CN102405216B - Crystal form A of furanodiene, preparation method and useful for preparing antitumor drug thereof - Google Patents
Crystal form A of furanodiene, preparation method and useful for preparing antitumor drug thereof Download PDFInfo
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Abstract
The crystal form A of furanodiene which characteristic peaks at 2 theta of 11.4 DEG (+-0.1 DEG ), 13.4 DEG (+-0.1 DEG ), 15.3 DEG (+-0.1 DEG ), 19.6 DEG (+-0.1 DEG ) and 24.6 DEG (+-0.1 DEG ) in x-ray powder diffraction pattern. This crystal has the absorption peak at 69 DEG in differential scanning calorimetry pattern. The preparation method of the crystal form A of furanodiene. The method of treating tumor by using the crystal form A of furanodiene. The crystal form A of furanodiene can improve the pharmacokinetics activity of the furanodiene and strengthen the drugability of the furanodiene. The present method overcomes the problem in the traditional method which uses the supercritical carbon dioxide extraction to obtain the furanodiene, such as the complex process and the expensive cost.
Description
Technical field
The present invention relates to a kind of crystal form A of Furanodiene, the preparation method of this Furanodiene crystal form A, and this Furanodiene crystal form A is in the application of preparing in antitumor drug.
Background technology
Traditional Chinese medicine Rhizoma curcumae is the dry rhizome of zingiberaceous plant zddoary Curcuma phaeocaulis Val. Guangxi zedoary C.kwangsinensis S.G.Lee et C.F.Liang. and RADIX CURCUMAE C.wenyujinY.H.chen et C.Ling, containing volatile oil 1%～2.5%.Its volatile oil main chemical compositions is terpenoid, as Curcumenol, Curgerenone, curzerene etc.Prove that through modern pharmacological research it has certain antibacterial, antitumour activity.
Rhizoma Curcumae volatile oil is to take extraction by steam distillation, the complicated component of volatile oil always.This separates to the effective constituent of next step zedoary turmeric oil volatile oil and brings difficulty.Because main effective constituent is terpene in volatile oil, the temperature and time of heating can affect effective constituent again, as excess Temperature or overlong time can cause that it occurs to decompose and conversion.
Furanodiene is first by Japanese Hikiw, and the people such as H report in nineteen sixty-eight, and its chemical name is: (5E, 9Z)-3,6,10-trimethylammonium-4,7,8,11-tetrahydro-cyclodeca-[b] furans, English chemical name: Cyclodeca[b] furan, 4,7,8,11-tetrahydro-3,6,10-trimethyl-(5E, 9Z).
Chemical structural formula is:
Molecular formula is: C
15h
20o molecular weight is: 216.15
The physico-chemical property of this product: white crystalline powder.Odorless, tasteless, at dehydrated alcohol, acetone, easily molten in chloroform, be insoluble in water.
Furanodiene is unstable, and heat is easily decomposed, flavescence.Rhizoma Curcumae volatile oil is to take extraction by steam distillation, the complicated component of volatile oil always.This separates to the effective constituent of next step zedoary turmeric oil volatile oil and brings difficulty.Because main effective constituent is terpene in volatile oil, the temperature and time of heating can affect effective constituent again, as excess Temperature or overlong time can cause that it occurs to decompose and conversion.Furanodiene is the main component in Rhizoma Curcumae volatile oil, but still there is no to prepare in a large number at present method and the simple separation method of this compound.
In compounding pharmaceutical composition process, the form that medicine becomes a kind of convenient operation and processing is very important.Be no matter the angle from obtaining a kind of production method that can industrialization, or from producing afterwards the angle of the medicinal compositions that contained described active compound, this point is all very important.Chemical stability, solid-state stability and the storage time of described activeconstituents is also very important factor.Medicine and the composition that comprises it should be able to effectively store and exceed the appreciable time cycle, and significant variation do not appear in the physical-chemical feature of described activeconstituents (as its chemical constitution, density, draw moist and solvability).In addition it is also important, can providing medicine with pure as far as possible form.Unformed material may have problems in this.For example, this type of material carrys out less stable compared with crystal type material, or purity is lower.If can obtain medicine with stable crystal formation simply, can overcome the above problems.In addition, the good crystal formation of crystalline state is likely being made after oral preparations, obviously increases the bioavailability of this material, improves its pharmacokinetics character in vivo, and then strengthens its pharmacologically active.
