CN105294649A - Ceritinib compound and pharmaceutical composition thereof - Google Patents
Ceritinib compound and pharmaceutical composition thereof Download PDFInfo
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- CN105294649A CN105294649A CN201410371118.5A CN201410371118A CN105294649A CN 105294649 A CN105294649 A CN 105294649A CN 201410371118 A CN201410371118 A CN 201410371118A CN 105294649 A CN105294649 A CN 105294649A
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- ceritinib
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Abstract
The invention belongs to the field of medical chemistry, and discloses an amorphous crystallization form of a ceritinib compound and a pharmaceutical composition of the ceritinib compound. The amorphous crystallization form of the compound has the characteristic of being high in stability, and the medicinal requirements are met. According to the invention, the preparation technology is stable, the reproducibility is good, and the requirements of industrial mass production are met.
Description
Technical field
The invention belongs to medicinal chemistry arts, specifically, relate to a kind of crystalline form, preparation method of Certinib compound, comprise the pharmaceutical composition containing this compound and application.
Background technology
Ceritinib (LDK378, again translated name: look auspicious is for Buddhist nun) is a kind of ALK inhibitor, is used for the treatment of polytype advanced metastatic nonsmall-cell lung cancer (NSCLC).Ceritinib is a kind of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor, the ALK+ patient that exploitation was treated for previously accepting Crizotinib (gram azoles is for Buddhist nun), and gram azoles was only granted ALK kinase inhibitor for Buddhist nun before Ceritinib.Structural formula is as shown in the formula shown in I:
Ceritinib is developed by Novartis Co., Ltd, and obtaining FDA approval listing on April 29th, 2014, is second ALK inhibitor of FDA approval, as the positive nonsmall-cell lung cancer specifics of ALK, for the patient that gram azoles replaces Buddhist nun's resistance or do not tolerate.In vitro tests shows, and its ALK inhibition and gram azoles compare for Buddhist nun will exceed 20 times.Security and a curative effect relating to the clinical research confirmation of 163 routine ALK+ transitivity NSCLC patients Ceritinib, accepts, in the patient of Ceritinib treatment, have experimenter's tumor regression of 1/2, and this effectiveness on average to maintain 7 months.The clinical common adverse reactions of Ceritinib comprises the gastrointestinal symptoms such as diarrhoea, Nausea and vomiting, stomachache, and laboratory abnormality comprises liver drug enzyme, pancreatin and glucose level and increases.
Polymorphism is that material exists more than one crystallized forms.The different crystallized forms of chemical substance can exert far reaching influence to the storage time of medicine, solvability, preparation nature and working properties.Therefore, when developing a kind of novel drugs, understanding and controlling polymorphism, selecting suitable crystal formation useful in preparing drug formulations to have great importance.
Chinese patent application CN200780051064.2 embodiment 7 discloses a kind of preparation method of Ceritinib hydrochloride, and preparation process does not obtain the solid form of free alkali, does not provide any crystal information of Certinib.
Chinese patent application CN201180060435.X A, B crystallized form disclosing Ceritinib and preparation method thereof.In addition, openly report there are no other new crystallized form of Ceritinib.
Summary of the invention
The object of this invention is to provide the substantially pure crystallized form of Ceritinib compound, the invention also discloses the preparation method of crystallized form simultaneously, and the pharmaceutical composition containing its crystallized form.
Those skilled in the art unexpectedly obtain the amorphous form of Ceritinib compound by great many of experiments, and amorphous form has the high feature of stability.
The invention provides a kind of Ceritinib compound, its structural formula is such as formula shown in I:
Described Ceritinib compound is imperfect crystal formation form.It is characterized in that: its powder x-ray diffraction collection of illustrative plates exists obvious amorphous characteristic peak, does not namely have sharp-pointed absorption peak.Described imperfect crystal formation uses Cu-Ka radiation, obtains the X-diffraction powder diffracting spectrum had as shown in Figure 1.
Present invention also offers a kind of preparation method of Ceritinib imperfect crystal formation form, its preparation method is: be dissolved in methylene dichloride by Ceritinib, then is evaporated to dry obtaining.
Preferably, the preparation method of Ceritinib imperfect crystal formation form is: be dissolved in by Ceritinib in 15 times of (V/m, i.e. 15ml:1g) methylene dichloride, be evaporated to dry obtaining at 30 DEG C.
More preferably, the preparation method of described Ceritinib imperfect crystal formation form, its preparation method is: be dissolved in by the dihydrochloride of Ceritinib in the purified water of 5 times of weight, add the methylene dichloride of 15 times of volumes (V/m), stir lower dropping 50% sodium hydroxide solution, regulate aqueous solution pH to 7-10, separate the dichloromethane solution that organic layer obtains Ceritinib after leaving standstill, organic layer 30 DEG C is evaporated to and dryly obtains foaming solid.
