CN100508969C - Nano particles of taxane cyclodextrin inclusion compound and preparation method thereof - Google Patents
Nano particles of taxane cyclodextrin inclusion compound and preparation method thereof Download PDFInfo
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- CN100508969C CN100508969C CNB2005100268779A CN200510026877A CN100508969C CN 100508969 C CN100508969 C CN 100508969C CN B2005100268779 A CNB2005100268779 A CN B2005100268779A CN 200510026877 A CN200510026877 A CN 200510026877A CN 100508969 C CN100508969 C CN 100508969C
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Abstract
The invention relates to a Paclitaxel cyclodextrin clathrate compound nanometer grain and relative medicine agent, wherein it uses hydroxypropyl-beta-cyclodextrin as carrier and PVP as stabilizer to prepare Paclitaxel clathrate compound nanometer grain, whose diameter is 40-200nm, to improve the dissolvability of Paclitaxel as 100-50times. The animal experiment has proven that: compared with present Paclitaxel, its resistant agent is improved 2.67tims with better cancer resistant effect. The invention uses general material and simple condition, with stable quality and the application to be processed into oral agent.
Description
Technical field
The present invention relates to nano particles of taxane cyclodextrin inclusion compound and preparation method thereof, be specifically related to the clathrate nanoparticle that hydroxypropyl-β-cyclodextrin prepares taxane.Cyclodextrin inclusion compound can play solubilising and slow releasing function to taxane, and then strengthens drug effect, thereby clinical a kind of new feasible approach that provides is provided the cancer therapy drug taxane.
Technical background
(paclitaxel Taxol) is isolated a kind of natural product from the bark of Pacific yew tree (pacific Yew) to paclitaxel.Paclitaxel has good anti-cancer activity, becomes the third generation antitumor drug after adriamycin and Platinol cisplatin, and it has toxicity to mitosis spindle and is stronger cytostatics.Paclitaxel treatment ovarian cancer, breast carcinoma have good effect, and is respond well to treatment carcinoma of prostate, last intestines and stomach cancer, cellule type and lung cancer in non-cellule type.On February 29th, 1992, U.S.'s food and drug administration's official approval paclitaxel went on the market as the novel anti-tumor medicine of treatment advanced ovarian cancer.
As everyone knows, paclitaxel has great application value and economic benefit, but its extensive use exists significant disadvantages: dissolubility is 0.006mg/ml in the water of paclitaxel, and the key technology of its venoclysis preparation is to solve its dissolubility in water.The formulation products of clinical practice at present, all be to adopt polyoxyethylene castor oil (Cremophor, surfactant) and dehydrated alcohol (v/v1:1) make solvent, make the solution of 30mg/5ml, be dissolved in water, and in 8-12hr stable (not separating out crystallization), instil with solvent for injection (as 5% glucose etc.) dilution posterior vein during clinical practice.There are major defects such as toxicity is big, application inconvenience in this dosage form.Preparation does not contain the paclitaxel intravenous formulations of polyoxyethylene castor oil, is a technical problem being badly in need of solution.
Nanometer formulation is the focus of present pharmaceutical preparation research as the new technique of non-intestinal of insoluble medicine in the water and enterally administer, and it can improve the dissolution rate of medicine, strengthens targeting, slow-releasing and the hypotoxicity of medicine.Yet nanometer formulation is as a kind of novel formulations form, and the safety of its used carrier, easy selectivity, process are the keys that nanometer product is succeeded in developing.
US5439686 discloses the paclitaxel particle form with albumin coating (as stabilizing agent).Albumen in the biocompatibility disperse medium and paclitaxel are accepted high shear and are handled, and produce diameter less than 1 micron granule, and the renewable nano sized particles that goes out diameter less than 200nm.This method, costs an arm and a leg as stabilizing agent with albumin, the production cost height.
