CN104288100A - Teniposide nanosuspension and preparation method thereof - Google Patents
Teniposide nanosuspension and preparation method thereof Download PDFInfo
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- CN104288100A CN104288100A CN201410241281.XA CN201410241281A CN104288100A CN 104288100 A CN104288100 A CN 104288100A CN 201410241281 A CN201410241281 A CN 201410241281A CN 104288100 A CN104288100 A CN 104288100A
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Abstract
The invention discloses a teniposide nanosuspension and a preparation method thereof. Each 1ml of the nanosuspension contains 0.1-50mg of teniposide, 0.1-500mg of a stabilizer, 0-500mg of an additive, and the balance of water. Compared with commercially available teniposide injections (VUMON), teniposide intravenous emulsions, teniposide solid lipid nanoparticles and phospholipid complex liposomes, the teniposide nanosuspension has the advantages of high drug load, good stability, no carriers or co-solvents, avoiding of the use of organic solvents, low toxic side effects, reduction of the untoward reactions of patients, good patient compliance; high-efficiency low-toxicity performance of the antitumor activity of teniposide, good clinical curative effect and good application prospect.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of teniposide nano suspension, also relate to a kind of preparation method of teniposide nano suspension simultaneously.
Background technology
Teniposide is with the podophyllotoxin extracted from cephalotaxus plant for raw material, through condensation, reduction, condensation and obtaining, has another name called sufficient leaf thiophene glycosides, Teniposide, chemistry 4 '-demethyl epipodophyllotoxin-β-D-thenylidene pyranglucoside by name.Teniposide is white or off-white color crystalline powder, and neutral lipophilic material, water insoluble and ether, is slightly soluble in methanol, and in dichloromethane, dissolubility is better.
Teniposide is the antitumor drug of cell cycle specific, its mechanism of action is by stoping cell to enter mitosis and work, make cells arrest in S late period or G2 early stage, the synthesis of eukaryotic cell protein can be suppressed, make polysome depolymerization, the ribosomal function of interference albumen; Also the sub-thread of DNA key and the fracture of bifilar property is caused by suppressing typeⅡtopoisomerase.Teniposide is usual and other Anticancer drug combination clinically, is mainly used in treatment malignant lymphoma, acute lymphoblastic leukemia, intracranial malignant tumor etc., one of first-selected chemotherapeutics having become clinical treatment tumour at present.On July 14th, 1992, U.S. FDA ratifies the anticarcinogen that teniposide is first-line treatment intractable children acute lymphoblastic leukaemia first, and commodity are called VUMON, and existing multiple state approval teniposide is used for the clinical treatment of kinds of tumors at present.The common untoward reaction of teniposide has bone marrow depression, Nausea and vomiting, alopecia, diarrhoea, stomachache etc., because teniposide is poorly soluble, the Cremophor EL-35 contained in preparation can cause allergic reaction, and these all limit teniposide application clinically.Therefore, the attention of people is caused to the be correlated with improvement of dosage form of teniposide, the dosage form of current teniposide has Emulsion used for intravenous injection, solid lipid nanoparticle, phosphatide composite liposome body etc., but it is larger that these dosage form ubiquities organic solvent toxic and side effects used, patient compliance is poor, and easily cause the untoward reaction of patient, drug loading is little, the problems such as entrapment efficiency is low, can't meet the requirement of use.
1994, M ü ller etc. proposes the concept of nano suspension (Nanosuspensions) first, it is the Stabilization utilizing the stabilizing agent such as surfactant or high molecular polymer, by drug particle dispersion in water, by pulverizing or control the stable nanometer colloidal dispersion system that crystallize technology is formed, be particularly suitable for the oral and drug administration by injection of heavy dose, insoluble drug.The technology of preparing of nano suspension can be divided into from top to bottom (Top down) and (Bottom up) two kinds from bottom to top.Wherein technology is the method large drug particle being broken into small-particle from top to bottom, mainly comprises high pressure homogenization method and media milling process etc.; Technology is a kind of method being formed nanoparticle by the molecule precipitation gathering in solution from bottom to top, mainly comprises the control sedimentation method, the anti-solvent sedimentation method, melting emulsion process and anti-solvent precipitation ultrasonic method etc.Although at present in suitability for industrialized production, what adopt is method from top to bottom more, and the method power consumption is high, apparatus expensive, and required preparation time is longer, is difficult to the product obtaining narrower particle size distribution, and therefore method have also been obtained and pays close attention to widely and study from bottom to top in recent years.
