CN104490797A - Multiphase-stable albumin conjunction type cabazitaxel - Google Patents
Multiphase-stable albumin conjunction type cabazitaxel Download PDFInfo
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- CN104490797A CN104490797A CN201410805215.0A CN201410805215A CN104490797A CN 104490797 A CN104490797 A CN 104490797A CN 201410805215 A CN201410805215 A CN 201410805215A CN 104490797 A CN104490797 A CN 104490797A
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- cabazitaxel
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Abstract
The invention belongs to the field of pharmaceutical preparations and discloses multiphase-stable albumin conjunction type cabazitaxel prepared by virtue of a novel albumin nanoparticle preparation technique. The prescription of a preparation comprises cabazitaxel, albumin, a stabilizer, a protective agent and a pH regulating agent. The preparation is prepared by virtue of the novel albumin nanoparticle preparation technique, and albumin conjunction type cabazitaxel is preferably prepared by virtue of high shearing force of a temperature-controllable planetary ball mill. According to the method, raw materials are crushed during the preparation, so that the particle size is reduced, and the solubility of drugs is increased.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to prescription of a kind of heterogeneous stable insoluble drug albumin bound type freeze-dried preparation and preparation method thereof.
Background technology
His plug of kappa is a newcomer of Ramulus et folium taxi cuspidatae alkanamine family, and its mechanism of anticancer action is similar to docetaxel with feature, belongs to anti-microtubule class medicine.Cabazitaxel by with tubulin binding, promote that it is assembled into microtubule, the microtubule that simultaneously these can be stoped to have assembled disintegrates, and makes microtubule stabilization, and then the performance of the mitosis of T suppression cell and Interphase cells function.Compared with the taxanes medicine gone on the market with other, the drug row pump that this medicine and P glycoprotein mediate has lower affinity, and the probability that Drug tolerance occurs is lower, and can be used for treating multidrug-resistant carcinoma, this medicine can pass through blood brain barrier in addition.Transitivity hormone difficult control type carcinoma of prostate (mHRPC) patient being used for the treatment of and having accepted docetaxel therapy is before this joined with prednisone or andrographolide.In vitro study shows, and Cabazitaxel shows activity in the cell strain to amycin, vinblastine, paclitaxel and docetaxel drug resistance.Cabazitaxel, to the people's late tumor display anti-tumor activity transplanted in mice, shows activity comprising chemotherapy in the insensitive tumor model of docetaxel.
active component to be his plug of kappa be in recent years first approved proof can accept the medicine of the life span of the transitivity hormone difficult control type patients with prostate cancer of docetaxel treatment by significant prolongation.755 had accepted in the test of the patients enter of docetaxel therapy for treating before this,
(25mg/m
2) treatment group overall patient life span is 15.1 months, mitoxantrone group (12mg/m
2) Overall survival be 12.7 months, two groups have marked difference, use Cabazitaxel treatment that those can be made not had the life span of the selectable advanced prostate cancer patients of medicine to extend nearly 2.5 months, become the selection that the advanced prostate cancer patients after docetaxel Endodontic failure is last.
His plug of kappa is a kind of medicine of poorly water-soluble, makes it dissolve for intravenously administrable at present for clinical taxane amine drug by share with alcohols and nonpolar surfactant.
be exactly use ethanol and tween 80 to reach the object of intravenously administrable, the wherein concentrated solution yellow that he fills in and tween 80 forms by kappa or brown yellow oil liquid, diluent is 13% (w/w) alcoholic solution simultaneously.A large amount of surfactants and the introducing of organic solvent easily cause serious anaphylaxis.The surfactant that do not use of current report is prepared albumin bound type medicine to the method reaching desirable administration object for using the methods such as high pressure homogenization and prepares albumin nano granular.The methods such as high pressure homogenization not easily realize amplifying and produce, and preparation process is complicated, and influence factor is many.Chinese patent [publication number CN 102784109A] discloses a kind of injection taxone albumin nano granular preparation and preparation method thereof, post processing uses rotary evaporation, concentrated solution after evaporation not easily carries out the operations such as fill, and does not study its stability.
