CN106137943A - A kind of teniposide intravenous administration formulation and preparation method thereof - Google Patents
A kind of teniposide intravenous administration formulation and preparation method thereof Download PDFInfo
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- CN106137943A CN106137943A CN201510149352.8A CN201510149352A CN106137943A CN 106137943 A CN106137943 A CN 106137943A CN 201510149352 A CN201510149352 A CN 201510149352A CN 106137943 A CN106137943 A CN 106137943A
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Abstract
The present invention relates to pharmaceutical technology field, it is provided that a kind of teniposide intravenous administration formulation, be to be mixed by teniposide solution and nanometer lipomul to form.Teniposide solution is made up of teniposide, pH adjusting agent and solvent for injection；Nanometer lipomul is made up of oil for injection, emulsifying agent, stabilizer, antioxidant, pH adjusting agent, isoosmotic adjusting agent and water for injection.Before Clinical practice, teniposide solution is injected jog in nanometer lipomul and i.e. can be directly used for intravenous drip to being uniformly dispersed for several times.The teniposide intravenous administration formulation of the present invention is using nanometer lipomul as pharmaceutical carrier, simple to operation, and without solubilizing agent, improves the drug loading of teniposide, reduce its toxicity and blood vessel irritation.
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of teniposide intravenous administration formulation and preparation method thereof.
Background technology
Teniposide (Teniposide, VM-26) is the glycosides derivatives of a kind of podophyllotoxin, belongs to and acts on DNA and open up
Flutter the non-embedded type antitumor drug of isomerase-.It is the cancer therapy drug of cell cycle specific, mainly acts on DNA
TypeⅡtopoisomerase, causes sub-thread and the fracture of bifilar property of DNA key, it is possible to act on cell cycle S late period and G2
Early stage, blocks cell mitogen, thus plays active function, have the advantages such as antitumor spectra is wide, toxicity is low, evident in efficacy.
Clinically generally and other Anticancer drug combinations: be mainly used in malignant lymphoma, lymphogranulomatosis, acute lymphoblastic
Other of property leukemia, glioblastoma multiforme, blank pipe film tumor, astrocytoma, bladder cancer, neuroblastoma and child
Solid tumor, is also used for treating small cell carcinoma, ovarian cancer, breast carcinoma, multiple myeloma, nonsmall-cell lung cancer etc., because of it
The characteristic of neutral lipophilic, therefore blood brain barrier, one of first-selected chemotherapeutics the most having become clinical treatment cerebroma can be passed through.
Teniposide is neutral lipophilic medicine, is practically insoluble in water, dissolves in organic solvent.Commercial preparation is teniposide
Injection, its prescription consists of: every 5mL is containing teniposide 50mg, N,N-dimethylacetamide 300mg, benzyl alcohol
150mg, polyoxyethylene castor oil (Cremophor EL) 2.5g, dehydrated alcohol 2.1mL, organic solvent in prescription and
Surfactant can increase the dissolubility of teniposide.During Clinical practice, after diluting with normal saline or glucose injection
Intravenous drip.Organic solvent benzyl alcohol in prescription, N,N-dimethylacetamide have certain toxicity and hemolytic, table
Face activating agent polyoxyethylene castor oil heavy dose can cause internal histamine release after using, thus causes serious anaphylaxis.
Additionally, there will be crystallization during clinical transfusion, cause phlebitis etc., increase the weight of medication dangerous.Therefore, clinical
During use, medical worker needs the situation of close observation patient, uses antihistamine drug to alleviate Cremophor EL if desired and makes
The serious anaphylaxis become, causes should using clinically very inconvenient, brings the biggest misery, compliance to patient
Difference.
In recent years, in order to improve the dissolubility of teniposide, improve the curative effect of teniposide, reduce the toxic and side effects of preparation,
Chinese scholars is devoted to research and reduces or substitute the Novel Drug Delivery Systems that Cremophor EL uses, as liposome, ring are stuck with paste
Inclusion compounds, phosphatide complexes, Emulsion, microsphere, gel etc..Such as relating to the teniposide microemulsion pre-concentration liquid of injection
Patent (CN200610167688.8, CN201010541537.0) in, although the N,N-dimethylacetamide in prescription
Consumption reduce, but still containing a certain amount of N,N-dimethylacetamide and Cremophor EL；Relate to a kind of for note
In the patent of the Teniposide injection (CN200710198956.7) penetrated, containing surface active agent tween 80 in prescription,
Tween 80 easily causes hemolytic reaction；Relate to teniposide pharmaceutical composition patent (CN200710099846.5,
CN201010268946.8), in, N,N-dimethylacetamide, tween etc. are still employed.But these Novel Drug Delivery Systems
Prescription still contains a certain amount of surfactant such as Cremophor EL or Tween 80, still there is a certain degree of allergy
Property, and cost is high, complicated process of preparation.