Summary of the invention
The object of this invention is to provide a kind of teniposide nano suspension, solve the problem that existing teniposide preparation drug loading is little, toxic and side effects is comparatively large, patient compliance is poor.
Second object of the present invention is to provide a kind of preparation method of teniposide nano suspension.
In order to realize above object, the technical solution adopted in the present invention is: a kind of teniposide nano suspension, comprises teniposide 0.1 ~ 50mg, stabilizing agent 0.1 ~ 500mg, additives 0 ~ 500mg in every 1ml nano suspension, and surplus is water.
In described teniposide nano suspension, the mass ratio of teniposide and stabilizing agent is 1 ~ 10:1 ~ 50.
Preferably, the mass ratio of teniposide and stabilizing agent is 1 ~ 3:1 ~ 10.
Described stabilizing agent be in polyvinylpyrrolidone, polyvinyl alcohol, dodecyl sodium sulfate, sodium lauryl sulphate, lecithin, lecithin derivative, docosahexenoic acid, polyoxyethylene castor oil, Tween 80, poloxamer, Polyethylene Glycol, vitamin E, TPGS (TPGS), cholic acid, chlolic acid derivatives, cellulose, cellulose derivative any one or multiple.
Described lecithin derivative be in hydrolecithin, hydroxylated lecithin, synthetic phospholipid any one or multiple.
Described synthetic phospholipid be in dimyristoyl phosphatidyl choline (DMPC), dipalmitoyl phosphatidyl choline (DPPC), DSPG (DSPG) any one or multiple.
Described chlolic acid derivatives be in bile acid, lithocholic acid, deoxycholic acid any one or multiple.
Described deoxycholic acid is any one or two kinds in chenodeoxycholic acid, ursodesoxycholic acid.
Described cellulose derivative is any one or combination in cellulose nitrate, cellulose ethanoate, cellulose acetate butyrate, cellulose xanthate, methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl-cellulose, cyanethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose.
Described additives be in osmotic pressure regulator, pH value regulator, complexing of metal ion agent, antioxidant any one or multiple.
Described osmotic pressure regulator be in propylene glycol, glycerol, mannitol any one or multiple; Described pH value regulator be in hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, sorbic acid, sodium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate any one or multiple; Described complexing of metal ion agent be in ethylenediaminetetraacetic acid, disodium edta, ethylene diamine tetraacetic acid sylvite any one or multiple; Described antioxidant be in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, vitamin C any one or multiple.
A preparation method for above-mentioned teniposide nano suspension, comprises the following steps:
1) get stabilizing agent to be dissolved in organic solvent and to form organic facies A, getting water for injection is aqueous phase; Or get stabilizing agent to be dissolved in water for injection and to form aqueous phase, getting organic solvent is organic facies A;
2) get teniposide, be dissolved in organic facies A, form organic facies B;
3) by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, removing organic solvent, adds additives and disperses, obtain teniposide nano suspension.
Step 3) can also be replaced by following steps:
Get step 2) gained organic facies B, removing organic solvent, forms thin film; By step 1) after gained aqueous phase carries out aquation to thin film, add additives and disperse again, obtain teniposide nano suspension.
Described organic solvent is acetone, methanol or chloroform.
Step 3) described in mixing method be mechanical agitation, ultrasonic, high tissue dispersion or high pressure homogenize.
Step 3) in removing organic solvent method be rotary evaporation and/or vacuum drying; Step 3) alternative steps in remove that the film forming method of organic solvent is rotary evaporation, vacuum drying, nitrogen blow in any one or multiple.
Described vacuum drying temperature is 30 ~ 40 DEG C, and the time is 12 ~ 24h.
Step 3) alternative steps in, described aquation is carried out under water bath sonicator, high-speed stirred or high speed shear condition.
The method of described dispersion be in high-speed stirred, high speed shear, ultrasonic, high pressure homogenize any one or multiple.