Given this, the invention provides a kind of novel stable Furanodiene crystal form A and preparation method and the application of Furanodiene crystal form A.
Summary of the invention
An object of the present invention is to provide a kind of Furanodiene crystal form A of the pharmacokinetic property with improvement.
Another object of the present invention is to provide the preparation method of described Furanodiene crystal form A.
Further object of the present invention is to provide this Furanodiene crystal form A in the application of preparing in antitumor drug.
Further aim of the present invention is to provide a kind of method for the treatment of tumour, comprises and gives Furanodiene crystal form A to the object of needs treatment.
The invention provides a kind of Furanodiene crystal form A, its X-ray powder diffraction pattern has characteristic peak at 11.4 ° (± 0.1 °), 13.4 ° (± 0.1 °), 15.3 ° (± 0.1 °), 19.6 ° (± 0.1 °) and 24.6 ° of (± 0.1 °) 2 θ.Described X-ray diffraction characterizes and adopts the Rigaku D/max2550PC type powder diffractometer of Rigaku Electric Co., Ltd (Rigaku) to carry out, use Cu K alpha-ray and Ni spectral filter, under the working conditions of tube voltage 40kV and tube current 300mA, scan, scanning wavelength is 0.01 °, and speed is 0.1 °/min.
In the differential scanning characteristic pattern of described Furanodiene crystal form A, there is absorption peak at 69 ℃ ± 1 ℃.
On the other hand, the preparation method of Furanodiene crystal form A of the present invention comprises the steps:
(1) use alcohols or ketones solvent to dissolve Furanodiene powder;
(2) after crystal is separated out, filter, collect crystal.
Wherein, described alcoholic solvent is preferably selected from methyl alcohol, ethanol, Virahol, propyl carbinol or their combination, most preferably ethanol; Described ketones solvent is preferably selected from one or more in acetone, butanone or pentanone, most preferably acetone.The weightmeasurement ratio (g:ml) of Furanodiene powder and alcohols or ketones solvent is preferably 1:6-12.In described step (1), preferably, at 20～70 ℃, be more preferably 30～40 ℃, preferably dissolve at 35 ℃.
The Furanodiene crystal form A that provides on the one hand more of the present invention is in the application of preparing in the medicine for the treatment of tumor disease.
Wherein, described tumor disease includes, but not limited to ovarian cancer, cervical cancer, cancer of the stomach, liver cancer, leukemia, lung cancer, rectal adenocarcinoma, nasopharyngeal carcinoma.
The present invention further provides a kind of method for the treatment of tumour, comprised the Furanodiene crystal form A of the object of needs treatment being treated to significant quantity.
Wherein, described tumour includes, but not limited to ovarian cancer, cervical cancer, cancer of the stomach, liver cancer, leukemia, lung cancer, rectal adenocarcinoma, nasopharyngeal carcinoma.
Described treatment significant quantity is, with respect to the individuality of about 60kg body weight, and 0.01-3.0 gram of Furanodiene crystal form A/sky.
The described mode that gives includes, but not limited to emulsion intravenous injection or oral.
