CN101984961B - Furanodiene-containing medicinal composition, technology for preparing preparation thereof and medicinal use thereof - Google Patents
Furanodiene-containing medicinal composition, technology for preparing preparation thereof and medicinal use thereof Download PDFInfo
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- CN101984961B CN101984961B CN 200910101005 CN200910101005A CN101984961B CN 101984961 B CN101984961 B CN 101984961B CN 200910101005 CN200910101005 CN 200910101005 CN 200910101005 A CN200910101005 A CN 200910101005A CN 101984961 B CN101984961 B CN 101984961B
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- ZTKVJHVJKDVVES-UHFFFAOYSA-N furanodiene Natural products CC1CCC=C(/C)Cc2occ(C)c2CC1 ZTKVJHVJKDVVES-UHFFFAOYSA-N 0.000 title claims abstract description 260
- 238000002360 preparation method Methods 0.000 title claims abstract description 74
- 239000000203 mixture Substances 0.000 title claims abstract description 37
- VMDXHYHOJPKFEK-IAVOFVOCSA-N furanodiene Chemical compound C1\C(C)=C\CC\C(C)=C\CC2=C1OC=C2C VMDXHYHOJPKFEK-IAVOFVOCSA-N 0.000 title claims abstract 7
- 238000005516 engineering process Methods 0.000 title abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 69
- 239000007924 injection Substances 0.000 claims abstract description 69
- 239000003814 drug Substances 0.000 claims abstract description 37
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000008215 water for injection Substances 0.000 claims description 15
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 14
- -1 polyoxyethylene Polymers 0.000 claims description 14
- 239000004359 castor oil Substances 0.000 claims description 9
- 235000019438 castor oil Nutrition 0.000 claims description 9
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 8
- 229920000053 polysorbate 80 Polymers 0.000 claims description 8
- 208000035126 Facies Diseases 0.000 claims description 7
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 5
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- 230000036210 malignancy Effects 0.000 abstract 2
- VMDXHYHOJPKFEK-RZWYOFBOSA-N Furanodiene Chemical compound C1\C(C)=C/CC\C(C)=C\CC2=C1OC=C2C VMDXHYHOJPKFEK-RZWYOFBOSA-N 0.000 description 254
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 6
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 5
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a furanodiene-containing medicinal composition with the administration frequency of once per day or less than once for treating or adjunctively treating malignancy. The composition is prepared into an injection administration preparation or an oral administration preparation, wherein the content of the furanodiene in the medicinal composition is 48 to 2,430mg. The preparation of the composition is preferably water-soluble injection, soft capsules, or tablets and hard capsules prepared through specific technology, and solves the problem that the conventional preparation is easy to separate out and is low in stability and bioavailability. The invention also provides application of the furanodiene-containing medicinal composition in preparing medicaments for treating or adjunctively treating the malignancy.
Description
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 contain pharmaceutical composition, its preparation process thereof and the medical usage thereof of Furanodiene..
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
20The O molecular weight is: 216.15
The application of currently reported Furanodiene. aspect the treatment tumor disease, but not yet relevant for the research report of effective dose and the preparation prescription research report of system.In addition, because this compound water soluble is minimum, the water soluble parenteral solution according to the conventional method preparation is very easy to separate out, and stability can not be guaranteed, and this has increased the difficulty of water soluble preparation research greatly.Given this, the invention provides a kind of preparation method of stablizing and effectively containing pharmaceutical composition and the preparation thereof of Furanodiene..
Although this compound dissolubility in oil medium is larger, the Emulsion that makes with conventional method or oil preparation have placement easily separates out, poor stability, and especially entering can not be miscible in oil phase and body in body, and drug absorption is difficult, the shortcoming that bioavailability is low.Therefore need to study its pharmaceutical preparation, obtain the pharmaceutical preparation that good stability, absorption and drug effect contain the pharmaceutical composition of Furanodiene. preferably, with the safety that satisfies the different sufferers of hospital market, the needs of rational use of drug.
Summary of the invention
The present invention is intended to by prescription screening and the special process that is different from common process, provide that preparation technology is simple, good stability and drug effect contain pharmaceutical composition and multi-medicament preparation and their preparation method of Furanodiene. preferably, and be applied to treat or the preparation of the medicine of 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 be administered once every day or be administered once every several days.Each dosage is certain value.
The invention provides a kind of administration frequency once a day or be less than and once be used for the treatment of or the pharmaceutical composition that contains Furanodiene. of adjuvant therapy of malignant tumor, 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 that contains 48～800mg Furanodiene., said composition is administered once and is used for the treatment of tumor every day.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 that contains the oral administration of Furanodiene., said composition is administered once and is used for the treatment of tumor every day, contains Furanodiene. 480～2430mg in compositions, and preferred content is about 608 ~ 1940mg, preferred approximately 970～1600mg, most preferably 1460mg again.
The invention provides a kind of water solublity injecting and administering preparations that contains the pharmaceutical composition of Furanodiene..Due to this compound little this particularity of dissolubility in water and conventional non-aqueous media, need to add specific solubilizing agent.The combination consumption of finding the selected solubilizing agent of the present invention and organic facies in test can well increase its water solublity within the specific limits.According to pharmacological test data be able to water be medium the injection drug effect better and side effect little, we select the injection medium is water for injection.
The water solublity injecting and administering preparations that contains the pharmaceutical composition of Furanodiene. is injection, wherein comprises: the about Furanodiene. of 800mg of 48mg ~ approximately; The amount that accounts for described compositions is the organic facies of 4%～10%v/v; The amount that accounts 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 is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Tween-80 the mixture of one or more.
The Furanodiene. water type injection of making has the following advantages:
1, creationary suitable solubilizing agent and the acceptable organic solvent of human body of adding of this injection, this portfolio ratio is suitable, has greatly increased dissolubility and the stability of Furanodiene. in water, has solved the problem of easily separating out of placing.The injection that makes is complete clear and bright water type injection, than injectable emulsion, and the dosage forms such as oil for injection solution, human body is more acceptant, has avoided stimulation and the toxic and side effects of fat-soluble solvent to human body.
2, the form input human body that this injection can be by intravenous injection or intravenous drip does not have absorption process, can quick acting, be conducive to clinical practice.Thereby the medicament selection of utmost point indissoluble is made aqueous solvent but not fat-soluble dose.