Summary of the invention
The object of this invention is to provide a kind of stable albumin bound type kappa he plug with and preparation method thereof.
First object of the present invention is to provide heterogeneous stable albumin bound type kappa, and he fills in preparation, and mass percent component is as follows:
Further, prescription is composed as follows:
In said components, albuminous kind can be human serum albumin, bovine serum albumin, sheep blood serum albumin and other types albumin, wherein preferred human serum albumin and bovine serum albumin.One or more in polyethylene glycol-polylactic acid (PEG-PLGA), phospholipid, alkylphenol polyoxyethylene selected by stabilizing agent, the stabilizer type wherein added respectively in aqueous phase and oil phase can be identical or different, preferred polyethylene glycol-polylactic acid (PEG-PLGA).
PH adjusting agent is selected from one or more in hydrochloric acid, citric acid, phosphoric acid, nitric acid, optimization citric acid.Freezing drying protective agent is selected from one or more in mannitol, lactose, glucose, preferred mannitol.
Second object of the present invention is to provide stable albumin bound type kappa, and he fills in the preparation method of preparation: be dissolved in appropriate chloroform/dichloromethane the kappa of recipe quantity described above he plug, stabilizing agent and pH adjusting agent as oil phase; Albumin and stabilizing agent, freezing drying protective agent are dissolved in appropriate amount of deionized water as aqueous phase.Utilize high shear force that oil phase is fully contacted with aqueous phase, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.
Novel albumin nanoparticle technology of preparing under high shear will comprise oil phase and the mixing of albumin aqueous phase of water-insoluble drug, conventional mode has high pressure homogenization, comminution by gas stream etc., the present invention preferably utilizes the high shear force of temperature-controllable ball-milling method to realize the mixing of aqueous phase and oil phase, the method influence factor is less, simple to operate, be easy to reappear and amplify, can strict temperature control in preparation process, compared with additive method, the change of the albumin structure caused due to the high temperature of instrument in preparation process can be avoided, thus affect the combination of albumin and medicine, cause preparation stability poor.
In the present invention, utilizing high shear force that oil phase and aqueous phase are fully contacted is utilize the high shear force of temperature-controllable planetary ball mill to realize the oil phase of insoluble drugs and the mixing containing albumin aqueous phase, and technological parameter is as follows:
Rotational speed of ball-mill 25-40Hz
Ball milling temperature-20 DEG C-0 DEG C
Ball-milling Time 0.5-5h
Result display uses above parameter area can well realize the combination of albumin and medicine, preferably uses rotational speed of ball-mill 38Hz, ball milling temperature-20 DEG C, Ball-milling Time 1.8 hours.
The present invention utilizes Novel albumin nanoparticle technology of preparing, under the prerequisite not changing albumin structure, medicine is loaded into wherein, in biphase, all add stabilizing agent simultaneously, reduce his gathering of plug of albumin bound type kappa to be on the one hand separated with albuminous with medicine, contribute to the dispersion of his plug of kappa in preparation process on the other hand, increase the probability of medicine and albumin bound, the sterically hindered of stabilizing agent and electrostatic interaction can also be utilized to improve the stability of his plug of albumin bound type kappa.
The controlled planetary ball mill of serviceability temperature of the present invention prepares stable albumin bound type kappa, and he fills in, have simple to operate compared with high pressure homogenization and comminution by gas stream, Effect Factors for Sythetic Technology is few, have the advantages that strictly to control preparation process temperature, the high shear force of this method is utilized to pulverize material, can by crushing material to desirable particle size range, efficiently convenient.
Below with reference to drawings and Examples, the present invention is described in detail.
Accompanying drawing explanation
Fig. 1 be heterogeneous stable albumin bound type kappa of the present invention he fill in placement 0 hour particle size determination result.
Fig. 2 is that Comparative formulation places 0 hour particle size determination result.
