Cucurbitacin B 0.1g, amylum pregelatinisatum 100g, spherical Wei Jing Xian Victoria elements 10g, superfine silica gel powder lg.
(flexible glue Nang（Calculated according to 1000 single doses）It is as follows：Cucurbitacin B 0.1g, midchain oil（Pungent certain herbaceous plants with big flowers acid glyceride, MCT) 50 ~ 500g.）
So far, there is not yet relevant improve leucocyte using cucurbitacin in institute ^ Γ document, the toxic side effect of reduction Radiotherapy chemotherapy improves the antitumous effect of drug combination.Cucurbitacin or curbitacin combination are used to prepare the medicine for improving leucocyte by the present invention, can improve leucocyte, and bright ^ improves injury effect of the chemotherapeutics to marrow, can improve curative effect with chemotherapy drugs in combination, lower bone marrow inhibition.Above effect has already been through substantial amounts of experiment inspection Face.
Embodiment
The detailed component of the present invention is provided by the following example, but protection scope of the present invention, is not only limited to this.
Embodiment 1, cucurbit extract（Cucurbitacin B content is more than 50%, about 56%)
1st, the preparation of pharmacological evaluation sample-Cucurbitacine supensoid agent
Using the Cucurbitacine raw material of purchase, using CMC-Na as suspending agent, supensoid agent is conventionally prepared, concentration is 0.1mg/ml.'
2nd, pharmacological evaluation
Normal Kunming small white mouse 48, is randomly divided into 8 groups, every group 6.It is administered, CTX intraperitoneal injections, cucurbitacin supensoid agent gastric infusion is administered every other day, is administered 5 times every other day, the μ 1 of venous blood collection 20 after second day mouse orbit, is counted with normal white blood cell count(WBC) method ten after administration terminates.It the results are shown in Table 1.
White blood cell count(WBC) result (the xlO of the raw material suspension oral medication group of table 1 and control group9 · L"1) group dose animals number（Start/last）Leukocyte count (± SD) normal group -6/6 7.88 ± 2.01
CTX (IP) ' 60mg/kg 6/6 3.62±0.86
CTX (IP)+high 60mg/kg, 0.2mg/kg 6/6 6.57 ± 172χχ
30 mg/kg, 0.1mg/kg 6/6 7.03 ± 1.81 in CTX (IP) tenxx
CTX (IP)+low 30 mg/kg, 0.05mg/kg 6/6 6.12 ± 1.55xxHigh 0.2mg/kg 6/6 9.71 ± 2.58xxIn the 10.2+2.61 of 0.1 mg/kg 6/6oxxLow 0.05mg/kg 6/6 9.03 ± 2.26xxNote：Compared p with positive ^ groups<0.05;Compared with CTX groupsxp<0.05 xxp<0.01 (wherein p be significant difference；For average value；SD is standard deviation）Embodiment 2, cucurbit extract（Cucurbitacin B content is more than 80%, about 85.3%)
1st, the preparation of pharmacological evaluation sample-cucurbitacin liposome
By cucurbitacin and egg yolk lecithin according to 1:300 (W/W) feed intake, and are dissolved with the ethanol of appropriate amount, evaporated under reduced pressure ethanol, add aquation Jie's Wide 7Jization lipid films, are most disperseed afterwards through microjet, and 0.22 μ π ι miillpore filters excessively are degerming, and granularity about 160nm is produced.
2nd, pharmacology is real
H22Tumor-bearing mice cuts tail vein blood with scalpel and (determines white blood cell）, select the soil of body weight 20 2g, basic peripheral white blood cells (WBC) and be randomly divided into 7 groups, every group 10 close to person.Separately setting one group of normal mouse makees blank control（Give glucose injection）.It is administered since after modeling second day, fluorouracil control group is in the 1st, administration in 3,5,7,9 days, remaining group successive administration 10 days, once a day.Remaining group method of administration is tail vein injection in addition to gavage Group.The μ 1 of venous blood collection 20, is counted with conventional white cell counting after 11st day each group mouse orbit.It the results are shown in Table 2.
