CN103405396B

CN103405396B - A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof

Info

Publication number: CN103405396B
Application number: CN201310310198.9A
Authority: CN
Inventors: 孟昭珂; 郭殿武; 吴耀东
Original assignee: HANGZHOU MINSHENG PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd; Hangzhou Minsheng Pharmaceutical Co Ltd
Current assignee: HANGZHOU MINSHENG PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd; Hangzhou Minsheng Pharmaceutical Co Ltd
Priority date: 2009-07-29
Filing date: 2009-07-29
Publication date: 2015-08-05
Anticipated expiration: 2029-07-29
Also published as: CN101984961A; CN103565787B; CN103565787A; CN103405396A; CN101984961B

Abstract

The invention provides a kind of pharmaceutical composition containing Furanodiene., the dosage form of said composition is soft capsule.After soft capsule of the present invention enters human gastric juice, the fusion of aqueous body fluid in oils and fats and body can be promoted, the profit improving Furanodiene. distributes character, greatly promotes speed and the degree of Furanodiene. permeate through cell membranes, improves the bioavailability of preparation.The toxicity of this soft capsule preparation is starkly lower than the toxicity of general Orally taken emulsion simultaneously, improves its pharmacological property.

Description

A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof

The application is application number is 200910101005.2, and the applying date is on July 29th, 2009, and denomination of invention is the divisional application of " containing the pharmaceutical composition of Furanodiene., its preparation process thereof and medical usage thereof ".

Technical field

The present invention relates to Effective Component of Chinese Medicine, pharmaceutical composition and preparation method and medical usage, specifically, the present invention relates to a kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof.

Background technology

Furanodiene. is a main component in Oleum Curcumae, and first in the Hikiw of Japan, the people such as H reported in nineteen sixty-eight.Its chemical name is (5E, 9Z)-3,6,10-trimethyl-4,7,8,11-tetrahydro cyclodeca-[b] furan.

Chemical structural formula is:

Molecular formula is: C ₁₅h ₂₀o molecular weight is: 216.15

The application of currently reported Furanodiene. in treatment tumor disease, but not yet have the preparation prescription research report about the research report of effective dose and system.In addition, because this compound water soluble is minimum, the water soluble parenteral solution conventionally prepared, be very easy to separate out, stability can not be guaranteed, and this considerably increases the difficulty of water soluble preparation research.Given this, the invention provides a kind of stable and effective containing the pharmaceutical composition of Furanodiene. and the preparation method of preparation thereof.

Although this compound dissolubility in oil medium is comparatively large, the Emulsion obtained by conventional method or oil preparation have to place easily separates out, poor stability, and especially entering can not be miscible in oil phase and body in body, drug absorption difficulty, the shortcoming that bioavailability is low.Therefore need to study its pharmaceutical preparation, obtain the pharmaceutical preparation of good stability, absorption and the drug effect pharmaceutical composition preferably containing Furanodiene., to meet the hospital market different safety of sufferer, the needs of rational use of drug.

Summary of the invention

The present invention is intended to by prescription screening and the special process being different from common process, there is provided that preparation technology is simple, good stability and drug effect preferably containing the pharmaceutical composition of Furanodiene. and multi-medicament preparation thereof and their preparation method, and be applied to the preparation of medicine for the treatment of or adjuvant therapy of malignant tumor.The administering mode of its pharmaceutical preparation is drug administration by injection or oral administration.Administration number of times is for daily once or every several days to be administered once.Each dosage is certain value.

The invention provides a kind of administration frequency once a day or be less than once be used for the treatment of or adjuvant therapy of malignant tumor containing the pharmaceutical composition of Furanodiene., adopt injecting and administering preparations or oral Preparation, in wherein said pharmaceutical composition, the content of Furanodiene. is 48mg ~ 2430mg.The preferred injection of ejection preparation, injection breast and lyophilized preparation, oral formulations preferred oral breast, tablet, hard capsule and soft capsule.

The invention provides a kind of pharmaceutical composition injecting and administering preparations containing 48 ~ 800mg Furanodiene., said composition is daily once used for the treatment of tumor.Preferred pharmaceutical composition contains the Furanodiene. of 240 ~ 580mg, and most preferred pharmaceutical composition contains the Furanodiene. of 490mg.The invention still further relates to a kind of pharmaceutical composition of the oral administration containing Furanodiene., said composition is daily once used for the treatment of tumor, containing Furanodiene. 480 ~ 2430mg in compositions, preferred content is about 608 ~ 1940mg, preferred about 970 ~ 1600mg, most preferably 1460mg again.

The invention provides a kind of Aqueous injection drug-delivery preparation of the pharmaceutical composition containing Furanodiene..Due to this compound dissolubility this particularity little in water and conventional non-aqueous media, specific solubilizing agent need be added.Find in test that the combination consumption of solubilizing agent selected by the present invention and organic facies can well increase its water solublity within the specific limits.According to pharmacological test data be able to water be medium injection drug effect better and side effect little, we select injection medium to be water for injection.

The Aqueous injection drug-delivery preparation of the pharmaceutical composition containing Furanodiene. is injection, wherein comprises: the Furanodiene. of about 48mg ~ about 800mg; The amount accounting for described compositions is the organic facies of 4% ~ 10%v/v; The amount accounting for described compositions is the solubilizing agent of 1% ~ 5%v/v; Water for injection is settled to 80ml.Wherein said organic facies is one or more mixture in propylene glycol, PEG400, glycerol and ethanol, preferred alcohol.Wherein said solubilizing agent to be selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Tween-80 one or more mixture.

The Furanodiene. water type injection made has the following advantages:

1, this injection is creationary adds suitable solubilizing agent and the acceptable organic solvent of human body, and this portfolio ratio is suitable, considerably increases the dissolubility of Furanodiene. in water and stability, solves the problem of placing and easily separating out.Obtained injection is the dosage forms such as completely clear and bright water type injection, comparatively injectable emulsion, oil for injection solution, and human body is more acceptant, avoids fat-soluble solvent to the stimulation of human body and toxic and side effects.

2, this injection by the form input human body of intravenous injection or intravenous drip, can not have absorption process, can quick acting, is conducive to clinical practice.Thus the medicament selection of pole indissoluble makes aqueous solvent but not fat-soluble dose.