Fig. 3 be heterogeneous stable albumin bound type kappa of the present invention he fill in placement 24 hours particle size determination results.
Fig. 4 is that Comparative formulation places 24 hours particle size determination results.
Fig. 5 be of the present invention heterogeneous stable have no use hundred conjunction type kappas he fill in placement 48 hours particle size determination results.
Fig. 6 is that Comparative formulation places 48 hours particle size determination results.
Detailed description of the invention
The present invention to be described in further detail, but the non-scope being only limitted to these embodiments of scope of the present invention in conjunction with the embodiments, in embodiment use his plug of kappa to be marketable material medicine.
Embodiment 1
A component ratio (mg) in his plug of heterogeneous stable albumin bound type kappa
Preparation method:
(1) kappa of recipe quantity he plug, phospholipid and citric acid are dissolved in appropriate chloroform/dichloromethane as oil phase;
(2) recipe quantity albumin and phospholipid, mannitol are dissolved in appropriate amount of deionized water as aqueous phase;
(3) oil phase obtained in (1) is added drop-wise in (2), the controlled planetary ball mill of serviceability temperature grinds (rotational speed of ball-mill 38Hz to it, ball milling temperature 4 DEG C, Ball-milling Time 1.5 hours), taking-up, fill, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.Use laser particle analyzer to measure particle diameter, result is 321nm.
Embodiment 2
A component ratio (mg) in his plug of heterogeneous stable albumin bound type kappa
Preparation method:
(1) kappa of recipe quantity he plug, PEG-PLGA and citric acid are dissolved in appropriate chloroform/dichloromethane as oil phase;
(2) recipe quantity albumin and PEG-PLGA, mannitol are dissolved in appropriate amount of deionized water as aqueous phase;
(3) be added drop-wise in (2) by oil phase obtained in (1), after the controlled planetary ball mill of serviceability temperature grinds it, taking-up, fill, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.Use laser particle analyzer to measure particle diameter, result is 386nm.
Embodiment 3
A component ratio (mg) in his plug of heterogeneous stable albumin bound type kappa
Preparation method:
(1) kappa of recipe quantity he plug, PEG-PLGA and citric acid are dissolved in appropriate chloroform/dichloromethane as oil phase;
(2) recipe quantity albumin and PEG-PLGA, mannitol are dissolved in appropriate amount of deionized water as aqueous phase;
(3) be added drop-wise in (2) by oil phase obtained in (1), after the controlled planetary ball mill of serviceability temperature grinds it, taking-up, fill, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.Use laser particle analyzer to measure particle diameter, result is 263nm.
Embodiment 4
A component ratio (mg) in his plug of heterogeneous stable albumin bound type kappa
Preparation method:
(1) kappa of recipe quantity he plug, PEG-PLGA and citric acid are dissolved in appropriate chloroform/dichloromethane as oil phase;
(2) recipe quantity albumin and phospholipid, mannitol are dissolved in appropriate amount of deionized water as aqueous phase;
(3) be added drop-wise in (2) by oil phase obtained in (1), after the controlled planetary ball mill of serviceability temperature grinds it, taking-up, fill, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.Use laser particle analyzer to measure particle diameter, result is 117nm.
Embodiment 5
A component ratio (mg) in his plug of heterogeneous stable albumin bound type kappa
Preparation method:
(1) kappa of recipe quantity he plug, PEG-PLGA and citric acid are dissolved in appropriate chloroform/dichloromethane as oil phase;
(2) recipe quantity albumin and PEG-PLGA, mannitol are dissolved in appropriate amount of deionized water as aqueous phase;
(3) be added drop-wise in (2) by oil phase obtained in (1), after high pressure homogenization, fill, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.Use laser particle analyzer to measure particle diameter, result is 563nm.
Embodiment 6
He fills in prepare albumin bound type kappa with reference to patent [CN 102784109 B], contrasts with formula preparation sample in embodiment 5, respectively at placement 0 hour, 24 hours, 48 hours sampling and measuring particle diameters, and both contrasts stability.