White blood cell count(WBC) result (the xlO of table 2, lipidosome injection treatment group and control group9 · L"1) group dose animals number（Start/last）Leukocyte count ± SD) -10,/10 6.74 ± 2.59 fluorouracil 15mg/kg 10,/10 3.82 ± 1.14 of 10,/10 8.00 ± 2.96 model group of normal groupΔΔ..High 0.11mg/kg 10,/10 1034 ± 4.04χχMiddle 0.055mg/kg 10,/10 914 ± 2.45.xx
Low 0.0275mg/kg 10,/10 9.27 ± 186x xThe 9.72+2.28 of gavage 0.11mg/kg 10/10 are noted：Compared with Normal groupΔ ρ<0.05 ΔΔ ρ<0.01
Compared p with model control group<0.05 °°p<0.01
Compared with fluorouracil groupxp<0.05 x xp<0.01 leukocyte counts test result indicates that, high, medium and low dosage group has significant differences relative to Gas uracil groups（), PO.01 prompting cucurbitacin lipidosome injection is while tumour is treated（Tumour inhibiting rate is respectively 48.2% 45.2%, and 40.4% 25.4%, 32.9%), no bone marrow inhibition, which even has, rises a white trend, hence it is evident that better than the chemotherapy medicine treatment for suppressing hemopoietic function of bone marrow.
(Cucurbitacin B content is more than 90%, about 91.5%) for embodiment 3, cucurbit extract
1st, the preparation of the real face sample-cucurbitacin emulsion of pharmacology
Composition:Cucurbitacin O.Olg, HS15 1.5g, soybean lecithin lg, midchain oil（Pungent certain herbaceous plants with big flowers acid glyceride）5g, soybean oil 5g, vitamin E O.lg, glycerine 2.5g, appropriate hydrochloric acid, remaining is water for injection, common 100ml manufacture methods：
1) midchain oil, soybean oil, vitamin E are placed in beaker, are heated to 60 °C, add soybean lecithin, HS15, strong agitation is dispersed to dissolving, adds medicine, stirring and dissolving；
2) preparation of aqueous phase：Glycerine is added in water for injection, and (activated carbon depyrogenation is used if necessary in 40 °C of lower stirring and dissolvings）；3) aqueous phase is added into oil phase, strong agitation 5min forms colostrum；
4) homogeneous Tong is crossed, the first step adjusts homogenization pressure to 4000psi, and second step is adjusted to 18000psi again, and solution is homogenized repeatedly, uniform emulsion is obtained, 0.3 μ ι η miillpore filters excessively are degerming, packing, inflated with nitrogen, sealing, sterilizing, thus obtaining the product this product.Average grain diameter is 183nm
2nd, pharmacology reality r
Normal Kunming small white mouse 78, is randomly divided into 13 groups, every group 6.It is administered every other day, CTX (endoxan）And its compound group is administered 5 times, Docetaxel, taxol, adriamycin（DXR) and respective joint group be administered 3 times, give glucose injection as blank control.After administration terminates, the μ 1 of venous blood collection 20, is counted with conventional white cell counting after each group mouse orbit.It the results are shown in Table influence result (xlO of the 3 cucurbitacin emulsions to white blood cell count(WBC)9 · L-1) group ■ dose animals numbers（The Jian beginnings/last）Leukocyte count (^ soil SD)
Normal group -6/6 8.51 ± 2.23
CTX 40mg/kg 6/6 3.11 ±1.36。。
20mg/kg 6/6 4.38±2.02
The compound CTX CTX40mg/kg of 10mg/kg 6/6 4.51 ± 1.96, cucurbitacin 6/6 7.36 ± 1.81x
The mg/kg of O.lmg/kg compound CTX CTX 20, cucurbitacin 6/6 7.52 ± 2.11x
The mg/kg of 0.05mg/kg compound CTX CTX 10, cucurbitacin 6/6 6.88 ± 1.72x
0.025mg/kg
TAXOL lOmg/kg 6/6 3.62±0.67xCompound TAXOLlOmg/kg, cucurbitacin 6/6 7.86 ± 2.03x
The ll of 0.03mg/kg docetaxels lOmg/kg 6/6 2.86+1.xCompound docetaxel 10mg/kg, cucurbitacin 6/6 7.12 ± 1.93x
0.06mg/kg
DXR lmg/kg 6/6 4.18±2.15x
DXR DXR lmg/kg, cucurbitacin 6/6 6.15 ± 1.88x
0.02mg/kg
Compound is noted：Compared p with blank control group.<0.05、 po<0.01;Compared p with corresponding chemotherapy groupx<0.05 note：The ratio of CTX and cucurbitacin is 40mg/0.1mg (400/1)；The ratio of DXR and cucurbitacin is 10 mg/0.2mg (50/1)；The ratio of Docetaxel and cucurbitacin is 50mg/0.3mg (500/3)；The use in conjunction ratio of taxol and cucurbitacin is： 100mg/0.3mg (1000/3).
