CN105367521A - Cabazitaxel N4 crystal form substance, and preparation method, composition and use thereof - Google Patents
Cabazitaxel N4 crystal form substance, and preparation method, composition and use thereof Download PDFInfo
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- CN105367521A CN105367521A CN201410413600.0A CN201410413600A CN105367521A CN 105367521 A CN105367521 A CN 105367521A CN 201410413600 A CN201410413600 A CN 201410413600A CN 105367521 A CN105367521 A CN 105367521A
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Abstract
The invention relates to a cabazitaxel N4 crystal form substance, and a preparation method, a composition and a use thereof, and discloses an N4 crystal form of a cabazitaxel composition (chemically named as 4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-7beta, 10beta-dimethoxy-9- epoxytax-11-en-13alpha-yl(2R, 2S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, and having an English Name of cabazitaxel), and a preparation method, a composition and a use thereof. The invention concretely discloses an N4 crystal form solid substance state form of cabazitaxel in a solid state, a preparation method of the N4 crystal form solid substance sample, and an application of the cabazitaxel N4 crystal form substance in the preparation of anticancer medicines.
Description
Technical field
The present invention relates to the one brilliant N4 type solid matter stastus format having found that Cabazitaxel exists in the solid state; Relate to the preparation method having invented brilliant N4 type; Relate to the pharmaceutical composition invented containing the brilliant N4 type of Cabazitaxel and the mixing crystal formation containing the brilliant N4 type of arbitrary proportion; The invention still further relates to Cabazitaxel brilliant N4 type material as effective ingredient, prepare the application in cancer therapy drug.
Background technology
Cabazitaxel (Cabazitaxel) is bearing taxanes, chemistry 4-acetoxyl group-2 α-benzoyloxy-5 β by name, 20-epoxy group(ing)-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo Japanese yew-11-alkene-13 α-Ji (2R, 3S)-3-tertbutyloxycarbonylamino-PLA ester, its structural formula is as follows, it is the antitumor drug researched and developed by French Sanofi-Aventis (Sanofi-Aventis) company, mainly be applicable to Docetaxel (advanced prostate cancer common medicine) treatments period or afterwards the state of an illness occurred worsen transitivity hormone-refractory prostate cancer (mHRPC) patient.This medicine on June 17th, 2010 preferentially ratify listing, be the medicine of FDA Priority Review status, because of its treatment on advantage and get the Green Light in advance, it originally audits closing day is on September 30th, 2010.
Cabazitaxel molecular structural formula
H Bai Chade is disclosed at international monopoly WO9630355 (Chinese patent families CN1213042C); JD Parsa is special; " taxoid, its preparation method and the pharmaceutical composition thereof " of A Como health invention.Its invention relate to synthesis preparation method and the pharmaceutical composition thereof of the multiple taxoid comprising Cabazitaxel.
E Di Diai is disclosed at international monopoly WO2005028462 (Chinese patent families CN100429207C); " acetone solvate of dimethoxy docetaxel and preparation method thereof " of M-A Perrin invention.Its invention relate to Cabazitaxel crystal type A (Cabazitaxel: acetone=1:1) and preparation method thereof.
" crystallized form of dimethoxy docetaxel and preparation method thereof " that Pascal invents than Lip river top grade is disclosed at international monopoly WO2009115655 (Chinese patent families CN101918385A).Its invention relate to form and their preparation method of Cabazitaxel anhydride, solvate, the different solvate of ethanol/water and hydrate.
Disclose at international monopoly WO9925704 (Chinese patent families CN100375744C) " preparation method of taxoid analog derivative " of the inventions such as E enlightening Deere.Its invention relate to a kind of 13 bit esterified derivatives by deacetylation baccatin or this compound at 7 and 10 direct alkylations, prepares the novel method comprising the dialkoxylated derivative of taxoid class of Cabazitaxel.
Chinese patent CN102503913A discloses the inventions such as Chen Lei " being directly used in the preparation method of the dimethoxy monocrystalline crystal that X-ray single crystal diffraction is analyzed ".Its invention relate to the preparation method of the dimethoxy monocrystalline crystal comprising Cabazitaxel.
Chinese patent CN102675257A discloses a big medium invention " a kind of Cabazitaxel crystal and preparation method thereof ".Its invention relate to that a kind of Cabazitaxel is solvent-free, the crystalline form of nodeless mesh water and preparation method thereof.
Chinese patent CN102746258A discloses Li Jing; " crystallized form of Cabazitaxel and preparation method thereof " of Yao Quanxing invention.Its invention relate to three kinds of crystallized forms and the ester solvate form crystal formation J of Cabazitaxel, the hydrate forms crystal formation G of Cabazitaxel and Cabazitaxel crystal formation I and their preparation method of Cabazitaxel.
Chinese patent CN102898406A discloses a big medium invention " a kind of Cabazitaxel crystal and preparation method thereof ".Its invention relate to that a kind of Cabazitaxel is solvent-free, the crystalline form of nodeless mesh water and preparation method thereof.
Chinese patent CN103333138A discloses " Cabazitaxel new crystal, its preparation method, its purposes and the pharmaceutical composition " of the inventions such as Sun Zhiguo.Its invention relate to a kind of Cabazitaxel new crystal, its preparation method, its purposes and pharmaceutical composition.
Chinese patent CN103450119A discloses Song Honghai; Wang Xingfeng; " a kind of Cabazitaxel crystal formation W and preparation method thereof " of Lin Song invention.Its invention relate to a kind of Cabazitaxel crystal formation W and preparation method thereof.
Chinese patent CN103467414A discloses " a kind of Cabazitaxel pyridine adduct crystallized form " of the inventions such as Lv Yang.Its invention relate to a kind of Cabazitaxel pyridine adduct crystallized form and preparation method thereof.
Chinese patent CN103467415A discloses the inventions such as Lv Yang " a kind of Cabazitaxel crystallized form and preparation method thereof ".Its invention relate to a kind of crystallized form of Cabazitaxel.
Chinese patent CN103467416A discloses the inventions such as Lv Yang " a kind of Cabazitaxel crystallized form and preparation method thereof ".Its invention relate to a kind of crystallized form of Cabazitaxel.
International monopoly WO2012142117A1 discloses Cabazitaxel many kinds of solids form and preparation method thereof.Its invention relate to Cabazitaxel amorphous article, toluene solvate, methyl tert-butyl ether solvent compound, iso-propanol solvate, n-butanol solvate, n-propanol solvate and preparation method thereof; Also relate to the novel method adopting novel intermediate synthesis Cabazitaxel.
Chinese patent CN102659722A discloses grandson and to wave etc. invention " amorphous Cabazitaxel and preparation method thereof ".Its invention relate to a kind of Cabazitaxel amorphous substance and preparation method thereof, relates to Cabazitaxel amorphous substance further in application pharmaceutically.
Chinese patent CN103044364A discloses Li Jing; " amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof " of Yao Quanxing invention.Its invention relate to amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof.
Chinese patent CN103601704A discloses Zhao Junxu; Liu Zilong; " preparation of amorphous Cabazitaxel " of Wang Lu invention.Its invention relate to the preparation of amorphous Cabazitaxel.
Chinese patent CN103058960A discloses " Cabazitaxel polymorphic forms and preparation method thereof of the inventions such as Zhao Jun.The new crystal form that its invention relate to the anhydride of Cabazitaxel, monohydrate and dihydrate with and preparation method thereof.
Chinese patent CN102532064A discloses Chen Bo; Yao Quanxing; " synthetic method of imethoxy docetaxel " of Li Jing invention.Its invention relate to a kind of synthetic method of imethoxy docetaxel, and this synthetic method decreases reactions steps, shortens reaction time, improves product purity.
Chinese patent CN102786502A discloses " a kind of synthetic method of taxoid drug 7,10-methoxyl group docetaxel " of the inventions such as Chen Lei.Its invention relate to a kind of synthetic method of taxoid drug 7,10-methoxyl group docetaxel, the easy gentleness of reaction conditions of method, and equipment is simple, easy handling.
Chinese patent CN102887877A discloses " a kind of method of purifying Cabazitaxel " of the inventions such as Wang Yongyi.Its invention relate to a kind of method adopting the separation and purification Cabazitaxel of crystallization and absorption coupling.
It is raw that Chinese patent CN102675256A discloses platinum; Chen great Hai; Old " synthetic method of Cabazitaxel " from all inventing.Its invention relate to a kind of novel method of synthesizing Cabazitaxel.
Chinese patent CN102336726A discloses Chen Bo; Yao Quanxing; " a kind of preparation method of Cabazitaxel " of Li Jing invention.Its invention relate to a kind of novel method preparing Cabazitaxel.
Chinese patent CN102532065A discloses " a kind of synthetic method of Cabazitaxel " of the inventions such as Yao Quanxing.Its invention relate to a kind of novel method of synthesizing Cabazitaxel.
Chinese patent CN102311410A discloses " a kind of preparation method of Cabazitaxel " of a big medium invention.Its invention relate to a kind of method adopting the novel process of three-step reaction to prepare Cabazitaxel.
Chinese patent CN102285947A discloses " synthetic method of Cabazitaxel " of the inventions such as Sun little Qiang.Its invention relate to a kind of novel method of synthesizing Cabazitaxel.
Chinese patent CN102659721A discloses Liu Ping; " a kind of synthetic method of Cabazitaxel " of Yuan Jiandong invention.Its invention relate to a kind of novel method of synthesizing Cabazitaxel.
Chinese patent CN102895183A discloses the inventions such as Li Sai " a kind of injection Cabazitaxel and preparation method thereof ".Its invention relate to a kind of stable in properties, can the injection Cabazitaxel and preparation method thereof of clinical application.
Chinese patent CN103012331A discloses " preparation method of Cabazitaxel and intermediate thereof " of the inventions such as Sun Zhiguo.Its invention relate to a kind of preparation method of Cabazitaxel intermediate, relates to a kind of preparation method of Cabazitaxel further.
Chinese patent CN102458392A discloses E maguari Buddhist nun invention " comprising the antineoplastic combinations of Cabazitaxel and capecitabine ".Its invention relate to antitumor combination, comprises Cabazitaxel and capecitabine.
Chinese patent CN102417491A discloses " with the 10-deacetylate-baccatin III for the method for Cabazitaxel prepared by raw material " of the invention such as Cai Qiang.This invention relate to a kind of novel method preparing Cabazitaxel.
Chinese patent CN102952102A disclose Zhao Jun invention " a kind of compound and preparation method thereof with its Cabazitaxel preparation in application ".This invention relate to a kind of compound and applies the method for this compou nd synthesis Cabazitaxel.
Chinese patent CN102408397A discloses Zheng Yunman; " new taxane derivatives and preparation method thereof " of Xu Tianhui invention.This invention relate to a kind of new taxanes isoserine ester and preparation method thereof, and utilizes new taxanes isoserine ester to prepare the method for antitumor drug Cabazitaxel, docetaxel and taxol.
Chinese patent CN103172654A discloses the inventions such as Hu Xuefeng " bearing taxanes and preparation method thereof ".This invention relate to a kind of bearing taxanes and preparation method thereof, relates to intermediate formula V compound, its preparation method for the preparation of Cabazitaxel particularly, and prepares the method for Cabazitaxel with this compound.
Chinese patent CN103172625A discloses " midbody compound of Cabazitaxel " of the inventions such as Hu Xuefeng.This invention relate to the midbody compound of Cabazitaxel, relates to midbody compound 6, its preparation method for the preparation of Cabazitaxel particularly, and prepares the method for Cabazitaxel with this compound.
Chinese patent CN103242267A discloses " preparation method of Cabazitaxel and intermediate thereof and the Cabazitaxel intermediate " of the inventions such as Shen Xin.This invention relate to a kind of preparation method of Cabazitaxel and a kind of preparation method of Cabazitaxel intermediate.
Chinese patent CN103421036A discloses the inventions such as Guo Maojun " a kind of Cabazitaxel intermediate and its preparation method and application ".This invention relate to a kind of Cabazitaxel intermediate and its preparation method and application.
Chinese patent CN103664837A discloses " a kind of preparation method of high purity Cabazitaxel intermediate " of the inventions such as Kang Yanlong.This invention relate to a kind of preparation method of high purity Cabazitaxel intermediate.
Chinese patent CN102060815A discloses " a kind of preparation method of bearing taxanes " of the inventions such as Li Cheng.This invention relate to a kind of preparation method of Cabazitaxel.
Chinese patent CN103012328A discloses " a kind of method preparing s-generation paclitaxel kind anti-cancer drugs Cabazitaxel " of the inventions such as Li Yingxia.This invention relates to the method for synthesis s-generation taxanes PTS Cabazitaxel.
Chinese patent CN103012329A discloses " a kind of method preparing paclitaxel kind anti-cancer drugs CabazitaxelXRP6258 " of the inventions such as Li Yingxia.This invention relates to the method for synthesis s-generation paclitaxel kind anti-cancer drugs CabazitaxelXRP6258.
Chinese patent CN103012330A discloses " preparation method of a kind of paclitaxel kind anti-cancer drugs XRP6258 " of the inventions such as Li Yingxia.This invention relates to the preparation method of paclitaxel kind anti-cancer drugs XRP6258.
US Patent No. 20130065955A1 discloses multiple crystal formation of Cabazitaxel and preparation method thereof.Its invention relate to Cabazitaxel iso-propanol solvate, ethyl acetate solvate, tetrahydrofuran solvent compound, toluene solvate, butanone solvent compound, diethyl ketone solvate, diethyl carbonate solvate, dimethyl sulfoxide solvent compound and acetate solvate compound and preparation method thereof.
International monopoly WO2013080217 discloses multiple crystallized form of Cabazitaxel (brilliant 1 type, brilliant 2 types, brilliant 3 types, brilliant 4 types, brilliant 5 types, brilliant 6 types, brilliant 7 types, brilliant 8 types, brilliant 9 types, brilliant 10 types, brilliant 11 types, brilliant 12 types, brilliant 13 types) and preparation method thereof.
International monopoly WO2013088335 discloses Cabazitaxel ethyl acetate compound and preparation method thereof, and proves that Cabazitaxel ethyl acetate compound has higher purity than acetone compound by purity testing.
US Patent No. 20130109870 discloses a kind of Cabazitaxel amorphous article and preparation method thereof, and Cabazitaxel dissolves in a suitable solvent by method, obtains Cabazitaxel amorphous article by removal of solvents.
International monopoly WO2013111157 discloses Cabazitaxel amorphous article and preparation method thereof, and Cabazitaxel is dissolved in suitable polar solvent by method, obtains Cabazitaxel amorphous article by removal of solvents.
US Patent No. 20130116444 discloses the preparation method of Cabazitaxel, Cabazitaxel analogue and intermediate thereof, and invention provides a kind of compounds for the synthesis of Cabazitaxel.
International monopoly WO2013054204 discloses a kind of preparation method of Cabazitaxel intermediate, and invention provides a kind of compounds for the synthesis of Cabazitaxel.
International monopoly WO2013069027 discloses a kind of preparation method of Cabazitaxel and the preparation method of Cabazitaxel iso-propanol solvate.
International monopoly WO2013134534 discloses Cabazitaxel many kinds of solids form (brilliant VII type, brilliant VIII type, brilliant IX type, brilliant X-type, brilliant XI type, brilliant XII type, brilliant XIII type, brilliant XIV type, brilliant XV type, brilliant XVI type, brilliant XVII type, brilliant XVIII type, brilliant XIX type, brilliant XX type, brilliant XXI type, brilliant XXII type) and preparation method thereof.
US Patent No. 2014022237 discloses Cabazitaxel amorphous article and preparation method thereof, and Cabazitaxel is dissolved in suitable organic solvent by method, obtains Cabazitaxel amorphous article by removal of solvents.
US Patent No. 20120149925 discloses the method preparing bearing taxanes under Louis acid catalysis with Tetraol.
Present invention finds a kind of Cabazitaxel brilliant N4 type solid matter state different from above-mentioned patent report content and preparation method thereof.
Research purpose of the present invention is started with from the crystal formation solid matter existence research of Cabazitaxel, by crystal formation triage techniques, crystal formation evaluated biological activity technology, the active ingredient raw materials aspect of medicine is found, finds that crystal formation solid matter exists kind and status flag, crystal-form substances is combined with pharmacodynamic study, for the advantage medicinal crystal-form solid matter found, find, exploitation has the Cabazitaxel of optimal clinical curative effect provides basic science data; Meanwhile, also for providing scientific basis from Cabazitaxel solid pharmaceutical raw material basis application country or international intellecture property invention patent protection.
Summary of the invention
One of the object of the invention: the brilliant N4 type solid matter existence of Cabazitaxel and describing mode are provided.
The object of the invention two: the preparation method that Cabazitaxel brilliant N4 type solid matter is provided.
The object of the invention three: the solid pharmaceutical containing the brilliant N4 type sterling of Cabazitaxel or the mixing crystal formation containing the brilliant N4 type of arbitrary proportion and composition thereof are provided.
The object of the invention four: provide the pharmaceutical composition using Cabazitaxel brilliant N4 type solid matter as active constituents of medicine, its, dosage was within the scope of 5 ~ 500mg every day.
The object of the invention five: provide and use Cabazitaxel brilliant N4 type solid matter to manufacture out the tablet, capsule, pill, injection, slowly-releasing or the controlled release preparation medicine that supply Clinical practice as active constituents of medicine raw material.
The object of the invention six: provide Cabazitaxel brilliant N4 type solid matter improve Plasma Concentration in organism due to crystal-form substances and play the effective therapeutic action of medicine in disease therapy process.
The object of the invention seven: provide and use Cabazitaxel brilliant N4 type solid matter as active raw materials, preparing the application in cancer therapy drug.
The invention provides Cabazitaxel compound brilliant N4 type solid matter form in the solid state, the preparation method of brilliant N4 type sample; The medicine finding to use the brilliant N4 type material of Cabazitaxel to develop as active fraction preparation and composition thereof are for the preparation of the application in cancer therapy drug.
Technical characteristic
1. the brilliant N4 type solid sample morphological specificity of Cabazitaxel:
1.1 Cabazitaxel that the present invention relates to brilliant N4 type solid matter, is characterized in that, when use powder x-ray diffraction analysis adopts CuK
αduring radiation experiments condition, show as diffraction peak position: 2-Theta value (°) or d value
with diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) have the solid matter (table 1, Fig. 1) during following characteristic peaks:
The powder x-ray diffraction peak value of table 1 Cabazitaxel brilliant N4 type sample
1.2 Cabazitaxel that the present invention relates to brilliant N4 type solid matter, it is characterized in that, use infrared spectra when analyzing 3500,3366,2979,2939,2896,2828,1750,1710,1637,1602,1509,1498,1451,1412,1392,1365,1348,1315,1266,1244,1198,1172,1161,1115,1092,1070,1051,1024,985,977,949,924,913,899,886,855,844,831,798,779,769,756,746,734,711,704,684cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1(Fig. 2).
1.3 Cabazitaxel of the present invention brilliant N4 type solid matter, it is characterized in that, when using differential canning calorimetry to analyze, show as when temperature rise rate is there are 2 endotherm(ic)peaks in the DSC collection of illustrative plates of per minute 10 DEG C respectively 93 DEG C ± 3 DEG C and 150 DEG C ± 3 DEG C places (Fig. 3).
1.4 Cabazitaxel of the present invention brilliant N4 type solid matter, is characterized in that, when using thermogravimetric technical Analysis, show as when temperature rise rate is there is 1 weightless step (Fig. 4) at 73 DEG C of temperature places in the TG collection of illustrative plates of per minute 5 DEG C.
2. the preparation method characteristic of Cabazitaxel brilliant N4 type sample:
The preparation method of the Cabazitaxel that the present invention relates to brilliant N4 type sample, it is characterized in that, use the mixed solvent that ethanol and water form, at 15 DEG C ~ 80 DEG C temperature, Cabazitaxel sample dissolved completely and go down desolventize through envrionment temperature 4 DEG C ~ 40 DEG C, ambient relative humidity 10% ~ 75%, normal pressure experiment condition, the Cabazitaxel solid matter obtained through 100 DEG C of heat dryings after 6 ~ 10 hours, then can obtain Cabazitaxel brilliant N4 type solid matter through pressure 2 ~ 8T.
3. the crystal formation composition of Cabazitaxel, dosage and pharmaceutical preparations composition feature:
The 3.1 Cabazitaxel mixing crystal formation solid matters that the present invention relates to, is characterized in that, the brilliant N4 type of the Cabazitaxel containing arbitrary proportion composition.
3.2 pharmaceutical compositions that the present invention relates to, is characterized in that, containing the brilliant N4 type of Cabazitaxel, or containing Cabazitaxel mixed crystal solid matter and pharmaceutically acceptable carrier.
3.3 pharmaceutical compositions that the present invention relates to, Cabazitaxel every day dosage within the scope of 5 ~ 500mg.
3.4 pharmaceutical compositions that the present invention relates to, is characterized in that, described pharmaceutical composition is various tablet, capsule, pill, injection preparation, sustained release preparation, controlled release preparation.
The 3.5 Cabazitaxel brilliant N4 type mixed crystal compositions that the present invention relates to the brilliant N4 type of Cabazitaxel or contain arbitrary proportion are preparing the application in cancer therapy drug.
Accompanying drawing explanation
The x-ray diffractogram of powder spectrum of Fig. 1 Cabazitaxel brilliant N4 type solid matter
The infrared absorpting light spectra of Fig. 2 Cabazitaxel brilliant N4 type solid matter
The Differential Scanning Calorimetry of Fig. 3 Cabazitaxel brilliant N4 type solid matter
The thermogravimetric collection of illustrative plates of Fig. 4 Cabazitaxel brilliant N4 type solid matter
Embodiment
For technical scheme of the present invention is better described, spy provides following examples, but the present invention is not limited to this.
Embodiment 1
The preparation method 1 of Cabazitaxel brilliant N4 type sample:
By 0.1g Cabazitaxel sample dissolution in 2.0mL95% ethanol, add 1.0mL water, be placed in 50 DEG C of water-baths, sample is dissolved completely, slowly cool to room temperature, leave standstill 24 hours crystallizatioies, 100 DEG C of electric heating constant-temperature blowing drying box heating are placed in after 8 hours by collecting the solid obtained, under being placed in 8T pressure, turn crystalline substance by pressure and prepare brilliant N4 type sample, yield 61%, powder x-ray diffraction analysis is carried out to the sample obtained, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is Cabazitaxel brilliant N4 type solid matter.
The preparation method 2 of Cabazitaxel brilliant N4 type sample:
By 0.2g Cabazitaxel sample dissolution in 5.0mL95% ethanol, add 5.0mL water, be placed in 60 DEG C of water-baths, sample is dissolved completely, slowly cool to room temperature, leave standstill 8 hours crystallizatioies, 100 DEG C of electric heating constant-temperature blowing drying box heating are placed in after 8 hours by collecting the solid obtained, under being placed in 6T pressure, turn crystalline substance by pressure and prepare brilliant N4 type sample, yield 63%, powder x-ray diffraction analysis is carried out to the sample obtained, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is Cabazitaxel brilliant N4 type solid matter.
The preparation method 3 of Cabazitaxel brilliant N4 type sample:
By 0.5g Cabazitaxel sample dissolution in 10.0mL95% ethanol, add 8.0mL water, be placed in 50 DEG C of water-baths, sample is dissolved completely, slowly cool to room temperature, leave standstill 12 hours crystallizatioies, 100 DEG C of electric heating constant-temperature blowing drying box heating are placed in after 8 hours by collecting the solid obtained, under being placed in 4T pressure, turn crystalline substance by pressure and prepare brilliant N4 type sample, yield 66%, powder x-ray diffraction analysis is carried out to the sample obtained, its diffracting spectrum is consistent with Fig. 1, shows that gained sample is Cabazitaxel brilliant N4 type solid matter.
Embodiment 2
The preparation method 1 (tablet) of combined pharmaceutical formulation:
A kind of preparation method of medicinal composition tablet, it is characterized in that using the brilliant N4 type sterling of Cabazitaxel or the mixed crystal solid matter containing the brilliant N4 type of arbitrary proportion as medicinal composition bulk drug, use several vehicle as the adjunct ingredient preparing medicinal composition tablet, proportioning makes the tablet samples of every sheet content of dispersion at 25 ~ 250mg according to a certain percentage, and table 2 provides tablet formulation ratio:
The preparation formula of table 2 Cabazitaxel composite medicine tablet
By the method that brilliant for Cabazitaxel N4 type sterling or the mixed crystal bulk drug containing the brilliant N4 type of arbitrary proportion are prepared into tablet formulation be: several vehicle is mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make soft material, to sieve granulation, wet grain is dried, and sieve whole grain, adds Magnesium Stearate and talcum powder mixes, compressing tablet, to obtain final product.
The preparation method 2 (capsule) of combined pharmaceutical formulation:
A kind of preparation method of medicinal composition capsule, it is characterized in that using the brilliant N4 type sterling of Cabazitaxel or the mixed crystal solid matter containing the brilliant N4 type of arbitrary proportion as medicinal composition bulk drug, use several vehicle as the adjunct ingredient preparing medicinal composition capsule, proportioning makes the capsule sample of every sheet content of dispersion at 25 ~ 250mg according to a certain percentage, and table 3 provides capsule formula ratio:
The bulk drug of table 3 Cabazitaxel medicinal composition capsule preparations and accessory formula
By the method that brilliant for Cabazitaxel N4 type sterling or the mixed crystal bulk drug containing the brilliant N4 type of arbitrary proportion are prepared into tablet formulation be: several vehicle is mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, add Magnesium Stearate to mix, insert capsule and obtain; Or do not use granulation step, and directly Cabazitaxel brilliant N4 type bulk drug is mixed with several excipients, after sieving, directly incapsulate obtained.
Embodiment 3
The dosage 1 (tablet) of Cabazitaxel crystal formation medicinal composition:
Use the pharmaceutical composition that crystal formation Cabazitaxel sample manufactures as active constituents of medicine, it is characterized in that the activeconstituents using brilliant N4 type Cabazitaxel as medicine, daily dosage is 50mg, 1 time/each 1 50mg conventional tablet every day can be prepared into respectively, every day 2 times/each 1 25mg conventional tablet type.
The dosage 2 (capsule) of Cabazitaxel crystal formation medicinal composition:
Use the pharmaceutical composition that crystal formation Cabazitaxel sample manufactures as active constituents of medicine, it is characterized in that the activeconstituents using brilliant N4 type Cabazitaxel as medicine, daily dosage is 100mg, 2 times/each 1 50mg capsule every day can be prepared into respectively, every day 1 time/each 1 100mg capsule.
Need the problem illustrated: the Cabazitaxel crystal formation pharmaceutical composition that the present invention relates to has multifactor impact perhaps on the dosage of effective constituent, such as: the difference causing dosage every day for the purposes difference of prevention and therapy; Ill character is different from ill severity and cause the different of dosage every day; The difference of Gender, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day; In addition, the absorption existed between crystal form samples and Plasma Concentration are equal, also cause the present invention to be 0.01-300mg/kg body weight at Suitable dosage ranges every day of use Cabazitaxel crystal formation composition, are preferably 0.1-50mg/kg body weight.Different Cabazitaxels brilliant N4 type effective constituent total dose scheme should be formulated according to the prevention of reality and treatment different situations demand during use, and can be divided into repeatedly or single administration mode complete.
Reference
1. international monopoly, publication number WO9630355 (Chinese patent families CN1213042C)
2. international monopoly, publication number WO2005028462 (Chinese patent families CN100429207C)
3. international monopoly, publication number WO2009115655 (Chinese patent families CN101918385A)
4. international monopoly, publication number WO9925704 (Chinese patent families CN100375744C)
5. Chinese patent, publication number CN102503913A
6. Chinese patent, publication number CN102675257A
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8. Chinese patent, publication number CN102898406A
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Claims (14)
1. Cabazitaxel brilliant N4 type solid matter, is characterized in that, when use powder x-ray diffraction analysis adopts CuK
αduring radiation experiments condition, diffraction peak position 2-Theta value (°) or d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
2. Cabazitaxel according to claim 1 brilliant N4 type solid matter, it is characterized in that, use infrared spectra when analyzing 3500,3366,2979,2939,2896,2828,1750,1710,1637,1602,1509,1498,1451,1412,1392,1365,1348,1315,1266,1244,1198,1172,1161,1115,1092,1070,1051,1024,985,977,949,924,913,899,886,855,844,831,798,779,769,756,746,734,711,704,684cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1.
3. the brilliant N4 type of the Cabazitaxel according to any one of claim 1 or 2 solid matter, it is characterized in that, when using differential canning calorimetry to analyze, show as when temperature rise rate is there are 2 endotherm(ic)peaks in the DSC collection of illustrative plates of per minute 10 DEG C respectively at 93 DEG C ± 3 DEG C and 150 DEG C ± 3 DEG C places.
4. the brilliant N4 type of the Cabazitaxel according to any one of claim 1 or 2 solid matter, is characterized in that, when using thermogravimetric technical Analysis, show as when temperature rise rate is there is 1 weightless step at 73 DEG C of temperature places in the TG collection of illustrative plates of per minute 5 DEG C.
5. the preparation method of the brilliant N4 type of the Cabazitaxel according to any one of a claim 1-4 solid matter, it is characterized in that, use the mixed solvent that ethanol and water form, at 15 DEG C ~ 80 DEG C temperature, Cabazitaxel sample dissolved completely and go down desolventize through envrionment temperature 4 DEG C ~ 40 DEG C, ambient relative humidity 10% ~ 75%, normal pressure experiment condition, the Cabazitaxel solid matter obtained through 100 DEG C of heat dryings after 6 ~ 10 hours, then can obtain Cabazitaxel brilliant N4 type solid matter through pressure 2 ~ 8T.
6. a mixing crystal formation solid matter for Cabazitaxel, is characterized in that, the brilliant N4 type of the Cabazitaxel described in any one of the claim 1-4 containing arbitrary proportion solid matter composition.
7. a pharmaceutical composition, is characterized in that, the brilliant N4 type solid matter of the Cabazitaxel described in any one of the claim 1-4 containing effective dose and pharmaceutically acceptable carrier.
8. a pharmaceutical composition, is characterized in that, the Cabazitaxel mixing crystal formation solid matter described in the claim 6 containing effective dose and pharmaceutically acceptable carrier.
9. the pharmaceutical composition any one of claim 7 or 8, is characterized in that, Cabazitaxel every day dosage within the scope of 5mg ~ 500mg.
10. the pharmaceutical composition any one of claim 7 or 8, is characterized in that, the formulation of described composition is tablet, capsule, pill or injection preparation.
11. pharmaceutical compositions any one of claim 7 or 8, it is characterized in that, the formulation of described composition is sustained release preparation or controlled release preparation.
Cabazitaxel according to any one of 12. claim 1-4 brilliant N4 type solid matter is preparing the application in cancer therapy drug.
The mixing crystal formation solid matter of the Cabazitaxel described in 13. claims 6 is preparing the application in cancer therapy drug.
Pharmaceutical composition according to any one of 14. claim 7-11 is preparing the application in cancer therapy drug.
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| CN102675257A (en) * | 2012-05-10 | 2012-09-19 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
| WO2013111157A1 (en) * | 2012-01-03 | 2013-08-01 | Shilpa Medicare Limited | Process for preparing amorphous cabazitaxel |
| CN103450119A (en) * | 2013-09-24 | 2013-12-18 | 天津炜捷制药有限公司 | Cabazitaxel with crystal form W and method for preparing same |
| CN103467414A (en) * | 2013-07-24 | 2013-12-25 | 神威药业集团有限公司 | Crystalline form of cabazitaxel pyridine compound |
| CN103467416A (en) * | 2013-07-24 | 2013-12-25 | 神威药业集团有限公司 | Crystalline form of cabazitaxel and preparation method thereof |
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| WO2013111157A1 (en) * | 2012-01-03 | 2013-08-01 | Shilpa Medicare Limited | Process for preparing amorphous cabazitaxel |
| CN102675257A (en) * | 2012-05-10 | 2012-09-19 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
| CN103467414A (en) * | 2013-07-24 | 2013-12-25 | 神威药业集团有限公司 | Crystalline form of cabazitaxel pyridine compound |
| CN103467416A (en) * | 2013-07-24 | 2013-12-25 | 神威药业集团有限公司 | Crystalline form of cabazitaxel and preparation method thereof |
| CN103450119A (en) * | 2013-09-24 | 2013-12-18 | 天津炜捷制药有限公司 | Cabazitaxel with crystal form W and method for preparing same |
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