The present invention also provides a kind of oral Preparation that contains the pharmaceutical composition of Furanodiene., it is oral solid formulation---tablet or capsule, comprising: a) Furanodiene. of 10g～20g, b) filler of 10g～50g, described filler is a kind of in cyclodextrin, microcrystalline Cellulose, amylum pregelatinisatum, lactose, preferred amylum pregelatinisatum; C) disintegrating agent of 0～30g, described disintegrating agent are a kind of in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, pre-gelatinized starch, preferred cross-linking sodium carboxymethyl cellulose; D) 0～2g lubricant, described lubricant are a kind of 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, make its particle diameter reach 200 orders.Improved the mobility of medicine, increased the bioavailability of oral formulations, reduced the content of oral solid formulation Chinese medicine, indirectly reduced cost, more be conducive to the patient and use and take.
2, after creationary employing medicine and the suitable abundant mix homogeneously of excipient, without pelletization direct compression or fill capsule.This technique has avoided the wet granulation must be through super-dry, and common dry run all needs heating, and this product is to thermally labile, and the preparation process can increase medicine and decompose probability.Adopt direct powder compression, can greatly improve the stability of medicine and the Maturity of technique.
It is oral solid formulation---soft capsule that the present invention also provides a kind of oral Preparation that contains the pharmaceutical composition of Furanodiene., per overall volume 24ml, wherein comprise: the Furanodiene. of 480～2430mg, the surfactant of 0.024～0.24mg; 0.024 the antiseptic of～0.24mg adds suitable carrier matrix standardize solution to 24ml.Wherein said carrier matrix is selected from one or more the mixture in soybean oil, Semen Maydis oil, Semen arachidis hypogaeae wet goods vegetable oil.Wherein said surfactant is selected from soybean phospholipid, lecithin, Tween-80.Further comprise the component antiseptic.Wherein said antiseptic is selected from methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate, potassium sorbate and its combination in any.Further also can add antioxidant, such as butylated hydroxyarisol (BHA), 2,6-di-t-butyl hydroxy-methylbenzene (BHT), vitamin E, ascorbyl palmitate etc.
The oral soft capsule that adopts above formulation and technology to make has following advantage and advantage:
1, in conjunction with the fat-soluble strong character of Furanodiene., adopt the oil dissolving of homogeneous make can be oral soft capsule, solved its problem of easily separating 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 homogeneous that obtains, preparation method is easy, is conducive to industrialization production.
2, on this basis, from add the w/o type surfactant different in traditional soft capsule, our creativeness adds several specific O/W type surfactants (soybean phospholipid, lecithin, Tween-80), its purpose is not to 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 that improves Furanodiene. distributes character, greatly promote speed and the degree of Furanodiene. permeate through cell membranes, improve the bioavailability of preparation.
3, enter to absorb in body with the soft capsule of this formulation and technology preparation and have unique mechanism of absorption: under the body temperature environment, run into after liquid can be under the impelling of gastrointestinal motility spontaneous formation oil-in-water emulsion.Improve drug dissolution, improve absorption.The microemulsion interfacial area is large, and surface tension is low, is easy to the hydrated sheath by gastrointestinal wall, can increase penetrance, promotes to absorb.Microemulsion can absorb through lymphatic vessel, thus the obstacle when overcoming first pass effect and macromole by the gastrointestinal tract epithelium.The Dispersed Phase Size of microemulsion is tiny and even, is beneficial to medicine absorption in vivo, thereby improves the bioavailability of medicine.
4, under the prerequisite of the mechanism of absorption that has possessed special formulation and technology and uniqueness, through pharmacology's checking, the toxicity of this soft capsule preparation obviously reduces than Emulsion, and its pharmacological property improves.
5, in addition, this soft capsule also has taking convenience, is easy to produce, and preservation condition without specific (special) requirements, is fit to the advantage of transportation and clinical use.
Being fit to the preparation that contains the pharmaceutical composition of Furanodiene. of the present invention can also be oral liquid, as Orally taken emulsion, can comprise oil phase (as soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen), emulsifying agent (as soybean phospholipid, lecithin), can be further including but not limited to following one or more component: antiseptic, pH adjusting agent, pharmacy acceptable solvent, the 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 exists to regulate the amount of described compositions pH value to 4 to 8.Wherein said pharmacy acceptable solvent is water for injection, PEG400, propylene glycol, ethanol, glycerol and combination in any thereof, preferred water for injection.
The specific embodiment
The present invention is further detailed explanation below in conjunction with specific embodiment, but the present invention is not limited thereto.
Preparation Furanodiene. emulsion injection embodiment 1-8
Embodiment 1:1g Furanodiene.
The 50g soybean oil
The 10g soybean phospholipid
Inject water to scale 1000ml altogether
Preparation: first emulsifying agent (soybean phospholipid) is dissolved in oil phase (soybean oil), add the principal agent Furanodiene., stirring makes its dissolving, after stirring, the filtering with microporous membrane of aperture 0.22 μ m is standby, add water for injection to recipe quantity, the homogenate machine is made colostrum, makes by homogenizer to reach the injectable emulsion size.Microporous filter membrane by aperture 0.22 μ m carries out aseptic filtration, and last embedding is in the sterilization ampoule of the drying of 1ml.Make the Emulsion injection that every ampoule 1ml contains Furanodiene. 1mg.
Embodiment 2:10g Furanodiene., 50g soybean oil, 20g soybean phospholipid, inject water to altogether 1000ml of scale.
Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 10mg.
Embodiment 3:40g Furanodiene., 100g Semen Maydis oil, 20g Ovum Gallus domesticus Flavus lecithin, inject water to altogether 1000ml of scale.
Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 40mg.
Embodiment 4:12g Furanodiene., 100g Oleum Arachidis hypogaeae semen, 20g hydrogenated soya phosphatide, inject water to altogether 1000ml of scale.
Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 12mg.
Embodiment 5:1g Furanodiene., 50g soybean oil, 10g synthetic phospholipid, inject water to altogether 1000ml of scale.
Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 1mg.
Embodiment 6:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene castor oil, inject water to altogether 1000ml of scale.Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 1mg.
Embodiment 7:10g Furanodiene., 100g soybean oil, 20g polyoxyethylene hydrogenated Oleum Ricini, inject water to altogether 1000ml of scale.Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 10mg.
Embodiment 8:2.5g Furanodiene., 100g soybean oil and Semen Maydis oil compositions, 10g Tween-80, inject water to altogether 1000ml of scale.Prepare the method for Furanodiene. emulsion injection with embodiment 1, make the Emulsion injection that every ampoule 1ml contains Furanodiene. 2.5mg.
Preparation Furanodiene. injection embodiment 9-12
Embodiment 9:0.8g Furanodiene.