Cyclodextrin (Cyclodextrin abbreviates CD usually as), be a class by D type glucopyranose units with the end to end frustum-like shape macrocycle molecule of α-1,4 glycosidic bond, have hydrophobic cavity and hydrophilic surface.Therefore, various inorganic, the organic and biomolecule formation supramolecular complexs of the alternative bonding of cyclodextrin.Cyclodextrin is represented its glucose unit number with a Greek alphabet traditionally, and wherein modal is α, β, γ cyclodextrin, has 6,7 and 8 glucose units respectively.The beta cyclodextrin that contains 7 glucose units can prepare in a large number by the enzymatic degradation of starch, and is cheap, and stable in properties, nonhazardous.Use cyclodextrin to construct functional molecular, can create good condition the inclusion effect of drug molecule as parent.
(HP-β-CD) not only chemical compound lot is had good envelope effect improves by the envelope Stability of Substance hydroxypropyl-β-cyclodextrin, and it also has the water solublity height and improves by the rate of release of envelope medicine and bioavailability in vivo.HP-β-CD hemolytic activity is low on the other hand, and surface activity is low, to skin and muscle nonirritant, is a kind of good cosolvent.
Belgian Thissen Lab. S.A is to mixing paclitaxel and acetyl γ cyclodextrin and hydroxypropyl-β-cyclodextrin in ethanol, and lyophilization gained solid has carried out water solublity research, and applied for Chinese patent (application number 98811010.5), but and not mentioned nanoparticle.
Summary of the invention
The purpose of this invention is to provide a kind of nano particles of taxane cyclodextrin inclusion compound.By discovering: as carrier, bag and taxanes material obtain the clathrate nanoparticle and can reach good solubilizing effect with HP-β-CD.The present invention also provides the method for preparing nano particles of taxane cyclodextrin inclusion compound, and the pharmaceutical dosage forms of being made up of nano particles of taxane cyclodextrin inclusion compound.
Selecting HYDROXYPROPYL BETA-CYCLODEXTRIN for use is the carrier of taxone, prepares taxane-HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate nanoparticle, and particle diameter is 40-200nm, and this nano-particle has certain tumor-targeting and long cyclicity.It can be water-soluble rapidly, makes the dissolubility of paclitaxel bring up to 0.6-3mg/ml from 0.006mg/ml, and 100-500 times of solubilisings, envelop rate are 80-90%.Under normal temperature condition, has good stable.
Clathrate nanoparticle of the present invention prepares by the following method:
1, preparation HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution;
2, add stabilizing agent, mix homogeneously also is heated to 30 ℃-80 ℃;
3, under agitation add taxone solution, keep temperature and stir 1-6hr;
4, lyophilization or rotary evaporation are removed organic solvent.
By the taxane cyclodextrin inclusion compound that the present invention makes, in the animal test of pesticide effectiveness, tolerance dose, tumour inhibiting rate obviously increase.
Conventional adjuvant and process conditions are adopted in preparation of the present invention, but commercial scale, high efficiency production, constant product quality, can be directly or secondary operations be prepared into injection or oral formulations, be a kind of uniqueness and blanket, low-cost industrial preparation method.
In the present invention,
Taxane comprises paclitaxel and Docetaxel (docetaxel), preferred paclitaxel.Be dissolved in organic solvent in advance, in ethanol.
HYDROXYPROPYL BETA-CYCLODEXTRIN is meant the chemical compound that the ring of the 7D-glucose unit that is connected by α-1,4 glycosidic bond is formed, and wherein a certain proportion of hydroxyl is replaced by ehter bond by hydroxypropyl functional group.Wherein, the mol ratio of HYDROXYPROPYL BETA-CYCLODEXTRIN and taxane is 1-100:1, preferred 10:1.