Embodiment 4, self-emulsifying prescription are administered orally, and Cucurbitacine (the big what 60% of Cucurbitacin B content, about 62.6%):
1st, pharmacology reality-long-mouth dog sample（Milligram）：
Cucurbitacin 0.1
Propane diols 100
C8-C10 triglycerides 100
HS15 50
2nd, pharmacological evaluation
Normal Kunming small white mouse 30, is randomly divided into 5 groups of , Mei Group 6.It is administered every other day, CTX intraperitoneal injections（IP) it is administered, cucurbitacin self-emulsifying prescription gastric infusion is administered every other day, is administered 5 times, the μ 1 of venous blood collection 20 after second day mouse orbit, is counted with conventional white cell counting after administration terminates.It the results are shown in Table 4.
White blood cell count(WBC) result (the xlO of table 4, self-emulsifying prescription oral medication group and control group9 · L"1)
Note：Compared ρ with normal group<0.05;Compared with CTX groupsxp<0.05 embodiment 5, use in conjunction improve curative effect
Will27 groups, every group 10 are randomly divided into after model mice inoculation 24h：1. model control group（Give glucose injection）2. CTX (5mg/kg) (account for compound 98.9%) 3. CTX (10mg/kg) (account for compound 99.45%) 4. CTX (20mg/kg) (account for compound 99.7%) 5. cucurbitacin lipidosome injections（O.OSSmg'kg) 6. cucurbitacin lipidosome injection（ O.i^mg'kg-1)+CTX (5mg/kg) 7. cucurbitacin lipidosome injection (O.OSSmg'kg-1) (the basic, normal, high chemotherapy groups of lOmg/kgX CTX are respectively at the 1st, 3,5,7 days 0.1ml/10g intraperitoneal injections 5mg/kg, 10mg/kg, and 20mg/kg is administered four times by+CTX.Cucurbitacin lipidosome injection group one time a day in continuous 7 days tail vein injection O.OSSmg'kg^ cucurbitacins lipidosome injection merges CTX chemotherapeutic groups（5mg/kg, lOmg/kg) corresponding to the 1st, 3,5,7 days intraperitoneal injection CTX, be administered four times.Execution of weighing in 8th day, takes tumor mass to weigh, and calculates.It the results are shown in Table 5.
Table 5, the tumor-inhibiting action research (scholar SD) with CTX combinations to rat liver cancer H22
Compared with model group, * Ρ<0.05 * * Ρ<0.01 compares with corresponding CTX groups,Δ ρ<0.05 ΔΔρ<It is 0.01 embodiment 6, substantially the same manner as Example 1, but be with the following changes：The form of administration of described cucurbitacin is tablet, and wherein cucurbitacin Β content is 99.9%.The basic composition of tablet（Calculated according to 1000 single doses）It is as follows：Cucurbitacin B 0.1g, amylum pregelatinisatum 100g, lactose 20g, microcrystalline cellulose 10g, superfine silica gel powder lg.Can be using conventional pelletizing press sheet, it would however also be possible to employ direct powder compression；Gained tablet is still to be coated.
It is embodiment 7, substantially the same manner as Example 1, but be with the following changes：Form of administration is powder.Its his Group beyond Cucurbitacin B divides to enter for cucurbitacin.The basic composition of powder（Calculated according to 1000 single doses）It is as follows：Cucurbitacin B 0.1g, xylitol 1000g, hydroxypropyl methyl cellulose（HPMC) lg, superfine silica gel powder lg essence, appropriate sweetener.
Embodiment 8, are substantially the same manner as Example 1, but are with the following changes：Form of administration is glue Nang.Other components beyond Cucurbitacin B are cucurbitacin..Glue Nang basic composition（Calculated according to 1000 single doses）It is as follows：Cucurbitacin B 0.1g, amylum pregelatinisatum 100g, spherical microcrystalline cellulose 10g, superfine silica gel powder lg.
It is embodiment 9, substantially the same manner as Example 6, but be with the following changes：Form of administration is granule.Other components beyond Cucurbitacin B are cucurbitacin D.
It is embodiment 10, substantially the same manner as Example 1, but be with the following changes：Form of administration is supensoid agent.Cucurbitacin B
Other components in addition are cucurbitacin I.
It is embodiment 11, substantially the same manner as Example 1, but be with the following changes：Form of administration is syrup.It is cucurbitacin 0 that its his Group beyond Cucurbitacin B, which divides,.
It is embodiment 12, substantially the same manner as Example 1, but be with the following changes：Form of administration is oral liquid.
It is embodiment 13, essentially identical with embodiment 3 or 4, but be with the following changes：Form of administration is emulsion, Docetaxel and cucurbitacin, and ratio is 50mg/0.3mg (500/3).
It is embodiment 14, substantially the same manner as Example 13, but be with the following changes：Formulation is tablet.
It is embodiment 15, substantially the same manner as Example 13, but be with the following changes：Formulation is powder.
It is embodiment 16, substantially the same manner as Example 13, but be with the following changes：Formulation is capsule.
Embodiment 17 is substantially the same manner as Example 13, but is with the following changes：Formulation is injection.
It is embodiment 18 ~ 22, essentially identical with embodiment 13 ~ 17 respectively, but be with the following changes：
Docetaxel and cucurbitacin, ratio are 50mg/0.2mg (500/2).
The ratio of embodiment 23 27, Docetaxel and cucurbitacin is 50mg/0.4mg (500/4).
It is embodiment 28, substantially the same manner as Example 4, but be with the following changes：Form of administration is cucurbitacin lipidosome injection, and cucurbitacin is with Dan Huang Luan Lin fat according to 1: 200 ( w/w X
It is embodiment 29, substantially the same manner as Example 2, but be with the following changes：Cucurbitacin is with Dan Huang Luan Scales fat according to 1: 500 ( w/w )o
It is embodiment 30, substantially the same manner as Example 2, but be with the following changes：Cucurbitacin is with egg yolk lecithin according to 1: 10000 ( w/w )„ '
It is embodiment 31, substantially the same manner as Example 2, but be with the following changes：Cucurbitacin is with egg yolk lecithin according to 1:
600 ( w/w )o
It is embodiment 32, substantially the same manner as Example 2, but be with the following changes：Cucurbitacin is with yolk ovum upright stone tablet fat according to 1: 300 ( w/w X
It is embodiment 33 ~ 37, substantially the same manner as Example 2, but be with the following changes respectively:Formulation is respectively tablet, powder, glue Nang, emulsion and ointment.
It is embodiment 38, substantially the same manner as Example 3, but be with the following changes：Form of administration is cucurbitacin emulsion, CTX (endoxan）With cucurbitacin, ratio is 40 mg/O.lmg (400/1).
Embodiment 39, and embodiment 37 are essentially identical, but are with the following changes：CTX (endoxan）It is 30 mg/O.lmg (300/1) with cucurbitacin mass ratio.
It is embodiment 40, essentially identical with embodiment 37, but be with the following changes：CTX (endoxan）With cucurbit quality
Amount ratio is 50 mg/0.1mg (500/1).
It is embodiment 41, substantially the same manner as Example 3, but be with the following changes：Form of administration is cucurbitacin emulsion, adriamycin（DXR it is) 10 mg/0.2mg (100/2) with cucurbitacin mass ratio.