The present invention also provides a kind of pharmaceutical composition, and it contains described Furanodiene crystal form A and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutically acceptable carrier is the well known usual excipients for the preparation of above-mentioned preparation or auxiliary material.For example, for oral preparations, conventional vehicle or auxiliary material include, but are not limited to, weighting agent or thinner, lubricant or glidant or antitack agent, dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent etc.Described tackiness agent can be selected from, Mierocrystalline cellulose and derivative, gum arabic, gelatin (slurry), sorbyl alcohol, tragacanth, syrup, starch slurry or the polyvinylpyrrolidones such as such as Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose, HPMC; Described weighting agent can be selected from, inorganic calcium salt, lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, sorbyl alcohol or the glycine such as such as calcium sulfate, calcium phosphate, secondary calcium phosphate, precipitated calcium carbonate; Described lubricant can be selected from, for example micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyoxyethylene glycol; Described disintegrating agent can be selected from, starch and derivative, polyvinylpyrrolidone or the Microcrystalline Celluloses such as such as sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum; Described wetting agent can be, such as sodium lauryl sulphate, water or alcohol etc.
For injection preparation, its usual excipients or auxiliary material include but not limited to: oxidation inhibitor, such as Sulfothiorine, S-WAT, sodium bisulfite, dibutyl benzoic acid or Sodium Pyrosulfite etc.; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; PH adjusting agent, for example potassium hydroxide (sodium), Sodium Citrate and buffer reagent phosphoric acid dioxy sodium and Sodium phosphate dibasic; Emulsifying agent, for example Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, fabaceous lecithin; Solubilizing agent, such as tween-80, glycerine etc.
Accompanying drawing explanation
Fig. 1 is the space structure schematic diagram of Furanodiene.
Fig. 2 is the X-ray powder diffraction pattern of the Furanodiene crystal form A that obtains of embodiment 2.
Fig. 3 is the X-ray powder diffraction pattern of the Furanodiene crystal form A that obtains of embodiment 5.
Fig. 4 is the differential scanning spectrogram of Furanodiene crystal form A of the present invention.
Embodiment
Below in conjunction with drawings and Examples, the present invention is further detailed explanation, but the present invention is not limited thereto.
Comparative example:
Adopt traditional carbon dioxide upercritical fluid extraction technique to prepare Furanodiene product: to get curcuma zedoary medicinal material 1.5kg, be ground into meal (crossing sieve No. 2), drop in HA221-50-06 type supercritical extraction unit, with pressure 28Mpa, 60 ℃, CO2 flow is 25kg/hr extraction 1.5 hours, extraction-container I, the pressure of II is respectively 10, 6Mpa, temperature is respectively 50, 45 ℃, obtain yellow extract 118g extract, extract refrigerator is placed, crystallization adds methanol wash, obtain white needle-like crystals, through UV, IR, NMR, the spectroscopic techniques such as MS are identified, molecular formula is C
15h
20o, molecular weight 216, structure is Furanodiene, for relatively convenient, we are by the material called after Furanodiene product obtaining by this method.
embodiment 1: the preparation of Furanodiene crude product
Get the dry rhizome 1kg of curcuma zedoary, distill by steam distillation apparatus, obtain altogether 376g oil-water mixture, extract with ether and sherwood oil, separate oil reservoir, abandon or adopt water layer, and concentrated, obtain Rhizoma Curcumae volatile oil 42.1g, separate with silicagel column, sherwood oil wash-out, every bottle of 250ml collects, merge 10～18 components, pump solvent, obtain yellow solid 13.7g, going up silicagel column separates again, sherwood oil wash-out, every bottle of 50ml, merge 11～22 components, pump solvent, obtain white solid 9.6g, high resolution mass spectrum is analyzed positive ion and is detected the quasi-molecular ion peak [M+H] that shows sample
+be 217.16, infer that its molecular weight is 216, inspection Match of elemental composition, it is elementary composition is C
15h
20o, error is less than 5ppm, and the molecular formula that shows this sample is C
15h
20o.Infrared detection collection of illustrative plates shows: sample 3434,2968,2931,2892,2855,1445,1385,1133,1078,1025, there is charateristic avsorption band at 754cm-1 place; Magnetic resonance detection demonstration, at δ 7.228ppm, δ 4.996ppm, δ 4.691ppm, δ 3.378ppm, δ 3.107ppm, δ 2.211ppm, δ 2.104ppm, δ 1.874ppm, δ 1.760ppm, δ 1.559ppm, there is absorption group peak at δ 1.200ppm place, resolves by detailed ownership, proves that this isolate is Furanodiene.