The rotating speed of described high-speed stirred, high speed shear is 10000 ~ 25000rpm, and the time is 5 ~ 10min.
Described ultrasonic power is 400 ~ 500W, and the time is 3 ~ 5min.
The pressure of described high pressure homogenize is 20MPa, circulates 4 times or 5 times.
Carrying out frozen dried by adding freeze drying protectant in gained teniposide nano suspension, obtaining teniposide lyophilized powder.During use, teniposide lyophilized powder is dispersed in water, obtains teniposide nano suspension.
Described freeze drying protectant be in glucose, trehalose, mannitol, lactose, sucrose, sodium chloride, dextran, sorbitol, glycine any one or multiple.
The addition of described freeze drying protectant is: the quality of freeze drying protectant is 1% ~ 40% of teniposide nano suspension quality.
The method of described frozen dried is: the teniposide nano suspension adding freeze drying protectant is placed in freezer dryer; pre-freeze 6h under-45 DEG C of conditions; then-50 DEG C are cooled to the speed of 5 DEG C/h; after maintaining 12h; again with the ramp to 0 DEG C of 5 DEG C/h; maintain 6h, take out after being finally warming up to 10 DEG C of insulation 12h, sealing is preserved.
In teniposide nano suspension of the present invention, the effect of additives increases formulation stabilizer agent, non-oxidizability, regulates osmotic pressure etc.
Teniposide nano suspension of the present invention, comprise teniposide 0.1 ~ 50mg, stabilizing agent 0.1 ~ 500mg, additives 0 ~ 500mg in every 1ml nano suspension, gained nano suspension drug loading is high, and mean diameter is 80-200nm, good stability; Not containing carrier and cosolvent, avoid the use of organic solvent; Toxic and side effects is low, reduces the untoward reaction of patient, and patient compliance is good; Give full play to the anti-tumor activity of teniposide with advantage that is efficient, low toxicity, reached better clinical efficacy, have a good application prospect.
Compared with commercially available teniposide injection (VUMON), teniposide nano suspension of the present invention is not containing Cremophor (castor oil hydrogenated), benzoic acid and N,N-dimethylacetamide, and toxic and side effects is little, reduce the untoward reaction of patient, patient compliance is good; Compared with teniposide Emulsion used for intravenous injection, teniposide nano suspension drug loading of the present invention is large, and almost organic solvent-free remains, good stability; Compared with Teniposide solid lipid nanoparticle and phosphatide composite liposome body, the drug loading of teniposide nano suspension of the present invention is high, and there is not the low problem with leaking of envelop rate, preparation technology is simple, and cost is low.
The preparation method of teniposide nano suspension of the present invention, is dissolved in teniposide in organic facies, organic facies rear removing organic solvent mixed with water, teniposide is separated out and is dispersed in aqueous phase; Or first remove and the organic solvent in organic facies is formed thin film, then with aqueous phase, hydration process is carried out to thin film, make teniposide be dispersed in aqueous phase, in gained nanosuspension, almost organic solvent-free remains, toxic and side effects is low, reduces the untoward reaction of patient, and patient compliance is good; In gained nano suspension, the particle diameter of suspended solid is 80-200nm, good stability; Lyophilized powder is prepared in further lyophilization, can preserve for a long time; Also be 80-200nm to mean diameter after lyophilized powder multiple dispersion during Clinical practice, multiple dispersion is easy, easy to use; Technique is simple, easy to operate, is applicable to large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the grain size distribution of embodiment 1 gained teniposide nano suspension;
Fig. 2 is the transmission electron microscope picture of embodiment 1 gained teniposide nano suspension;
Fig. 3 is that in experimental example 2, gross tumor volume changes schematic diagram in time;
Fig. 4 is the tumor weight comparative result schematic diagram using different agents in experimental example 2;
Fig. 5 is the appearance of tumors comparative result schematic diagram using different agents in experimental example 2, and wherein A is 5% glucose group, and B is reference preparation (VUMON) group, and C is teniposide nano suspension group.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further illustrated.
