CN101984961A - 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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- CN101984961A CN101984961A CN2009101010052A CN200910101005A CN101984961A CN 101984961 A CN101984961 A CN 101984961A CN 2009101010052 A CN2009101010052 A CN 2009101010052A CN 200910101005 A CN200910101005 A CN 200910101005A CN 101984961 A CN101984961 A CN 101984961A
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- furanodiene
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- injection
- pharmaceutical composition
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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 272
- 238000002360 preparation method Methods 0.000 title claims abstract description 76
- 239000000203 mixture Substances 0.000 title claims abstract description 41
- 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 19
- 238000005516 engineering process Methods 0.000 title abstract description 10
- 238000002347 injection Methods 0.000 claims abstract description 91
- 239000007924 injection Substances 0.000 claims abstract description 91
- 239000003814 drug Substances 0.000 claims abstract description 35
- 239000007901 soft capsule Substances 0.000 claims abstract description 24
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000003921 oil Substances 0.000 claims description 31
- 235000019198 oils Nutrition 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 21
- 235000012424 soybean oil Nutrition 0.000 claims description 21
- 239000003549 soybean oil Substances 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 210000000582 semen Anatomy 0.000 claims description 18
- 239000002775 capsule Substances 0.000 claims description 15
- 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
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 12
- 239000008347 soybean phospholipid Substances 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- 239000004359 castor oil Substances 0.000 claims description 9
- 235000019438 castor oil Nutrition 0.000 claims description 9
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 9
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 9
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 9
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 9
- 229960002216 methylparaben Drugs 0.000 claims description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 9
- 229920000053 polysorbate 80 Polymers 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 230000002421 anti-septic effect Effects 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 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 claims description 7
- 208000035126 Facies Diseases 0.000 claims description 7
- 235000010445 lecithin Nutrition 0.000 claims description 7
- 239000000787 lecithin Substances 0.000 claims description 7
- 229940067606 lecithin Drugs 0.000 claims description 7
- 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 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 6
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 6
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 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
- 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 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 5
- 235000010241 potassium sorbate Nutrition 0.000 claims description 5
- 239000004302 potassium sorbate Substances 0.000 claims description 5
- 229940069338 potassium sorbate Drugs 0.000 claims description 5
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 5
- 235000010234 sodium benzoate Nutrition 0.000 claims description 5
- 239000004299 sodium benzoate Substances 0.000 claims description 5
- 235000019890 Amylum Nutrition 0.000 claims description 4
- 238000009098 adjuvant therapy Methods 0.000 claims description 4
- 238000004132 cross linking Methods 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 3
- 238000007907 direct compression Methods 0.000 claims description 3
- 238000001647 drug administration Methods 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000011159 matrix material Substances 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 92
- 239000003826 tablet Substances 0.000 abstract description 6
- 239000007902 hard capsule Substances 0.000 abstract description 2
- 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
- 241001465754 Metazoa Species 0.000 description 60
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- 238000003756 stirring Methods 0.000 description 15
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 14
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
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- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 240000002853 Nelumbo nucifera Species 0.000 description 4
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- 230000005760 tumorsuppression Effects 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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- RJKPEKIHHFNMGS-UHFFFAOYSA-N 2,4-ditert-butyl-3-methylphenol Chemical compound CC1=C(C(C)(C)C)C=CC(O)=C1C(C)(C)C RJKPEKIHHFNMGS-UHFFFAOYSA-N 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
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Landscapes
- 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 middle pharmaceutically active ingredient, 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 the Oleum Curcumae, and first in the Hikiw of Japan, people such as H reported in nineteen sixty-eight.Its chemical name be (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 as yet not 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 the pharmaceutical composition and the preparation thereof of Furanodiene..
Though this chemical compound dissolubility in oil medium is bigger, Emulsion that makes with conventional method or oil preparation have placement separates out easily, poor stability, and especially entering can not be miscible in the oil phase and body in the body, drug absorption difficulty, the shortcoming that bioavailability is low.Therefore need 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 in 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 the multiple pharmaceutical 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 to be administered once every day or to be administered once every several days.Each dosage is a 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, the content of Furanodiene. is 48mg～2430mg in the wherein said pharmaceutical composition.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 for oral administration that contains Furanodiene., said composition is administered once and is used for the treatment of tumor every day, contain Furanodiene. 480～2430mg in the compositions, preferred content is about 608～1940mg, preferred more about 970～1600mg, most preferably 1460mg.