The present invention also provides a kind of oral Preparation of the pharmaceutical composition containing Furanodiene., it is oral solid formulation---tablet or capsule, comprising: a) Furanodiene. of 10g ~ 20g, b) filler of 10g ~ 50g, described filler is the one in cyclodextrin, microcrystalline Cellulose, amylum pregelatinisatum, lactose, preferred amylum pregelatinisatum; C) disintegrating agent of 0 ~ 30g, described disintegrating agent is the one in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, pre-gelatinized starch, preferred cross-linking sodium carboxymethyl cellulose; D) 0 ~ 2g lubricant, described lubricant is the one in magnesium stearate, silicon dioxide; Make 100 or capsule.

Oral solid pharmaceutical formulation---tablet or capsule adopt unique preparation technology's preparation:

1, adopt freeze grinding technology, Furanodiene. is carried out micronization processes, makes its particle diameter reach 200 orders.Improve the mobility of medicine, increase the bioavailability of oral formulations, reduce the content of oral solid formulation Chinese medicine, indirectly reduce cost, be more conducive to patient and use and take.

2, after creationary employing medicine is fully mixed homogeneously with suitable excipient, without pelletization direct compression or fill capsule.Process avoids wet granulation and have to pass through drying, common dry run all needs heating, and this product is to thermally labile, and production process can increase medicament decomposes probability.Adopt direct powder compression, greatly can improve the stability of medicine and the Maturity of technique.

The present invention also provides a kind of oral Preparation of the pharmaceutical composition containing Furanodiene. to be oral solid formulation---soft capsule, per overall volume 24ml, wherein comprise: the Furanodiene. of 480 ~ 2430mg, the surfactant of 0.024 ~ 0.24mg; The antiseptic of 0.024 ~ 0.24mg, adds suitable carrier matrix standardize solution to 24ml.Wherein said carrier matrix is selected from the mixture of one or more in soybean oil, Semen Maydis oil, Semen arachidis hypogaeae wet goods vegetable oil.Wherein said surfactant is selected from soybean phospholipid, lecithin, Tween-80.Comprise component antiseptic further.Wherein said antiseptic is selected from methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate, potassium sorbate and its combination in any.Further also antioxidant can be added, such as butylated hydroxyarisol (BHA), 2,6-di-t-butyl hydroxy-methylbenzenes (BHT), vitamin E, ascorbyl palmitate etc.

The oral soft capsule adopting above formulation and technology to make has following advantage and advantage:

1, in conjunction with the fat-soluble strong character of Furanodiene., adopt homogeneous oil to dissolve to make can be oral soft capsule, solve the problem that it easily separates out in aqueous solvent, greatly improve the stability of said preparation.Adopt the acceptable oils and fats of human body to make solvent, the Furanodiene. oil content character obtained is homogeneous, and preparation method is easy, is conducive to industrialization and produces.

2, on this basis, from to add w/o type surfactant in traditional soft capsule different, our creativeness adds several specific O/W type surfactant (soybean phospholipid, lecithin, Tween-80), its object is not increase the dissolubility of Furanodiene. in oils and fats, but after soft capsule enters human gastric juice, promote the fusion of aqueous body fluid in oils and fats and body, the profit improving Furanodiene. distributes character, greatly promote speed and the degree of Furanodiene. permeate through cell membranes, improve the bioavailability of preparation.

3, enter body absorption with soft capsule prepared by this formulation and technology and there is unique mechanism of absorption: under body temperature environment, to run into after liquid can under the impelling of gastrointestinal motility spontaneous formation oil-in-water emulsion.Improve drug dissolution, improve and absorb.Microemulsion interfacial area is large, and surface tension is low, easily through the hydrated sheath of gastrointestinal wall, can increase penetrance, penetration enhancement.Microemulsion can through lymphatic absorption, thus overcomes first pass effect and macromole by obstacle during GI epithelium.The Dispersed Phase Size of microemulsion is tiny and even, is beneficial to medicine absorption in vivo, thus improves the bioavailability of medicine.

4, under the prerequisite of mechanism of absorption having possessed special formulation and technology and uniqueness, through pharmacology's checking, the toxicity of this soft capsule preparation comparatively Emulsion obviously reduces, and its pharmacological property improves.

5, in addition, this soft capsule also has taking convenience, is easy to produce, and to preservation condition without particular/special requirement, is applicable to the advantage of transport and Clinical practice.

The preparation being applicable to the pharmaceutical composition containing Furanodiene. of the present invention can also be oral liquid, as Orally taken emulsion, oil phase (as soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen) can be comprised, emulsifying agent (as soybean phospholipid, lecithin), can further including but not limited to one or more component following: antiseptic, pH adjusting agent, pharmaceutical acceptable solvents, forms of pharmacologically active agents except Furanodiene., or its combination in any.Wherein said antiseptic is methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate, potassium sorbate and its combination in any, and its amount is 0.01% to 1.0%w/v.Wherein said pH adjusting agent is diluted acid, diluted alkaline or its combination in any, and to regulate the amount of described composition pH to 4 to 8 to exist.Wherein said pharmaceutical acceptable solvents is water for injection, PEG400, propylene glycol, ethanol, glycerol and combination in any thereof, preferred water for injection.

Detailed description of the invention

Below in conjunction with specific embodiment, the present invention is further detailed explanation, but the present invention is not limited thereto.

Prepare Furanodiene. emulsion injection embodiment 1-8

Embodiment 1:1g Furanodiene.

50g soybean oil

10g soybean phospholipid

Inject water to scale 1000ml altogether

Preparation: first emulsifying agent (soybean phospholipid) is dissolved in oil phase (soybean oil), add principal agent Furanodiene., stirring makes it dissolve, after stirring, the filtering with microporous membrane that aperture is 0.22 μm is for subsequent use, add water for injection to recipe quantity, colostrum made by homogenate machine, makes to reach injectable emulsion size by homogenizer.Carry out aseptic filtration by the microporous filter membrane in 0.22 μm, aperture, last embedding is in the sterilizing ampoule of the drying of 1ml.Make and often prop up the Emulsion injection of ampoule 1ml containing Furanodiene. 1mg.

Embodiment 2:10g Furanodiene., 50g soybean oil, 20g soybean phospholipid, inject water to scale altogether 1000ml.

The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 10mg.

Embodiment 3:40g Furanodiene., 100g Semen Maydis oil, 20g Ovum Gallus domesticus Flavus lecithin, inject water to scale altogether 1000ml.

The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 40mg.

Embodiment 4:12g Furanodiene., 100g Oleum Arachidis hypogaeae semen, 20g hydrogenated soya phosphatide, inject water to scale altogether 1000ml.