8ml ethanol
The 4ml polyoxyethylene castor oil
Inject water to scale 80ml altogether.
Preparation: first with solubilizing agent (polyoxyethylene castor oil, other embodiment are corresponding solubilizing agent) be dissolved in organic facies (ethanol, other embodiment are corresponding organic facies) in, add the principal agent Furanodiene., stir and make its dissolving, after stirring, add water for injection to recipe quantity, microporous filter membrane by aperture 0.22 μ m carries out aseptic filtration, is filled at last in the sterilization ampoule of drying of 20ml, makes the injection that every 1ml contains Furanodiene. 10mg.
Embodiment 10:0.048g Furanodiene., 3.8ml ethanol, 0.8ml hydrogenation polyoxyethylene castor oil, inject water to altogether 80ml of scale.Preparation method makes with embodiment 9 injection that every 1ml contains Furanodiene. 0.6mg.
Embodiment 11:0.4g Furanodiene., 5ml ethanol, 2ml Tween-80, inject water to altogether 80ml of scale.Preparation method makes with embodiment 9 injection that every 1ml contains Furanodiene. 5mg.
Embodiment 12:0.8g Furanodiene., 6ml ethanol, 4ml polyoxyethylene hydrogenated Oleum Ricini, inject water to altogether 80ml of scale.Preparation method makes with embodiment 9 injection that every 1ml contains Furanodiene. 10mg.
The oral newborn embodiment 13-21 of preparation Furanodiene.
Embodiment 13:1g Furanodiene.
The 50g soybean oil
The 10g soybean phospholipid
0.1g methyl parahydroxybenzoate
Inject water to scale
Be total to 1000ml
Preparation: first emulsifying agent (soybean phospholipid) is dissolved in oil phase (soybean oil), add the principal agent Furanodiene., stirring makes its dissolving, after adding again antiseptic (methyl parahydroxybenzoate) to stir, the filtering with microporous membrane of aperture 0.22 μ m is standby, add water for injection to recipe quantity, the homogenate machine is made colostrum, makes by homogenizer to reach the injectable emulsion size.Microporous filter membrane by aperture 0.22 μ m carries out aseptic filtration, and last fill is jumped a queue in 20ml sterilization vial, Zha Gai.Make the Orally taken emulsion that every 1ml contains Furanodiene. 1mg.
Embodiment 14:100g Furanodiene., 100g soybean oil, 50g soybean phospholipid, 5g methyl parahydroxybenzoate, inject water to altogether 1000ml of scale.Preparation method makes with embodiment 13 Orally taken emulsion that every 1ml contains 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 makes with embodiment 13 Orally taken emulsion that every 1ml contains 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 makes with embodiment 13 Orally taken emulsion that every 1ml contains Furanodiene. 10mg.
Embodiment 17:1g Furanodiene., 100g soybean oil, 10g synthetic phospholipid, 0.1g sodium benzoate, inject water to altogether 1000ml of scale.Preparation method makes with embodiment 13 Orally taken emulsion that every 1ml contains Furanodiene. 1mg.
Embodiment 18:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene castor oil, 0.1g potassium sorbate, inject water to altogether 1000ml of scale.Preparation method makes with embodiment 13 Orally taken emulsion that every 1ml contains 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 makes with embodiment 13 Orally taken emulsion that every 1ml contains Furanodiene. 1mg.
Embodiment 20:1g Furanodiene., 100g soybean oil and Semen Maydis oil compositions, 10g Tween-80,0.1g methyl parahydroxybenzoate, inject water to altogether 1000ml of scale.Prepare the method for the oral breast of Furanodiene. with embodiment 13, make the Orally taken emulsion that every 1ml contains 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 altogether 1000ml of scale.Preparation method makes with embodiment 13 Orally taken emulsion that every 1ml contains Furanodiene. 1mg.
Preparation Furanodiene. capsule is implemented 22,24-25
Embodiment 22:20g Furanodiene.
The 50g amylum pregelatinisatum
The 2g magnesium stearate
100 of fill capsules
Preparation: the Furanodiene. of recipe quantity is put into Lowtemperaturepulverizer, under temperature-10～0 ℃, pulverize, make powder can pass through smoothly 200 eye mesh screens, filler, disintegrating agent and mix lubricant with recipe quantity is even again, direct fill capsule contains the capsule of Furanodiene. 200mg in making every.
Embodiment 24:15g Furanodiene., 50g soluble starch, 5g polyvinylpolypyrrolidone, 1g magnesium stearate, 100 of fill capsules.Preparation Furanodiene. oral capsule is with embodiment 22, contains the capsule of Furanodiene. 150mg in making every.
Embodiment 25:20g Furanodiene., 10g microcrystalline Cellulose, 30g pre-gelatinized starch, 2g silicon dioxide, 100 of fill capsules.Preparation Furanodiene. oral capsule is with embodiment 22, contains the capsule of Furanodiene. 200mg in every.
Preparation Furanodiene. tablet embodiment 23:10g Furanodiene.
The 50g lactose
The 10g cross-linking sodium carboxymethyl cellulose
1g silicon dioxide
Direct compression is total to get 100
Preparation with embodiment 22 fills before step, with the direct powder compression of mix homogeneously, contain the tablet of Furanodiene. 100mg in making every.
Preparation Furanodiene. oral soft capsule embodiment 26-28
Embodiment 26:2.4g Furanodiene.
0.24mg soybean phospholipid
0.24mg methyl parahydroxybenzoate
Add injection soybean oil dissolving said components and be settled to 24ml
Preparation: get injection soybean oil 1000ml, 150 ℃ of dry heat sterilizations 1 hour, let cool to 25 ℃, take out part fluid and add above-mentioned principal agent and adjuvant, stirring is dissolved it fully, is settled at last 24ml, No. 6 molten funnels that hang down with drying filter, embedding is in soft capsule, and ultraviolet sterilization 60 minutes contains 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 dissolving said components and are settled to 24ml.Prepare the method for Furanodiene. oral soft capsule with embodiment 26, contain 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 dissolving said components and are settled to 24ml.Preparation Furanodiene. oral soft capsule is with embodiment 26, contains the soft capsule of Furanodiene. 50mg in making every.
For the present invention is described better, below be influence factor's experiment and result:
Influence factor: illumination, high temperature, high humidity
Table 1 Furanodiene. preparation influence factor (illumination) result of the test
Table 2 Furanodiene. preparation influence factor (high temperature) result of the test
Table 3 Furanodiene. preparation influence factor (high humidity) result of the test
Experimental result shows that the 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 better essence of the present invention, below pharmacological toxicology test and the result of Furanodiene. illustrated that it is in the treatment of malignant tumor or the application on auxiliary treatment.