The invention provides a kind of water solublity injecting and administering preparations that contains the pharmaceutical composition of Furanodiene..Because this chemical compound little this particularity of dissolubility in water and conventional non-aqueous media needs to add specific solubilizing agent.The combination consumption of finding selected solubilizing agent of the present invention and organic facies in the 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 an injection, wherein comprises: the Furanodiene. of about 48mg～about 800mg; 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 a mixture in propylene glycol, PEG400, glycerol and the ethanol, preferred alcohol.Wherein said solubilizing agent is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, the Tween-80 one or more mixture.
The Furanodiene. water type injection of making has the following advantages:
1, suitable solubilizing agent and the acceptable organic solvent of human body of the creationary adding of this injection, this portfolio ratio is suitable, has increased dissolubility and the stability of Furanodiene. in water greatly, has solved the problem of separating out easily of placing.The injection that makes is complete clear and bright water type injection, than injectable emulsion, and 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, help 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 an 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, the lactose, preferred amylum pregelatinisatum; C) disintegrating agent of 0～30g, described disintegrating agent are a kind of in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the pre-gelatinized starch, preferred cross-linking sodium carboxymethyl cellulose; D) 0～2g lubricant, described lubricant are a kind of in magnesium stearate, the silicon dioxide; Make 100 or capsule.
Oral solid pharmaceutical formulation---tablet or capsule adopt the unique preparation process preparation:
1, adopts freeze grinding technology, Furanodiene. is carried out micronization processes, make its particle diameter reach 200 orders.Improved the flowability of medicine, increased the bioavailability of oral formulations, reduced the content of oral solid formulation Chinese medicine, indirect reduction cost, more help the patient and use and take.
2, behind creationary employing medicine and the suitable abundant mix homogeneously of excipient, without pelletization direct compression or fill capsule.This technology 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 improve the Maturity of stability of drug and technology greatly.
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 appropriate carriers substrate standardize solution to 24ml.Wherein said carrier matrix is selected from one or more the mixture in soybean oil, Semen Maydis oil, the 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 in aqueous solvent, separating out easily, improve the stability of said preparation greatly.Adopt the acceptable oils and fats of human body to make solvent, the Furanodiene. oil content character homogeneous that obtains, preparation method is easy, helps industrialization production.
2, on this basis, with to add the w/o type surfactant in the traditional soft capsule different, several specific O/W type surfactants (soybean phospholipid, lecithin, Tween-80) of our creative addings, 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 the body, the profit that improves Furanodiene. distributes character, promote the speed and the degree of Furanodiene. permeate through cell membranes greatly, improve the bioavailability of preparation.
3, enter to absorb in the body with the soft capsule of this formulation and technology preparation and have unique mechanism of absorption: under the body temperature environment, run into behind the 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 big, 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 decentralized photo particle diameter of microemulsion is tiny and even, is beneficial to the medicine absorption in vivo, thereby improves bioavailability of medicament.
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 is not had 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 regulator agent, pharmacy acceptable solvent, the forms of pharmacologically active agents except that 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 regulator 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
Add injection water to scale and be total to 1000ml
Preparation: earlier emulsifying agent (soybean phospholipid) is dissolved in the 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 exsiccant sterilization ampoule of 1ml.Make the Emulsion injection that every ampoule 1ml contains Furanodiene. 1mg.
Embodiment 2:10g Furanodiene., 50g soybean oil, 20g soybean phospholipid, add the injection water to scale 1000ml altogether.
The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 10mg with embodiment 1.
Embodiment 3:40g Furanodiene., 100g Semen Maydis oil, 20g Ovum Gallus domesticus Flavus lecithin, add the injection water to scale 1000ml altogether.
The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 40mg with embodiment 1.