Two hydrochloric acid of Ceritinib of the present invention can obtain with reference to method disclosed in CN200780051064.2 embodiment 7 or CN201180060435.X embodiment 1.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that, described composition comprises Ceritinib compound imperfect crystal formation form of the present invention or obtains by the imperfect crystal formation form of Ceritinib compound of the present invention.Preferably, described pharmaceutical composition comprises imperfect crystal formation form and at least one pharmaceutically acceptable carrier of Ceritinib compound of the present invention.
Further preferably, the dosage form of described composition can be solid preparation, injection, as oral tablet, capsule, lyophilized injectable powder etc.
According to the present invention, described composition also comprises pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier normally those of ordinary skill in the art specifically can be selected according to concrete form of medication.Available well known technology such as the preparation process such as conventional granulation, mixing, dissolving freeze-drying form tablet, capsule, freeze-dried powder etc., manufacture and obtain pharmaceutical composition of the present invention.
Ceritinib compound imperfect crystal formation form provided by the invention conventionally can be prepared into and be suitable for medicinal pharmaceutical composition.Prior art is as the Ceritinib capsule (Novartis, trade(brand)name: ZYKADIA) of listing.
The invention provides a kind of pharmaceutical composition of the amorphous form substantially pure containing Ceritinib compound.Preferably, described Ceritinib pharmaceutical composition is capsule.More preferably, silicon-dioxide, L hydroxypropylcellulose, Magnesium Stearate, Microcrystalline Cellulose, sodium carboxymethylstarch, hard gelatin capsule shell is contained in described pharmaceutical composition.Further preferably, described Ceritinib capsule contains the imperfect crystal formation form of 150mgCeritinib compound.
The imperfect crystal formation form of the present invention to the Ceritinib compound obtained has carried out the investigation of the aspects such as stability, accelerated stability test shows that described stability of crystal form is good, active substance is without noticeable change, total assorted without significantly increasing, and stablizes crystalline form in investigation process and obvious change does not occur.
The present invention also provides the imperfect crystal formation form of described Ceritinib compound to may be used for the application prepared in the medicine of ALK inhibitor.Preferably, nonsmall-cell lung cancer, cancer of the stomach, liver cancer, colon and rectum carcinoma, colorectal cancer, mammary cancer, melanoma, leukemic treatment is mainly used in.
The aspects such as the imperfect crystal formation form stable of Ceritinib compound provided by the invention all meet medicinal requirement.The preparation technology of Ceritinib compound crystal form provided by the invention is simple, and favorable reproducibility, meets the requirement of industrialized production.
Accompanying drawing explanation
The X-ray powder diffraction figure (XRD) of Fig. 1: Ceritinib amorphous forms.
The differential scanning calorimetric curve (DSC) of Fig. 2: Ceritinib amorphous forms.
The thermogravimetric curve (TGA) of Fig. 3: Ceritinib amorphous forms.
Embodiment
Mode below by embodiment further illustrates the present invention, but following embodiment is not limiting the scope of the invention, and the improvement that those skilled in the art make on basis of the present invention and polishing should within protection scope of the present invention.
The preparation of embodiment 1Ceritinib compound imperfect crystal formation form
Under room temperature, the dihydrochloride (5g) getting Ceritinib is dissolved in purified water (25g), add methylene dichloride (75ml), 50% sodium hydroxide solution is slowly dripped under stirring, regulate aqueous solution pH to 7-10, separate organic layer after leaving standstill, obtain the dichloromethane solution of Ceritinib, organic layer is evaporated at 30 DEG C and dryly obtains foaming solid.X-ray powder diffraction shows it for imperfect crystal formation form, and X-ray powder diffraction pattern, DSC figure, TGA figure are respectively as shown in accompanying drawing 1, Fig. 2, Fig. 3.
Embodiment 2Ceritinib compound imperfect crystal formation form preparation
Under room temperature, get Ceritinib (10g), add methylene dichloride (150ml), stir and make whole dissolving, filter and be evaporated at 30 DEG C and dryly obtain foaming solid.The same Fig. 1 of X-ray powder diffraction pattern.
Embodiment 3
The imperfect crystal formation form of the Ceritinib compound prepared according to the method for embodiment 1, sampling, stores 1 month physico-chemical property, crystalline form and cotton thread change does not occur under room temperature, RH (relative humidity) 45-65%.At 40 DEG C, carry out accelerated test, investigate stability under under the environment of RH75%, test-results is respectively in table 2.
Table 2Ceritinib compound imperfect crystal formation form accelerated test (40 DEG C, RH75%)
Investigate result from accelerated stability, the imperfect crystal formation form stable excellent effect that the present invention obtains, be applicable to pharmaceutical applications.