Prepare the HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution with conventional method, add stabilizing agent, described stabilizing agent is that (CMC-Na) or in the hydroxypropyl emthylcellulose (HPMC) one or more, consumption is 1-10 times of taxane quality for polyvinylpyrrolidone (polyvidone) or sodium carboxymethyl cellulose.In the preferred scheme of the present invention, stabilizing agent is a polyvidone, and especially 30 POVIDONE K 30 BP/USP 29/32.
After stabilizing agent and HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution are even, be heated to 30 ℃-80 ℃, be preferably 40 ℃-70 ℃.
The speed that stirs when adding taxane solution is 300-1200rpm, preferred 900rpm.
Keep temperature and stir 1-6hr, preferred 3hr.
In order to remove organic solvent, can utilize lyophilization or rotary evaporation.In this process, can add bulking agent such as mannitol, dextran.
Taxanes cyclodextrin clathrate of the present invention has the dissolubility of obvious improvement at aqueous phase, therefore, can more effective mode be delivered in cancer patient's body.
In the present invention, the aqueous solution of the hydroxypropyl-β of paclitaxel-cyclodextrin inclusion compound product can be dried to form powder, the paclitaxel cyclodextrin clathrate that can obtain having highly dissoluble, high stability in view of the above.
Paclitaxel cyclodextrin clathrate of the present invention can be used by various forms.For example can be prepared into injectable medicine or use with powder, also can with medicinal diluent, carrier or mixed with excipients, form pharmaceutical composition.Can vein, oral or through other approach to patient's administration.By this administering mode, can provide the paclitaxel of effective dose to the patient.
In the present invention, the detection method that is adopted is as follows:
Nanometer particle size: the Nicomp380 particle size analyzer H120 of Hitachi transmissioning electric mirror determining
Dissolubility: a certain amount of clathrate is soluble in water, and sonic oscillation filters to no longer including the solid dissolving, and the gained solid drying is weighed, and the solubility values of clathrate is calculated in the back of converting.
Stability: after placing 6-8hr at ambient temperature, detect the clathrate particle diameter.
Zoopery---
Tolerance dose: give white mice 50mg/kg, every day 1 time, for three days on end.Observed for 1 week.Increase dosage to 75mg/kg, 100mg/kg, repeated experiments.Observe the animal Signs and change, determine maximum tolerated dose.
Evaluating drug effect: nude mice is in right side axillary fossa subcutaneous vaccination Lewis lung cancer cell, grow to a week after, inject paclitaxel cyclodextrin bag and thing nanoparticle or commercially available paclitaxel respectively; dosage is 40mg/kg; at the 4th day and the 8th day rechallenge, after 2 weeks, observe the variation of gross tumor volume size.
Description of drawings
Fig. 1 paclitaxel cyclodextrin clathrate nanoparticle electron scanning micrograph
Fig. 2 Nicomp380 particle size analyzer particle size distribution figure, wherein:
99.2% average particle size is 77.9nm
0.8% average particle size is 327.1nm.
Fig. 3 paclitaxel cyclodextrin clathrate nanoparticle and commercially available paclitaxel tumor killing effect are relatively
The big or small audio-visual picture of 2 week of A administration back nude mice lotus tumor volume
Upper left is matched group;
Upper right is commercially available paclitaxel group;
The lower-left is a clathrate nanoparticle group.
Nude mice lotus tumor change in volume curve after the B administration
Specific embodiment
The preparation of paclitaxel cyclodextrin nano grain--
It is as follows to write out a prescription:
Paclitaxel 2mg
HYDROXYPROPYL BETA-CYCLODEXTRIN 15mg
30 POVIDONE K 30 BP/USP 29/32 10mg
Method: in HYDROXYPROPYL BETA-CYCLODEXTRIN solution, add 30 POVIDONE K 30 BP/USP 29/32, mix homogeneously also is heated to 40 ℃, under magnetic agitation 900rpm, add taxol drug solution, keep temperature to stir 3hr, remove organic solvent through lyophilization (adding bulking agent such as mannitol, dextran) or rotary evaporation, obtain lyophilized injectable powder.