It is embodiment 42, essentially identical with embodiment 40, but be with the following changes：Adriamycin（DXR it is) 10 mg/O.lmg (100/1) with cucurbitacin mass ratio.
It is embodiment 43, essentially identical with embodiment 40, but be with the following changes：Adriamycin（DXR it is) 10 mg/0.3mg (100/3) with cucurbitacin mass ratio.
It is embodiment 44, substantially the same manner as Example 3, but be with the following changes：Form of administration is cucurbitacin emulsion, and taxol is 40 mg/O.lmg (400/1) with cucurbitacin mass ratio.
It is embodiment 45, substantially the same manner as Example 3, but be with the following changes：Form of administration is cucurbitacin emulsion, and taxol is 100mg/0.3mg (1000/3) with cucurbitacin mass ratio.
It is embodiment 46, substantially the same manner as Example 3, but be with the following changes：Form of administration is cucurbitacin emulsion, and taxol is lOOmg/O.lmg (1000/ 1) with cucurbitacin mass ratio.
It is embodiment 47, substantially the same manner as Example 3, but be with the following changes：Form of administration is cucurbitacin emulsion, and taxol is 10mg/0.5mg (100/5) with cucurbitacin mass ratio.
Embodiment 48, cucurbit essence injecta folk prescription：
Cucurbitacin and ethanol-HS15- water 0.1: 800 ： 500: 800.
It is embodiment 49, essentially identical with embodiment 48, but ratio is：
Cucurbitacin and ethanol-HS15- water 0.1: 200 ： 50: 0.
It is embodiment 50, essentially identical with embodiment 48, but ratio is：
Cucurbitacin and ethanol-HS15- water 0.1: 300 ： 100: 50.
Embodiment 51 and the base ^ mesh of embodiment 48 are same, but ratio is：
Cucurbitacin and ethanol-HS15- water 0.1: 500 ： 300: 500.
It is embodiment 52 ~ 56, essentially identical with embodiment 48, but be with the following changes：Water for injection therein is changed to pharmaceutical excipient, and formulation is respectively tablet, powder, glue Nang, emulsion and ointment.
It is embodiment 57, essentially identical with above example, but be with the following changes：Form of administration is nanoparticle.
Embodiment 58, ' essentially identical with above example, but be with the following changes：Form of administration is liposome.
It is embodiment 59, essentially identical with above example, but be with the following changes：Form of administration is ointment.
It is embodiment 60, essentially identical with above example, but be with the following changes：Form of administration is patch.
Embodiment61st, flexible glue Nang（Calculated according to 1000 single doses）：Cucurbitacin B 0.1g, midchain oil（ MCT ) 50g.
After dissolving, flexible glue Chinese bush cherry is suppressed.
Embodiment 62, flexible glue Nang（Calculated according to 1000 single doses）：Cucurbitacin B 0.1g, midchain oil（MCT) after 200g. dissolvings, compacting flexible glue is most.
Embodiment 63, flexible glue Nang（Calculated according to 1000 single doses）：Cucurbitacin B 0.1g, midchain oil（ MCT ) 500goAfter dissolving, soft capsule is suppressed.