Embodiment 1
The teniposide nano suspension of the present embodiment, comprise teniposide 5mg, polyvinylpyrrolidone (PVP K30) 5mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) getting 500mg polyvinylpyrrolidone is dissolved in water for injection, forms aqueous phase; Getting acetone is organic facies A, for subsequent use;
2) getting 500mg teniposide is dissolved in organic facies A, forms organic facies B;
3) under room temperature, rotating speed 10000rpm stirring condition, by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, form transparent, to have blue-opalescent teniposide emulsion, then rotary evaporation removing acetone, and in vacuum drying oven under 40 DEG C of conditions dry 12h remove organic solvent further, be settled to 100ml with water for injection, high pressure homogenize (20MPa, circulate 4 times) disperse, obtain teniposide nano suspension.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, as shown in Figure 1, its mean diameter is 147nm, PDI0.126 to result.
Adopt the form of transmission electron microscope to gained teniposide suspensoid to measure, result as shown in Figure 2.As can be seen from Figure 2, in gained teniposide nano suspension, teniposide is corynebacterium crystallization, and size is comparatively even, basically identical with particle size determination result, may be used for intravenous administration.
Frozen dried is carried out by adding trehalose in the present embodiment gained teniposide nano suspension; be specially: the teniposide nano suspension adding freeze drying protectant is placed in freezer dryer; pre-freeze 6h under-45 DEG C of conditions; then-50 DEG C are cooled to the speed of 5 DEG C/h; after maintaining 12h, then with the ramp to 0 DEG C of 5 DEG C/h, maintain 6h; take out after being finally warming up to 10 DEG C of insulation 12h, obtain teniposide lyophilized powder.Wherein, the mass concentration of described trehalose is 15%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 151nm.
Embodiment 2
The teniposide nano suspension of the present embodiment, comprise teniposide 5mg, TPGS (TPGS) 10mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) getting 100mg TPGS is dissolved in water for injection, forms aqueous phase; Getting methanol is organic facies A, for subsequent use;
2) getting 50mg teniposide is dissolved in organic facies A, forms organic facies B;
3) under room temperature, ultrasonic (400W) condition, by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, form translucent, to have blue-opalescent teniposide emulsion, then rotary evaporation removing methanol, and in vacuum drying oven under 40 DEG C of conditions dry 12h remove organic solvent further, be settled to 10ml with water for injection, high-speed stirred (10000rpm, 5min), teniposide nano suspension is obtained.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 136nm, PDI0.131.
Mannitol will be added in the present embodiment gained teniposide nano suspension and sucrose carries out frozen dried (frozen dried method is with embodiment 1), obtain teniposide lyophilized powder.Wherein, the mass ratio of mannitol and sucrose is 1:1, and the total mass concentration of mannitol and sucrose is 10%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 135nm.
Embodiment 3
The teniposide nano suspension of the present embodiment, comprises teniposide 2mg, lecithin 1mg, vitamin E 0.5mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) get 1000mg lecithin, 500mg vitamin E is dissolved in chloroform, form organic facies A; Getting water for injection is aqueous phase, for subsequent use;
2) getting 2000mg teniposide is dissolved in organic facies A, forms organic facies B;
3) by step 2) gained organic facies B rotary evaporation chloroform removed under pressure, and in vacuum drying oven under 35 DEG C of conditions dry 10h, formed thin film; With aqueous phase by thin film aquation vortex, after the ultrasonic 4min of 400W, be settled to 1000ml with water for injection, with high pressure homogenizer (20MPa circulates 5 times) homogenizing process, obtain teniposide nano suspension.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 114nm, PDI0.121.
Lactose will be added in the present embodiment gained teniposide nano suspension and Sargassum sucrose carries out frozen dried (frozen dried method is with embodiment 1), obtain teniposide lyophilized powder.Wherein, the mass ratio of lactose and trehalose is 1:1, and the total mass concentration of lactose and trehalose is 10%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 130nm.
Embodiment 4
The teniposide nano suspension of the present embodiment, comprise teniposide 25mg, poloxamer (PLURONICS F87) 100mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) getting 1000mg PLURONICS F87 is dissolved in water for injection, forms aqueous phase; Getting chloroform is organic facies A, for subsequent use;
2) getting 250mg teniposide is dissolved in organic facies A, forms organic facies B;
3) under room temperature, rotating speed 6000rpm stirring condition, by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, form teniposide emulsion, then rotary evaporation removing chloroform, and in vacuum drying oven under 35 DEG C of conditions dry 24h, be settled to 10ml with water for injection, supersound process (500W, 3min), teniposide nano suspension is obtained.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 127nm, PDI0.237.
Carrying out frozen dried (frozen dried method is with embodiment 1) by adding dextrose plus saccharose in the present embodiment gained teniposide nano suspension, obtaining teniposide lyophilized powder.Wherein, the mass ratio of glucose and sucrose is 1:1, and the total mass concentration of dextrose plus saccharose is 1%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 136nm.
Embodiment 5
The teniposide nano suspension of the present embodiment, comprises teniposide 0.1mg, dodecyl sodium sulfate 5mg, sodium ethylene diamine tetracetate 8mg, sodium sulfite 2mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) getting 500mg dodecyl sodium sulfate is dissolved in water for injection, forms aqueous phase; Getting chloroform is organic facies A, for subsequent use;
2) getting 10mg teniposide is dissolved in organic facies A, forms organic facies B;
3) by step 2) gained organic facies B nitrogen blow down dechlorination imitate, and in vacuum drying oven under 35 DEG C of conditions dry 12h, formed thin film; With aqueous phase by thin film aquation vortex, after the ultrasonic 4min of 400W, add the sodium ethylene diamine tetracetate of 800mg, the sodium sulfite of 200mg, 100ml is settled to water for injection, with high pressure homogenizer (20MPa circulates 5 times) homogenizing process, obtain teniposide nano suspension.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 125nm.
Carrying out frozen dried (frozen dried method is with embodiment 1) by adding mannitol in the present embodiment gained teniposide nano suspension, obtaining teniposide lyophilized powder.Wherein, mannitol mass concentration is 5%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 127nm.
Embodiment 6
The teniposide nano suspension of the present embodiment, comprises teniposide 50mg, cholic acid 450mg, ursodesoxycholic acid 50mg, vitamin C 0.5mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) get 4500mg cholic acid, 50mg ursodesoxycholic acid is dissolved in chloroform, form organic facies A; Getting water for injection is aqueous phase;
2) getting 500mg teniposide is dissolved in organic facies A, forms organic facies B;
3) by step 2) gained organic facies B rotary evaporation chloroform removed under pressure, and in vacuum drying oven under 35 DEG C of conditions dry 12h, formed thin film; With aqueous phase by thin film aquation vortex, after the ultrasonic 4min of 400W, add 5mg vitamin C, be settled to 10ml with water for injection, high speed shear (20000rpm, 10min) carries out dispersion treatment, obtains teniposide nano suspension.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 126nm.
Carrying out frozen dried (frozen dried method is with embodiment 1) by adding dextran in the present embodiment gained teniposide nano suspension, obtaining teniposide lyophilized powder.Wherein, the mass concentration of dextran is 40%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 128nm.
Embodiment 7
The teniposide nano suspension of the present embodiment, comprises teniposide 30mg, Tween 80 3mg, mannitol 30mg, citric acid 20mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) getting 30mg Tween 80 is dissolved in water for injection, forms aqueous phase; Getting methanol is organic facies A, for subsequent use;
2) getting 300mg teniposide is dissolved in organic facies A, forms organic facies B;
3) under room temperature, ultrasonic (400W) condition, by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, form teniposide emulsion, then rotary evaporation removing methanol, and in vacuum drying oven under 30 DEG C of conditions dry 12h remove methanol further, then add 300mg mannitol, 200mg citric acid, 10ml is settled to water for injection, high speed shear (25000rpm, 5min) is disperseed, and obtains teniposide nano suspension.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 143nm.
Carrying out frozen dried (frozen dried method is with embodiment 1) by adding sorbitol in the present embodiment gained teniposide nano suspension, obtaining teniposide lyophilized powder.Wherein, the mass concentration of sorbitol is 30%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 152nm.
Embodiment 8
The teniposide nano suspension of the present embodiment, comprises teniposide 40mg, cellulose 100mg, carboxymethyl cellulose 50mg, glycerol 300mg, ethylenediaminetetraacetic acid 100mg, sodium hydrogen phosphate 100mg in every 1ml nano suspension, surplus is water for injection.
The preparation method of the teniposide nano suspension of the present embodiment, comprises the following steps:
1) get 1000mg cellulose, 500mg carboxymethyl cellulose is dissolved in methanol, form organic facies A; Getting water for injection is aqueous phase, for subsequent use;
2) getting 400mg teniposide is dissolved in organic facies A, forms organic facies B;
3) under room temperature, ultrasonic (400W) condition, by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, form teniposide emulsion, then rotary evaporation removing methanol, and residue methanol is removed further at 40 DEG C of dry 12h in vacuum drying oven, add 3000mg glycerol, 1000mg ethylenediaminetetraacetic acid, 1000mg sodium hydrogen phosphate again, 10ml is settled to water for injection, ultrasonic carrying out disperses (500W, 5min), teniposide nano suspension is obtained.
Gained teniposide nano suspension is placed in 4 DEG C of condition lower seals and preserves, and directly can use as intravenous injection, or join in 5% glucose solution or normal saline for intravenous drip.
Adopt dynamic light scattering method to measure gained teniposide nano suspension, its mean diameter is 134nm.
Carrying out frozen dried (frozen dried method is with embodiment 1) by adding glycine in the present embodiment gained teniposide nano suspension, obtaining teniposide lyophilized powder.Wherein, the mass concentration of glycine is 5%.During use, teniposide lyophilized powder is dispersed in water for injection in proportion, obtains the teniposide nano suspension of multiple dispersion.Adopt the teniposide nano suspension of dynamic light scattering method to gained multiple dispersion to measure, its mean diameter is 130nm.
Experimental example 1
This experimental example carries out Cavia porcellus sensitivity test to embodiment 1 gained teniposide nanosuspension.This test is carried out according to " chemical drugs investigative technique guideline ", and result is as shown in table 1.
Table 1 Cavia porcellus sensitivity test result
Wherein ,-: represent anaphylaxis for negative;
+: represent the weak positive of anaphylaxis;
++: anaphylaxis is positive;
+++: anaphylaxis strong positive;
The extremely strong positive of ++++: anaphylaxis.
As can be seen from Table 1, embodiment 1 gained teniposide nano suspension, without anaphylaxis, compared with the VUMON of commercial preparation, has significant advantage.The Cavia porcellus sensitivity test result of embodiment 2-8 is with embodiment 1.
Experimental example 2
This experimental example is studied the antitumor pharmacodynamics of embodiment 1 gained teniposide nano suspension to the Wistar rat of load C6MG tumor.
Extracting male Wistar rat (190 ~ 210g), in right side groin subcutaneous vaccination 0.5 × 10
6individual C6 cell, inoculate latter 5 days, gross tumor volume reaches about 100mm
3after carry out experiment grouping, be divided into 5% glucose negative control group A, reference preparation group B (teniposide injection, and teniposide nano suspension group C VUMON), tail intravenously administrable, dosage is 10mg/Kg, and 5% glucose group administration volume is identical with preparation group, successive administration 3 days.Before each administration, observe sign and the behavioral activity of animal, and use vernier caliper measurement respectively to organize the line of apsides of tumor, calculate gross tumor volume V (V=[Length × (Width)
2]/2), draw tumor volume versus time variation diagram.Within the 2nd day after last administration, put to death animal, peel off tumor, weigh tumor weight, and carry out film recording.The results are shown in Figure 3-5.
As seen from Figure 3, during administration, teniposide nano suspension group and VUMON group gross tumor volume no significant difference, but along with administration terminates, nano suspension group gross tumor volume increasess slowly, have significant difference with VUMON group, this is owing to can produce " EPR " effect increase antitumous effect in tumor by passive target after nano suspension administration.Complex chart 3-5, can find out that teniposide nano suspension group has significant antitumous effect.Embodiment 2-8 gained teniposide nano suspension to the antitumor results of pharmacodynamic test of the Wistar rat of load C6MG tumor with embodiment 1.
Claims (10)
1. a teniposide nano suspension, is characterized in that: comprise teniposide 0.1 ~ 50mg, stabilizing agent 0.1 ~ 500mg, additives 0 ~ 500mg in every 1ml nano suspension, surplus is water.