Therefore, clinical need a kind of without non-toxic surfactants, safety be good and also drug loading, the good stability of medicine
Teniposide intravenous administration formulation.
Summary of the invention
Object of the present invention is to provide a kind of without non-toxic surfactants, safety be good and also drug loading, medicine
The teniposide intravenous administration formulation of good stability；Another object of the present invention is to provide above-mentioned teniposide intravenously administrable
The preparation method of preparation.
The main technical schemes of the present invention is: provide a kind of teniposide intravenous administration formulation, using nanometer lipomul as replacing
Buddhist nun moors glycosides pharmaceutical carrier, and without non-toxic surfactants, safety is good, can improve again the drug loading of medicine, increases medicine
Stability.Additionally, containing a certain amount of fat in nanometer lipomul, can be that patient provides nutrition, and particle diameter is
50 300nm, have slow release and targeting, thus can improve the curative effect of teniposide, reduce toxicity.The present invention is with existing
Some Teniposide injections are compared, said preparation stable in properties, and preparation method is simple and convenient, it is possible to decrease the poison such as hemolytic reaction is secondary
Effect, improves the compliance of patient, has good curative effect.
A first aspect of the present invention, it is provided that a kind of teniposide intravenous administration formulation, particular make-up and formula are as follows:
It is made up of with nanometer lipomul two parts teniposide solution.During use, by clinical administration dosage, teniposide is molten
Liquid injects in nanometer lipomul and shakes up, and i.e. can be directly used for intravenous drip.
The teniposide intravenous administration formulation of the present invention is made up of with nanometer lipomul two parts drug solution, component and proportioning
As follows:
1. teniposide solution
2. nanometer lipomul
The teniposide solution of the present invention, nanometer lipomul are independent packaging；Before Clinical practice, dense according to required medicine
Degree, mixes teniposide solution and nanometer lipomul with the volume ratio of 1:10 1:100 and shakes up, i.e. can be directly used for
Intravenous drip.
In described teniposide solution, teniposide content is 1 25%；PH adjusting agent selected from citric acid, malic acid,
One or more in acetic acid, hydrochloric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide；Solvent for injection selected from polyethylene glycol 200,
Liquid Macrogol, one or more in PEG400, Macrogol 600, propylene glycol, dehydrated alcohol, glycerol.
In described nanometer lipomul, oil for injection is sweet selected from pungent tricaprin, pungent capric acid diglyceride, pungent capric acid
Oil monoesters, octanoic acid monoglyceride, Sunfat GDC-S, Trivent OCG, capric acid monoglyceride, capric acid diglyceride,
One or more in tricaprin, soybean oil；Emulsifying agent is in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, poloxamer
One or more；Antioxidant is tocopherol；One or more in oleic acid, enuatrol of stabilizer；Isoosmotic adjusting agent
One or more in glycerol, sorbitol, mannitol, glucose, sodium chloride；PH adjusting agent selected from citric acid,
One or more in malic acid, hydrochloric acid, acetic acid, sodium carbonate, sodium bicarbonate, sodium hydroxide.
In teniposide intravenous administration formulation, teniposide solution is 1:10 1:50 with the volume ratio of nanometer lipomul.
In described teniposide solution, pH adjusting agent is selected from citric acid or malic acid, and regulation pH is 4.0 7.0；Injection
It is PEG400 with solvent.
The described oil for injection in nanometer lipomul is sweet with pungent capric acid selected from soybean oil, pungent tricaprin or soybean oil
The mixed liquor of oil three esters, content is 5% 30%；Emulsifying agent is selected from soybean phospholipid or Ovum Gallus domesticus Flavus lecithin, and content is 1.2% 5%；
Isoosmotic adjusting agent is glycerol, and regulation is to isotonic with human body；Stabilizer is selected from oleic acid or enuatrol, and content is 0.03%；PH adjusts
Joint agent is selected from hydrochloric acid or sodium bicarbonate, and regulation pH is 6.0 9.0；The Average Particle Diameters of nanometer lipomul is
50—300nm。
In a preferred embodiment of the invention, it is provided that a kind of teniposide intravenous administration formulation,
1. component and the formula of teniposide solution are as follows:
2. component and the formula of nanometer lipomul are as follows:
3. the preparation of teniposide intravenous administration formulation
Draw teniposide solution with syringe before Clinical practice, inject in nanometer lipomul, will teniposide solution with
Nanometer lipomul mixes with the volume ratio of 1:10 50 (optimum as 1:24) and shakes up, and obtains teniposide intravenously administrable system
Agent.