Result show, heterogeneous stable albumin bound type kappa he plug be respectively 78nm, 156nm, 154nm 0 hour, 24 hours, 48 hours particle size determination results; Comparative formulation 0 hour, 24 hours, 48 hours particle size determination results are respectively 124nm, 389nm, 864nm.
Claims (10)
1. a heterogeneous stable albumin bound type Cabazitaxel, is characterized in that being made up of the component of following mass percent:
。
2. heterogeneous stable albumin bound type kappa as claimed in claim 1 he plug, it is characterized in that being made up of the component of following mass percent:
。
3. heterogeneous stable albumin bound type kappa as claimed in claim 1 or 2 he plug, it is characterized in that, described albumin is one or more in human serum albumin, bovine serum albumin, sheep blood serum albumin; Stabilizing agent is one or more in polyethylene glycol-polylactic acid (PEG-PLGA), phospholipid, alkylphenol polyoxyethylene; PH adjusting agent is one or more in hydrochloric acid, citric acid, phosphoric acid, nitric acid; Freezing drying protective agent is one or more in mannitol, lactose, glucose.
4. heterogeneous stable albumin bound type kappa as claimed in claim 3 he plug; it is characterized in that; described albumin is human serum albumin or bovine serum albumin; stabilizing agent is polyethylene glycol-polylactic acid (PEG-PLGA); pH adjusting agent is citric acid, and freezing drying protective agent is mannitol.
5. heterogeneous stable albumin bound type Cabazitaxel medicine as claimed in claim 1 or 2, is characterized in that: medicine is injection preparation prepared by freeze-drying.
6. heterogeneous stable albumin bound type Cabazitaxel preparation method as claimed in claim 1 or 2, is characterized in that preparing in accordance with the following methods: be dissolved in appropriate chloroform/dichloromethane kappa he plug, stabilizing agent and pH adjusting agent as oil phase; Be dissolved in as aqueous phase in appropriate amount of deionized water using albumin and stabilizing agent, freezing drying protective agent, utilize high shear force that oil phase is fully contacted with aqueous phase, he fills in obtain heterogeneous stable albumin bound type kappa after lyophilization.
7. heterogeneous stable albumin bound type Cabazitaxel process for preparing medicine as claimed in claim 6, is characterized in that: adopt high shear force to make his plug and albumin bound of kappa in preparation process.
8. heterogeneous stable albumin bound type Cabazitaxel process for preparing medicine as claimed in claim 7, is characterized in that: adopt high shear force to make his plug of kappa select high-energy ball milling method with during albumin bound.
9. heterogeneous stable albumin bound type Cabazitaxel process for preparing medicine as claimed in claim 8, is characterized in that: the rotational speed of ball-mill of described high-energy ball milling method is 25-40Hz, ball milling temperature-20 DEG C-0 DEG C, Ball-milling Time 0.5-5h.
10. heterogeneous stable albumin bound type Cabazitaxel process for preparing medicine as claimed in claim 9, is characterized in that: the rotational speed of ball-mill 38Hz of described high-energy ball milling method, ball milling temperature-20 DEG C, Ball-milling Time 1.8 hours.
