CN1324032C - Novel 9-nitro campotothecin crystal form and medicinal composition - Google Patents
Novel 9-nitro campotothecin crystal form and medicinal composition Download PDFInfo
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- CN1324032C CN1324032C CNB2004100021076A CN200410002107A CN1324032C CN 1324032 C CN1324032 C CN 1324032C CN B2004100021076 A CNB2004100021076 A CN B2004100021076A CN 200410002107 A CN200410002107 A CN 200410002107A CN 1324032 C CN1324032 C CN 1324032C
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Abstract
The present invention discloses a crystal form of 9-nitro-20(S)-camptothecin (rubitecan). The endothermic peak of the differential thermal analysis value of the crystal form is in the range of 254 to 162 DEG C, and the exothermic peak is in the range of 265 to 270 DEG C. In the powder X-ray diffraction picture of the crystal form, the characteristic 2 theta value of the crystal form is 10.2(+/-)0.2, 15.3(+/-)0.2, 20.4(+/-)0.2, 27.0(+/-)0.2 and 30.9(+/-)0.2. A method for preparing the crystal form comprises: a crude product of 9-nitro camptothecin is added to methanol solvent to be heated, stirred and cooled; the mixture is put in a refrigerator to be frozen for separating crystals; after filtration, washing and baking, the crystal form is obtained. An oral medical composition prepared from the crystal form and the medical auxiliary materials, which is in the forms of tablets and capsules, is used for treating cancer.
Description
Technical field
The present invention relates to a kind of specific crystal formation of 9-nitro-20 (S)-camptothecine (rubitecan) and preparation method thereof; Pharmaceutical preparation that this crystal formation and pharmaceutical carrier are combined into and the application in preparation treatment cancer drug thereof.
Background technology
9-nitro-20 (S)-camptothecine is a kind of camptothecin anticarcinogen, and it has demonstrated unique curative effect in the cancer of some types of treatment.
W003/072027 disclosed 9 one nitrocamptothecin polymorphics and has prepared polymorphous method on September 4th, 2003.This patent claims: between crystal because the existence of exclusion power, between contiguous molecule, form together barrier physically, therefore the 9-nitrocamptothecin exists with crystal state and has relative smaller particles, its stability is better than the unformed noncrystal and vitreum of identical particle size, and have higher bioavailability and therapeutic activity, and the longer quality guaranteed period.WO03/072027 discloses the differential thermal value of seven kinds of crystal formations: endotherm(ic)peak is between 175.5-177.5 ℃, and exothermic peak is at 181.7-183.7 ℃; Or endotherm(ic)peak is at 273.9-275.9 ℃, and exothermic peak is at 279.3-281.3 ℃.Infrared spectra is 3625-3675cm at wavelength
-1Between do not have to absorb.The feature 2 θ values that WO03/072027 discloses powder x-ray diffraction figure under the Cu, Ka optical radiation that polymorphic is 1.5406 at wavelength are 8.0,25.7; Or 6.7,12.5,14.0,23.9; Or 4.8,14.2,19.1,26.8; Or 11.0,14.0,16.4,27.0.The solvent that discloses recrystallization is: acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile.And use DMF and water mixing recrystallization again with acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile recrystallization after product respectively.WO03/072027 also discloses and has removed the methanol solution that contains the 9-nitrocamptothecin by evaporation and obtain unformed 9-NC powder (do not have obviously can debate powder x-ray diffraction figure feature 2 θ values).
Characteristic indicates in the WO03/072027 specification sheets: any can be with 9-nitrocamptothecin treatment disease the time, in fact all adopt the polymorphic of 9-nitrocamptothecin.The polymorphic raw material is when being used for the preparation process, and the polymorphic of 9-nitrocamptothecin mixes.Specifically, in being used for the treatment of the formulation of disease, should comprise the polymorphic of one or more 9-nitrocamptothecins.
I have found a kind of specific crystal formation of new 9-nitrocamptothecin unexpectedly in the crystal formation process of research 9-nitrocamptothecin, it is different from the disclosed seven kinds of crystal formations of WO03/072027.It is better than above seven kinds of crystal formations to the stability of heat and humidity.