A second aspect of the present invention, it is provided that the preparation method of a kind of teniposide intravenous administration formulation is as follows:
1. the preparation of teniposide solution: by proportioning, teniposide is dissolved completely in solvent for injection, uses pH adjusting agent
Regulation pH is 4.0 7.0, adds after proper amount of active carbon, adsorb, filter, subpackage, sterilizing, obtain teniposide solution,
Drug solution is clear transparent solutions.
2. the preparation of nanometer lipomul: after emulsifying agent, stabilizer being dissolved in injection oil by prescription, heating for dissolving,
Obtain oil phase；Adding in water for injection by stabilizer, emulsifying agent, isoosmotic adjusting agent, heating also shears mixing with boxshear apparatus,
Aqueous phase.At 50 100 DEG C oil phase is mixed with water, and shear 2 30min with boxshear apparatus, rotating speed is
300 8000rpm, obtain colostrum；Colostrum pH adjusting agent regulation pH is 4.0 9.0, after further emulsifying, with note
Penetrate and use water constant volume, filter, subpackage, nitrogen charging, sterilizing, obtain nanometer lipomul；The nanometer lipomul of gained be white or
Off-white color emulsion liquid, has opalescence, and Average Particle Diameters is 10 300nm.
Emulsifying agent and stabilizer can add at the same time or separately when preparing oil phase or aqueous phase；During the further emulsifying of colostrum, can use
Including but not limited to high pressure homogenizer emulsifying, mechanical agitation emulsifying, ultrasonic emulsification or colloid mill emulsifying etc., preferably high pressure is equal
Matter machine emulsifying, pressure is 5000 25000psi.When preparing teniposide solution, nanometer lipomul, used goes out
Bacterium method includes but not limited to the sterilizings, preferably rotating type high-pressure such as rotating type high-pressure Sterilization Kettle, flowing steam or microporous filter membrane
Steam sterilization still, temperature 100 121 DEG C, time 15 60min；The defecator used, includes but not limited to micro-
Hole filter membrane, sand stick, sintered filter funnel or bag type filter etc..
3. the preparation of teniposide intravenous administration formulation: according to a certain volume teniposide solution is noted by clinical administration dosage
Enter in nanometer lipomul and jog is for several times to being uniformly dispersed, obtain teniposide intravenous administration formulation, i.e. can be directly used for vein
Instil.
Nanometer lipomul is the one in Emulsion, is made up of aqueous phase and oil phase, belongs to oil-in-water emulsion, emulsion particles
Structure can be divided into kernel and outer layer two large divisions, and kernel is nonpolar hydrophobic district, the oil less by polarity and surfactant
Hydrophobic group is constituted；Outer layer polarity is relatively strong, is made up of the surfactants-polar group of aquation.Using nanometer lipomul as
Pharmaceutical carrier, the medicine that teniposide isopolarity is little can be wrapped in nonpolar hydrophobic district.In view of teniposide oil-soluble and
Water solublity inequality, after being joined in nanometer lipomul by teniposide solution, a part of nanometer lipomul microgranule is as load
Body carries medicine, and the emulsion particles of these medicine carryings is evenly dispersed in again in the emulsion particles of non-medicine carrying, thus is formed steady
Fixed preparation.Additionally, the middle chain fat compared with chain fatty acid triglyceride isometric with soybean oil, with pungent tricaprin as representative
Fat acid glycerol three ester has more preferable dissolubility, absorbability, the compatibility and antioxidant, chain and long-chain during therefore the present invention uses
Triglyceride prepares nanometer lipomul.