The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 12mg.

Embodiment 5:1g Furanodiene., 50g soybean oil, 10g synthetic phospholipid, inject water to scale altogether 1000ml.

The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 1mg.

Embodiment 6:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene castor oil, inject water to scale altogether 1000ml.The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 1mg.

Embodiment 7:10g Furanodiene., 100g soybean oil, 20g polyoxyethylene hydrogenated Oleum Ricini, inject water to scale altogether 1000ml.The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 10mg.

Embodiment 8:2.5g Furanodiene., 100g soybean oil and Semen Maydis oil compositions, 10g Tween-80, inject water to scale altogether 1000ml.The method preparing Furanodiene. emulsion injection, with embodiment 1, is made and is often propped up the Emulsion injection of ampoule 1ml containing Furanodiene. 2.5mg.

Prepare Furanodiene. injection embodiment 9-12

Embodiment 9:0.8g Furanodiene.

8ml ethanol

4ml polyoxyethylene castor oil

Inject water to scale 80ml altogether.

Preparation: first by solubilizing agent (polyoxyethylene castor oil, other embodiments are corresponding solubilizing agent) be dissolved in organic facies (ethanol, other embodiments are corresponding organic facies) in, add principal agent Furanodiene., stir and make it dissolve, after stirring, add water for injection to recipe quantity, carry out aseptic filtration by the microporous filter membrane in 0.22 μm, aperture, be finally filled in the sterilizing ampoule of the drying of 20ml, make the injection of every 1ml containing Furanodiene. 10mg.

Embodiment 10:0.048g Furanodiene., 3.8ml ethanol, 0.8ml hydrogenation polyoxyethylene castor oil, inject water to scale altogether 80ml.Preparation method, with embodiment 9, makes the injection of every 1ml containing Furanodiene. 0.6mg.

Embodiment 11:0.4g Furanodiene., 5ml ethanol, 2ml Tween-80, inject water to scale altogether 80ml.Preparation method, with embodiment 9, makes the injection of every 1ml containing Furanodiene. 5mg.

Embodiment 12:0.8g Furanodiene., 6ml ethanol, 4ml polyoxyethylene hydrogenated Oleum Ricini, inject water to scale altogether 80ml.Preparation method, with embodiment 9, makes the injection of every 1ml containing Furanodiene. 10mg.

Prepare Furanodiene. oral emulsion embodiment 13---21

Embodiment 13:1g Furanodiene.

50g soybean oil

10g soybean phospholipid

0.1g methyl parahydroxybenzoate

Inject water to scale

1000ml altogether

Preparation: first emulsifying agent (soybean phospholipid) is dissolved in oil phase (soybean oil), add principal agent Furanodiene., stirring makes it dissolve, add after antiseptic (methyl parahydroxybenzoate) stirs again, the filtering with microporous membrane that aperture is 0.22 μm is for subsequent use, add water for injection to recipe quantity, colostrum made by homogenate machine, makes to reach injectable emulsion size by homogenizer.Carry out aseptic filtration by the microporous filter membrane in 0.22 μm, aperture, last fill, in 20ml sterilized glass bottle, is jumped a queue, Zha Gai.Make the Orally taken emulsion of every 1ml containing Furanodiene. 1mg.

Embodiment 14:100g Furanodiene., 100g soybean oil, 50g soybean phospholipid, 5g methyl parahydroxybenzoate, inject water to scale altogether 1000ml.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 100mg.

Embodiment 15:50g Furanodiene., 100g Semen Maydis oil, 20g Ovum Gallus domesticus Flavus lecithin, 10g propyl p-hydroxybenzoate inject water to scale 1000ml altogether.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 50mg.

Embodiment 16:10g Furanodiene., 100g Oleum Arachidis hypogaeae semen, 20g hydrogenated soya phosphatide, 0.1g propyl p-hydroxybenzoate inject water to scale 1000ml altogether.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 10mg.

Embodiment 17:1g Furanodiene., 100g soybean oil, 10g synthetic phospholipid, 0.1g sodium benzoate, inject water to scale altogether 1000ml.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 1mg.

Embodiment 18:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene castor oil, 0.1g potassium sorbate, inject water to scale altogether 1000ml.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 1mg.

Embodiment 19:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene hydrogenated Oleum Ricini, 0.1g potassium sorbate inject water to scale 1000ml altogether.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 1mg.

Embodiment 20:1g Furanodiene., 100g soybean oil and Semen Maydis oil compositions, 10g Tween-80,0.1g methyl parahydroxybenzoate, inject water to scale altogether 1000ml.The method preparing Furanodiene. oral emulsion, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 1mg.

Embodiment 21:1g Furanodiene., 100g soybean oil and Oleum Arachidis hypogaeae semen compositions, 10g Tween-80,0.1g methyl parahydroxybenzoate, inject water to scale altogether 1000ml.Preparation method, with embodiment 13, makes the Orally taken emulsion of every 1ml containing Furanodiene. 1mg.

Prepare Furanodiene. capsule and implement 22,24-25

Embodiment 22:20g Furanodiene.

50g amylum pregelatinisatum

2g magnesium stearate

Fill capsule 100

Preparation: the Furanodiene. of recipe quantity is put into Lowtemperaturepulverizer, at temperature-10 ~ 0 DEG C, pulverize, make powder can smoothly by 200 eye mesh screens, even with the filler of recipe quantity, disintegrating agent and mix lubricant again, direct fill capsule, containing the capsule of Furanodiene. 200mg in making every.

Embodiment 24:15g Furanodiene., 50g soluble starch, 5g polyvinylpolypyrrolidone, 1g magnesium stearate, fill capsule 100.Prepare Furanodiene. oral capsule with embodiment 22, containing the capsule of Furanodiene. 150mg in making every.

Embodiment 25:20g Furanodiene., 10g microcrystalline Cellulose, 30g pre-gelatinized starch, 2g silicon dioxide, fill capsule 100.Prepare Furanodiene. oral capsule with embodiment 22, containing the capsule of Furanodiene. 200mg in every.

Prepare Furanodiene. Tablets Example 23:10g Furanodiene.

50g lactose

10g cross-linking sodium carboxymethyl cellulose

1g silicon dioxide

Direct compression is total to obtain 100

Preparation, with step before embodiment 22 fill, by the direct powder compression of mix homogeneously, makes the tablet containing Furanodiene. 100mg in every sheet.

Prepare Furanodiene. oral soft capsule embodiment 26-28

Embodiment 26:2.4g Furanodiene.

0.24mg soybean phospholipid

0.24mg methyl parahydroxybenzoate

Add injection soybean oil dissolve said components and be settled to 24ml

Preparation: get injection soybean oil 1000ml, 150 DEG C of dry heat sterilizations 1 hour, let cool to 25 DEG C, take out part fluid and add above-mentioned principal agent and adjuvant, stir and make it dissolve completely, be finally settled to 24ml, filter with No. 6 molten funnels that hang down of drying, embedding is in soft capsule, and ultraviolet sterilization 60 minutes, containing the soft capsule of Furanodiene. 200mg in making every.

Embodiment 27:0.48g Furanodiene., 0.1mg lecithin, 0.1mg propyl p-hydroxybenzoate, add injection Oleum Arachidis hypogaeae semen and dissolve said components and be settled to 24ml.Prepare the method for Furanodiene. oral soft capsule with embodiment 26, containing the soft capsule of Furanodiene. 20mg in making every.

Embodiment 28:1.2g Furanodiene., 0.024mg Tween-80,0.024mg sodium benzoate, add injection Semen Maydis oil and dissolve said components and be settled to 24ml.Prepare Furanodiene. oral soft capsule with embodiment 26, containing the soft capsule of Furanodiene. 50mg in making every.

In order to better the present invention is described, be below influence factor's experiment and result:

Influence factor: illumination, high temperature, high humidity

Table 1 Furanodiene. preparation influence factor's (illumination) result of the test

Table 2 Furanodiene. preparation influence factor's (high temperature) result of the test

Table 3 Furanodiene. preparation influence factor's (high humidity) result of the test

Experimental result shows that said medicine preparation has higher stability, but due to the impact of the thermo-labile character of Furanodiene. itself, all preparations all need lower temperature to preserve.

In order to understand essence of the present invention better, below the test of the pharmacological toxicology of Furanodiene. and result are illustrated the application in its treatment in malignant tumor or auxiliary treatment.

One, the animal pharmacology pharmacodynamics test of Furanodiene.

1, Furanodiene. is to the therapeutical effect of people's hepatocarcinoma Nude Mice Bel-7402 hepatocarcinoma

Experiment 1:

Adopt Furanodiene. injection 25,50 and 100mg/kg every day after tumor inoculation each intravenously administrable once.Within after tumor inoculation the 22nd day, put to death animal to get tumor and weigh, 25,50 and 100mg/kg group tumour inhibiting rate be respectively 38.9,48.6 and 55.5%

The dosage of animal and the dosage of adult convert: be that 60kg calculates by the standard body weight of being grown up,

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 25mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=2.03mg.kg ^-1

Standard body weight=9.72mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=583.2mg

1-2 mice dosage is 50mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=4.05mg.kg ^-1

Standard body weight=4.05mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=243mg

1-3 mice dosage is 100mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=8.10mg.kg ^-1

Standard body weight=8.10mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=486mg

Concrete test method and result as follows:

Laboratory animal: nude mouse: Balb/c strain, male, 36, body weight 19.1 ± 1.0g.Thered is provided by Shanghai Slac Experimental Animal Co., Ltd..

Inoculated tumour cell: in the animal experimental center of SPF level, takes the tumor of lotus Bel-7402 kind Mus, is cut into 1.0mm ³large tubercle block, plants the oxter in test nude mouse, treats that tumor average volume grows to 45mm ³left and right, starts administration by animal random packet.

Experimental technique: negative control group lumbar injection every day water for injection 0.1ml/10g, the CTX0.1ml/10g of CTX group (fresh before administration be configured in normal saline) tail vein injection 3mg/ml every other day, the Furanodiene. 0.1ml/10g of Furanodiene. 25mg/kg group tail vein injection every day 2.5mg/ml, the Furanodiene. 0.1ml/10g of Furanodiene. 50mg/kg group tail vein injection every day 5mg/ml, Furanodiene. 100mg/kg group tail vein injection every day 10mg/ml Furanodiene. 0.1ml/10g, within every 3 days, weigh and measure gross tumor volume, successive administration 21 days, mice is put to death in the 22nd day, weigh, measure tumor block to amass, calculate relative tumour volume (RTV), Relative tumor appreciation rate (T/C) and tumor suppression percentage rate, do statistics to detect.

Grouping: 36 inoculation Bel-7402 tumor cell nude mouses are divided into 6 groups at random, 1) negative control group 12,2) CTX30mg/kg group 6,3) Furanodiene. 25mg/kg group 6,4) Furanodiene. 50mg/kg group 6,5) Furanodiene. 100mg/kg group 6

Positive drug: cisplatin (Dezhou De Yao company limited).

Prepared by test sample: prepare Furanodiene. injection

First polyoxyethylene castor oil is dissolved in ethanol, add principal agent Furanodiene., stirring makes it dissolve, after stirring, add water for injection to recipe quantity, carry out aseptic filtration by the microporous filter membrane in 0.22 μm, aperture, be finally filled in the sterilizing ampoule of the drying of 20ml, make the injection for injection of every 1ml containing Furanodiene. 2.5mg, 5mg and 10mg respectively.

Dosage: according to preliminary result, adopt 25,50,100mg/kg tri-dosage, solvent control adopt coordinative solvent.Positive drug group cisplatin administration dosage is 30mg/kg.

Route of administration: solvent control group and Furanodiene. three dosage groups adopt i.v form administration, and cisplatin group adopts i.p form administration.

Administration volume: 0.1ml/10g

Administration time: solvent control group and Furanodiene. three dosage component groups played successive administration 21 days the same day, (wherein have 2 days and find nude mice out of order, drug withdrawal on the same day).Cisplatin component group played successive administration 4 days the same day, then drug withdrawal 15 days, then successive administration 4 days.

Observing time: weigh 1 time for every 3 days.

Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.