One, the animal pharmacology pharmacodynamics test of Furanodiene.
1, the therapeutical effect of Furanodiene. to people's hepatocarcinoma Nude Mice Bel-7402 hepatocarcinoma
Experiment 1:
Adopt Furanodiene. injection 25,50 and 100mg/kg after tumor inoculation every day each intravenously administrable once.Put to death animal after tumor inoculation on the 22nd and 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 adult's dosage convert: the standard body weight by the adult is that 60kg calculates,
Table look-up, mice a is capable, the R of adult b row
ab=0.081,
1-1 mice dosage is 25mg/kg
Dosage=D of adult
b.R
ab=d*0.081=2.03mg.kg
-1
Standard body weight=9.72mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=583.2mg
1-2 mice dosage is 50mg/kg
Dosage=D of adult
b.R
ab=d*0.081=4.05mg.kg
-1
Standard body weight=4.05mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=243mg
1-3 mice dosage is 100mg/kg
Dosage=D of adult
b.R
ab=d*0.081=8.10mg.kg
-1
Standard body weight=8.10mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=486mg
Concrete test method and result are as follows:
Laboratory animal: nude mouse: Balb/c strain, hero, 36, body weight 19.1 ± 1.0g.Provided by Shanghai Slac Experimental Animal Co., Ltd..
The inoculated tumour cell: intracardiac in the zoopery of SPF level, cut open the tumor of getting lotus Bel-7402 kind Mus, be cut into 1.0mm
3Large tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3The left and right begins administration with the animal random packet.
experimental technique: negative control group lumbar injection every day water for injection 0.1ml/10g, CTX group (fresh being disposed in normal saline before administration) is the CTX 0.1ml/10g of tail vein injection 3mg/ml every other day, the Furanodiene. 0.1ml/10g of Furanodiene. 25mg/kg group tail vein injection 2.5mg/ml every day, the Furanodiene. 0.1ml/10g of Furanodiene. 50mg/kg group tail vein injection 5mg/ml every day, Furanodiene. 100mg/kg group tail vein injection 10mg/ml Furanodiene. 0.1ml/10g every day, weighed and measured gross tumor volume in every 3 days, successive administration 21 days, put to death mice in the 22nd day, weigh, measure the tumor block long-pending, calculate relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, doing statistics detects.
Grouping: 36 inoculation Bel-7402 tumor cell nude mouses are divided into 6 groups at random, 1) negative control group is 12,2) CTX 30mg/kg group is 6,3) Furanodiene. 25mg/kg group is 6,4) Furanodiene. 50mg/kg group is 6,5) Furanodiene. 100mg/kg group is 6
Positive drug: cisplatin (Dezhou moral medicine company limited).
Test sample preparation: preparation Furanodiene. injection
First polyoxyethylene castor oil is dissolved in ethanol, add the principal agent Furanodiene., stirring makes its dissolving, after stirring, add water for injection to recipe quantity, the microporous filter membrane by aperture 0.22 μ m carries out aseptic filtration, is filled at last in the sterilization ampoule of drying of 20ml, make respectively every 1ml and contain Furanodiene. 2.5mg, the injection for injection of 5mg and 10mg.
Dosage: according to the preliminary experiment result, employing 25,50, three dosage of 100mg/kg, solvent control adopts coordinative solvent.Positive drug group cisplatin dosage is 30mg/kg.
Route of administration: three dosage groups of solvent control group and Furanodiene. adopt the i.v form administration, and the cisplatin group adopts the i.p form administration.
Administration volume: 0.1ml/10g
Administration time: three dosage component groups of solvent control group and Furanodiene. 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, and then drug withdrawal is 15 days, then successive administration 4 days.
Observing time: weighed 1 time in every 3 days.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
Experimental result:
Negative control group nude mouse body weight before and after the experimental therapy all without significant change, CTX 30mg/kg, Furanodiene. 50mg/kg and Furanodiene. 100mg/kg group nude mouse body weight obviously under (p＜0.05).Each group is none animal dead all.Negative control group relatively, the beginning in the 10th day after the administration of Furanodiene. 100mg/kg and CTX 30mg/kg group people Bel-7402 hepatocarcinoma Nude Mice volume significantly reduces (P＜0.05).The relative tumor volume of negative control group (RTV) is 24.4, CTX 30mg/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 tumor appreciation rate (T/C) relatively is respectively 21.7%, 43.4%, 31.0% and 26.7%.Administration is cutd open after 22 days to kill and is got the tumor piece 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 is 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, and tumour inhibiting rate (%) is 65.3.Treatment group mice-transplanted tumor average weight all has significance decline (P＜0.001) with the negative control group ratio.(seeing Table 4, table 5).The nude mouse administration of Furanodiene. 100mg/kg group was slow in action later in 15 days, the movable minimizing.
The experimental therapy effect of table 4. Furanodiene. to people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Matched group ratio: * * *: P＜0.001, *: P＜0.05.
D1: minute 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: negative matched group RTV.
The standard of curative effect evaluation: T/C (%)＞40 is invalid; T/C (%)≤40, and processing P＜0.05 is effective by statistics.
The impact of table 5. Furanodiene. on people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight
Matched group ratio: * * *: P＜0.001.
Experiment 2:
Adopt Furanodiene. injection breast 50,100,120 and 165mg/kg after tumor inoculation every day each intravenously administrable once.Put to death animal after tumor inoculation on the 22nd and get tumor and weigh, 50,100,120 and 165mg/kg group tumour inhibiting rate be respectively 36.2,46.4,55.1% and 58%.
The dosage of animal and adult's dosage convert: the standard body weight by the adult is that 60kg calculates,
Table look-up, mice a is capable, the R of adult b row
ab=0.081,
1-1 mice dosage is 50mg/kg
Dosage=D of adult
b.R
ab=d*0.081=4.05mg.kg
-1
Standard body weight=4.05mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=243mg
1-2 mice dosage is 100mg/kg
Dosage=D of adult
b.R
ab=d*0.081=8.10mg.kg
-1
Standard body weight=8.10mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=486mg
1-3 mice dosage is 120mg/kg
Dosage=D of adult
b.R
ab=d*0.081=9.72mg.kg
-1
Standard body weight=9.72mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=583.2mg
1-4 mice dosage is 165mg/kg
Dosage=D of adult
b.R
ab=d*0.081=13.37mg.kg
-1
Standard body weight=13.37mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=802mg
Concrete test method and result are as follows:
Laboratory animal: nude mouse: Balb/c strain, hero, 42, body weight 19.1 ± 1.0g.Provided by Shanghai Slac Experimental Animal Co., Ltd..