Claims (1)
- Claim1st, a kind of application process of cucurbitacin：The application of cucurbitacin or curbitacin combination in the medicine for improving leucocyte is prepared.2nd, the application of cucurbitacin or curbitacin combination according to claim 1 in the medicine for improving leucocyte is prepared, characterized in that, described cucurbitacin is the class tetracyclic triterpenoids compound extracted in cucurbitaceous plant, Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae plant and some macro fungis.3rd, the application of cucurbitacin or curbitacin combination according to claim 2 in the medicine for improving leucocyte is prepared, it is characterised in that described cucurbitacin or curbitacin combination refers to：The exclusive use of the cucurbitacin of single component；Or the curbitacin combination of two or more composition composition in cucurbitacin A, B, C, D, E, I, Q；Or the composition that cucurbitacin is constituted with other antineoplastics.4th, the application of cucurbitacin or curbitacin combination according to claim 3 in the medicine for improving leucocyte is prepared, it is characterised in that Cucurbitacin B content is 50% ~ 100% in described cucurbitacin or curbitacin combination；Remaining component includes the one or more kinds of compositions sprouted in Lu Su A, cucurbitacin C, cucurbitacin D, cucurbatacin E, cucurbitacin I, cucurbitacin Q；Or antineoplastic.5th, application of the cucurbitacin or curbitacin combination according to one of claim 1 ~ 4 in the medicine for improving leucocyte is prepared, it is characterised in that described cucurbitacin or the method for administration of curbitacin combination include：External application, oral and drug administration by injection；Administration type is tablet, powder, capsule, granule, supensoid agent, syrup, mouth ^-liquid, emulsion, nanoparticle, liposome, ointment, patch, injection.6th, the application of cucurbitacin according to claim 5 or calabash Lu Su Group compounds in the medicine for improving leucocyte is prepared, it is characterized in that, cucurbitacin or the curbitacin combination dosage according to Cucurbitacin B content be more than 50%, total cucurbitacin that cucurbitacin enters, two or more composition in B, C, D, E, I, Q is constituted calculates, mouse with 0.001 mg/kilogram ~ 1 mg/kg body weight is administered, health adult is 0.1mg ~ 5mg/ days with dosage.7th, the application of cucurbitacin or curbitacin combination according to claim 5 in the medicine for improving leucocyte is prepared, its spy is past to be, calabash Lu Su Group compounds in composition outside antineoplastic are the Cucurbitacines as Chinese medicine muskmelon pedicel extract, mainly containing Cucurbitacin B, cucurbatacin E.8th, the application of cucurbitacin or curbitacin combination according to claim 5 in the medicine for improving leucocyte is prepared, it is characterised in that in folk prescription or composing prescription preparation, cucurbitacin accounts for 0.0001% ~ 99.9% weight.9th, application of the cucurbitacin or curbitacin combination according to one of claim 6 ~ 8 in the medicine for improving leucocyte is prepared, it is characterised in that described cucurbitacin is cucurbitacin folk prescription；Either cucurbitacin is collectively formed with other drugs Prescription, described prescription is selected from order side or prescription：Cucurbit essence injecta folk prescription：Cucurbitacin or curbitacin combination and lecithin mass ratio 1: 10000;Described lecithin includes egg yolk lecithin or soybean lecithin；Cucurbitacin and ethanol-HS15- water 0.1: 200-800 ： 50-500: 0-800;Cucurbitacin or curbitacin combination and the prescription of antineoplastic use in conjunction：Endoxan and cucurbitacin mass ratio 30,0/1 500/1；Docetaxel and cucurbitacin mass ratio 50,0/2 500/4；Adriamycin and cucurbitacin mass ratio 10,0/1 30/1；Taxol and cucurbitacin mass ratio 1000/1 ~ 100/5；Or, cucurbitacin emulsion prescription, each component mass ratio is：Cucurbitacin 0.005 ~ 0.015g, the HS15 pungent certain herbaceous plants with big flowers acid glyceride of l ~ 2g, soybean lecithin 0.5 1.5g, 0 ~ 20g, 0 ~ 20g of soybean oil, 0 ~ 0.15g of vitamin E, 2 ~ 3g of glycerine;In Liang Group points of pungent certain herbaceous plants with big flowers acid glyceride therein and soybean oil, the consumption of at least one is not 0.10th, curbitacin combination according to claim 9 prepare improve leucocyte