Summary of the invention
The purpose of this invention is to provide a kind of from methyl alcohol recrystallization obtain a kind of specific crystal formation of 9-nitrocamptothecin.And this specific crystal formation applied to be used for the treatment of cancer in the medicine composition.
Method of the present invention is that the crude product with 9-nitro-20 (S)-camptothecine joins in the methanol solvate; The crystal formation of 9-nitro-20 (S)-camptothecine that recrystallization obtains newly.The differential thermal analysis result of this crystal formation shows: endotherm(ic)peak is 254 ℃～262 ℃ scopes, and exothermic peak is 265 ℃～270 ℃ scopes.Preferred differential thermal analysis value, endotherm(ic)peak is 256 ℃～260 ℃ scopes, and exothermic peak is 266 ℃～269 ℃ scopes.The powder x-ray diffraction figure of this crystal formation is 1.5406 dusts at wavelength, and with the K α spectral line of Cu target, its feature 2 θ values are: 10.2 ± 0.2,15.3 ± 0.2,20.4 ± 0.2,27.0 ± 0.2,30.9 ± 0.2.The fusing point of this crystal formation is 254 ℃～260 ℃ (decomposition).Specific optical rotation [α]
D 25=-102 °～-117 ° (c=0.100 pyridine).Infrared spectra is at 1754cm
-1～2934cm
-1Between do not have to absorb, at 3333cm
-1～3335cm
-1Charateristic avsorption band is arranged.
Use the medicine that cancer is treated in this new specific 9-nitro-20 (S)-camptothecine crystal formation manufacturing.
This new specific crystal formation and pharmaceutically useful auxiliary material are formed combination of oral medication, and its auxiliary material comprises weighting agent (as lactose, cyclodextrin, N.F,USP MANNITOL, pregelatinized Starch etc.); Or glidant (as micropowder silica gel, Magnesium Stearate, talcum powder etc.); Or tackiness agent (as starch slurry, dextrin, hypromellose, low-substituted hydroxypropyl cellulose etc.).
The formulation of described combination of oral medication is tablet and capsule, and this tablet and capsule can method routinely make.
The tablet of described combination of oral medication and capsule can be treated cancer, as carcinoma of the pancreas, mammary cancer, cervical cancer, colorectal carcinoma, tumor of head and neck, liver cancer, lung cancer, prostate cancer, the cancer of the brain, ovarian cancer, cancer of the stomach, melanoma, sarcoma, tumor of biliary tract, chronic myelogenous leukemia, MLC, myelodysplasia syndromes and leukemia.
According to saying in the WO03/072027 specification sheets, during 9-nitrocamptothecin treatment disease, in fact all adopt one or more polymorphics of 9-nitrocamptothecin.In other words, arbitrary crystal formation of 9-nitrocamptothecin all be have bioactive.Equally, also biologically active of this new specific crystal formation provided by the invention.
The invention technical scheme: the crude product of 9-nitrocamptothecin is joined in the methanol solvate, after the stirring that heats up is molten entirely, cooling; Put refrigerator-freezer and place freezing crystallization; Filter, wash, dry.
The differential thermal analysis value of gained crystal formation, endotherm(ic)peak at 258.6 ℃, exothermic peak is at 267.1 ℃.Powder x-ray diffraction figure is 1.5406 dusts at wavelength, and with the K α spectral line of Cu target, its feature 2 θ values are: 10.2,15.3,20.4,27.0,30.9.Fusing point is 254 ℃～260 ℃ (decomposition).Specific optical rotation [α]
D 25=-108 ° (c=0.100 pyridine).Its infrared spectra is at 1754cm
-1～2934cm
-1Between do not have to absorb; At 3333cm
-1～3335cm
-1Charateristic avsorption band is arranged.
And above specific crystal formation applied in the medicine composition (regular dosage form such as tablet and capsule).