The inoculated tumour cell: intracardiac in the zoopery of SPF level, cut open the tumor of getting lotus Bel-7402 kind Mus, be cut into 1.0mm
3Large tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3The left and right begins administration with the animal random packet.
experimental technique: negative control group lumbar injection every day water for injection 0.1ml/10g, CTX group (fresh being disposed in normal saline before administration) is the CTX 0.1ml/10g of tail vein injection 3mg/ml every other day, the Furanodiene. 0.1ml/10g of Furanodiene. 50mg/kg group tail vein injection 5.0mg/ml every day, the Furanodiene. 0.1ml/10g of Furanodiene. 100mg/kg group tail vein injection 10mg/ml every day, Furanodiene. 120mg/kg group tail vein injection 12mg/ml Furanodiene. 0.1ml/10g every day, Furanodiene. 165mg/kg group tail vein injection 16.5mg/ml Furanodiene. 0.1ml/10g every day.The every 3 days gross tumor volumes of weighing and measure, successive administration 21 days was put to death mice in the 22nd day, weighed, and measured the tumor block long-pending, calculated relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, did statistics and detected.
Grouping: 42 inoculation Bel-7402 tumor cell nude mouses are divided into 6 groups at random, 1) negative control group is 12,2) CTX 30mg/kg group is 6,3) Furanodiene. 50mg/kg group is 6,4) Furanodiene. 100mg/kg group is 6,5) Furanodiene. 120mg/kg group is 6 6) 6 of Furanodiene. 165mg/kg groups.
Positive drug: cisplatin (Dezhou moral medicine company limited).
Test sample preparation: Furanodiene. injection breast
First soybean phospholipid is dissolved in soybean oil, adds the principal agent Furanodiene., after stirring is uniformly dissolved it, the filtering with microporous membrane of aperture 0.22 μ m is standby, add water for injection to recipe quantity, the homogenate machine is made colostrum, makes by homogenizer to reach the Emulsion size.Microporous filter membrane by aperture 0.22 μ m carries out aseptic filtration, and last embedding is to the ampoule of the drying of 20ml.Make respectively injection breast that every ampoule 1ml of notes that every ampoule 1ml contains Furanodiene. 5mg contains Furanodiene. 10mg, every ampoule 1ml and contain the injection breast that the injection breast of Furanodiene. 12mg, every ampoule 1ml contain Furanodiene. 16.5mg.
Dosage: according to the preliminary experiment result, employing 50,100,120, three dosage of 165mg/kg, solvent control adopts coordinative solvent.Positive drug group cisplatin dosage is 30mg/kg.
Route of administration: four dosage groups of solvent control group and Furanodiene. adopt the i.v form administration, and the cisplatin group adopts the i.p form administration.
Administration volume: 0.1ml/10g
Administration time: four dosage component groups of solvent control group and Furanodiene. 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, and then drug withdrawal is 15 days, then successive administration 4 days.
Observing time: weighed 1 time in every 3 days.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
Experimental result: see Table 6 and table 7.
The experimental therapy effect of table 6. Furanodiene. to people's cancer Nude Mice Bel-7402 hepatocarcinoma.
With the matched group ratio: * * *: P＜0.001.
D1: minute 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: negative matched group RTV.
The standard of curative effect evaluation: T/C (%)＞40 is invalid; T/C (%)≤40, and processing P＜0.05 is effective by statistics. matched group ratio: * * *: P＜0.001, *: P＜0.05.
The impact of table 7. Furanodiene. on people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight
Experimental result explanation 100mg/kg, 120mg/kg and three animals administer dosage of 165mg/kg all have therapeutic effect preferably, but than 120mg/kg and two animals administer dosage of 165mg/kg, 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.Putting to death animal after tumor inoculation on the 22nd gets tumor and weighs.
The dosage of animal and adult's dosage convert: supposition adult's standard body weight 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=D of adult
b.R
ab=d*0.081=8.10mg.kg
-1
Standard body weight=8.10mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=486mg
1-2 mice dosage is 200mg/kg
Dosage=D of adult
b.R
ab=d*0.081=16.2mg.kg
-1
Standard body weight=16.2mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=972mg
1-3 mice dosage is 400mg/kg
Dosage=D of adult
b.R
ab=d*0.081=3.24mg.kg
-1
Standard body weight=3.24mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=1944mg
Concrete test method and result are as follows: laboratory animal: nude mouse: Balb/c strain, hero, 36, body weight 19.1 ± 1.0g.Provided by Shanghai Slac Experimental Animal Co., Ltd..
The inoculated tumour cell: intracardiac in the zoopery of SPF level, cut open the tumor of getting lotus Bel-7402 kind Mus, be cut into 1.0mm
3Large tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3The left and right begins administration with the animal random packet.
Experimental technique: negative control group gavage every day water for injection 0.1ml/10g, CTX group (fresh being disposed in normal saline before administration) is the CTX 0.1ml/10g of 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 Furanodiene. 0.1ml/10g every day.The every 3 days gross tumor volumes of weighing and measure, successive administration 21 days was put to death mice in the 22nd day, weighed, and measured the tumor block long-pending, calculated relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, did statistics and detected.
Grouping: 36 inoculation Bel-7402 tumor cell nude mouses are divided into 5 groups at random, 1) negative control group is 12,2) CTX 30mg/kg group is 6,3) Furanodiene. 25mg/kg group is 6,4) Furanodiene. 50mg/kg group is 6,5) Furanodiene. 100mg/kg group is 6.
Positive drug: cisplatin (Dezhou moral medicine company limited).
The test sample preparation: Furanodiene. suspendible oral liquid takes the Furanodiene. of recipe quantity, the Tween 80 that adds recipe quantity, add again 0.5%CMC-Na aqueous solution (that is: sodium carboxymethyl cellulose solution) to recipe quantity, used again ultrasonic disintegrator ultrasonic 15 minutes, to the requirement that reaches suspension.Be filled at last in the sterilization vial of drying of 10ml, jump a queue, Zha Gai.Make respectively the oral suspension of confession that every 1ml contains Furanodiene. 10mg, every 1ml contains the oral suspension of confession that the oral suspension of the confession of Furanodiene. 20mg and every 1ml contain Furanodiene. 40mg.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
Experimental result: see Table 8 and table 9
The experimental therapy effect of table 8 Furanodiene. to people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Matched group ratio: * *: P＜0.001, *: P＜0.05.