Embodiment 4:12g Furanodiene., 100g Oleum Arachidis hypogaeae semen, 20g hydrogenated soya phosphatide, add the injection water to scale 1000ml altogether.
The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 12mg with embodiment 1.
Embodiment 5:1g Furanodiene., 50g soybean oil, 10g synthetic phospholipid, add the injection water to scale 1000ml altogether.
The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 1mg with embodiment 1.
Embodiment 6:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene castor oil, add the injection water to scale 1000ml altogether.The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 1mg with embodiment 1.
Embodiment 7:10g Furanodiene., 100g soybean oil, 20g polyoxyethylene hydrogenated Oleum Ricini, add the injection water to scale 1000ml altogether.The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 10mg with embodiment 1.
Embodiment 8:2.5g Furanodiene., 100g soybean oil and Semen Maydis oil compositions, 10g Tween-80, add the injection water to scale 1000ml altogether.The method for preparing the Furanodiene. emulsion injection is made the Emulsion injection that every ampoule 1ml contains Furanodiene. 2.5mg with embodiment 1.
Preparation Furanodiene. injection embodiment 9-12
Embodiment 9:0.8g Furanodiene.
8ml ethanol
The 4ml polyoxyethylene castor oil
Add injection water to scale and be total to 80ml.
Preparation: earlier 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 exsiccant sterilization ampoule 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, add the injection water to scale 80ml altogether.Preparation method is made the injection that every 1ml contains Furanodiene. 0.6mg with embodiment 9.
Embodiment 11:0.4g Furanodiene., 5ml ethanol, 2ml Tween-80, add the injection water to scale 80ml altogether.Preparation method is made the injection that every 1ml contains Furanodiene. 5mg with embodiment 9.
Embodiment 12:0.8g Furanodiene., 6ml ethanol, 4ml polyoxyethylene hydrogenated Oleum Ricini, add the injection water to scale 80ml altogether.Preparation method is made the injection that every 1ml contains Furanodiene. 10mg with embodiment 9.
The oral newborn embodiment 13 of preparation Furanodiene.---21
Embodiment 13:1g Furanodiene.
The 50g soybean oil
The 10g soybean phospholipid
0.1g methyl parahydroxybenzoate
Add the injection water to scale
Be total to 1000ml
Preparation: earlier emulsifying agent (soybean phospholipid) is dissolved in the oil phase (soybean oil), add the principal agent Furanodiene., stirring makes its dissolving, add again after antiseptic (methyl parahydroxybenzoate) stirs, 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 Zha Gai in 20ml sterilization vial.Make the Orally taken emulsion that every 1ml contains Furanodiene. 1mg.
Embodiment 14:100g Furanodiene., 100g soybean oil, 50g soybean phospholipid, 5g methyl parahydroxybenzoate, add the injection water to scale 1000ml altogether.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 100mg with embodiment 13.
Embodiment 15:50g Furanodiene., 100g Semen Maydis oil, 20g Ovum Gallus domesticus Flavus lecithin, 10g propyl p-hydroxybenzoate add injection water to scale and are total to 1000ml.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 50mg with embodiment 13.
Embodiment 16:10g Furanodiene., 100g Oleum Arachidis hypogaeae semen, 20g hydrogenated soya phosphatide, 0.1g propyl p-hydroxybenzoate add injection water to scale and are total to 1000ml.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 10mg with embodiment 13.
Embodiment 17:1g Furanodiene., 100g soybean oil, 10g synthetic phospholipid, 0.1g sodium benzoate, add the injection water to scale 1000ml altogether.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 1mg with embodiment 13.
Embodiment 18:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene castor oil, 0.1g potassium sorbate, add the injection water to scale 1000ml altogether.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 1mg with embodiment 13.
Embodiment 19:1g Furanodiene., 50g soybean oil, 20g polyoxyethylene hydrogenated Oleum Ricini, 0.1g potassium sorbate add injection water to scale and are total to 1000ml.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 1mg with embodiment 13.
Embodiment 20:1g Furanodiene., 100g soybean oil and Semen Maydis oil compositions, 10g Tween-80,0.1g methyl parahydroxybenzoate, add the injection water to scale 1000ml altogether.The method for preparing the oral breast of Furanodiene. is made the Orally taken emulsion that every 1ml contains Furanodiene. 1mg with embodiment 13.