embodiment 2
The Furanodiene crude product 120ml dissolve with ethanol of 10g embodiment 1 gained, is heated to 20 ℃ slightly to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4,15.3 °, 19.6 ° and 24.7 ° of 2 θ, and its relative intensity (I/I0%) is respectively 100,20.7,66.8,16.2,11.7.Adopt differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 3
The Furanodiene crude product 60ml dissolve with methanol of 10g embodiment 1 gained, is heated to 70 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.5 °, 13.5 °, 15.3 °, 19.7 ° and 24.7 ° of 2 θ, and the Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 4
The Furanodiene crude product that 10g embodiment 1 obtains dissolves with 80ml butanone, is heated to 65 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.5 °, 15.3 °, 19.6 ° and 24.7 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 5
10g Furanodiene crude product 70ml acetone solution, is heated to 45 ℃ slightly to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.5 °, 13.5 °, 15.3 °, 19.7 ° and 24.7 ° of 2 θ, and its relative intensity (I/I0%) is respectively 0.7,8.7,100,5.0,28.9; Adopt differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 6
The Furanodiene crude product of 10g embodiment 1 gained dissolves with 100ml pentanone, is heated to slightly 60 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.5 °, 15.4 °, 19.7 ° and 24.7 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSCQ100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 7
The Furanodiene crude product of 10g embodiment 1 gained dissolves with the mixed solvent of 80ml methanol/ethanol (1:1 by volume), is heated to slightly 50 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.3 °, 13.4 °, 15.2 °, 19.5 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 8
The Furanodiene crude product of 10g embodiment 1 gained dissolves with 120ml propyl carbinol, is heated to slightly 70 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4 °, 15.3 °, 19.6 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 9
The Furanodiene crude product of 10g embodiment 1 gained dissolves with the mixed solvent of 90ml acetone pentanone (volume ratio 1:1), is heated to slightly 35 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.5 °, 13.5 °, 15.3 °, 19.7 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 10
The Furanodiene crude product of 10g embodiment 1 gained dissolves with 120ml Virahol, is heated to slightly 40 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4 °, 15.3 °, 19.7 ° and 24.5 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 11
The Furanodiene crude product of 10g embodiment 1 gained dissolves with the mixed solvent of 110ml methanol/ethanol Virahol (volume ratio 1:1:1), is heated to slightly 30 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.5 °, 13.3 °, 15.4 °, 19.6 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 12
The Furanodiene crude product of 10g embodiment 1 gained dissolves with the mixed solvent of 120ml methanol/ethanol propyl carbinol (volume ratio 1:1:1), is heated to slightly 35 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4 °, 15.3 °, 19.6 ° and 24.5 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 13
The Furanodiene crude product 70ml dissolve with ethanol of 10g embodiment 1 gained, is heated to 40 ℃ slightly to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 3.2g.By 3.2g plate crystal 16ml acetone solution, be heated to slightly 50 ℃ to dissolving completely, place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4 °, 15.3 °, 19.7 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 14
The Furanodiene crude product 80ml dissolve with methanol of 10g embodiment 1 gained, is heated to 55 ℃ slightly to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 2.8g.2.8g plate crystal is dissolved with 20ml butanone, be heated to slightly 45 ℃ to dissolving completely, place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.3 °, 15.3 °, 19.5 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 15
The Furanodiene crude product of 10g embodiment 1 gained is joined in 80ml pentanone, be heated to slightly 60 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 4.5g.By the plate crystal of 4.5g gained 27ml dissolve with ethanol, be heated to slightly 55 ℃ to dissolving completely, place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4 °, 15.4 °, 19.6 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 16