D1: minute 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: negative matched group RTV.
The standard of curative effect evaluation: T/C (%)＞40 is invalid; T/C (%)≤40, and processing P＜0.05 is effective by statistics.
The impact of table 9. Furanodiene. on people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight
With the 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.
The dosage of animal and adult's dosage convert: supposition adult's standard body weight 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=D of adult
b.R
ab=d*0.081=8.10mg.kg
-1
Standard body weight=8.10mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=486mg
1-2 mice dosage is 200mg/kg
Dosage=D of adult
b.R
ab=d*0.081=16.2mg.kg
-1
Standard body weight=16.2mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=972mg
1-3 mice dosage is 400mg/kg
Dosage=D of adult
b.R
ab=d*0.081=3.24mg.kg
-1
Standard body weight=3.24mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=1944mg
Concrete test method and result are as follows:
Laboratory animal: nude mouse: Balb/c strain, hero, 36, body weight 19.1 ± 1.0g.Provided by Shanghai Slac Experimental Animal Co., Ltd..
The inoculated tumour cell: intracardiac in the zoopery of SPF level, cut open the tumor of getting lotus Bel-7402 kind Mus, be cut into 1.0mm
3Large tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3The left and right begins administration with the animal random packet.
Experimental technique: negative control group gavage every day water for injection 0.1ml/10g, CTX group (fresh being disposed in normal saline before administration) is the CTX 0.1ml/10g of 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 Furanodiene. 0.1ml/10g every day.The every 3 days gross tumor volumes of weighing and measure, successive administration 21 days was put to death mice in the 22nd day, weighed, and measured the tumor block long-pending, calculated relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, did statistics and detected.
Grouping: 36 inoculation Bel-7402 tumor cell nude mouses are divided into 5 groups at random, 1) negative control group is 12,2) CTX 30mg/kg group is 6,3) Furanodiene. 25mg/kg group is 6,4) Furanodiene. 50mg/kg group is 6,5) Furanodiene. 100mg/kg group is 6.
Positive drug: cisplatin (Dezhou moral medicine company limited).
The test sample preparation: the Furanodiene. oil solution is got injection vegetable oil (Oleum Camelliae, the Semen sojae atricolor wet goods) 1000ml, 150 ℃ of dry heat sterilizations 1 hour, let cool to 25 ℃, take out part fluid and add the 20g Furanodiene., be stirred to dissolve, add at last solvent to full dose, filter with No. 6 dry molten funnels that hang down, be filled at last in the sterilization vial of drying of 10ml, jump a queue, Zha Gai.Make respectively the oral oil solution of confession that every 1ml contains Furanodiene. 10mg, every 1ml contains the oral oil solution of confession that the oral oil solution of the confession of Furanodiene. 20mg and every 1ml contain Furanodiene. 40mg.
Dosage: according to the preliminary experiment result, (adopt Furanodiene. 400,200 and 100mg/kg, negative control adopts the respective volume solvent.Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
Experimental result: see Table 10
The experimental therapy effect of table 10. Furanodiene. to people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Matched group ratio: * *: P＜0.001, *: P＜0.05.
D1: minute 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: negative matched group RTV.
The standard of curative effect evaluation: T/C (%)＞40 is invalid; T/C (%)≤40, and processing P＜0.05 is effective by statistics.
Experimental result explanation 200mg/kg and three animals administer dosage of 400mg/kg all have therapeutic effect preferably, but than two animals administer dosage of 400mg/kg, under the animals administer dosage of 200mg/kg, toxic and side effects is less.So each dosage of corresponding adult is preferably 970mg.
2, the experimentation of Furanodiene. to BGC-823 transplanted tumor in nude mice growth effect
Experiment one: adopt Furanodiene. oil solution 125,250 and 500mg/kg after tumor inoculation every day each gastric infusion once.Put to death animal after tumor inoculation on the 22nd and get tumor and weigh, 125,250 and the middle and high dosage of 500mg/kg group certain inhibitory action is arranged.
The dosage of animal and adult's dosage convert: supposition adult's standard body weight is 60kg
Table look-up, mice a is capable, the R of adult b row
ab=0.081,
1-1 mice dosage is 125mg/kg
Dosage=D of adult
b.R
ab=d*0.081=10.12mg.kg
-1
Standard body weight=10.12mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=607.5mg
1-2 mice dosage is 250mg/kg
Dosage=D of adult
b.R
ab=d*0.081=20.25mg.kg
-1
Standard body weight=20.25mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=1215mg
1-3 mice dosage is 500mg/kg
Dosage=D of adult
b.R
ab=d*0.081=40.50mg.kg
-1
Standard body weight=40.05mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=2430mg
Concrete test method and result are as follows:
Laboratory animal: the BALB/c nude mice, female, age in 4-5 week, 40; Provided by Shanghai Si Laike Experimental Animal Center, raise the clinical pharmacology Animal Lab. in product development department, 25 ℃ of room temperatures, the drinking-water of freely ingesting.
The strain of BGC-823 tumor: Chinese Academy of Sciences's Shanghai cell bank provides, and 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 is by every animal 2 * 10
6Be inoculated in right oxter.See " cell toxicant series antineoplastic medicament investigative technique guideline " for details.
Grouping: observe the tumor growth state, when tumor growth to 100-300mm
3The time, animal is divided into 5 groups at random by gross tumor volume, be 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 moral medicine company limited).
Test sample preparation: Furanodiene. oil solution
Get injection vegetable oil (Oleum Camelliae, the Semen sojae atricolor wet goods) 1000ml, 150 ℃ of dry heat sterilizations 1 hour, let cool to 25 ℃, take out part fluid and add the 20g Furanodiene., be stirred to dissolve, add at last solvent to full dose, filter with No. 6 dry molten funnels that hang down, be filled at last in the sterilization vial of drying of 10ml, jump a queue, Zha Gai.Make respectively the oral oil solution of confession that every 1ml contains Furanodiene. 12.5mg, every 1ml contains the oral oil solution of confession that the oral oil solution of the confession of Furanodiene. 25mg and every 1ml contain Furanodiene. 50mg.
Dosage: employing 125,250, the low middle Senior Three dosage of 500mg/kg, the solvent control group adopts coordinative solvent.
Route of administration: i.p.
Administration volume: 0.1ml/10g.
Administration number of times: three of solvent control group and Furanodiene .s dosage component group played administration every day, successive administration 14 days (wherein have 2 days and find nude mice out of order, drug withdrawal on the same day) same day.Cisplatin component group began successive administration 4 days the same day, one week of drug withdrawal, then administration 3 days.
Observing time: every 2-4 day weighs 1 time, adopts vernier caliper measurement gross tumor volume size.After experiment finishes, put to death animal, get tumor, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, Mann-Whitney Test.
Experimental result: see Table 11,12.
The experimentation of table 11 Furanodiene. to BGC-823 transplanted tumor in nude mice growth effect
Compare with negative control:
▲P＜0.01;
*P＜0.05
The experimentation of table 12 Furanodiene. to BGC-823 transplanted tumor in nude mice growth effect
Compare with the Control group:
▲P＜0.01
3, contain 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 used ultrasonic disintegrator ultrasonic 15 minutes, to the requirement that reaches suspension.Be filled at last in the sterilization vial of drying of 10ml, jump a queue, Zha Gai.Make respectively the oral suspension of confession that every 1ml contains Furanodiene. 5mg, every 1ml contains the oral suspension of confession that the oral suspension of the confession of Furanodiene. 10mg and every 1ml contain Furanodiene. 20mg.
Laboratory animal: the BALB/c nude mice, female, age in 4-5 week, 38; Provided by Shanghai Si Laike Experimental Animal Center, raise the clinical pharmacology Animal Lab. in product development department, 25 ℃ of room temperatures, the drinking-water of freely ingesting.
The strain of Ho-8910 tumor: Chinese Academy of Sciences's Shanghai cell bank provides, and 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 is by every animal 2 * 10
6Be inoculated in right oxter.See " cell toxicant series antineoplastic medicament investigative technique guideline " for details.
Grouping: observe the tumor growth state, when tumor growth to 100-300mm
3The time, animal is divided into 4 groups at random by gross tumor volume, be 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 the preliminary experiment result, employing 50,100, three dosage of 200mg/kg, negative control adopts coordinative solvent.The administering drug combinations group is cisplatin and Furanodiene., the 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, played successive administration 3 days the same day, drug withdrawal one day, administration 15 times (wherein have 2 days and find nude mice out of order, drug withdrawal on the same day) altogether.
Observing time: every 2-4 day weighs 1 time, adopts vernier caliper measurement gross tumor volume size.After experiment finishes, put to death animal, get tumor, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, Mann-Whitney Test.
The dosage of animal and adult's dosage convert: supposition adult's standard body weight is 60kg
Table look-up, mice a is capable, the R of adult b row
ab=0.081,
1-1 mice dosage is 50mg/kg
Dosage=D of adult
b.R
ab=d*0.081=4.05mg.kg
-1
Standard body weight=4.05mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=243mg
1-2 mice dosage is 100mg/kg
Dosage=D of adult
b.R
ab=d*0.081=8.10mg.kg
-1
Standard body weight=8.1mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=486mg
1-3 mice dosage is 200mg/kg
Dosage=D of adult
b.R
ab=d*0.081=16.2mg.kg
-1
Standard body weight=16.2mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=972mg
Experimental result: see Table 13
The experimentation of table 13 Furanodiene. to Ho-8910 transplanted tumor in nude mice growth effect
Compare with negative control group:
▲P＜0.05
Annotate: T﹠amp; The Furanodiene. group administering drug combinations group of the positive medicine of D and middle dosage
In the compositions of experimental result explanation oral administration, the individually dosed drug effect of animals administer dosage of 100mg/kg is general, and that the administering drug combinations drug effect is better than is individually dosed, and drug effect is preferably arranged.The each dosage of corresponding adult is 490mg.
4, the experimentation (administering drug combinations effective, auxiliary antitumor) of Furanodiene. (code name Furanodiene .) to S180 mice-transplanted tumor growth effect
Experiment one
Materials and methods: test sample: Furanodiene. oil solution
Get injection vegetable oil (Oleum Camelliae, the Semen sojae atricolor wet goods) 1000ml, 150 ℃ of dry heat sterilizations 1 hour, let cool to 25 ℃, take out part fluid and add the 20g Furanodiene., be stirred to dissolve, add at last solvent to full dose, filter with No. 6 dry molten funnels that hang down, be filled at last in the sterilization vial of drying of 10ml, jump a queue, Zha Gai.Make respectively the oral oil solution of confession that every 1ml contains Furanodiene. 10mg, every 1ml contains the oral oil solution of confession that the oral oil solution of the confession of Furanodiene. 20mg and every 1ml contain Furanodiene. 30mg.
Laboratory animal: the ICR mice, single sex is female, 18-22g, 45; Provided by Zhejiang Province's Experimental Animal Center, raise the clinical pharmacology Animal Lab. in product development department, 25 ℃ of room temperatures, the drinking-water of freely ingesting.
The strain of S180 tumor: Zhejiang Province medical scientific institute provides, and 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 is by every animal 2 * 10
6Be inoculated in right oxter.
Grouping: grouping: divide at random four groups, 10 of model group animals, cyclophosphamide group, Furanodiene. group, drug combination group, 5 of each treated animals.
Administering mode: cyclophosphamide subcutaneous injection, Furanodiene. gastric infusion.
Administration volume: 0.1ml/10g
Administration number of times: after modeling, rise next day, continuous 7 days
Observing time: after modeling, Continuous Observation is 7.After experiment finishes, put to death animal, get tumor, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
The dosage of animal and adult's dosage convert: supposition adult's standard body weight 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=D of adult
b.R
ab=d*0.081=8.10mg.kg
-1
Standard body weight=8.1mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=486mg
1-2 mice dosage is 200mg/kg
Dosage=D of adult
b.R
ab=d*0.081=16.2mg.kg
-1
Standard body weight=16.2mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=972mg
1-3 mice dosage is 300mg/kg
Dosage=D of adult
b.R
ab=d*0.081=24.3mg.kg
-1
Standard body weight=24.3mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=1458mg
Experimental result: see Table 14
The experimentation of table 14 Furanodiene. to S180 mice-transplanted tumor growth effect
Compare with model control group:
*P＜0.05
*P＜0.01
Experiment two:
Materials and methods:
Test sample: Furanodiene. injection
First first polyoxyethylene castor oil is dissolved in ethanol, add the principal agent Furanodiene., stirring makes its dissolving, after stirring, add water for injection to recipe quantity, the microporous filter membrane by aperture 0.22 μ m carries out aseptic filtration, is filled at last in the sterilization vial of drying of 20ml, jump a queue, Zha Gai.Make every 1ml and contain Furanodiene. 1mg, every 1ml contains Furanodiene. 2.5mg, and every 1ml contains the injection for injection of Furanodiene. 5mg.