Embodiment 21:1g Furanodiene., 100g soybean oil and Oleum Arachidis hypogaeae semen compositions, 10g Tween-80,0.1g methyl parahydroxybenzoate, add the injection water to scale 1000ml altogether.Preparation method is made the Orally taken emulsion that every 1ml contains Furanodiene. 1mg with embodiment 13.
Preparation Furanodiene. capsule implements 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 200 eye mesh screens smoothly, 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 altogether 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, put and be chilled to 25 ℃, take out part fluid and add above-mentioned principal agent and adjuvant, stirring is dissolved it fully, is settled to 24ml at last, filter with the exsiccant No. 6 molten funnels that hang down, 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.The method for preparing the Furanodiene. oral soft capsule is with embodiment 26, contains 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 advantages of higher stability, but because the influence 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 pharmacological toxicology test and the result of Furanodiene. illustrated that it is in the treatment of malignant tumor or the application on the 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 behind tumor inoculation every day each intravenously administrable once.Put to death animal behind the 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%
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.Provide 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
3Big tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3About, the animal random packet is begun administration.
Experimental technique: negative control group lumbar injection every day water for injection 0.1ml/10g, CTX group (fresh being disposed in the normal saline before the 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 in per 3 days and measure gross tumor volume, successive administration 21 days, put to death mice in the 22nd day, weigh, it is long-pending to measure the tumor block, calculate relative tumour volume (RTV), tumor appreciation rate (T/C) and tumor suppression percentage rate are done statistics and are detected relatively.
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
Earlier polyoxyethylene castor oil is dissolved in the 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 exsiccant sterilization ampoule of 20ml, make every 1ml respectively and contain Furanodiene. 2.5mg, the injection of 5mg and 10mg for injection.
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: solvent control group and three dosage components of Furanodiene. group 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 drug withdrawal is 15 days then, and successive administration is 4 days again.
Observing time: weighed 1 time in per 3 days.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
Experimental result:
Negative control group nude mouse body weight does not all have significant change before and after experimental therapy, CTX 30mg/kg, Furanodiene. 50mg/kg and Furanodiene. 100mg/kg group nude mouse body weight be following (p＜0.05) obviously.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 and is got the tumor piece extremely and weigh, Furanodiene. low dosage 25mg/kg, dosage 50mg/kg and Furanodiene. high dose 100mg/kg group people Bel-7402 hepatocarcinoma Nude Mice average weight is respectively 0.46g in the Furanodiene., 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.
Table 4. Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Matched group ratio: * * *: P＜0.001, *: P＜0.05.
D1: divide the 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
RTVX 100.T
RTV: be treatment group RTV; C
RTV: negative matched group RTV.
Therapeutic evaluation standard: T/C (%)＞40 is invalid; T/C (%)≤40, and processing P＜0.05 is effective by statistics.
Table 5. Furanodiene. is to the influence of 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 behind tumor inoculation every day each intravenously administrable once.Put to death animal behind the 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%.
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.Provide 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
3Big tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3About, the animal random packet is begun administration.
Experimental technique: negative control group lumbar injection every day water for injection 0.1ml/10g, CTX group (fresh being disposed in the normal saline before the 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 per 3 days gross tumor volumes of weighing and measure, successive administration 21 days was put to death mice in the 22nd day, weighed, and it is long-pending to measure the tumor block, calculates relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, does statistics and detects.
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
Earlier soybean phospholipid is dissolved in the soybean oil, adds the principal agent Furanodiene., after stirring makes its dissolving evenly, 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 exsiccant ampoule of 20ml.Make injection breast that every ampoule 1ml of notes that every ampoule 1ml contains Furanodiene. 5mg contains Furanodiene. 10mg, every ampoule 1ml respectively 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: solvent control group and four dosage components of Furanodiene. group 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 drug withdrawal is 15 days then, and successive administration is 4 days again.
Observing time: weighed 1 time in per 3 days.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
Experimental result: see Table 6 and table 7.
Table 6. Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Compare with matched group: * * *: P＜0.001.