After testing, gained paclitaxel nano grain particle diameter is 70-80nm more than 90%, and taxol solubility 0.6mg/ml can stablize 6-8 hours at ambient temperature.
With the obtained freeze-drying injectable powder water-soluble after, give tumor bearing nude mice 40mg/kg, after 2 weeks, recording paclitaxel nano grain group tumour inhibiting rate is 99.85%, commercially available group of tumour inhibiting rate is 85.79%, and significant difference is arranged.
Claims (2)
1. a clathrate is made up of taxane, HYDROXYPROPYL BETA-CYCLODEXTRIN and stabilizing agent; Described taxane is a paclitaxel, and described stabilizing agent is a polyvidone, it is characterized in that, the mol ratio of described taxane and HYDROXYPROPYL BETA-CYCLODEXTRIN is 1:1-10, and the consumption of described stabilizing agent is 1-10 a times of taxane quality, and the particle diameter of clathrate is 40-200nm.
2. a kind of pharmaceutical composition that comprises the described clathrate of claim 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102671210A (en) * | 2012-05-09 | 2012-09-19 | 张奎昌 | Clathrate compound of beta-cyclodextrin or derivatives of beta-cyclodextrin for Nifuroxazide and preparation method for preparation of clathrate compound |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101502533B1 (en) * | 2007-11-22 | 2015-03-13 | 에스케이케미칼주식회사 | Stable pharmaceutical composition containing Taxane derivatives, and method of manufacturing the same |
| CN101843591A (en) * | 2010-05-31 | 2010-09-29 | 南昌弘益科技有限公司 | 1'-acetoxyl chavicol acetate naonparticle |
| CN102302786A (en) * | 2011-08-01 | 2012-01-04 | 扬州大学 | Preparation method for beta-cyclodextrin polymer-paclitaxel inclusion compound |
| CN103505737B (en) * | 2012-06-15 | 2015-07-01 | 华东理工大学 | Method for preparing docetaxel/beta-cyclodextrin clathrates |
| CN102949347B (en) * | 2012-10-23 | 2014-10-15 | 上海交通大学 | Docetaxel-coated polylactic-co-glycolic acid (PLGA) nano particles and preparation method thereof |
| PL3270912T4 (en) * | 2015-03-16 | 2022-04-19 | Meridian Lab | Pharmaceutical compositions containing taxane-cyclodextrin complexes, method of making and methods of use |
| CN110170058B (en) * | 2019-06-24 | 2022-02-11 | 李建恒 | Abiraterone clathrate compound and preparation method thereof |
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| CN1475205A (en) * | 2002-08-15 | 2004-02-18 | 刘云清 | Medicine conveying system--preparation method of solid nano medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102671210A (en) * | 2012-05-09 | 2012-09-19 | 张奎昌 | Clathrate compound of beta-cyclodextrin or derivatives of beta-cyclodextrin for Nifuroxazide and preparation method for preparation of clathrate compound |
| CN102671210B (en) * | 2012-05-09 | 2013-06-26 | 张奎昌 | Clathrate compound of beta-cyclodextrin or derivatives of beta-cyclodextrin for Nifuroxazide and preparation method for preparation of clathrate compound |
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Address after: 201210, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201210, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: SHANGHAI ALLIST PHARMACEUTICALS, Inc. |
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Address after: 201203 floor 5, building 1, No. 1118, Halley Road, No. 1227, zhangheng Road, Shanghai pilot Free Trade Zone Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201210, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: Shanghai ALLIST medicine Polytron Technologies Inc. |
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Address after: No. 268 Lingxiaohua Road, Zhoupu Town, Pudong New Area, Shanghai, 201318 Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 5 / F, building 1, 1118 Harley Road, 1227 zhangheng Road, Shanghai pilot Free Trade Zone, 201203 Patentee before: Shanghai ALLIST medicine Polytron Technologies Inc. |
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