The Furanodiene crude product of 10g embodiment 1 gained is dissolved with the mixed solvent of 60ml acetone pentanone (1:1 by volume), be heated to slightly 55 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 5.3g.The plate crystal of 5.3g gained is dissolved with the mixed solvent of 37ml methanol/ethanol (1:1 by volume), be heated to slightly 65 ℃ to dissolving completely, place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.3 °, 13.4 °, 15.2 °, 19.6 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 17
The Furanodiene crude product of 10g embodiment 1 gained is dissolved with the mixed solvent of 90ml methanol/ethanol Virahol (1:1:1 by volume), be heated to slightly 50 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 2.9g.The plate crystal of 2.9g gained is dissolved with the mixed solvent of 23ml methanol/ethanol (1:1 by volume), be heated to slightly 60 ℃ to dissolving completely, place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.5 °, 13.4 °, 15.3 °, 19.6 ° and 24.7 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 18
The Furanodiene crude product of 10g embodiment 1 gained dissolves with the mixed solvent of 100ml methanol/ethanol propyl carbinol (volume ratio 1:1:1), is heated to slightly 63 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 3.6g.The plate crystal of 3.6g gained is dissolved with 30ml butanone, be heated to slightly 55 ℃ to dissolving completely, place after having crystal to separate out and filter, obtain water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.4 °, 13.4 °, 15.2 °, 19.6 ° and 24.5 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC0100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
embodiment 19
The Furanodiene crude product of 10g embodiment 1 gained dissolves with 80ml butanone, is heated to slightly 60 ℃ to dissolving completely.Place after having crystal to separate out and filter, obtain water white tabular crystal 5.8g.The mixed solvent of pressing the plate crystal 35ml acetone pentanone (1:1 by volume) of 5.8g gained dissolves, and is heated to slightly 60 ℃ to dissolving completely, places after having crystal to separate out and filters, and obtains water white tabular crystal.The Furanodiene crystallization of gained adopts full-automatic polycrystal X ray diffractometer (model: Rigaku D/max2550PC; Rigaku Electric Co., Ltd produces) carry out X-ray powder diffraction, its X-ray powder diffraction pattern of result has special high strength peak at 11.5 °, 13.4 °, 15.4 °, 19.6 ° and 24.6 ° of 2 θ.The Furanodiene crystallization of gained adopts differential thermal analysis instrument (model: DSC Q100; TA company of the U.S. produces) detect, in its differential scanning characteristic pattern, there is absorption peak at 69 ℃.Prove that this crystal formation is Furanodiene crystal form A.
For the present invention is described better, be below pharmacological toxicology test and the result of described Furanodiene crystal form A.
embodiment 20: the In-vitro Inhibitory Effect of Furanodiene crystal form A to kinds of tumor cells
Get one bottle of cultivation people's lung cancer A549 cell of 3～4 days, add appropriate trypsinase that attached cell is come off, use containing the RPMI1640 nutritive medium of 10% foetal calf serum and be made into cell suspension, after counting, be diluted to concentration with complete culture solution and be about 4 × 10
4the cell suspension of individual/ml, get 96 orifice plates, every hole adds cell suspension 200 μ l, put into incubator after 24 hours, change experiment nutrient solution, add tested material (Furanodiene crystal form A of the present invention, positive control drug cis-platinum, Curcumenol), final concentration is respectively: Furanodiene crystal form A 100 μ g/ml of the present invention, 10 μ g/ml, 1 μ g/ml, 0.1 μ g/ml, each concentration 4 holes, after dosing, cultivate 48 hours, every hole adds 5mg/ml MTT10 μ l, incubation sucks supernatant liquor for 4 hours, add 150 μ lDMSO to shake up, measure the OD value of each aperture in 570nm place by microplate reader, the calculation formula of cell survival rate is:
Cell survival rate %=(dosing cell OD value/compared with control cells OD value) × 100%.
Obtain IC by Logit method
50.In triplicate.