D1: divide the 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
RTVX 100.T
RTV: be treatment group RTV; C
RTV: negative matched group RTV.
Therapeutic evaluation standard: 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.
Table 7. Furanodiene. is to the influence of 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 better therapeutic effect, but than 120mg/kg and two animals administer dosage of 165mg/kg, toxic and side effects is less under the animals administer dosage of 100mg/kg.So each dosage of corresponding adult is preferably 490mg.
Experiment 3:
The day each gastric infusion be once behind tumor inoculation to adopt Furanodiene. suspendible oral liquid 100,200 and 400mg/kg.Putting to death animal behind the tumor inoculation on the 22nd gets tumor and weighs.
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.Provide 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
3Big tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3About, the animal random packet is begun administration.
Experimental technique: negative control group is irritated stomach water for injection 0.1ml/10g every day, CTX group (fresh being disposed in the normal saline before the administration) is irritated the CTX 0.1ml/10g of stomach 3mg/ml every other day, Furanodiene. 100mg/kg group is irritated the Furanodiene. 0.1ml/10g of stomach 10mg/ml every day, Furanodiene. 200mg/kg group is irritated the Furanodiene. 0.1ml/10g of stomach 20mg/ml every day, and Furanodiene. 400mg/kg organizes and irritates stomach 40mg/ml Furanodiene. 0.1ml/10g every day.The per 3 days gross tumor volumes of weighing and measure, successive administration 21 days was put to death mice in the 22nd day, weighed, and it is long-pending to measure the tumor block, calculates relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, does statistics and detects.
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 by weighing the Furanodiene. of recipe quantity, the Tween 80 that adds recipe quantity, add 0.5%CMC-Na aqueous solution (that is: sodium carboxymethyl cellulose solution) again to recipe quantity, ultrasonic 15 minutes of reuse ultrasonic disintegrator is to the requirement that reaches suspension.Be filled at last in the exsiccant sterilization vial of 10ml, jump a queue Zha Gai.Make the oral suspension of confession that every 1ml contains Furanodiene. 10mg respectively, 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
Table 8 Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Matched group ratio: * *: P＜0.001, *: P＜0.05.
D1: divide the 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
RTVX 100.T
RTV: be treatment group RTV; C
RTV: negative matched group RTV.
Therapeutic evaluation standard: T/C (%)＞40 is invalid; T/C (%)≤40, and processing P＜0.05 is effective by statistics.
Table 9. Furanodiene. is to the influence of people's cancer Nude Mice Bel-7402 hepatocarcinoma tumor weight
Compare with matched group: * *: P＜0.001.
Experiment 4:
The day each gastric infusion be once behind tumor inoculation to adopt Furanodiene. oil solution 100,200 and 400mg/kg.The 22nd puts to death animal and gets tumor and weigh behind the tumor inoculation.
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.Provide 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
3Big tubercle piece is planted in the oxter of test nude mouse, treats that tumor average volume grows to 45mm
3About, the animal random packet is begun administration.
Experimental technique: negative control group is irritated stomach water for injection 0.1ml/10g every day, CTX group (fresh being disposed in the normal saline before the administration) is irritated the CTX 0.1ml/10g of stomach 3mg/ml every other day, Furanodiene. 100mg/kg group is irritated the Furanodiene. 0.1ml/10g of stomach 10mg/ml every day, Furanodiene. 200mg/kg group is irritated the Furanodiene. 0.1ml/10g of stomach 20mg/ml every day, and Furanodiene. 400mg/kg organizes and irritates stomach 40mg/ml Furanodiene. 0.1ml/10g every day.The per 3 days gross tumor volumes of weighing and measure, successive administration 21 days was put to death mice in the 22nd day, weighed, and it is long-pending to measure the tumor block, calculates relative tumour volume (RTV), relative tumor appreciation rate (T/C) and tumor suppression percentage rate, does statistics and detects.
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, put and be chilled to 25 ℃, take out part fluid and add the 20g Furanodiene., stirring makes dissolving, add solvent at last to full dose, filter, be filled at last in the exsiccant sterilization vial of 10ml with the exsiccant No. 6 molten funnels that hang down, jump a queue Zha Gai.Make the oral oil solution of confession that every 1ml contains Furanodiene. 10mg respectively, 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
Table 10. Furanodiene. is to the experimental therapy effect of people's cancer Nude Mice Bel-7402 hepatocarcinoma.
Matched group ratio: * *: P＜0.001, *: P＜0.05.
D1: divide the 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
RTVX 100.T
RTV: be treatment group RTV; C
RTV: negative matched group RTV.
Therapeutic evaluation standard: 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 better therapeutic effect, but than two animals administer dosage of 400mg/kg, toxic and side effects is less under the animals administer dosage of 200mg/kg.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 behind tumor inoculation every day each gastric infusion once.Put to death animal behind the tumor inoculation on the 22nd and get tumor and weigh, 125,250 and 500mg/kg organize middle and high dosage certain inhibitory action arranged.
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; Provide by Shanghai Si Laike Experimental Animal Center, raise clinical pharmacology Animal Lab., 25 ℃ of room temperatures, the drinking-water of freely ingesting in product development department.
The strain of BGC-823 tumor: Chinese Academy of Sciences's Shanghai cell bank provides, and conventional cultivation the in our company clinical pharmacology research department gone down to posterity.
Modeling: get the strain of In vitro culture BGC-823 tumor, be diluted to 1 * 10 with normal saline
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, put and be chilled to 25 ℃, take out part fluid and add the 20g Furanodiene., stirring makes dissolving, add solvent at last to full dose, filter, be filled at last in the exsiccant sterilization vial of 10ml with the exsiccant No. 6 molten funnels that hang down, jump a queue Zha Gai.Make the oral oil solution of confession that every 1ml contains Furanodiene. 12.5mg respectively, 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: solvent control group and three dosage components of Furanodiene. group played the administration every day 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 began successive administration 4 days the same day, and in one week of drug withdrawal, administration is 3 days again.
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.
Table 11 Furanodiene. is to the experimentation of BGC-823 transplanted tumor in nude mice growth effect
Compare 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
Compare with the Control group:
▲P＜0.01
3, contain the experimentation of the administering drug combinations compositions of Furanodiene. to Ho-8910 transplanted tumor in nude mice growth effect
Material and method:
Supply test agent: Furanodiene. suspendible oral liquid
Take by weighing 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, ultrasonic 15 minutes of reuse ultrasonic disintegrator is to the requirement that reaches suspension.Be filled at last in the exsiccant sterilization vial of 10ml, jump a queue Zha Gai.Make the oral suspension of confession that every 1ml contains Furanodiene. 5mg respectively, 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; Provide by Shanghai Si Laike Experimental Animal Center, raise clinical pharmacology Animal Lab., 25 ℃ of room temperatures, the drinking-water of freely ingesting in product development department.
The strain of Ho-8910 tumor: Chinese Academy of Sciences's Shanghai cell bank provides, and conventional cultivation the in our company clinical pharmacology research department gone down to posterity.
Modeling: get the strain of In vitro culture Ho-8910 tumor, be diluted to 1 * 10 with normal saline
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 (bio-pharmaceuticals of Geju City, Yunnan).
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: successive administration was played 3 days the same day in the grouping back, 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.
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
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
Annotate: T﹠amp; The Furanodiene. group administering drug combinations group of positive medicine of D and middle dosage
The individually dosed drug effect of animals administer dosage of 100mg/kg is general in the experimental result explanation liquid preparations for oral administration, 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, Furanodiene. (code name Furanodiene .) is to the experimentation (administering drug combinations is effective, auxiliary antitumor) of S180 mice-transplanted tumor growth effect
Experiment one
Material and method: supply test agent: the Furanodiene. oil solution
Get injection vegetable oil (Oleum Camelliae, the Semen sojae atricolor wet goods) 1000ml, 150 ℃ of dry heat sterilizations 1 hour, put and be chilled to 25 ℃, take out part fluid and add the 20g Furanodiene., stirring makes dissolving, add solvent at last to full dose, filter, be filled at last in the exsiccant sterilization vial of 10ml with the exsiccant No. 6 molten funnels that hang down, jump a queue Zha Gai.Make the oral oil solution of confession that every 1ml contains Furanodiene. 10mg respectively, 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; Provide by Zhejiang Province's Experimental Animal Center, raise clinical pharmacology Animal Lab., 25 ℃ of room temperatures, the drinking-water of freely ingesting in product development department.
The strain of S180 tumor: medical scientific institute in Zhejiang Province's provides, and every 7-9 goes down to posterity once in a days abdominal cavity.
Modeling: get S180 mouse-borne tumor animal ascites, be diluted to 1 * 10 with normal saline
7/ ml is by every animal 2 * 10
6Be inoculated in right oxter.
Grouping: grouping: divide four groups at random, 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: rise next day after the modeling, continuous 7 days
Observing time: observed 7 continuously after the modeling.After experiment finishes, put to death animal, get tumor, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
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
Table 14 Furanodiene. is to the experimentation of S180 mice-transplanted tumor growth effect
Compare with model control group: * p＜0.05**p＜0.01
Experiment two:
Material and method:
Supply test agent: the Furanodiene. injection
Earlier polyoxyethylene castor oil is dissolved in the 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 exsiccant sterilization vial 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; Provide by Zhejiang Province's Experimental Animal Center, raise clinical pharmacology Animal Lab., 25 ℃ of room temperatures, the drinking-water of freely ingesting in product development department.
The strain of S180 tumor: medical scientific institute in Zhejiang Province's provides, and every 7-9 goes down to posterity once in a days abdominal cavity.
Modeling: get S180 mouse-borne tumor animal ascites, be diluted to 1 * 10 with normal saline
7/ ml is by every animal 2 * 10
6Be inoculated in right oxter.
Grouping: grouping: divide four groups at random, 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: rise next day after the modeling, continuous 7 days
Observing time: observed 7 continuously after the modeling.After experiment finishes, put to death animal, get tumor, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, one factor analysis of variance method.
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
Table 15 Furanodiene. is to the experimentation of S180 mice-transplanted tumor growth effect
Compare with model control group: * p＜0.05**p＜0.01
The animals administer dosage drug effect of 300mg/kg is better in the experimental result explanation liquid preparations for oral administration, and side effect is little.Thereby each dosage of corresponding adult 1460mg/kg more preferably.
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 in the liquid preparations for oral administration.
According to document " Chinese clinical pharmacology and therapeutics " 2004 the 9th the 09th phase of volume, carry out in the 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
50The 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 capsules of the present invention, Furanodiene. Emulsion and the Furanodiene. suspension solution difference on the drug effect in animal body, the three has been carried out the experimental study of animal drug disposition dynamic metabolism.
This test selects for use the SD rat to carry out pharmacokinetic studies, adopt high performance liquid chromatography to detect Furanodiene. blood drug level dynamic change in vivo, with the non-CLINICAL PHARMACOKINETIS STUDY ON technological guidance's principle of chemicals (CDE) is experimental basis, and, calculate pharmacokinetic parameters with the matched curve on computers of the 3P87 of Chinese Pharmacological Society program.
Test sample: Furanodiene. crystal A suspension; Furanodiene. product suspension.Administering mode: irritate stomach; 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, calculate relative bioavailability then, the Furanodiene. soft capsule is with respect to relative bioavailability F (0～the 48h)=78615.39/52561.64 * 100%=149.6% of Furanodiene. suspension, (0～48h)=63569.79/49113.25 * 100%=129.4%, Furanodiene. soft capsule enter intravital absorption and are better than Emulsion and suspension solution the Furanodiene. soft capsule with respect to the relative bioavailability F of Furanodiene. Emulsion.
Claims (10)
1. an 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 drug administration by injection or oral administration, the content of Furanodiene. is 48mg～2430mg in the wherein said pharmaceutical composition.
2. the pharmaceutical composition that contains Furanodiene. according to claim 1, wherein said drug administration by injection compositions is an injection, per overall volume is 80ml, wherein comprises:
A) Furanodiene. of 48mg～800mg, the amount that accounts for described compositions are 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.
3. the pharmaceutical composition that contains Furanodiene. according to claim 2, wherein said organic facies are one or more mixture in propylene glycol, PEG400, glycerol and the ethanol, preferred alcohol; Described solubilizing agent is one or more a mixture in polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, the Tween-80.
4. the pharmaceutical composition that contains Furanodiene. according to claim 1, described composition for oral administration are soft capsule, and 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) the carrier matrix standardize solution is to 24ml.
5. the pharmaceutical composition that contains Furanodiene. according to claim 4, wherein said surfactant are one or more mixture in soybean phospholipid, lecithin, the Tween-80.
6. the pharmaceutical composition that contains Furanodiene. according to claim 4, wherein said antiseptic are one or more mixture in methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate, the potassium sorbate.
7. the pharmaceutical composition that contains Furanodiene. according to claim 4, wherein said carrier matrix are one or more the mixture in soybean oil, Semen Maydis oil, the Oleum Arachidis hypogaeae semen.
8. the pharmaceutical composition that contains Furanodiene. according to claim 1, described oral administration are capsule or tablet oral solid formulation, wherein comprise in 100 or the capsule:
A) Furanodiene. of 10g～20g;
B) filler of 10g～50g, described filler are a kind of in cyclodextrin, microcrystalline Cellulose, amylum pregelatinisatum, the lactose;
C) disintegrating agent of 0～30g, described disintegrating agent are a kind of in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the pre-gelatinized starch;
D) 0～2g lubricant, described lubricant are a kind of in magnesium stearate, the silicon dioxide.
9. the preparation method for preparing the oral solid formulation of the pharmaceutical composition that contains Furanodiene. as claimed in claim 8, it is characterized in that the Furanodiene. of recipe quantity is put into Lowtemperaturepulverizer, under temperature-10～0 ℃, pulverize, make powder can pass through 200 eye mesh screens smoothly, filler, disintegrating agent and mix lubricant with recipe quantity is even again, directly fill capsule or direct compression.
10. the described pharmaceutical composition that contains Furanodiene. of claim 1 is applied to treat or the preparation of the medicine of adjuvant therapy of malignant tumor.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310310831.4A CN103565787B (en) | 2009-07-29 | 2009-07-29 | A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof |
| CN201310310198.9A CN103405396B (en) | 2009-07-29 | 2009-07-29 | A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof |
| CN 200910101005 CN101984961B (en) | 2009-07-29 | 2009-07-29 | Furanodiene-containing medicinal composition, technology for preparing preparation thereof and medicinal use thereof |
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| CN 200910101005 CN101984961B (en) | 2009-07-29 | 2009-07-29 | Furanodiene-containing medicinal composition, technology for preparing preparation thereof and medicinal use thereof |
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| CN201310310198.9A Division CN103405396B (en) | 2009-07-29 | 2009-07-29 | A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof |
| CN201310310831.4A Division CN103565787B (en) | 2009-07-29 | 2009-07-29 | A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof |
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| CN101984961A true CN101984961A (en) | 2011-03-16 |
| CN101984961B CN101984961B (en) | 2013-11-06 |
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| CN201310310198.9A Expired - Fee Related CN103405396B (en) | 2009-07-29 | 2009-07-29 | A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof |
| CN 200910101005 Expired - Fee Related CN101984961B (en) | 2009-07-29 | 2009-07-29 | Furanodiene-containing medicinal composition, technology for preparing preparation thereof and medicinal use thereof |
| CN201310310831.4A Expired - Fee Related CN103565787B (en) | 2009-07-29 | 2009-07-29 | A kind of pharmaceutical composition containing Furanodiene. and pharmaceutical applications thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103463565A (en) * | 2013-05-23 | 2013-12-25 | 张蕊 | Zedoary oil injection and preparation method thereof |
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 |
-
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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103463565A (en) * | 2013-05-23 | 2013-12-25 | 张蕊 | Zedoary oil injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103405396B (en) | 2015-08-05 |
| CN103565787B (en) | 2016-02-17 |
| CN103565787A (en) | 2014-02-12 |
| CN103405396A (en) | 2013-11-27 |
| CN101984961B (en) | 2013-11-06 |
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