Technique effect of the present invention is:
1, with the crystal formation product that above feature is arranged of technical scheme gained of the present invention, its stability is better than using respectively the polymorphic of acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile recrystallization gained, particularly to the heat and the stability of humidity.For example, with acetone, methylene dichloride purified crystal formation, under high temperature (60 ℃), high humidity (RH75%) condition, detected its appearance color intensification respectively at 5,10 days; Hygroscopic effect is arranged; Content was compared with 0 day significantly and is descended.And, under high temperature (60 ℃), high humidity (RH75%) condition, detected only slight moisture absorption respectively at 5,10 days with the crystal formation of technical scheme gained of the present invention; Appearance color, content are consistent with 0 day.
2, with the method for the refining 9-nitrocamptothecin of the present invention, can access high 9-nitrocamptothecin yield.For example, have only about 70% with acetone, the refining yield of methylene dichloride.And can reach about 90% with technical scheme refining methanol yield of the present invention.
3, with the crystal formation of technical scheme gained of the present invention, apply in the medicine composition, can increase the stability of pharmaceutical composition heat and humidity.
Description of drawings
Fig. 1: the differential thermal of 9-nitro-20 (S)-camptothecine-thermogravimetric analysis figure, wherein thick black line is a differential thermal curve, endotherm(ic)peak at 258.6 ℃, exothermic peak is at 267.1 ℃.Thin black line is a thermogravimetric curve.
Fig. 2: powder art X one x ray diffration pattern x of 9-nitro-20 (S)-camptothecine is 1.5406 dusts at wavelength, uses the feature 2 θ values of the K α spectral line of Cu target.
Fig. 3: the infrared spectrogram of 9-nitro-20 (S)-camptothecine.
Certainly, top explanation and the following examples only are exemplary and explanat, and its protection should be not limited to this.
Invention is described
In 1 liter of reaction flask, drop into 9-nitrocamptothecin crude product 1g, add methyl alcohol 600ml, be warming up to 40 ℃, stir complete molten after, stop heating and stir, be cooled to room temperature gradually after, putting refrigerator-freezer spends the night for about one 15 ℃, freezing crystallization filters and collects crystal, after a little methyl alcohol embathes crystal next day, drying under reduced pressure is 12 hours under 45～50 ℃/0.09Mpa, put in 105 ℃ of baking ovens constant pressure and dry 10 hours again to constant weight, the about 0.9g of 9-nitrocamptothecin salable product, make with extra care yield about 90%.Fusing point: 254-256 ℃ (decomposition).Specific optical rotation [α]
D 25=-108 ° (c=0.100 pyridine).The differential thermal analysis value: endotherm(ic)peak at 258.6 ℃, exothermic peak is at 267.1 ℃ (Fig. 1).Powder x-ray diffraction figure is 1.5406 dusts at wavelength, and with the K α spectral line of Cu target, its feature 2 θ values are: 10.2,15.3,20.4,27.0,30.9 (Fig. 2).Infrared spectra is at 1754cm
-1～2934cm
-1Between do not have to absorb, at 3333cm
-1～3335cm
-1Charateristic avsorption band (Fig. 3) is arranged.
Embodiment 2
With pregelatinized Starch in 80 ℃ of dryings, cross 60 mesh sieves, standby, 9-nitrocamptothecin salable product and a small amount of pregelatinized Starch that embodiment 1 described method is obtained grinds in mortar, mixing, cross 80 mesh sieves, make work in-process with all the other pregelatinized Starch equivalent mixing that progressively increases again, be loaded on opaque capsule, promptly.
Embodiment 3
After the 9-nitrocamptothecin that embodiment 1 described method is obtained is crossed 200 mesh sieves, and cross 100 mesh sieves behind the low-substituted hydroxypropyl cellulose mixing, grind mixing with lactose again and make work in-process, be loaded on opaque capsule, promptly.
Claims (8)
1, the crystal formation of a kind of 9-nitro-20 (S)-camptothecine, it is characterized in that the powder x-ray diffraction figure of this crystal formation is 1.5406 dusts at wavelength, with the K α spectral line of Cu target, its feature 2 θ values are: 10.2 ± 0.2,15.3 ± 0.2,20.4 ± 0.2,27.0 ± 0.2 and 30.9 ± 0.2; The differential thermal analysis value of this crystal formation, endotherm(ic)peak are 254 ℃～262 ℃ scopes, and exothermic peak is 265 ℃～270 ℃ scopes.