Claims (10)
1. a Ceritinib compound, its structural formula such as formula shown in I,
It is characterized in that, described Ceritinib compound is imperfect crystal formation form.
2. Ceritinib compound according to claim 1, is characterized in that, the X-ray powder diffraction figure of described imperfect crystal formation form substantially as shown in Figure 1.
3. Ceritinib compound according to claim 1, it is characterized in that, the preparation method of described imperfect crystal formation form is: be dissolved in methylene dichloride by Ceritinib, then is evaporated to dry obtaining.
4. Ceritinib compound according to claim 3, it is characterized in that, the preparation method of described imperfect crystal formation form is: be dissolved in by Ceritinib in 15 times of (V/m) methylene dichloride, be evaporated to dry obtaining at 30 DEG C;
Preferably, the preparation method of described imperfect crystal formation form is: be dissolved in by the dihydrochloride of Ceritinib in the purified water of 5 times of weight, add the methylene dichloride of 15 times of volumes (V/m), stir lower dropping 50% sodium hydroxide solution, regulate aqueous solution pH to 7-10, separate the dichloromethane solution that organic layer obtains Ceritinib after leaving standstill, organic layer 30 DEG C is evaporated to and dryly obtains foaming solid.
5. the pharmaceutical composition containing Ceritinib, comprise the Ceritinib compound according to any one of Claims 1 to 4, described Ceritinib compound is imperfect crystal formation form.
6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition comprises imperfect crystal formation form and the pharmaceutically acceptable carrier of at least one of Ceritinib compound.
7. the pharmaceutical composition according to claim 5-6, is characterized in that, described pharmaceutical composition is capsule.
8. pharmaceutical composition according to claim 7, is characterized in that, in described capsule Chinese materia medica, acceptable carrier comprises silicon-dioxide, L hydroxypropylcellulose, Magnesium Stearate, Microcrystalline Cellulose, sodium carboxymethylstarch, hard gelatin capsule shell; Preferably, described capsule contains the imperfect crystal formation form of 150mgCeritinib compound.
9. the application of the Ceritinib compound described in any one of claim 1-4 in the medicine of preparation ALK inhibitor, described Ceritinib compound is imperfect crystal formation form.
10. application according to claim 9, is characterized in that, mainly for the preparation for the treatment of nonsmall-cell lung cancer, cancer of the stomach, liver cancer, colon and rectum carcinoma, colorectal cancer, mammary cancer, melanoma, leukemic medicine.
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| CN201410371118.5A CN105294649B (en) | 2014-07-30 | 2014-07-30 | A kind of Ceritinib compound and its pharmaceutical composition |
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| CN105294649B CN105294649B (en) | 2019-05-14 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110551102A (en) * | 2018-06-01 | 2019-12-10 | 四川大学 | ALK covalent inhibitors and uses thereof |
| CN114191435A (en) * | 2021-12-08 | 2022-03-18 | 深圳市泰力生物医药有限公司 | Cabotinib, neritinib and ceritinib pharmaceutical composition as well as preparation method and application thereof |
| CN114901289A (en) * | 2019-10-28 | 2022-08-12 | 奥斯陆大学 | ALK inhibitors for the treatment of ALK negative cancers and plasma cell mediated diseases |
| CN116370476A (en) * | 2023-04-21 | 2023-07-04 | 遵义医科大学 | Chemotherapy medicine composition and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
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2014
- 2014-07-30 CN CN201410371118.5A patent/CN105294649B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
Non-Patent Citations (1)
| Title |
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| 应剑等: "固体药物无定型状态的研究进展", 《药学学报》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110551102A (en) * | 2018-06-01 | 2019-12-10 | 四川大学 | ALK covalent inhibitors and uses thereof |
| CN110551102B (en) * | 2018-06-01 | 2021-01-12 | 四川大学 | ALK covalent inhibitors and uses thereof |
| CN114901289A (en) * | 2019-10-28 | 2022-08-12 | 奥斯陆大学 | ALK inhibitors for the treatment of ALK negative cancers and plasma cell mediated diseases |
| CN114191435A (en) * | 2021-12-08 | 2022-03-18 | 深圳市泰力生物医药有限公司 | Cabotinib, neritinib and ceritinib pharmaceutical composition as well as preparation method and application thereof |
| CN116370476A (en) * | 2023-04-21 | 2023-07-04 | 遵义医科大学 | Chemotherapy medicine composition and application thereof |
| CN116370476B (en) * | 2023-04-21 | 2024-01-30 | 遵义医科大学 | Chemotherapy medicine composition and application thereof |
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| Publication number | Publication date |
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| CN105294649B (en) | 2019-05-14 |
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Address after: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |