CN104257608A - Nano suspension containing hydroxycamptothecin and preparation method of nano suspension - Google Patents
Nano suspension containing hydroxycamptothecin and preparation method of nano suspension Download PDFInfo
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- CN104257608A CN104257608A CN201410540806.XA CN201410540806A CN104257608A CN 104257608 A CN104257608 A CN 104257608A CN 201410540806 A CN201410540806 A CN 201410540806A CN 104257608 A CN104257608 A CN 104257608A
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- hydroxycamptothecin
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- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 title claims abstract description 66
- 239000006070 nanosuspension Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000002245 particle Substances 0.000 claims abstract description 21
- 239000003381 stabilizer Substances 0.000 claims abstract description 21
- 239000000725 suspension Substances 0.000 claims abstract description 11
- 238000000265 homogenisation Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000004945 emulsification Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000012071 phase Substances 0.000 claims description 20
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 18
- 229960000502 poloxamer Drugs 0.000 claims description 18
- 229920001983 poloxamer Polymers 0.000 claims description 18
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 17
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 17
- 229960003943 hypromellose Drugs 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000008346 aqueous phase Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000004108 freeze drying Methods 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 239000000839 emulsion Substances 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000012153 distilled water Substances 0.000 claims description 7
- 238000002390 rotary evaporation Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229920003081 Povidone K 30 Polymers 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 229940067606 lecithin Drugs 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 3
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- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 3
- 125000000647 trehalose group Chemical group 0.000 claims description 2
- 238000002347 injection Methods 0.000 abstract description 8
- 239000007924 injection Substances 0.000 abstract description 8
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- 238000004090 dissolution Methods 0.000 abstract description 4
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- XCUCMLUTCAKSOZ-FIRIVFDPSA-N Liensinine Chemical compound C([C@@H]1C=2C=C(C(=CC=2CCN1C)OC)OC=1C(O)=CC=C(C=1)C[C@H]1N(C)CCC=2C=C(C(=CC=21)OC)OC)C1=CC=C(O)C=C1 XCUCMLUTCAKSOZ-FIRIVFDPSA-N 0.000 abstract 1
- XCUCMLUTCAKSOZ-JSOSNVBQSA-N Liensinine Natural products C([C@@H]1C=2C=C(C(=CC=2CCN1C)OC)OC=1C(O)=CC=C(C=1)C[C@@H]1N(C)CCC=2C=C(C(=CC=21)OC)OC)C1=CC=C(O)C=C1 XCUCMLUTCAKSOZ-JSOSNVBQSA-N 0.000 abstract 1
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
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- 229910021641 deionized water Inorganic materials 0.000 description 3
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- 239000012905 visible particle Substances 0.000 description 2
- AVWFCOAUPSRLKL-UHFFFAOYSA-N 4-(4,5-diphenyl-1h-imidazol-2-yl)benzohydrazide Chemical compound C1=CC(C(=O)NN)=CC=C1C1=NC(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)N1 AVWFCOAUPSRLKL-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 241000759905 Camptotheca acuminata Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
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- 230000018199 S phase Effects 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a nano suspension containing hydroxycamptothecin and a preparation method of the nano suspension, and relates to the field of pharmaceutical preparation, in particular to a nano suspension containing hydroxycamptothecine and a preparation method of liensinine freeze-dried powder of the nano suspension. The suspension comprises components in percentage by weight as follows: 2%-45% of hydroxycamptothecine, 8%-55% of a stabilizer and 0%-90% of a freezing and drying protecting agent, wherein the proportion of hydroxycamptothecine and the stabilizer is (1:1.5)-(1:4), and the particle size ranges from 180 nm to 300 nm. The invention further relates to a preparation method of the suspension. The suspension is prepared through combination of an emulsion method and a high-pressure homogenization method, and the preparation method is suitable for industrial production; and compared with hydroxycamptothecine injection sold in the market, the suspension has the advantages that the dissolution speed of hydroxycamptothecine is increased while a lactonic ring of the nano suspension is not damaged, and the pesticide effect can be increased.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically relate to a kind of hydroxycamptothecin nano suspension and preparation method thereof
.
Background technology
Camptothecine (CPT) is the alkaloid with antitumor action of 20th century six the seventies separation and Extraction from distinctive Qi Tong section of China plant camptotheca acuminata, but limits its application because its toxicity is large.Hydroxycamptothecin (HCPT) is its semi-synthetic derivant, in body and zoopery show that its antitumor action is strong, antitumor spectra is wide, its antitumaous effect is equivalent to 30 times of camptothecine.Zoopery proves, HCPT is cell cycle specific agents, to the effect of S phase comparatively the G phase obvious, have inhibitory action when higher concentration to karyokinesis, cell can be stoped to enter division stage.Different from antimetabolite and alkylating agent, HCPT optionally suppresses topoisomerase I, thus disturbs copying of DNA.This kind of medicine and other conventional anticarcinogens, without crossing drug resistant, therefore have certain therapeutical effect to drug-resistant tumor.
Hydroxycamptothecin (HCPT) is clinical mainly applies to cancer in digestive system, as gastric cancer, the esophageal carcinoma, rectal cancer, hepatocarcinoma etc.; Correct cervical epithelium also has good therapeutic effect; To chorionic epithelioma, pulmonary carcinoma, acute and chronic neutrophilic leukemia, psoriasis etc., also there is certain therapeutical effect.Such medicine belongs to time dependence medicine on Therapy characteristics, is mainly used in treating poky tumor, therefore requires long-term prescription.But the half-life of HCPT short (5-30 about min), fat, water solublity are all poor, and tool unstability.Mainly contain sodium-salt parenteral solution and sodium salt powder pin for clinical HCPT preparation at present, after lactonic ring being opened with sodium hydroxide, its anti-tumor activity reduces, remaining time short (half-life about 5min) in vivo after salify, facile hydrolysis, and be difficult to enter tissue and cell, as cell cycle specific agents by biomembrane, these features limit its use, and appearing as of nanometer formulation retains its lactonic ring in vivo and become possibility.
For the defect of HCPT and preparation, often utilize nanotechnology, reach and improve its dissolubility and lactonic ring stability, to extend in blood circulation time and reduce the objects such as untoward reaction, studying more has the forms such as microsphere, Emulsion, micelle, liposome, nanoparticle.Publication number is that hydroxycamptothecin is wrapped in PLGA and prepares microsphere by the patent of CN102908318A, changes HCPT hydrophobic property, improves the time of staying in bioavailability and body.Publication number is that camptothecine hydrophilic group is modified formation prodrug by the patent of CN101628919A, then forms nano-micelle by self emulsifying technology, and drug loading reaches 50%, and the nano-micelle cytotoxicity of formation is higher.Publication number is the preparation method that patent discloses a kind of hydroxycamptothecin nanoparticle of CN101219144A, mainly through PLGA and surfactant by medicine parcel wherein, thus improves the holdup time in the stability of medicine and body.Publication number is that hydroxycamptothecin is made nanometer liposome by patent reports of CN1883455A, and particle diameter is at about 100nm.But all there is respective defect in above nano-formulation, synthesis prodrug intricate operation, cost is high; Be prepared into microspherulite diameter large, distribution in vivo may be uneven, is not suitable for intravenous injection; The manufacturing cost of nanoparticle and liposome is high, and technological requirement is high, and stability is a large problem, and its drug loading is generally lower than 20%, and when identical administration concentration, consumption is large.
In sum, although these drug-supplying systems of exploitation at present can stablize the lactonic ring active site of HCPI' to some extent, improve dissolubility, all there is respective problem, be unfavorable for suitability for industrialized production.Therefore, this invention exploits a kind of high pressure homogenization technique and prepare hydroxycamptothecin nano suspension.Nano suspension is the submicron colloidal dispersion systems of the pure medicament nano granule taking surfactant as stabilizing agent and suspending agent, the nominal particle size (10-1000nm) of its Nano grade can increase dissolubility and the dissolution rate of medicine, and then raising bioavailability, and obtain certain targeting.It has become the hot research direction solving insoluble drug formulation problems in recent years, has important using value and wide market prospect.
Summary of the invention
The object of this invention is to provide a kind of can the hydroxycamptothecin nano suspension of intravenously administrable.
The present invention also provides the method being prepared hydroxycamptothecin nano suspension by nanotechnology.
The object of the present invention is achieved like this: a kind of nano suspension containing hydroxycamptothecin; by weight percentage; comprise the hydroxycamptothecin of 2% to 45%, the stabilizing agent of 8% to 55% and 0% to 90% freeze drying protectant; the ratio of hydroxycamptothecin and stabilizing agent is 1:1.5 ~ 1:4, and the particle diameter of this suspensoid is 190 ~ 300nm.
Suspensoid of the present invention, wherein stabilizing agent is one or more in poloxamer F68, polyvinyl alcohol, lecithin, sodium lauryl sulphate, hypromellose E5, PVP K30, Tween 80; Freeze drying protectant is trehalose, sucrose, mannitol.
In stabilizing agent, preferred poloxamer F68 and hypromellose E5 is composite, and both weight ratios are 3:1 ~ 1:1; The preferred mannitol of freeze drying protectant, its content accounts for 2 ~ 5% of this suspensoid weight.
Suspensoid of the present invention, its preparation method, for being prepared in conjunction with high pressure homogenization method by emulsion process, is carried out according to the following steps:
(1) hydroxycamptothecin is dissolved in organic solvent as oil phase, then stabilizing agent is dissolved in distilled water as aqueous phase, under room temperature, oil phase is slowly injected in aqueous phase, stir 10min with high-shear emulsion machine high speed rotating simultaneously;
(2) by first suspension rotary evaporation removing organic solvent, finally with high pressure homogenizer homogenisation cycle 20 times under pressure is 600 ~ 1000bar, nano suspension is obtained.
Suspensoid preparation method of the present invention, wherein organic solvent is ethyl acetate, ethanol, acetone or dichloromethane.Preferred dichloromethane.
Hydroxycamptothecin nano suspension of the present invention has the following advantages:
1. relative to commercially available hydroxycamptothecin injection, nano suspension of the present invention can reduce the particle diameter of medicine and not reduce the bioavailability of medicine, enables medicine stripping rapidly; Relative to the drug-supplying system such as liposome, nanoparticle, the drug loading of medicine is high, is convenient to clinical heavy dose application.
2. by vitro cytotoxicity test and the research of rat Internal pharmacokinetics, nano suspension of the present invention can reduce the IC of medicine
50value, improves remaining time in the bioavailability of medicine and body, the medicine distribution in vivo of improvement.
The preparation method of nano suspension of the present invention, technique is simple, uses high pressure homogenization method to be easy to suitability for industrialized production, cost comparatively liposome and nanoparticle low.
Accompanying drawing explanation
Fig. 1 represents the transmission electron microscope picture of hydroxycamptothecin nano suspension of the present invention;
Fig. 2 represents the grain size distribution of hydroxycamptothecin nano suspension of the present invention;
Fig. 3 represents hydroxycamptothecin nano suspension tablets in vitro curve chart of the present invention;
Fig. 4 represents the MTT cytotoxicity experiment result figure of commercially available hydroxycamptothecin injection and self-control nano suspension;
Fig. 5 represents the Drug-time curve figure of commercially available hydroxycamptothecin injection and self-control nano suspension;
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in detail.
Inventor is with reference to existing nano suspension technology of preparing, have studied different organic facies and different stabilizers to the impact of nano suspension character, wherein organic facies mainly screens dichloromethane, ethyl acetate, acetone, ethanol, and stabilizing agent mainly studies lecithin, poloxamer F68, Tween 80, polyvinyl alcohol, sodium lauryl sulphate, hypromellose E5, PVP K30.
In further research prescription, the composition of organic facies finds, use nano suspension prepared by acetone, the solution of formation has more floccule, and particle diameter is at about 500nm; Use ethyl acetate as solvent, after high pressure homogenize, solution has suspended material; Adopt ethanol as oil phase, after the nano suspension placement 2h of preparation, produce precipitation; And adopting dichloromethane as oil phase, the nano suspension of preparation has light blue opalescence, and without visible foreign matters, therefore preferred dichloromethane is as oil phase.
Simultaneously, inventors have investigated the Stabilization of different stabilizers to nano suspension, research finds that the kind of stabilizing agent and amount have material impact to the particle diameter of nano suspension and stability, detailed comparisons's result is as shown in the table, by screening, finally using poloxamer F68 and hypromellose E5 as the stabilizing agent of hydroxycamptothecin nano suspension.
| Stabilizing agent | Experimental phenomena and result |
| Tween 80 | Fine-powdered suspends, and easily flocculates between granule, difficult dispersion |
| Lecithin | Unstable, oxidizable under phospholipid high temperature |
| Poloxamer F68 | Ultrafine particle shape is dispersed in water |
| Polyvinyl alcohol | Fine-powdered suspends, and places postprecipitation at the bottom of cup |
| Hypromellose E5 | In granule, place postprecipitation |
| PVP K30 | Granule is comparatively large, prepares unsuccessfully |
| Sodium lauryl sulphate (SDS) | Fine-powdered suspends, and places postprecipitation at the bottom of cup |
| Poloxamer F68+ hypromellose E5 | Particle diameter is less, and after placing, system can keep the long period to stablize |
| Poloxamer F68+ polyvinyl alcohol | Particle diameter is comparatively large, places postprecipitation |
Owing to adopting composite adjuvant as the stabilizing agent of hydroxycamptothecin nano suspension, therefore inventor further study the ratio of poloxamer and hypromellose, with nano suspension particle diameter and polydispersity coefficient for index, when the ratio of poloxamer and hypromellose is 3:1 ~ 1:1, nano suspension particle diameter is less.
Inventor is by the stability of the made nano suspension of research, and the ratio of final preferably poloxamer and hypromellose is 2:1.
Hydroxycamptothecin nano suspension prepared by inventor is preferably freeze-dried powder, thus improves the stability of preparation, and wherein selected freeze drying protectant has mannitol, sucrose, trehalose.
The preferred mannitol of freeze drying protectant of the present invention, final utilization concentration is 4%.
Below all the present invention is further described, but be not limited only to content of the present invention.
Optimization formula of the present invention is as follows
| Prescription forms | Recipe quantity | Function |
| Hydroxycamptothecin | 50mg | Principal agent |
| Deionized water | 50ml | Aqueous phase solvent |
| Dichloromethane | 4ml | Oil phase solvent |
| Poloxamer F68 | 50mg | Stabilizing agent |
| Hypromellose E5 | 25mg | Suspending agent |
| Mannitol | 2g | Freeze drying protectant |
Embodiment 1
Get hydroxycamptothecin 50mg and be placed in beaker, add dichloromethane 4ml and make it dissolve, as oil phase; Get poloxamer 50mg, hypromellose 25mg and mannitol 2g again in another beaker, add the distilled water of 50ml wherein, magnetic agitation makes it fully dissolve, as aqueous phase.Under room temperature, oil phase is slowly injected in aqueous phase, stir 10min by high-shear emulsion machine with 10000rpm rotating speed simultaneously, first suspension rotary evaporation 1h is removed organic solvent, adds in high pressure homogenizer, with 1000bar homogenisation cycle 5min, must with the nano suspension of opalescence, use Malvern 2000 nano-particle size analysis instrument to record particle diameter 196nm, zeta current potential is-28.5mv, and polydispersity coefficient is 0.11.
Made nano suspension is divided and is filled in 7ml freeze-dried powder bottle, every bottle of 2ml, puts into freezer dryer-40 DEG C of pre-freeze 4h, and the 7h that once distils is warming up to-25 DEG C, keep 3h, continue 3h and be warming up to 0 DEG C, keep 2h, secondary distillation 2h is warming up to 25 DEG C, keep 2h, lyophilizing terminates rear every bottle of pastille 2mg, and detect freeze-dried powder moisture with karl Fischer moisture test apparatus, water content is 2.28%.After using deionized water to redissolve, without visible particle, detection particle diameter is 204nm, zeta current potential is-27.8mv, and polydispersity coefficient is 0.10.
Embodiment 2
Get hydroxycamptothecin 50mg and be placed in beaker, add ethyl acetate 4ml and make it dissolve, as oil phase; Get poloxamer 50mg, hypromellose 25mg again in another beaker, add the distilled water of 50ml wherein, magnetic agitation makes it fully dissolve, as aqueous phase.Under room temperature, oil phase is slowly injected in aqueous phase, stir 10min by high-shear emulsion machine with 10000 rpm rotating speeds simultaneously, first suspension rotary evaporation 1h is removed organic solvent, adds in high pressure homogenizer, with 1000bar homogenisation cycle 20 times, obtain nano suspension, use Malvern 2000 nano-particle size analysis instrument to record particle diameter 298nm, zeta current potential is-25.6mv, and polydispersity coefficient is 0.25.
Embodiment 3
Get hydroxycamptothecin 100mg and be placed in beaker, add dichloromethane 4ml and make it dissolve, as oil phase; Get poloxamer 100mg, hypromellose 100mg again in another beaker, add the distilled water of 50ml wherein, magnetic agitation makes it fully dissolve, as aqueous phase.Under room temperature, oil phase is slowly injected in aqueous phase, stir 10min by high-shear emulsion machine with 10000 rpm rotating speeds simultaneously, first suspension rotary evaporation 1h is removed organic solvent, adds in high pressure homogenizer, homogeneous condition is that 500bar circulates 10 times, 500bar circulates 5 times, and 1000bar circulates 5 times, and made nano suspension uses Malvern 2000 nano-particle size analysis instrument to record particle diameter for 254nm, zeta current potential is-26.6mv, and polydispersity coefficient is 0.15.
Embodiment 4
Get hydroxycamptothecin 50mg and be placed in beaker, add dichloromethane 4ml and make it dissolve, as oil phase; Get poloxamer 150mg, hypromellose 50mg again in another beaker, add the distilled water of 50ml wherein, magnetic agitation makes it fully dissolve, as aqueous phase.Under room temperature, oil phase is slowly injected in aqueous phase, stir 10min by high-shear emulsion machine with 10000 rpm rotating speeds simultaneously, first suspension rotary evaporation 1h is removed organic solvent, adds in high pressure homogenizer, homogeneous condition is that 500bar circulates 10 times, 500bar circulates 5 times, and 1000bar circulates 5 times, and made nano suspension uses Malvern 2000 nano-particle size analysis instrument to record particle diameter for 235nm, zeta current potential is-23.6mv, and polydispersity coefficient is 0.12.
Embodiment 5
Get hydroxycamptothecin 125mg and be placed in beaker, add dichloromethane 2ml and acetone 2ml makes it dissolve, as oil phase; Get poloxamer 100mg, hypromellose 50mg, sucrose 2g again in another beaker, add the distilled water of 50ml wherein, magnetic agitation makes it fully dissolve, as aqueous phase.Under room temperature, oil phase is slowly injected in aqueous phase, stir 10min by high-shear emulsion machine with 10000 rpm rotating speeds simultaneously, first suspension rotary evaporation 1h is removed organic solvent, add in high pressure homogenizer, with 1000bar homogenisation cycle 5min, made nano suspension uses Malvern 2000 nano-particle size analysis instrument to record particle diameter for 255nm, zeta current potential is-22.7mv, and polydispersity coefficient is 0.14.
Made nano suspension is divided and is filled in 7ml freeze-dried powder bottle, every bottle of 2ml, puts into freezer dryer-40 DEG C of pre-freeze 4h, and the 7h that once distils is warming up to-25 DEG C, keep 3h, continue 3h and be warming up to 0 DEG C, keep 2h, secondary distillation 2h is warming up to 25 DEG C, keep 2h, lyophilizing terminates rear every bottle of pastille 5mg, and detect freeze-dried powder moisture with karl Fischer moisture test apparatus, water content is 2.66%.After using deionized water to redissolve, without visible particle, detection particle diameter is 287nm, zeta current potential is-24.4mv, and polydispersity coefficient is 0.18.
The stability experiment of hydroxycamptothecin nano suspension in the present invention
Preparation three batches of hydroxycamptothecin nano suspensions are repeated according to embodiment 1, room temperature is placed, respectively at 0,1, the sample of different batches is got, by transmission electron microscope observation nano suspension form when 2,3 weeks, use Malvern 2000 nano-particle size analysis instrument to measure particle diameter, polydispersity coefficient and zeta current potential, the repeatability of investigation method and the stability of system simultaneously.Result shows, sample room temperature is placed 3 weeks, and particle diameter has faint growth, and whole system keeps good stability in a long time.
Hydroxycamptothecin nano suspension (embodiment 1) tablets in vitro behavioral study
Paddle method is adopted to investigate the In Vitro Dissolution characteristic of hydroxycamptothecin nano suspension.Leaching temperature (37 ± 0.5) DEG C, rotating speed 100 rpm, dissolution medium is the phosphate buffer of pH6.8, get and be equivalent to be respectively charged in pretreated bag filter containing the freeze-dried powder of hydroxycamptothecin 25mg and hydroxycamptothecin raw material 25mg seal two ends, put into digestion instrument, respectively at 5,10,20,30,45,60,90 min samplings, centrifugal, adopt ODS C
18post (4.6mm × 150mm, 5um) is with methanol-water (50:50) for mobile phase, and determined wavelength 266nm, calculate total release percentage, the visible homemade nano suspension of result significantly improves the dissolution rate of hydroxycamptothecin nano suspension.
Hydroxycamptothecin nano suspension (embodiment 1) Study of cytotoxicity
Be scattered in cell culture fluid by commercially available hydroxycamptothecin injection (HCPT-IJ) and hydroxycamptothecin nano suspension (HCPT-NO), doubling dilution configures 8 concentration, makes maximum final concentration be 400 μ g/mL.To take the logarithm the K562 cell of trophophase, with 2 × 10
4the density in individual/hole is inoculated into 96 well culture plates, adds each concentration liquid of above-mentioned configuration after 4 hours, and each concentration establishes 3 multiple holes, separately establish do not add cell, the matched group that do not add medicine puts 37 ° of C, 5 % CO
2incubator in cultivate after 48 hours, every hole adds MTT working solution 20 μ L and continues to hatch 4 hours, suck supernatant, every hole adds DMSO 150 μ L cessation reaction, 96 orifice plates are put into enzyme-linked immunosorbent assay instrument concussion 10 minutes, put enzyme-linked immunosorbent assay instrument and measure every hole absorbance (OD value) in 570 nm wavelength places.Formulae discovery cell proliferation rate is pressed: cell proliferation rate (%)=[OD experiment Zhi – OD blank value]/[OD contrast Zhi – OD blank value] × 100 % according to OD value.More than test and at least repeat 3 times, to measure the inhibitory action of HCPT-IJ and HCPT-NO to K562 Growth of Cells, assessment cytotoxic effect.From result, under same medicine concentration, self-control nano suspension can better suppress K562 cell.
Hydroxycamptothecin nano suspension (embodiment 1) pharmacokinetic
Get 12 SD rats, body weight is 250g ± 30g, is divided into two groups at random, and often organize 6, before administration, fasting 12 hours, freely drinks normal saline.To weigh before administration label, two groups of rats respectively according to dosage vena femoralis injection hydroxycamptothecin injection and the hydroxycamptothecin nano suspension of 10mg/kg, respectively at 5min after administration, 10min, 15min, 30min and 1,2,4,6,8,12,24h eye socket gets blood 0.5ml, puts in the centrifuge tube of 1% heparin sodium rinse, blood is got upper plasma with centrifugal 15 min of 3000 rpm, detects blood drug level by high performance liquid chromatography.By experiment, find relative to commercially available hydroxycamptothecin injection, the C of hydroxycamptothecin nano suspension
maxall be improved with AUC, point out the therapeutic effect that lower dosage can be adopted to reach identical, reduce toxic and side effects.
Claims (7)
1. the nano suspension containing hydroxycamptothecin; by weight percentage; comprise the hydroxycamptothecin of 2% to 45%, the stabilizing agent of 8% to 55% and 0% to 90% freeze drying protectant, the ratio of hydroxycamptothecin and stabilizing agent is 1:1.5 ~ 1:4, and the particle diameter of this suspensoid is 190 ~ 300nm.
2. suspensoid according to claim 1, wherein stabilizing agent is one or more in poloxamer F68, polyvinyl alcohol, lecithin, sodium lauryl sulphate, hypromellose E5, PVP K30, Tween 80; Freeze drying protectant is trehalose, sucrose or mannitol.
3. suspensoid according to claim 2, wherein in stabilizing agent, preferred poloxamer F68 and hypromellose E5 is composite, and both weight ratios are 3:1 ~ 1:1.
4. suspensoid according to claim 2, wherein freeze drying protectant is mannitol, and its content accounts for 2 ~ 5% of this suspensoid weight.
5. the nano suspension of hydroxycamptothecin described in claim 1, its preparation method, for being prepared in conjunction with high pressure homogenization method by emulsion process, is carried out according to the following steps:
(1) hydroxycamptothecin is dissolved in organic solvent as oil phase, then stabilizing agent is dissolved in distilled water as aqueous phase, under room temperature, oil phase is slowly injected in aqueous phase, stir 10min with high-shear emulsion machine high speed rotating simultaneously;
(2) by first suspension rotary evaporation removing organic solvent, finally with high pressure homogenizer homogenisation cycle 20 times under pressure is 600 ~ 1000bar, nano suspension is obtained.
6. hydroxycamptothecin nano suspension preparation method described in claim 5, wherein organic solvent is ethyl acetate, ethanol, acetone or dichloromethane.
7. suspensoid preparation method according to claim 6, wherein preferred dichloromethane in organic solvent.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107281100A (en) * | 2016-03-30 | 2017-10-24 | 上海现代药物制剂工程研究中心有限公司 | A kind of preparation method of insoluble drug nanosuspension |
| CN108349990A (en) * | 2015-11-11 | 2018-07-31 | Cao制药股份有限公司 | The nanometer of 20-camptothecin or derivatives thereof and the particle of micron-scale and comprising its pharmaceutical composition and use its treatment to cancer |
| CN109528737A (en) * | 2018-12-05 | 2019-03-29 | 天津医科大学 | Sodium alginate anti-tumor nano preparation and preparation method |
| CN112641950A (en) * | 2021-01-12 | 2021-04-13 | 北京德立福瑞医药科技有限公司 | Pharmaceutical composition containing insoluble antitumor active agent and preparation method thereof |
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| CN1368048A (en) * | 2001-02-07 | 2002-09-11 | 杨孟君 | Chemically synthetic nano medicine and its preparing process, products and usage |
| CN102232937A (en) * | 2010-04-30 | 2011-11-09 | 天津药物研究院 | Nanometer preparation and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1368048A (en) * | 2001-02-07 | 2002-09-11 | 杨孟君 | Chemically synthetic nano medicine and its preparing process, products and usage |
| CN102232937A (en) * | 2010-04-30 | 2011-11-09 | 天津药物研究院 | Nanometer preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108349990A (en) * | 2015-11-11 | 2018-07-31 | Cao制药股份有限公司 | The nanometer of 20-camptothecin or derivatives thereof and the particle of micron-scale and comprising its pharmaceutical composition and use its treatment to cancer |
| CN108349990B (en) * | 2015-11-11 | 2022-08-09 | Cao制药股份有限公司 | Particles of 20-camptothecin or derivatives thereof, pharmaceutical composition comprising the same, and treatment of cancer using the same |
| CN107281100A (en) * | 2016-03-30 | 2017-10-24 | 上海现代药物制剂工程研究中心有限公司 | A kind of preparation method of insoluble drug nanosuspension |
| CN107281100B (en) * | 2016-03-30 | 2021-05-07 | 上海现代药物制剂工程研究中心有限公司 | Preparation method of insoluble drug nanosuspension |
| CN109528737A (en) * | 2018-12-05 | 2019-03-29 | 天津医科大学 | Sodium alginate anti-tumor nano preparation and preparation method |
| CN109528737B (en) * | 2018-12-05 | 2021-08-13 | 天津医科大学 | Sodium alginate diester antitumor nano preparation and preparation method |
| CN112641950A (en) * | 2021-01-12 | 2021-04-13 | 北京德立福瑞医药科技有限公司 | Pharmaceutical composition containing insoluble antitumor active agent and preparation method thereof |
| WO2022152021A1 (en) * | 2021-01-12 | 2022-07-21 | 北京德立福瑞医药科技有限公司 | Pharmaceutical composition containing insoluble antitumor active agent, and preparation method therefor |
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Application publication date: 20150107 |