Adopt DDP (cis-platinum), as positive control drug, above tumor cell line is done to In-vitro Inhibitory Effect test simultaneously,
Furanodiene crystal form A is to human oral epidermoid carcinoma KB cell, the former leukemia K 562 cell of chronic marrow, human nasopharyngeal carcinoma CNE cell, human cervical carcinoma cell Hela cell, Human Prostate Cancer PC-3 Cell Line, Human hepatocarcinoma Bel-7402 cell, and the In-vitro Inhibitory Effect test method of people's SMMC-7721 liver cancer cells, low differentiation adenocarcinoma of stomach BGC-823, low differentiation cancer of the stomach MKN-45, malignant melanoma A375, mammary cancer Bcap-37, adenocarcinoma of colon LoVo, rectal adenocarcinoma HR-8348, human ovarian cancer cell line HO-8910 is the same.Adopt DDP (cis-platinum), as positive control drug, above tumor cell line is done to In-vitro Inhibitory Effect test, method as above simultaneously.
Result shows, Furanodiene crystal form A and cancer cells Hela, KB, K562, CNE, A549, PC-3, Bel-7402, SMMC-7721, BGC-823, MKN-45, A375, Bcap-37, LoVo, HR-8348, HO-8910 are hatched after 48 hours altogether, all show stronger inhibition cel l proliferation.Test-results is in table one.
48 hours In-vitro Inhibitory Effects to kinds of tumor cells of table one, the effect of Furanodiene crystal form A
embodiment 21: the therapeutic action of Furanodiene crystal form A to mouse S 180 sarcoma
Laboratory animal: ICR mouse, male and female half and half, 18-22g, 80; 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.
S180 knurl strain: medical scientific institute of Zhejiang Province provides, every 7-9 goes down to posterity once in a days abdominal cavity.
Modeling: get S180 mouse-borne tumor animal ascites, with normal saline dilution to 1 × 107/ml, be inoculated in right oxter by every animal 2 × 106.
Grouping: animal is divided into 8 groups at random, 10 every group.Be respectively model group, positive group and administration group (high, medium and low dosage).
Positive drug: endoxan (the permanent auspicious pharmacy in Jiangsu).
Dosage: according to preliminary experiment result, adopt dosage 400,200 and 100mg/kg, negative control adopts respective volume solvent.
Route of administration: gavage.
Administration volume: 0.4ml/10g
Administration number of times: to for examination drug toxicity reaction situation, after modeling the 1st, 5 days, be respectively administered once according to animal.
Observing time: Continuous Observation 8 days after modeling.After experiment finishes, put to death animal, get tumour, weigh, take pictures.
Statistical method: SPSS10.0 statistical package, one-way analysis of variance method.
Adopt the suspendible oral liquid 400,200 of the Furanodiene crystal form A preparation that embodiment 2 obtains and 100mg/kg after tumor inoculation the 1st, each gastric infusion on the 5th once.Within after tumor inoculation the 8th day, put to death animal and get tumour and weigh, adopt the suspendible oral liquid 400,200 of same formulation and technology of the Furanodiene product configuration that comparative example 1 obtains and 100mg/kg after tumor inoculation the 1st simultaneously, each gastric infusion on the 5th once.Within after tumor inoculation the 8th day, put to death animal and get tumour and weigh, Furanodiene crystal form A 400,200 and 100mg/kg group tumour inhibiting rate are respectively 57.82,30.33 and 9.84%.The Furanodiene product 400,200 that comparative example 1 obtains and 100mg/kg group tumour inhibiting rate are respectively 40.21.23.62 and 8.81%.
Experimental result: in table two.
Table two, the experimental study of Furanodiene crystal form A to S180 mice-transplanted tumor growth effect
▲ p < 0.05 (with respect to contrast)
Embodiment 22: the animal pharmacokinetics test of Furanodiene crystal form A
In order to explain Furanodiene product that Furanodiene crystal form A of the present invention and comparative example 1 the obtain difference in drug effect in animal body, both are carried out to pharmacokinetics experimental study in animal body.