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| CN201410805215.0A CN104490797A (en) | 2014-12-22 | 2014-12-22 | Multiphase-stable albumin conjunction type cabazitaxel |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105078904A (en) * | 2015-06-25 | 2015-11-25 | 南京优科生物医药有限公司 | Cabazitaxel lipid microsphere albumin freeze-dried powder injection and preparation method thereof |
| CN106580880A (en) * | 2016-12-22 | 2017-04-26 | 深圳海王医药科技研究院有限公司 | Stable cabazitaxel particle redispersible system |
| WO2017123760A1 (en) * | 2016-01-15 | 2017-07-20 | Qun Sun | Compositions and formulations including cabazitaxel and human serum albumin |
| CN107126564A (en) * | 2017-05-12 | 2017-09-05 | 辽宁大学 | A kind of albumin combination type Sorafenib nanometer formulation and preparation method thereof |
| CN109289053A (en) * | 2018-09-30 | 2019-02-01 | 浙江大学 | Cabazitaxel-widow/polylactic acid coupling prodrug, preparation and the preparation method and application thereof |
| CN110075073A (en) * | 2019-06-03 | 2019-08-02 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano injection and preparation method thereof |
| CN110123786A (en) * | 2019-06-03 | 2019-08-16 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano material and preparation method thereof |
| CN110384679A (en) * | 2018-04-16 | 2019-10-29 | 广州铠宝蕊医药科技有限公司 | Cabazitaxel albumin nano granular preparation and the preparation method and application thereof |
| CN111449055A (en) * | 2020-05-23 | 2020-07-28 | 河北康腾生物科技有限公司 | Adipose tissue cryopreservation liquid, preparation method and adipose tissue storage method |
| US11413265B2 (en) | 2018-04-20 | 2022-08-16 | Zhuhai Beihai Biotech Co., Ltd. | Formulations and compositions of Cabazitaxel |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105078904B (en) * | 2015-06-25 | 2018-09-21 | 南京优科生物医药有限公司 | A kind of Cabazitaxel lipid microspheres albumin freeze-dried powder and preparation method thereof |
| CN105078904A (en) * | 2015-06-25 | 2015-11-25 | 南京优科生物医药有限公司 | Cabazitaxel lipid microsphere albumin freeze-dried powder injection and preparation method thereof |
| WO2017123760A1 (en) * | 2016-01-15 | 2017-07-20 | Qun Sun | Compositions and formulations including cabazitaxel and human serum albumin |
| CN108883161A (en) * | 2016-01-15 | 2018-11-23 | 珠海贝海生物技术有限公司 | Composition and preparation comprising Cabazitaxel and human serum albumins |
| US11510895B2 (en) | 2016-01-15 | 2022-11-29 | Zhuhai Beihai Biotech Co., Ltd. | Compositions and formulations including cabazitaxel and human serum albumin |
| CN106580880A (en) * | 2016-12-22 | 2017-04-26 | 深圳海王医药科技研究院有限公司 | Stable cabazitaxel particle redispersible system |
| CN107126564A (en) * | 2017-05-12 | 2017-09-05 | 辽宁大学 | A kind of albumin combination type Sorafenib nanometer formulation and preparation method thereof |
| CN110384679A (en) * | 2018-04-16 | 2019-10-29 | 广州铠宝蕊医药科技有限公司 | Cabazitaxel albumin nano granular preparation and the preparation method and application thereof |
| US11413265B2 (en) | 2018-04-20 | 2022-08-16 | Zhuhai Beihai Biotech Co., Ltd. | Formulations and compositions of Cabazitaxel |
| CN109289053B (en) * | 2018-09-30 | 2020-10-13 | 浙江大学 | Cabazitaxel-oligo/polylactic acid coupled prodrug, preparation method and application thereof |
| CN109289053A (en) * | 2018-09-30 | 2019-02-01 | 浙江大学 | Cabazitaxel-widow/polylactic acid coupling prodrug, preparation and the preparation method and application thereof |
| CN110123786A (en) * | 2019-06-03 | 2019-08-16 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano material and preparation method thereof |
| CN110075073B (en) * | 2019-06-03 | 2021-09-07 | 深圳市健开医药有限公司 | Cabazitaxel protein nano injection and preparation method thereof |
| CN110075073A (en) * | 2019-06-03 | 2019-08-02 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano injection and preparation method thereof |
| CN111449055B (en) * | 2020-05-23 | 2021-07-23 | 河北康腾生物科技有限公司 | Adipose tissue cryopreservation liquid, preparation method and adipose tissue storage method |
| CN111449055A (en) * | 2020-05-23 | 2020-07-28 | 河北康腾生物科技有限公司 | Adipose tissue cryopreservation liquid, preparation method and adipose tissue storage method |
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Application publication date: 20150408 |