Laboratory animal: the ICR mice, single sex is female, 18-22g, 45; Provided by Zhejiang Province's Experimental Animal Center, raise the clinical pharmacology Animal Lab. in product development department, 25 ℃ of room temperatures, the drinking-water of freely ingesting.
The strain of S180 tumor: Zhejiang Province medical scientific institute provides, and 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 is by every animal 2 * 10
6Be inoculated in right oxter.
Grouping: grouping: divide at random four groups, 10 of model group animals, cyclophosphamide group, Furanodiene. group, drug combination group, 5 of each treated animals.
Administering mode: cyclophosphamide group lumbar injection, the intravenous injection of Furanodiene. administration group.
Administration volume: 0.1ml/10g
Administration number of times: after modeling, rise next day, continuous 7 days
Observing time: after modeling, Continuous Observation is 7.After experiment finishes, put to death animal, get tumor, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
The dosage of animal and adult's dosage convert: supposition adult's standard body weight is 60kg
Table look-up, mice a is capable, the R of adult b row
ab=0.081,
1-1 mice dosage is 10mg/kg
Dosage=D of adult
b.R
ab=d*0.081=0.81mg.kg
-1
Standard body weight=0.81mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=48.6mg
1-2 mice dosage is 25mg/kg
Dosage=D of adult
b.R
ab=d*0.081=2.02mg.kg
-1
Standard body weight=2.02mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=121.5mg
1-3 mice dosage is 50mg/kg
Dosage=D of adult
b.R
ab=d*0.081=4.05mg.kg
-1
Standard body weight=24.3mg.kg that the each dosage=adult's dosage * that is grown up is grown up
-1* 60kg=243mg
Experimental result: see Table 15
The experimentation of table 15 Furanodiene. to S180 mice-transplanted tumor growth effect
Compare with model control group:
*P＜0.05
*P＜0.01
In the compositions of experimental result explanation oral administration, the animals administer dosage drug effect of 300mg/kg is better, and side effect is little.Thereby each dosage of corresponding adult 1460mg/kg more preferably.
In the compositions of oral administration, the animals administer dosage of 100mg/kg, 200mg/kg and 300mg/kg drug effect when administering drug combinations all is better than when individually dosed.
According to document " Chinese Clinical pharmacology and therapeutics " the 9th the 09th phase of volume in 2004, carry out in pharmacological testing between animal and the dose,equivalent between the animals and human beings body converts.
Two, the acute toxicity test of Furanodiene.
The NIH mice respectively subcutaneous injection (sc) Furanodiene. injection and oral administration gavage Furanodiene. Furanodiene. soft capsule and Furanodiene. Emulsion, respectively establish 5 dosage groups, every group 10 (male and female half and half), observe the death toll in 14 days, press the BlissShi method and calculate LD
50Result 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 capsules of the present invention, Furanodiene. Emulsion and the Furanodiene. suspension solution difference on drug effect in animal body, the three has been carried out the experimental study of animal drug disposition dynamic metabolism.
This test selects the SD rat to carry out pharmacokinetic studies, adopt high performance liquid chromatography to detect Furanodiene. blood drug level dynamic change in vivo, take chemicals Non-clinical Pharmacokinetics investigative technique guideline (CDE) as experimental basis, and with the matched curve on computers of the 3P87 of Chinese Pharmacological Society program, calculate pharmacokinetic parameters.
Test sample: Furanodiene. crystal A suspension; Furanodiene. product suspension.Administering mode: gavage; Dosage: 100mg/kg administration volume: the 1.0ml/200g duration of taking a sample: 2880min statistical software: EXCEL
Experiment conclusion: calculate AUC by trapezoidal method, then calculate relative bioavailability, the Furanodiene. soft capsule is with respect to relative bioavailability F (0 ~ 48h)=78615.39/52561.64 * 100%=149.6% of Furanodiene. suspension, (absorption that 0 ~ 48h)=63569.79/49113.25 * 100%=129.4%, Furanodiene. soft capsule enter in body is better than Emulsion and suspension solution to the Furanodiene. soft capsule with respect to the relative bioavailability F of Furanodiene. Emulsion.
Claims (2)
1. pharmaceutical composition that contains Furanodiene., compositions adopts drug administration by injection, and the preparation of said composition is injection, and per overall volume is 80ml, wherein comprises:
A) Furanodiene. of 48mg～800mg, the amount that accounts for described compositions is 0.6%～10%w/v;
B) amount that accounts for described compositions is the organic facies of 4%～10%v/v;
C) amount that accounts for described compositions is the solubilizing agent of 1%～5%v/v; With
D) water for injection is settled to 80ml;
Wherein said organic facies is ethanol, and described solubilizing agent is one or more the mixture in polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Tween-80.
2. the application of pharmaceutical composition in the medicine of preparation treatment or adjuvant therapy of malignant tumor that contains Furanodiene. as claimed in claim 1.
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| CN101199507A (en) * | 2006-12-13 | 2008-06-18 | 烟台大学 | Application of furan diene and derivatives in preparing therapeautic cancer medicament |
| CN101219135A (en) * | 2007-01-08 | 2008-07-16 | 杭州民生药业集团有限公司 | Application of zedoary root cyclic diolefine in preparing medicament for treating tumour disease and disease caused by virus |
-
2009
- 2009-07-29 CN CN201310310198.9A patent/CN103405396B/en not_active Expired - Fee Related
- 2009-07-29 CN CN 200910101005 patent/CN101984961B/en not_active Expired - Fee Related
- 2009-07-29 CN CN201310310831.4A patent/CN103565787B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199507A (en) * | 2006-12-13 | 2008-06-18 | 烟台大学 | Application of furan diene and derivatives in preparing therapeautic cancer medicament |
| CN101219135A (en) * | 2007-01-08 | 2008-07-16 | 杭州民生药业集团有限公司 | Application of zedoary root cyclic diolefine in preparing medicament for treating tumour disease and disease caused by virus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103405396B (en) | 2015-08-05 |
| CN101984961A (en) | 2011-03-16 |
| CN103565787B (en) | 2016-02-17 |
| CN103565787A (en) | 2014-02-12 |
| CN103405396A (en) | 2013-11-27 |
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