It is demonstrated experimentally that the teniposide intravenous administration formulation of the present invention complies fully with clinical application demand, its advantage is: 1. pacify
Good perfection: invention formulation does not contains any solubilizing agent (such as dimethyl acetylamide, Tween 80 etc.), and toxic and side effects is little, institute
Using adjuvant good biocompatibility, internal toleration is high；2. good stability: after teniposide solution mixes with nanometer lipomul
Separating out without obvious medicine or degraded in 10 hours, the particle diameter of Emulsion, Zeta potential and pH have no significant change, and comply fully with
Clinical application demand；3. can be as nutrient: lipomul can be that tumor patient provides nutritional supplementation as pharmaceutical carrier, from
And reach more preferable therapeutic effect；4. targeting: nanometer lipomul has certain targeting, can be by medicine band to tumor
Or other diseased regions.
Teniposide intravenous administration formulation preparation method of the present invention is simple to operation, and drug loading is high, and without solubilizing agent, tool
Have safely, effectively, stable, economic advantage, it is suitable for prepare other medicinalization of oil-soluble and poorly water-soluble
The intravenous administration formulation of compound.
Detailed description of the invention
In conjunction with embodiment, the present invention is elaborated, but the enforcement of the present invention is not limited only to this.
Embodiment 1. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
400mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 5.8, adds 0.4g needle-use activated carbon, adsorb at 50 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 20g injection tricaprin and 20g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating also shear 5min mixing with boxshear apparatus 4500rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is used
Citric acid solution regulation pH is 7.0, and through high pressure homogenizer 10000psi homogenizing 1 circulation, 20000psi homogenizing 10 follows
Ring, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizing 15min of high steam,
Obtain nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 110.3nm, pH6.60.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 2. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 5mg citron acid for adjusting pH
It is 5.5, adds 0.4g needle-use activated carbon, adsorb at 70 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 30min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 10g injection tricaprin and 10g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating are also cut with boxshear apparatus 3500rpm shearing 5min, 5500rpm
Cut 5min mixing, obtain aqueous phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shears 5min with boxshear apparatus 4000rpm,
6000rpm shears 5min, obtains colostrum；Colostrum citric acid solution regulation pH is 7.0, through high pressure homogenizer 6000psi
Homogenizing 1 circulation, 12000psi homogenizing 4 circulation, 20000psi homogenizing 10 circulation, water for injection quantitatively to 400mL,
With 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizing 15min of high steam, obtain nanometer lipomul.After measured,
The particle diameter of gained nanometer lipomul is 70.2nm, pH6.81.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 3. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 5mg citron acid for adjusting pH
It is 5.5, adds 0.4g needle-use activated carbon, use with the filtering with microporous membrane of 0.45 μm, filtrate after adsorbing 30min at 40 DEG C
0.22 μm membrane filtration is degerming, and subpackage obtains teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
8g injection soybean phospholipid S-80 and 2g PLURONICS F87 are dissolved in the pungent tricaprin of 40g injection
In, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；9g glycerol is joined 300mL note
Penetrating with in water, 85 DEG C of heating also shear 8min mixing with boxshear apparatus 4000rpm, obtain aqueous phase.At 70 80 DEG C, oil phase is added
Enter in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum citric acid solution regulation pH is 7.0,
Through high pressure homogenizer 10000psi homogenizing 1 circulation, 20000psi homogenizing 10 circulation, water for injection quantitatively to 400mL,
Filter with sand stick, subpackage, 115 DEG C of sterilizing 30min of high steam, obtain nanometer lipomul.After measured, gained nanometer
The particle diameter of lipomul is 90nm, pH6.60.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 4. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
300mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 6.2, adds 0.5g needle-use activated carbon, adsorb at 80 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
115 DEG C of sterilizing 45min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 30g injection tricaprin and 30g injection soybean oil are mixed, adds 4.8g injection egg yolk ovum phosphorus
Fat E-80,85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g enuatrol, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating also shear 15min mixing with boxshear apparatus 5500rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is used
Citric acid solution and sodium bicarbonate solution regulation pH are 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 12000psi
Homogenizing 4 circulation, 20000psi homogenizing 10 circulation, water for injection is quantitatively to 400mL, with 0.45 μm microporous filter membrane
Filter, subpackage, 115 DEG C of sterilizing 45min of rotating type high-pressure steam sterilization still, obtain nanometer lipomul.After measured, gained
The particle diameter of nanometer lipomul is 117.2nm, pH7.23.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 5. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
200mg teniposide is joined in 20mL PEG400, after dissolving, add 6mg Fructus Mali pumilae acid for adjusting pH
It is 5.5, adds 0.4g needle-use activated carbon, adsorb at 30 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
115 DEG C of sterilizing 45min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 40g injection tricaprin and 40g injection soybean oil are mixed, adds 0.2g tocopherol, 0.08g oil
Acid, 85 DEG C of heating for dissolving, obtain oil phase；9g glycerol, 8.0g injection phosphotide PL-100M are joined 300mL injection
With in water, 85 DEG C of heating also shear 15min mixing with boxshear apparatus 5000rpm, obtain aqueous phase.At 70 80 DEG C, oil phase is added
Enter in aqueous phase, and shear 10min, 6500rpm shearing 5min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is with dilute
Hydrochloric acid and sodium carbonate liquor regulation pH are 7.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi homogenizing 2
Individual circulation, 15000psi homogenizing 4 circulation, 20000psi homogenizing 14 circulation, water for injection, quantitatively to 400mL, is used
0.45 μm filtering with microporous membrane, subpackage, 100 DEG C of sterilizing 30min of flowing steam, obtain nanometer lipomul.After measured, institute
The particle diameter obtaining nanometer lipomul is 131.6nm, pH6.25.
3. the preparation of teniposide intravenous administration formulation
Draw 2.0mL teniposide solution with syringe, inject in 100mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:50 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 6. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 5.5, adds 0.3g needle-use activated carbon, adsorb at 100 DEG C after 15min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 20g injection tricaprin and 20g injection soybean oil are mixed, add 0.08g oleic acid, 85 DEG C
Heating for dissolving, obtains oil phase；By 9g glycerol, 4.8g injection phosphotide PL-100M, 0.2g PLURONICS F87 joins 300mL
In water for injection, 85 DEG C of heating also shear 10min, 5000rpm shearing 10min mixing with boxshear apparatus 3500rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 15min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is used
Citric acid solution regulation pH is 7.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, and 10000psi homogenizing 2 circulation,
15000psi homogenizing 2 circulation, 20000psi homogenizing 10 circulation, water for injection is quantitatively to 400mL, through hanging down after cooling
Molten funnel filters, then the filtering with microporous membrane by 0.22 μm is degerming, the lower subpackage filtrate of nitrogen protection, obtains nanometer lipomul.
After measured, the particle diameter of gained nanometer lipomul is 85.6nm, pH6.12.
3. the preparation of teniposide intravenous administration formulation
Draw 1.0mL teniposide solution with syringe, inject in 100mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:100 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 7. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 4.4mg citron acid for adjusting pH
It is 5.3, adds 0.4g needle-use activated carbon, adsorb at 60 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 20g injection capric acid diglyceride and 20g injection soybean oil being mixed, add 0.08g enuatrol, 95 DEG C add
Heat of solution, obtains oil phase；By 9g glycerol, 8g injection phosphotide PL-100M joins in 300mL water for injection, 95 DEG C
Heat and use boxshear apparatus 6000rpm to shear 5min mixing, obtaining aqueous phase.At 80 90 DEG C, oil phase is joined in aqueous phase, and
Shear 10min with boxshear apparatus 6500rpm, obtain colostrum；Colostrum sodium bicarbonate solution and citric acid solution regulation pH are 8.0,
Through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi homogenizing 4 circulation, 20000psi homogenizing 10 circulation,
Water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, and subpackage, 121 DEG C of sterilizing 15min of high steam,
Obtain nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 100.2nm, pH7.22.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 8. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
200mg teniposide is joined in 20mL PEG400, after dissolving, add 3.6mg citron acid for adjusting pH
It is 6.5, adds 0.4g needle-use activated carbon, adsorb at 100 DEG C after 25min with the filtering with microporous membrane of 0.45 μm, subpackage,
115 DEG C of sterilizing 45min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 10g injection capric acid monoglyceride and 10g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating also shear 5min mixing with boxshear apparatus 4500rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is used
Sodium bicarbonate solution and citric acid solution regulation pH are 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi
Homogenizing 2 circulation, 15000psi homogenizing 4 circulation, 20000psi homogenizing 10 circulation, water for injection quantitatively to 400mL,
With 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizing 15min of high steam, obtain nanometer lipomul.After measured,
The particle diameter of gained nanometer lipomul is 57.5nm, pH7.68.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 9. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 5.5, adds 0.3g needle-use activated carbon, adsorb at 100 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
By 60g injection Trivent OCG and 0.2g tocopherol, 0.08g oleic acid mixes, and 100 DEG C of heating for dissolving obtain oily
Phase；By 9g glycerol, 7.2g injection Ovum Gallus domesticus Flavus lecithin E-80,0.08g PLURONICS F87 joins 300mL injection
In water, 100 DEG C of heating also shear 15min mixing with boxshear apparatus 4500rpm, obtain aqueous phase.At 80 90 DEG C, oil phase is added
In aqueous phase, and shear 10min with boxshear apparatus 6500rpm, obtain colostrum；Colostrum sodium bicarbonate solution and citric acid solution
Regulation pH is 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi homogenizing 3 circulation, 20000psi
Homogenizing 10 circulation, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, high steam 121 DEG C
Sterilizing 15min, obtains nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 116.3nm, pH7.14.