2, crystal formation according to claim 1, the differential thermal analysis value of this crystal formation, endotherm(ic)peak are 256 ℃～260 ℃ scopes, and exothermic peak is 266 ℃～269 ℃ scopes.
3, the crystal formation of 9-nitro-20 according to claim 1 (S)-camptothecine, the fusing point that it is characterized in that this crystal formation are 254 ℃～260 ℃; Specific optical rotation
Infrared spectra is at 1754cm
-1～2934cm
-1Between do not have to absorb, at 3333cm
-1～3335cm
-1Charateristic avsorption band is arranged.
4, the method for the crystal formation of the arbitrary described 9-nitro-20 of a kind of preparation claim 1～3 (S)-camptothecine, its process comprises:
A) crude product with the 9-nitrocamptothecin joins in the methanol solvate;
B) heat up to stir complete molten after, be cooled to room temperature;
C) put refrigerator-freezer and place freezing crystallization;
D) filter, wash and oven dry.
5, a kind of combination of oral medication comprises the crystal formation and the pharmaceutically acceptable auxiliary material of the arbitrary described 9-nitro-20 of claim 1-3 (S)-camptothecine.
6, combination of oral medication according to claim 5, said pharmaceutically useful auxiliary material is selected from:
Lactose, Magnesium Stearate, talcum powder etc., starch slurry, dextrin, hypromellose, cyclodextrin, micropowder silica gel, low-substituted hydroxypropyl cellulose, N.F,USP MANNITOL or pregelatinized Starch.
7, combination of oral medication according to claim 6 is characterized in that: formulation is tablet and capsule.
8, the application of the crystal formation of the described 9-nitro-20 of claim 1 (S)-camptothecine in making the treatment cancer drug.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100021076A CN1324032C (en) | 2004-01-07 | 2004-01-07 | Novel 9-nitro campotothecin crystal form and medicinal composition |
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| CNB2004100021076A CN1324032C (en) | 2004-01-07 | 2004-01-07 | Novel 9-nitro campotothecin crystal form and medicinal composition |
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| CN1324032C true CN1324032C (en) | 2007-07-04 |
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| CN103130814B (en) * | 2011-11-25 | 2016-03-09 | 上海医药工业研究院 | Two kinds of 9-nitrocamptothecin new crystal and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1048296C (en) * | 1993-08-06 | 2000-01-12 | 法玛西雅厄普约翰公司 | Process for the preparation of 9-amino camptothecin |
| CN1266435A (en) * | 1997-08-05 | 2000-09-13 | 斯特林癌症研究基金会 | Process for preparing and purifying 9-nitro-20-camptothecin |
| US6482830B1 (en) * | 2002-02-21 | 2002-11-19 | Supergen, Inc. | Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use therefor |
| CN1422618A (en) * | 2002-12-12 | 2003-06-11 | 复旦大学 | 9-nitrocamptothecin solid dispersant and preparation method |
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2004
- 2004-01-07 CN CNB2004100021076A patent/CN1324032C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1048296C (en) * | 1993-08-06 | 2000-01-12 | 法玛西雅厄普约翰公司 | Process for the preparation of 9-amino camptothecin |
| CN1266435A (en) * | 1997-08-05 | 2000-09-13 | 斯特林癌症研究基金会 | Process for preparing and purifying 9-nitro-20-camptothecin |
| US6482830B1 (en) * | 2002-02-21 | 2002-11-19 | Supergen, Inc. | Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use therefor |
| WO2003072027A2 (en) * | 2002-02-21 | 2003-09-04 | Supergen, Inc | Compositions and formulations of 9- nitrocamptothecin polymorphs and methods of use thereof |
| CN1422618A (en) * | 2002-12-12 | 2003-06-11 | 复旦大学 | 9-nitrocamptothecin solid dispersant and preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 抗癌新药7-NITROCAMPTOTHECIN 郑震寰等，药学进展，第25卷第5期 2001 * |
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