2. teniposide nano suspension according to claim 1, is characterized in that: described stabilizing agent be in polyvinylpyrrolidone, polyvinyl alcohol, dodecyl sodium sulfate, sodium lauryl sulphate, lecithin, lecithin derivative, docosahexenoic acid, polyoxyethylene castor oil, Tween 80, poloxamer, Polyethylene Glycol, vitamin E, TPGS, cholic acid, chlolic acid derivatives, cellulose, cellulose derivative any one or multiple.
3. teniposide nano suspension according to claim 1, is characterized in that: described additives be in osmotic pressure regulator, pH value regulator, complexing of metal ion agent, antioxidant any one or multiple.
4. teniposide nano suspension according to claim 3, is characterized in that: described osmotic pressure regulator be in propylene glycol, glycerol, mannitol any one or multiple; Described pH value regulator be in hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, sorbic acid, sodium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate any one or multiple; Described complexing of metal ion agent be in ethylenediaminetetraacetic acid, disodium edta, ethylene diamine tetraacetic acid sylvite any one or multiple; Described antioxidant be in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, vitamin C any one or multiple.
5. a preparation method for teniposide nano suspension as claimed in claim 1, is characterized in that: comprise the following steps:
1) get stabilizing agent to be dissolved in organic solvent and to form organic facies A, getting water for injection is aqueous phase; Or get stabilizing agent to be dissolved in water for injection and to form aqueous phase, getting organic solvent is organic facies A;
2) get teniposide, be dissolved in organic facies A, form organic facies B;
3) by step 2) gained organic facies B and step 1) after gained aqueous phase fully mixes, removing organic solvent, adds additives and disperses, obtain teniposide nano suspension.
6. the preparation method of teniposide nano suspension according to claim 5, is characterized in that: step 3) can also be replaced by following steps:
Get step 2) gained organic facies B, removing organic solvent, forms thin film; By step 1) after gained aqueous phase carries out aquation to thin film, add additives and disperse again, obtain teniposide nano suspension.
7. the preparation method of the teniposide nano suspension according to claim 5 or 6, is characterized in that: described organic solvent is acetone, methanol or chloroform.
8. the preparation method of the teniposide nano suspension according to claim 5 or 6, is characterized in that: step 3) in removing organic solvent method be rotary evaporation and/or vacuum drying; Step 3) alternative steps in remove that the film forming method of organic solvent is rotary evaporation, vacuum drying, nitrogen blow in any one or multiple.
9. the preparation method of the teniposide nano suspension according to claim 5 or 6, is characterized in that: carrying out frozen dried by adding freeze drying protectant in gained teniposide nano suspension, obtaining teniposide lyophilized powder.
10. the preparation method of teniposide nano suspension according to claim 9, is characterized in that: described freeze drying protectant be in glucose, trehalose, mannitol, lactose, sucrose, sodium chloride, dextran, sorbitol, glycine any one or multiple.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106137943A (en) * | 2015-04-01 | 2016-11-23 | 中国人民解放军第二军医大学 | A kind of teniposide intravenous administration formulation and preparation method thereof |
| CN109833483A (en) * | 2018-09-17 | 2019-06-04 | 山东大学 | The preparation of Sorafenib Nano medication based on mini-chaperone |
| 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 |
| JP2022505200A (en) * | 2018-10-17 | 2022-01-14 | 江▲蘇▼▲領▼航生物科技有限公司 | Teniposide injection solution with excellent dilution stability and its preparation method |
-
2014
- 2014-05-28 CN CN201410241281.XA patent/CN104288100A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106137943A (en) * | 2015-04-01 | 2016-11-23 | 中国人民解放军第二军医大学 | A kind of teniposide intravenous administration formulation and preparation method thereof |
| CN109833483A (en) * | 2018-09-17 | 2019-06-04 | 山东大学 | The preparation of Sorafenib Nano medication based on mini-chaperone |
| JP2022505200A (en) * | 2018-10-17 | 2022-01-14 | 江▲蘇▼▲領▼航生物科技有限公司 | Teniposide injection solution with excellent dilution stability and its preparation method |
| JP7267640B2 (en) | 2018-10-17 | 2023-05-02 | 江▲蘇▼▲領▼航生物科技有限公司 | Teniposide injection solution with excellent dilution stability and its 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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