3. the preparation of teniposide intravenous administration formulation
Draw 2.0mL teniposide solution with syringe, inject in 100mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:50 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 10. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
Being joined by 80mg teniposide in 40mL PEG400, adding 6mg Fructus Mali pumilae acid for adjusting pH after dissolving is
6.5, add 1.0g needle-use activated carbon, adsorb at 60 DEG C after 30min with the filtering with microporous membrane of 0.45 μm, 0.22 μm
Filtering with microporous membrane is degerming, subpackage, obtains teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
40g injection Sunfat GDC-S and 40g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating also shear 10min mixing with boxshear apparatus 5000rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 15min with boxshear apparatus 6500rpm, obtain colostrum；Colostrum is used
Sodium bicarbonate solution and citric acid solution regulation pH are 7.5, through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi
Homogenizing 2 circulation, 15000psi homogenizing 4 circulation, water for injection is quantitatively to 400mL, by 0.45 μm microporous filter membrane mistake
Filter, subpackage, 121 DEG C of sterilizing 15min of high steam, obtain nanometer lipomul.After measured, gained nanometer lipomul
Particle diameter is 223.8nm, pH6.82.
3. the preparation of teniposide intravenous administration formulation
Draw 8.0mL teniposide solution with syringe, inject in 80mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:10 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 11. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
400mg teniposide is joined in 40mL PEG400, after dissolving, add 10mg citron acid for adjusting pH
It is 5.3, adds 0.9g needle-use activated carbon, adsorb at 60 DEG C after 45min with the filtering with microporous membrane of 0.45 μm, subpackage,
100 DEG C of sterilizing 30min of flowing steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
20g injection octanoic acid monoglyceride and 20g injection soybean oil are mixed, addition 0.2g tocopherol, 0.08g oleic acid,
85 DEG C of heating for dissolving, obtain oil phase；By 9g glycerol, 4.8g injection phosphotide PL-100M, 0.2g PLURONICS F87 adds
In 300mL water for injection, 85 DEG C of heating also shear 5min mixing with boxshear apparatus 4500rpm, obtain aqueous phase.70—80℃
Lower oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum citric acid solution is adjusted
Joint pH is 7.0, and through high pressure homogenizer 5000psi homogenizing 1 circulation, 8000psi homogenizing 2 circulation, 18000psi is equal
Matter 4 circulation, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, high steam 115 DEG C
Sterilizing 45min, obtains nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 158.7nm, pH6.45.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 12. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
Being joined by 80mg teniposide in 40mL PEG400, adding 6mg Fructus Mali pumilae acid for adjusting pH after dissolving is
6.5, add 0.8g needle-use activated carbon, with the filtering with microporous membrane of 0.45 μm, subpackage, height after absorption 40min at 50 DEG C
Pressure 121 DEG C of sterilizing 30min of steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
20g injection tricaprin and 20g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating also shear 5min mixing with boxshear apparatus 4500rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is used
Malic acid solution regulation pH is 7.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, and 10000psi homogenizing 4 circulation,
Water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, and subpackage, 121 DEG C of sterilizing 15min of high steam,
Obtain nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 184.1nm, pH6.71.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 13. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 5.5, adds 0.4g needle-use activated carbon, adsorb at 30 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Weigh 32g injection capric acid diglyceride, add 4.8g injection phosphotide S-80,75 DEG C of heating for dissolving, add
0.2g tocopherol, 0.08g oleic acid, 75 DEG C of heating for dissolving, obtain oil phase；9g glycerol is joined in 300mL water for injection,
75 DEG C of heating also shear 15min mixing with boxshear apparatus 4500rpm, obtain aqueous phase.At 60 70 DEG C, oil phase is joined aqueous phase
In, and shear 20min with boxshear apparatus 6500rpm, obtain colostrum；Colostrum sodium carbonate liquor and malic acid solution regulation pH
It is 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 8000psi homogenizing 1 circulation, 10000psi homogenizing 4
Circulation, 15000psi homogenizing 4 circulation, 20000psi homogenizing 8 circulation, water for injection, quantitatively to 400mL, uses 0.45 μm