This test selects SD rat to carry out pharmacokinetic studies, adopt high performance liquid chromatography to detect Furanodiene Plasma Concentration dynamic change in vivo, take chemicals Non-clinical Pharmacokinetics investigative technique governing principle (CDE) as experimental basis, and with the matched curve on computers of the 3P87 of Chinese Pharmacological Society program, calculate pharmacokinetic parameters.
Trial-product: Furanodiene crystal A suspension; Furanodiene product suspension.
Administering mode: gavage;
Dosage: 100mg/kg
Administration volume: 1.0ml/200g
Sampling duration: 2880min
Statistical software: EXCEL
Experiment conclusion: calculate AUC by trapezoidal method, then calculate relative bioavailability, Furanodiene crystal A suspension is with respect to relative bioavailability F (0～48h)=74605.39/50171.75 × 100%=148.7% of Furanodiene product suspension, as can be seen here, under both this dosages, in bioavailability, be (F is considered as equivalence between 80-125%) of inequivalence.
embodiment 23: the preparation of Furanodiene emulsion injection
Preparation technology: first phosphatide is dissolved in soybean oil, the Furanodiene crystal A that adds embodiment 2 to obtain, stirring makes its dissolving, after adding again oleic acid to stir, the filtering with microporous membrane of aperture 0.22 μ m is for subsequent use, add water for injection to recipe quantity, homogenate machine is made colostrum, makes to reach emulsion size by homogenizer.Millipore filtration by aperture 0.22 μ m carries out sterile filtration, and last embedding is in the dry sterilizing ampoule of 1ml.Make the emulsion injection liquid of every ampoule 1ml containing Furanodiene crystal form A 10mg.
embodiment 24: the preparation of the oral breast of Furanodiene
Preparation technology: first phosphatide is dissolved in soybean oil, the Furanodiene crystal form A that adds embodiment 4 to prepare, stirring makes its dissolving, after adding again oleic acid to stir, the filtering with microporous membrane of aperture 0.22 μ m is for subsequent use, add water for injection to recipe quantity, homogenate machine is made colostrum, makes to reach emulsion size by homogenizer.Millipore filtration by aperture 0.22 μ m carries out sterile filtration, is finally filled in the dry sterilizing vial of 20ml, jump a queue, and Zha Gai.Make the confession oral emulsion of every 1ml containing Furanodiene crystal form A 20mg.
the preparation of embodiment 25 Furanodiene suspendible oral liquids
Take the Furanodiene crystal form A that the embodiment 5 of recipe quantity obtains, add the tween 80 of recipe quantity, add again the 0.5%CMC-Na aqueous solution (that is: sodium carboxymethyl cellulose solution) to recipe quantity, then use ultrasonic disintegrator ultrasonic 25 minutes, to the requirement that reaches suspension.Finally be filled in the dry sterilizing vial of 20ml, jump a queue, Zha Gai.Make the confession oral suspension of every 1ml containing Furanodiene crystal form A 200mg.
the preparation of embodiment 26 Furanodiene sheets
Take the sodium starch glycolate of Furanodiene, Microcrystalline Cellulose and the half recipe quantity of recipe quantity, mix, cross 80 mesh sieve and fully mix for three times.After supplementary material mixes, add 10% starch slurry appropriate, make dry wet suitable softwood, 20 mesh sieves are granulated, 45～50 ℃ of oven dry.With the whole grain of 20 mesh sieves.The sodium starch glycolate of the micropowder silica gel of recipe quantity, talcum powder and half recipe quantity is added in particle, fully mix, compressing tablet and get final product.