Experimental result:

Negative control group nude mice focuses on all without significant change before and after experimental therapy, and CTX30mg/kg, Furanodiene. 50mg/kg and Furanodiene. 100mg/kg group nude mouse body weight obviously decline 0.05).Each group of none animal dead equal.Compare with the negative control group of corresponding natural law, Furanodiene. 100mg/kg and CTX30mg/kg group people Bel-7402 hepatocarcinoma Nude Mice volume significantly reduced (P<0.05) from after administration the 10th day.The relative tumor volume (RTV) of negative control group is 24.4, CTX30mg/kg, Furanodiene. 25mg/kg, Furanodiene. 50mg/kg and Furanodiene. 100mg/kg group RTV value are respectively 5.6,11.2,8.0 and 6.9, corresponding Relative tumor appreciation rate (T/C) is respectively 21.7%, 43.4%, 31.0% and 26.7%.Administration is cutd open after 22 days to kill and is got tumor block and weigh, Furanodiene. low dosage 25mg/kg, in Furanodiene., dosage 50mg/kg and Furanodiene. high dose 100mg/kg group people Bel-7402 hepatocarcinoma Nude Mice average weight are respectively 0.46g, 0.40 and 0.32g, its tumour inhibiting rate (%) is respectively 36.1,44.4 and 55.6, and CTX30mg/kg group transplanted tumor in nude mice average weight is 0.25g, tumour inhibiting rate (%) is 65.3.Treatment group mice-transplanted tumor average weight and negative control group are than all having significance to decline (P<0.001).(see table 4, table 5).The nude mouse administration of Furanodiene. 100mg/kg group is slow in action for 15 days later, movable minimizing.

Table 4. Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.

Matched group compares: * * *: P<0.001, *: P<0.05.

D1: point cage administration time.TV: gross tumor volume, computing formula is: TV=is (long × wide ²)/2.RTV: relative tumour volume, computing formula is: RTV=V _t/ V ₀.T/C (%)=T _rTV/ C _rTVx100.T _rTV: be treatment group RTV; C _rTV: be negative control group RTV.

The standard of curative effect evaluation: T/C (%) >40 is invalid; T/C (%)≤40, and be effective through statistical procedures P<0.05.

Table 5. Furanodiene. is on the impact of people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight

Matched group compares: * * *: P<0.001.

Experiment 2:

Adopt Furanodiene. injection breast 50,100,120 and 165mg/kg every day after tumor inoculation each intravenously administrable once.Within after tumor inoculation the 22nd day, put to death animal to get tumor and weigh, 50,100,120 and 165mg/kg group tumour inhibiting rate be respectively 36.2,46.4,55.1% and 58%.

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 50mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=4.05mg.kg ^-1

1-2 mice dosage is 100mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=8.10mg.kg ^-1

1-3 mice dosage is 120mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=9.72mg.kg ^-1

1-4 mice dosage is 165mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=13.37mg.kg ^-1

Standard body weight=13.37mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=802mg

Concrete test method and result as follows:

Laboratory animal: nude mouse: Balb/c strain, male, 42, body weight 19.1 ± 1.0g.Thered is provided by Shanghai Slac Experimental Animal Co., Ltd..

Experimental technique: negative control group lumbar injection every day water for injection 0.1ml/10g, the CTX0.1ml/10g of CTX group (fresh before administration be configured in normal saline) tail vein injection 3mg/ml every other day, the Furanodiene. 0.1ml/10g of Furanodiene. 50mg/kg group tail vein injection every day 5.0mg/ml, the Furanodiene. 0.1ml/10g of Furanodiene. 100mg/kg group tail vein injection every day 10mg/ml, Furanodiene. 120mg/kg group tail vein injection every day 12mg/ml Furanodiene. 0.1ml/10g, Furanodiene. 165mg/kg group tail vein injection every day 16.5mg/ml Furanodiene. 0.1ml/10g.Within every 3 days, weigh and measure gross tumor volume, successive administration 21 days, putting to death mice in the 22nd day, weigh, measuring tumor block and amass, calculate relative tumour volume (RTV), Relative tumor appreciation rate (T/C) and tumor suppression percentage rate, doing statistics and detect.

Grouping: 42 inoculation Bel-7402 tumor cell nude mouses are divided into 6 groups at random, 1) negative control group 12,2) CTX30mg/kg group 6,3) Furanodiene. 50mg/kg group 6,4) Furanodiene. 100mg/kg group 6,5) Furanodiene. 120mg/kg group 6 6) Furanodiene. 165mg/kg group 6.

Positive drug: cisplatin (Dezhou De Yao company limited).

Prepared by test sample: Furanodiene. injection breast

First soybean phospholipid is dissolved in soybean oil, adds principal agent Furanodiene., stir after making it be uniformly dissolved, the filtering with microporous membrane that aperture is 0.22 μm is for subsequent use, add water for injection to recipe quantity, colostrum made by homogenate machine, makes to reach Emulsion size by homogenizer.Carry out aseptic filtration by the microporous filter membrane in 0.22 μm, aperture, last embedding is to the ampoule of the drying of 20ml.Make respectively often prop up ampoule 1ml containing the note of Furanodiene. 5mg often prop up ampoule 1ml containing Furanodiene. 10mg injection breast, often prop up ampoule 1ml containing Furanodiene. 12mg injection breast, often prop up the injection breast of ampoule 1ml containing Furanodiene. 16.5mg.

Dosage: according to preliminary result, adopt 50,100,120,165mg/kg tri-dosage, solvent control adopt coordinative solvent.Positive drug group cisplatin administration dosage is 30mg/kg.

Route of administration: solvent control group and Furanodiene. four dosage groups adopt i.v form administration, and cisplatin group adopts i.p form administration.

Administration volume: 0.1ml/10g

Administration time: solvent control group and Furanodiene. four dosage component groups played successive administration 21 days the same day, (wherein have 2 days and find nude mice out of order, drug withdrawal on the same day).Cisplatin component group played successive administration 4 days the same day, then drug withdrawal 15 days, then successive administration 4 days.

Observing time: weigh 1 time for every 3 days.

Experimental result: in table 6 and table 7.

Table 6. Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.

With matched group ratio: * * *: P<0.001.

The standard of curative effect evaluation: T/C (%) >40 is invalid; T/C (%)≤40, and be effective through statistical procedures P<0.05. with the matched group ratio of corresponding natural law: * * *: P<0.001, *: P<0.05.

Table 7. Furanodiene. is on the impact of people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight

Experimental result illustrates that 100mg/kg, 120mg/kg and 165mg/kg tri-animals administer dosage all have good therapeutic effect, but than 120mg/kg and 165mg/kg two animals administer dosage, under the animals administer dosage of 100mg/kg, toxic and side effects is less.So each dosage of corresponding adult is preferably 490mg.