Filtering with microporous membrane, subpackage, 121 DEG C of sterilizing 30min of high steam, obtain nanometer lipomul.After measured, gained nanometer
The particle diameter of lipomul is 90.3nm, pH7.67.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 14. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
400mg teniposide is joined in 40mL PEG400, after dissolving, add 8mg citron acid for adjusting pH
It is 5.5, adds 0.8g needle-use activated carbon, adsorb at 30 DEG C after 35min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
60g injection capric acid monoglyceride and 60g injection soybean oil are mixed, adds 5.2g injection soybean phospholipid
S-80,100 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g enuatrol, 100 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol, 0.08g poloxamer joins in 240mL water for injection, and 100 DEG C of heating are also sheared with boxshear apparatus 4500rpm
5min mixes, and obtains aqueous phase.At 90 100 DEG C, oil phase is joined in aqueous phase, and shears 10min with boxshear apparatus 5500rpm,
Obtain colostrum；Colostrum sodium bicarbonate solution regulation pH is 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 7000psi
Homogenizing 2 circulation, 10000psi homogenizing 4 circulation, 16000psi homogenizing 8 circulation, water for injection quantitatively to 400mL,
With 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizing 15min of high steam, obtain nanometer lipomul.After measured,
The particle diameter of gained nanometer lipomul is 267.3nm, pH7.39.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 15. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
300mg teniposide is joined in 20mL PEG400, after dissolving, add 3.6mg citron acid for adjusting pH
It is 5.7, adds 0.5g needle-use activated carbon, adsorb at 60 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of rotating type high-pressure steam sterilization still, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 20g injection tricaprin and 20g injection soybean oil are mixed, adds 0.2g tocopherol, 0.08g oil
Acid sodium, 65 DEG C of heating for dissolving, obtain oil phase；By 9g glycerol, 20g injection phosphotide PL-100M joins 300mL note
Penetrating with in water, 65 DEG C of heating also shear 10min mixing with boxshear apparatus 3500rpm, obtain aqueous phase.By oil phase at 50 60 DEG C
Join in aqueous phase, and shear 20min with boxshear apparatus 7500rpm, obtain colostrum；Colostrum sodium bicarbonate solution and citric acid
Solution regulation pH is 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi homogenizing 4 circulation, 20000psi
Homogenizing 14 circulation, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, rotating type high-pressure
121 DEG C of sterilizing 20min of steam sterilization still, obtain nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is
81.2nm, pH7.51.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 16. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 5.5, adds 0.4g needle-use activated carbon, adsorb at 50 DEG C after 20min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Weigh 40g injection Trivent OCG, add 0.2g tocopherol, 0.12g enuatrol, 85 DEG C of heating for dissolving, obtain
Oil phase；By 9g glycerol, 12.0g injection phosphotide S-80 joins in 300mL water for injection, and 85 DEG C are heated and with shearing
Instrument 4500rpm shears 5min mixing, obtains aqueous phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and use boxshear apparatus 5500rpm
Shear 10min, obtain colostrum；Colostrum sodium bicarbonate solution and citric acid solution regulation pH are 8.5, through high pressure homogenizer
5000psi homogenizing 1 circulation, 8000psi homogenizing 2 circulation, 16000psi homogenizing 4 circulation, 20000psi homogenizing 10
Individual circulation, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizings of high steam
15min, obtains nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 85.4nm, pH7.71.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 17. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
250mg teniposide is joined in 50mL PEG400, after dissolving, add 12mg citron acid for adjusting pH
It is 5.2, adds 1.2g needle-use activated carbon, adsorb at 30 DEG C after 40min with the filtering with microporous membrane of 0.45 μm, subpackage,
100 DEG C of sterilizing 30min of flowing steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 40g injection tricaprin and 40g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g enuatrol, 85 DEG C of heating for dissolving, obtain oil phase；
Being joined by 9g glycerol in 300mL water for injection, 85 DEG C of heating also shear 5min, 6500rpm with boxshear apparatus 3000rpm
Shear 5min mixing, obtain aqueous phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear with boxshear apparatus 3000rpm
5min, 5500rpm shear 10min, 7500rpm and shear 5min, obtain colostrum；Colostrum sodium bicarbonate solution and Fructus Citri Limoniae