Every containing Furanodiene crystal form A 100mg.
the system of embodiment 27 Furanodiene capsulesstandby
Take Furanodiene, Microcrystalline Cellulose and the sodium starch glycolate of recipe quantity, mix, cross 80 mesh sieve and fully mix for three times.After supplementary material mixes, add 10% starch slurry appropriate, make dry wet suitable softwood, 20 mesh sieves are granulated, 40～50 ℃ of oven dry.With the whole grain of 20 mesh sieves.Incapsulate in shell evengranular, fill altogether 1000.Pack and get final product.
Every containing Furanodiene crystal form A 100mg.
The present invention is by providing a kind of novel stable Furanodiene crystal form A, improve the pharmacokinetic property of Furanodiene, overcome the defect that adopts traditional carbon dioxide upercritical fluid extraction to prepare Furanodiene purifying process complexity and cost costliness, strengthened the one-tenth property of medicine of Furanodiene.
Claims (10)
1. the crystal form A of a Furanodiene, it is characterized in that, the X-ray powder diffraction pattern of the crystal form A of described Furanodiene has characteristic peak at 11.4 ° ± 0.1 °, 13.4 ° ± 0.1 °, 15.3 ° ± 0.1 °, 19.6 ° ± 0.1 ° and 24.6 ° ± 0.1 ° 2 θ
Described crystal uses alcohols or the ketones solvent of 20～70 ℃ to dissolve Furanodiene, places and obtains after crystal is separated out; Described alcoholic solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol or its combination, and described ketones solvent is selected from acetone, butanone, pentanone or its combination.
2. the crystal form A of Furanodiene as claimed in claim 1, is characterized in that, in the differential scanning characteristic pattern of described Furanodiene crystal form A, has absorption peak at 69 ℃.
3. the preparation method of the crystal form A of Furanodiene as claimed in claim 1 or 2, is characterized in that, described method comprises the steps:
(1) use alcohols or the ketones solvent of 20～70 ℃ to dissolve Furanodiene;
(2) after crystal is separated out, filter, collect crystal.
4. preparation method as claimed in claim 3, is characterized in that, described alcoholic solvent is ethanol.
5. the preparation method of the crystal form A of Furanodiene as claimed in claim 3, is characterized in that, described ketones solvent is acetone.
6. preparation method as claimed in claim 3, is characterized in that, described solvent temperature is 30～40 ℃.
7. the preparation method of the crystal form A of Furanodiene as claimed in claim 6, is characterized in that, described solvent temperature is 35 ℃.
8. the application of the crystal form A of Furanodiene as claimed in claim 1 or 2 in the medicine of preparation treatment tumor disease.
9. application as claimed in claim 8, is characterized in that, described tumor disease is selected from ovarian cancer, cervical cancer, cancer of the stomach, liver cancer, leukemia, lung cancer, rectal adenocarcinoma or nasopharyngeal carcinoma.
10. a pharmaceutical composition, is characterized in that, it contains Furanodiene crystal form A as claimed in claim 1 or 2 and the pharmaceutically acceptable carrier for the treatment of significant quantity.
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| CN200910097848.X | 2009-04-17 | ||
| PCT/CN2009/073995 WO2010118598A1 (en) | 2009-04-17 | 2009-09-17 | Crystal form a of furanodiene, the preparation method and the useful for preparing the antitumor drug thereof |
| CN200980158770.6A CN102405216B (en) | 2009-04-17 | 2009-09-17 | Crystal form A of furanodiene, preparation method and useful for preparing antitumor drug thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1704417A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Novel curcumenol derivatives |
| CN1884271A (en) * | 2005-06-23 | 2006-12-27 | 烟台大学 | Zedoary cyclo-diolefine and its derivatives preparation method and use |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1704417A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Novel curcumenol derivatives |
| CN1884271A (en) * | 2005-06-23 | 2006-12-27 | 烟台大学 | Zedoary cyclo-diolefine and its derivatives preparation method and use |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| Nicolas Baldovini，等.Identification and Quantitative Determination of Furanodiene，a Heat-sensitive Compound，in Essential Oil by 13C-NMR.《PHYTOCHEMICAL ANALYSIS》.2001,第12卷第58页. * |
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