Experiment 3:

The day each gastric infusion be once after tumor inoculation to adopt Furanodiene. suspendible oral liquid 100,200 and 400mg/kg.Within after tumor inoculation the 22nd day, put to death animal to get tumor and weigh.

The dosage of animal and the dosage of adult convert: assuming that the standard body weight of being grown up is 60kg

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 100mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=8.10mg.kg ^-1

1-2 mice dosage is 200mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=16.2mg.kg ^-1

Standard body weight=16.2mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=972mg

1-3 mice dosage is 400mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=3.24mg.kg ^-1

Standard body weight=3.24mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=1944mg

Concrete test method and result as follows: laboratory animal: nude mouse: Balb/c strain, male, 36, body weight 19.1 ± 1.0g.Thered is provided by Shanghai Slac Experimental Animal Co., Ltd..

Experimental technique: negative control group gavage every day water for injection 0.1ml/10g, the CTX0.1ml/10g of CTX group (fresh before administration be configured in normal saline) gavage 3mg/ml every other day, the Furanodiene. 0.1ml/10g of Furanodiene. 100mg/kg group gavage 10mg/ml every day, the Furanodiene. 0.1ml/10g of Furanodiene. 200mg/kg group gavage 20mg/ml every day, Furanodiene. 400mg/kg group gavage 40mg/ml every day Furanodiene. 0.1ml/10g.Within every 3 days, weigh and measure gross tumor volume, successive administration 21 days, putting to death mice in the 22nd day, weigh, measuring tumor block and amass, calculate relative tumour volume (RTV), Relative tumor appreciation rate (T/C) and tumor suppression percentage rate, doing statistics and detect.

Grouping: 36 inoculation Bel-7402 tumor cell nude mouses are divided into 5 groups, 1 at random) negative control group 12,2) CTX30mg/kg group 6,3) Furanodiene. 25mg/kg group 6,4) Furanodiene. 50mg/kg group 6,

5) Furanodiene. 100mg/kg group 6.

Positive drug: cisplatin (Dezhou De Yao company limited).

Prepared by test sample: Furanodiene. suspendible oral liquid takes the Furanodiene. of recipe quantity, add the Tween 80 of recipe quantity, add 0.5%CMC-Na aqueous solution (that is: sodium carboxymethyl cellulose solution) again to recipe quantity, use ultrasonic disintegrator more ultrasonic 15 minutes, to the requirement reaching suspension.Finally be filled in the sterilized glass bottle of the drying of 10ml, jump a queue, Zha Gai.Make every 1ml respectively containing the oral suspension of the confession of Furanodiene. 10mg, every 1ml containing the oral suspension of the confession of Furanodiene. 20mg and every 1ml containing the oral suspension of the confession of Furanodiene. 40mg.

Experimental result: in table 8 and table 9

Table 8 Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.

Matched group compares: * *: P<0.001, *: P<0.05.

The standard of curative effect evaluation: T/C (%) >40 is invalid; T/C (%)≤40, and be effective through statistical procedures P<0.05. with corresponding natural law

Table 9. Furanodiene. is on the impact of people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight

With matched group ratio: * *: P<0.001.

Experiment 4:

The day each gastric infusion be once after tumor inoculation to adopt Furanodiene. oil solution 100,200 and 400mg/kg.After tumor inoculation, the 22nd puts to death animal and gets tumor and weigh.

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 100mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=8.10mg.kg ^-1

1-2 mice dosage is 200mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=16.2mg.kg ^-1

1-3 mice dosage is 400mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=3.24mg.kg ^-1

Concrete test method and result as follows:

Grouping: 36 inoculation Bel-7402 tumor cell nude mouses are divided into 5 groups at random, 1) negative control group 12,2) CTX30mg/kg group 6,3) Furanodiene. 25mg/kg group 6,4) Furanodiene. 50mg/kg group 6,5) Furanodiene. 100mg/kg group 6.

Positive drug: cisplatin (Dezhou De Yao company limited).

Prepared by test sample: Furanodiene. oil solution gets injection vegetable oil (Oleum Camelliae, Semen sojae atricolor wet goods) 1000ml, 150 DEG C of dry heat sterilizations 1 hour, let cool to 25 DEG C, take out part fluid and add 20g Furanodiene., be stirred to dissolve, finally add solvent to full dose, filter with No. 6 molten funnels that hang down of drying, be finally filled in the sterilized glass bottle of the drying of 10ml, jump a queue, Zha Gai.Make every 1ml respectively containing the oral oil solution of the confession of Furanodiene. 10mg, every 1ml containing the oral oil solution of the confession of Furanodiene. 20mg and every 1ml containing the oral oil solution of the confession of Furanodiene. 40mg.

Dosage: according to preliminary result, (adopt Furanodiene. 400,200 and 100mg/kg, negative control adopts respective volume solvent.Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.

Experimental result: in table 10

Table 10. Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.

Matched group compares: * *: P<0.001, *: P<0.05.

Experimental result illustrates that 200mg/kg and 400mg/kg tri-animals administer dosage all have good therapeutic effect, but than 400mg/kg two animals administer dosage, under the animals administer dosage of 200mg/kg, toxic and side effects is less.So each dosage of corresponding adult is preferably 970mg.

2, Furanodiene. is to the experimentation of BGC-823 transplanted tumor in nude mice growth effect

Experiment one: adopt Furanodiene. oil solution 125,250 and 500mg/kg every day after tumor inoculation each gastric infusion once.Within after tumor inoculation the 22nd day, put to death animal to get tumor and weigh, 125,250 and the middle and high dosage of 500mg/kg group have certain inhibitory action.

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 125mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=10.12mg.kg ^-1

Standard body weight=10.12mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=607.5mg

1-2 mice dosage is 250mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=20.25mg.kg ^-1

Standard body weight=20.25mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=1215mg

1-3 mice dosage is 500mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=40.50mg.kg ^-1

Standard body weight=40.05mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=2430mg

Concrete test method and result as follows:

Laboratory animal: BALB/c nude mice, female, 4-5 week age, 40; Thered is provided by Shanghai Si Laike Experimental Animal Center, raise in product development department's clinical pharmacology Animal Lab., room temperature 25 DEG C, drinking-water of freely ingesting.

BGC-823 tumor strain: Chinese Academy of Sciences's Shanghai cell bank provides, our company's clinical pharmacology research department cellar culture goes down to posterity.

Modeling: get the strain of In vitro culture BGC-823 tumor, with normal saline dilution to 1 × 10 ⁷/ ml, by every animal 2 × 10 ⁶be inoculated in right oxter.Refer to " cell toxicant series antineoplastic medicament investigative technique guideline ".

Grouping: observe tumor growth state, when tumor growth is to 100-300mm ³time, animal is divided into 5 groups at random by gross tumor volume, is respectively solvent control group, positive drug group, low dose group (125mg/kg), middle dosage group (250mg/kg), high dose group (500mg/kg).

Positive drug: cisplatin (Dezhou De Yao company limited).

Prepared by test sample: Furanodiene. oil solution

Get injection vegetable oil (Oleum Camelliae, Semen sojae atricolor wet goods) 1000ml, 150 DEG C of dry heat sterilizations 1 hour, let cool to 25 DEG C, take out part fluid and add 20g Furanodiene., be stirred to dissolve, finally add solvent to full dose, filter with No. 6 molten funnels that hang down of drying, be finally filled in the sterilized glass bottle of the drying of 10ml, jump a queue, Zha Gai.Make every 1ml respectively containing the oral oil solution of the confession of Furanodiene. 12.5mg, every 1ml containing the oral oil solution of the confession of Furanodiene. 25mg and every 1ml containing the oral oil solution of the confession of Furanodiene. 50mg.

Dosage: adopt 125,250, low middle high three dosage of 500mg/kg, solvent control group adopt coordinative solvent.

Route of administration: i.p.

Administration volume: 0.1ml/10g.

Administration number of times: solvent control group and Furanodiene. three dosage component groups played administration every day the same day, successive administration 14 days (wherein have 2 days and find nude mice out of order, drug withdrawal on the same day).Cisplatin component group started successive administration 4 days, drug withdrawal one week the same day, then administration 3 days.

Observing time: often weigh 2-4 day 1 time, adopt vernier caliper measurement gross tumor volume size.After experiment terminates, put to death animal, get tumor, weigh, take pictures.

Statistical method: SPSS10.0 statistical package, Mann-Whitney Test.

Experimental result: in table 11,12.

Table 11 Furanodiene. is to the experimentation of BGC-823 transplanted tumor in nude mice growth effect

Compared with negative control: ^▲p < 0.01; ﹡ p < 0.05

Table 12 Furanodiene. is to the experimentation of BGC-823 transplanted tumor in nude mice growth effect

Compared with Control group: ^▲p < 0.01

3, containing the administering drug combinations compositions of Furanodiene. to the experimentation of Ho-8910 transplanted tumor in nude mice growth effect

Materials and methods:

Test sample: Furanodiene. suspendible oral liquid

Take the Furanodiene. of recipe quantity, add the Tween 80 of recipe quantity, then add 0.5%CMC-Na aqueous solution (that is: sodium carboxymethyl cellulose solution) to recipe quantity, then use ultrasonic disintegrator ultrasonic 15 minutes, to the requirement reaching suspension.Finally be filled in the sterilized glass bottle of the drying of 10ml, jump a queue, Zha Gai.Make every 1ml respectively containing the oral suspension of the confession of Furanodiene. 5mg, every 1ml containing the oral suspension of the confession of Furanodiene. 10mg and every 1ml containing the oral suspension of the confession of Furanodiene. 20mg.

Laboratory animal: BALB/c nude mice, female, 4-5 week age, 38; Thered is provided by Shanghai Si Laike Experimental Animal Center, raise in product development department's clinical pharmacology Animal Lab., room temperature 25 DEG C, drinking-water of freely ingesting.

Ho-8910 tumor strain: Chinese Academy of Sciences's Shanghai cell bank provides, our company's clinical pharmacology research department cellar culture goes down to posterity.

Modeling: get the strain of In vitro culture Ho-8910 tumor, with normal saline dilution to 1 × 10 ⁷/ ml, by every animal 2 × 10 ⁶be inoculated in right oxter.Refer to " cell toxicant series antineoplastic medicament investigative technique guideline ".

Grouping: observe tumor growth state, when tumor growth is to 100-300mm ³time, animal is divided into 4 groups at random by gross tumor volume, is respectively model group, low dose group (50mg/kg), middle dosage group (100mg/kg), high dose group (200mg/kg), positive group and administering drug combinations group.

Positive drug: cisplatin (Area, Gejiu District, Yunnan Province bio-pharmaceuticals).

Dosage: according to preliminary result, adopt 50,100,200mg/kg tri-dosage, negative control adopt coordinative solvent.Administering drug combinations group is cisplatin and Furanodiene., 200mg/kg administering drug combinations, and administration frequency is with positive group.

Route of administration: ig.

Administration volume: 0.1ml/10g

Administration number of times: after grouping, the same day plays successive administration 3 days, drug withdrawal one day, altogether administration 15 times (wherein have 2 days and find nude mice out of order, drug withdrawal on the same day).

Statistical method: SPSS10.0 statistical package, Mann-Whitney Test.

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 50mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=4.05mg.kg ^-1

1-2 mice dosage is 100mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=8.10mg.kg ^-1

Standard body weight=8.1mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=486mg

1-3 mice dosage is 200mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=16.2mg.kg ^-1

Experimental result: in table 13

Table 13 Furanodiene. is to the experimentation of Ho-8910 transplanted tumor in nude mice growth effect

Compare with negative control group: ^▲p < 0.05

Note: T & D is the Furanodiene. group administering drug combinations group of positive drug and middle dosage

Experimental result illustrates that the individually dosed drug effect of animals administer dosage of 100mg/kg in the compositions of oral administration is general, and administering drug combinations drug effect is better than individually dosed, has good drug effect.The each dosage of corresponding adult is 490mg.

4, Furanodiene. (code name Furanodiene .) is to the experimentation (administering drug combinations is effective, adjunct antineoplastic) of S180 mice-transplanted tumor growth effect

Experiment one

Materials and methods: test sample: Furanodiene. oil solution

Get injection vegetable oil (Oleum Camelliae, Semen sojae atricolor wet goods) 1000ml, 150 DEG C of dry heat sterilizations 1 hour, let cool to 25 DEG C, take out part fluid and add 20g Furanodiene., be stirred to dissolve, finally add solvent to full dose, filter with No. 6 molten funnels that hang down of drying, be finally filled in the sterilized glass bottle of the drying of 10ml, jump a queue, Zha Gai.Make every 1ml respectively containing the oral oil solution of the confession of Furanodiene. 10mg, every 1ml containing the oral oil solution of the confession of Furanodiene. 20mg and every 1ml containing the oral oil solution of the confession of Furanodiene. 30mg.

Laboratory animal: ICR mice, single sex is female, 18-22g, 45; Thered is provided by Zhejiang Province's Experimental Animal Center, raise in product development department's clinical pharmacology Animal Lab., room temperature 25 DEG C, drinking-water of freely ingesting.

S180 tumor strain: medical scientific institute of Zhejiang Province provides, every 7-9 goes down to posterity once in a days abdominal cavity.

Modeling: get S180 mouse-borne tumor animal ascites, with normal saline dilution to 1 × 10 ⁷/ ml, by every animal 2 × 10 ⁶be inoculated in right oxter.

Grouping: random point four groups, model group animal 10, cyclophosphamide group, Furanodiene. group, drug combination group, each treated animal 5.

Administering mode: cyclophosphamide subcutaneous injection, Furanodiene. gastric infusion.

Administration volume: 0.1ml/10g

Administration number of times: after modeling, next day rises, continuous 7 days

Observing time: Continuous Observation 7 days after modeling.After experiment terminates, put to death animal, get tumor, weigh, take pictures.

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 100mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=8.10mg.kg ^-1

1-2 mice dosage is 200mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=16.2mg.kg ^-1

1-3 mice dosage is 300mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=24.3mg.kg ^-1

Standard body weight=24.3mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=1458mg

Experimental result: in table 14

Table 14 Furanodiene. is to the experimentation of S180 mice-transplanted tumor growth effect

: ﹡ p < 0.05 ﹡ ﹡ p < 0.01 is compared with model control group

Experiment two:

Materials and methods:

Test sample: Furanodiene. injection

First polyoxyethylene castor oil is dissolved in ethanol, add principal agent Furanodiene., stirring makes it dissolve, after stirring, add water for injection to recipe quantity, carry out aseptic filtration by the microporous filter membrane in 0.22 μm, aperture, be finally filled in the sterilized glass bottle of the drying of 20ml, jump a queue, Zha Gai.Make every 1ml containing Furanodiene. 1mg, every 1ml containing Furanodiene. 2.5mg, the every 1ml injection for injection containing Furanodiene. 5mg.

Administering mode: cyclophosphamide group lumbar injection, the intravenous injection of Furanodiene. administration group.

Administration volume: 0.1ml/10g

Table look-up, mice a is capable, the R of adult b row _ab=0.081,

1-1 mice dosage is 10mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=0.81mg.kg ^-1

Standard body weight=0.81mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=48.6mg

1-2 mice dosage is 25mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=2.02mg.kg ^-1

Standard body weight=2.02mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=121.5mg

1-3 mice dosage is 50mg/kg

Dosage=the D of adult _b.R _ab=d*0.081=4.05mg.kg ^-1

Standard body weight=24.3mg.kg that each dosage=adult human dose * that is grown up is grown up ^-1* 60kg=243mg

Experimental result: in table 15

Table 15 Furanodiene. is to the experimentation of S180 mice-transplanted tumor growth effect

: ﹡ p < 0.05 ﹡ ﹡ p < 0.01 is compared with model control group

Experimental result illustrates that the animals administer dosage drug effect of 300mg/kg in the compositions of oral administration is better, and side effect is little.Thus each dosage of corresponding adult is more preferably 1460mg/kg.

In the compositions of oral administration, the animals administer dosage of 100mg/kg, 200mg/kg and 300mg/kg drug effect when administering drug combinations is all better than when individually dosed.

According to document << Chinese Clinical pharmacology and therapeutics >>2004 the 9th volume the 09th phase, the dose,equivalent carried out in pharmacological testing between animal and between animals and human beings body converts.

Two, the acute toxicity test of Furanodiene.

NIH mice is distinguished subcutaneous injection (sc) Furanodiene. injection and oral administration gavage Furanodiene. Furanodiene. soft capsule and Furanodiene. Emulsion, respectively establishes 5 dosage groups, often organize 10 (male and female half and half), observe the death toll in 14 days, calculate LD by BlissShi method ₅₀.Result is respectively: subcutaneous injection LD ₅₀=380mg/kg; Oral administration gavage soft capsule LD ₅₀=954mg/kg, Orally taken emulsion LD ₅₀=527mg/kg.

Three, the pharmacokinetic of Furanodiene.

In order to explain Rhizoma Curcumae ring two soft capsule of the present invention, Furanodiene. Emulsion and the Furanodiene. suspension solution difference in animal body in drug effect, the experimental study of animal vivo pharmacokinetic is carried out to three.

This test selects SD rat to carry out pharmacokinetic studies, high performance liquid chromatography is adopted to detect Furanodiene. blood drug level dynamic change in vivo, with chemicals Non-clinical Pharmacokinetics investigative technique guideline (CDE) for experimental basis, and with the matched curve on computers of Chinese Pharmacological Society 3P87 program, calculate pharmacokinetic parameters.

Test sample: Furanodiene. crystal A suspension; Furanodiene. product suspension.Administering mode: gavage; Dosage: 100mg/kg administration volume: 1.0ml/200g samples duration: 2880min statistical software: EXCEL

Experiment conclusion: calculate AUC by trapezoidal method, then relative bioavailability is calculated, Furanodiene. soft capsule is relative to the relative bioavailability F(0 ~ 48h of Furanodiene. suspension)=78615.39/52561.64 × 100%=149.6%, Furanodiene. soft capsule is relative to the relative bioavailability F(0 ~ 48h of Furanodiene. Emulsion)=63569.79/49113.25 × 100%=129.4%, the absorption entered in body of Furanodiene. soft capsule is better than Emulsion and suspension solution.

Claims

1., containing a pharmaceutical composition for Furanodiene., it is characterized in that the dosage form of said composition is soft capsule, per overall volume 24ml, wherein comprises:

A) Furanodiene. of 480 ~ 2400mg;

B) surfactant of 0.024 ~ 0.24mg;

C) antiseptic of 0.024 ~ 0.24mg;

D) carrier matrix standardize solution is to 24ml;

Wherein said surfactant is the mixture of one or more in soybean phospholipid, lecithin, Tween-80; Wherein said antiseptic is the mixture of one or more in methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate, potassium sorbate; Wherein said carrier matrix is the mixture of one or more in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen.

2. the pharmaceutical composition containing Furanodiene. according to claim 1 is applied to the preparation of the medicine for the treatment of or adjuvant therapy of malignant tumor.