medicine in application, it is characterised in that described prescription be selected from Yi Xia Group side,Cucurbit essence injecta folk prescription：Cucurbitacin and egg yolk lecithin 1： 300-1 ： 600;Cucurbitacin and ethanol-HS15- water 0.1: 300-500 ： 100-300: 50-500;Cucurbitacin or curbitacin combination and the prescription of antineoplastic use in conjunction：Endoxan and cucurbitacin 400/1;Docetaxel and cucurbitacin 500/3;Adriamycin and cucurbit quality 100/2;Taxol and cucurbitacin 400/1 ~ 1000/3;Described cucurbitacin emulsion prescription, each component mass ratio is：Cucurbitacin O.Olg, HS15 1.5g, soybean lecithin lg, pungent certain herbaceous plants with big flowers acid glyceride 4 ~ 6g, 4 ~ 6g of soybean oil, 0.05 ~ 0.15g of vitamin E, glycerine 2.5g;Powder, is calculated according to 1000 single doses：Cucurbitacin B 0.1g, xylitol 1000g, hydroxypropyl methyl cellulose lg superfine silica gel powders lg, essence, appropriate sweetener；Or,Glue Nang, is calculated according to 1000 single doses：Cucurbitacin B 0.1g, amylum pregelatinisatum 100g, spherical microcrystalline cellulose I0g, superfine silica gel powder lg;Or,Soft capsule, is calculated according to 1000 single doses：Cucurbitacin B 0.1g, midchain oil（Pungent certain herbaceous plants with big flowers acid glyceride, MCT) 50 ~ 500g.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610046738.7 | 2006-05-30 | ||
| CN200610046738A CN1883484B (en) | 2006-05-30 | 2006-05-30 | Novel pharmacological use of cucurbitacine |
| PCT/CN2007/000847 WO2007140681A1 (en) | 2006-05-30 | 2007-03-16 | The use of cucurbitacins or cucurbitacin compositions in preparation of medicaments for raising leukocytes |
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| Publication Number | Publication Date |
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| CN101309692A true CN101309692A (en) | 2008-11-19 |
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| CN200610046738A Expired - Fee Related CN1883484B (en) | 2006-05-30 | 2006-05-30 | Novel pharmacological use of cucurbitacine |
| CNA2007800001604A Pending CN101309692A (en) | 2006-05-30 | 2007-03-16 | Application of curbitacin or curbitacin combination in leucocyte increasing medicament preparation |
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| CN200610046738A Expired - Fee Related CN1883484B (en) | 2006-05-30 | 2006-05-30 | Novel pharmacological use of cucurbitacine |
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| WO (1) | WO2007140681A1 (en) |
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| CN114027294A (en) * | 2021-12-12 | 2022-02-11 | 杭州中赢生物医疗科技有限公司 | Immune cell cryopreservation liquid and immune cell cryopreservation method |
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| CN101062041B (en) * | 2007-05-31 | 2011-11-16 | 沈阳药科大学 | Novel medical function of cucurbitacin |
| US20100168451A1 (en) * | 2007-10-19 | 2010-07-01 | Xiane Fan | Preparative method of dihydrocucurbitacin f-25-o-acetate and the use thereof in the manufacture of medicaments for treating cancers |
| CN103169656A (en) * | 2011-12-21 | 2013-06-26 | 沈阳药科大学 | Cucurbitacin oral lipid nano emulsion and preparation method |
| CN107595859A (en) * | 2017-09-22 | 2018-01-19 | 中国农业科学院深圳农业基因组研究所 | Applications of the cucurbitacin C in broad-spectrum anti-cancer drug is prepared |
| CN111514290B (en) * | 2020-04-27 | 2023-03-28 | 德立唯（北京）生物科技有限公司 | Cucurbitacin composition and application thereof |
| CN115337313A (en) * | 2022-08-31 | 2022-11-15 | 南昌大学 | Application of cucurbitacin E in preparation of medicine for treating brain glioma through FAK/AKT/GSK3 beta pathway |
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| CN100377712C (en) * | 2002-11-28 | 2008-04-02 | 沈阳药科大学 | Cucurbitacin lipsome preparation method and formulation |
| CN1528317A (en) * | 2003-10-06 | 2004-09-15 | 南昌弘益科技有限公司 | Cucurbitacin drop pill and preparing method thereof |
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- 2006-05-30 CN CN200610046738A patent/CN1883484B/en not_active Expired - Fee Related
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| CN114027294A (en) * | 2021-12-12 | 2022-02-11 | 杭州中赢生物医疗科技有限公司 | Immune cell cryopreservation liquid and immune cell cryopreservation method |
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| WO2007140681A1 (en) | 2007-12-13 |
| CN1883484B (en) | 2012-09-12 |
| CN1883484A (en) | 2006-12-27 |
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Open date: 20081119 |