Acid solution regulation pH is 8.0, through high pressure homogenizer 5000psi homogenizing 1 circulation, and 10000psi homogenizing 1 circulation,
18000psi homogenizing 2 circulation, water for injection quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, rotates
121 DEG C of sterilizing 30min of formula high pressure steam sterilization still, obtain nanometer lipomul.After measured, the grain of gained nanometer lipomul
Footpath is 230.5nm, pH7.50.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 18. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
200mg teniposide is joined in 40mL PEG400, after dissolving, add 8mg citron acid for adjusting pH
It is 6.2, adds 1.0g needle-use activated carbon, adsorb at 30 DEG C after 30min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
By pungent for 20g injection tricaprin, 20g injection pungent capric acid diglyceride, 20g injection capric acid glycerol two
Ester and the mixing of 20g injection soybean oil, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol, 16g injection phosphotide PL-100M joins in 300mL water for injection, and 85 DEG C are heated and use boxshear apparatus
4500rpm shears 5min, 6500rpm and shears 5min, obtains aqueous phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and
Shear 10min, 6500rpm with boxshear apparatus 4500rpm and shear 5min, obtain colostrum；Colostrum citric acid solution regulates
PH is 7.0, through high pressure homogenizer 6000psi homogenizing 1 circulation, 12000psi homogenizing 4 circulation, 20000psi homogenizing
5 circulations, water for injection is quantitatively to 400mL, and with 0.45 μm filtering with microporous membrane, subpackage, high steam 121 DEG C goes out
Bacterium 15min, obtains nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 152.7nm, pH6.34.
3. the preparation of teniposide intravenous administration formulation
Draw 3.0mL teniposide solution with syringe, inject in 90mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:30 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 19. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
500mg teniposide is joined in 20mL PEG400, after dissolving, add 4mg citron acid for adjusting pH
It is 5.5, adds 0.4g needle-use activated carbon, adsorb at 40 DEG C after 15min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 10g injection tricaprin and 10g injection pungent capric acid monoglyceride are mixed, add 0.08g oleic acid,
65 DEG C of heating for dissolving, obtain oil phase；By 9g glycerol, 0.08g poloxamer, 4.8g injection phosphotide PL-100M joins
In 300mL water for injection, 65 DEG C of heating also shear 15min mixing with boxshear apparatus 3500rpm, obtain aqueous phase.55—60℃
Lower oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 7500rpm, obtain colostrum；Colostrum citric acid solution is adjusted
Joint pH is 7.0, and through high pressure homogenizer 5000psi homogenizing 1 circulation, 10000psi homogenizing 2 circulation, 15000psi is equal
Matter 4 circulation, 20000psi homogenizing 10 circulation, water for injection is quantitatively to 400mL, by 0.45 μm microporous filter membrane mistake
Filter, subpackage, 121 DEG C of sterilizing 15min of high steam, obtain nanometer lipomul.After measured, gained nanometer lipomul
Particle diameter is 63.2nm, pH6.53.
3. the preparation of teniposide intravenous administration formulation
Draw 2.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:48 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 20. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
400mg teniposide is joined in 40mL PEG400, after dissolving, add 6.4mg citron acid for adjusting pH
It is 6.5, adds 0.8g needle-use activated carbon, adsorb at 40 DEG C after 30min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
Pungent for 20g injection tricaprin and 20g injection soybean oil are mixed, adds 4.8g injection phosphotide
PL-100M, 85 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 85 DEG C of heating for dissolving, obtain oil phase；Will
9g glycerol joins in 300mL water for injection, and 85 DEG C of heating also shear 5min mixing with boxshear apparatus 4500rpm, obtain water
Phase.At 70 80 DEG C, oil phase is joined in aqueous phase, and shear 10min with boxshear apparatus 5500rpm, obtain colostrum；Colostrum is used
Citric acid solution regulation pH is 7.0, and through high pressure homogenizer 10000psi homogenizing 1 circulation, 15000psi homogenizing 2 follows
Ring, 20000psi homogenizing 2 circulation, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is
150.5nm, pH6.49.
3. the preparation of teniposide intravenous administration formulation
Draw 3.0mL teniposide solution with syringe, inject in 90mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:30 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 21. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
480mg teniposide is joined in 40mL PEG400, after dissolving, add 8mg citron acid for adjusting pH
It is 5.5, adds 0.8g needle-use activated carbon, adsorb at 40 DEG C after 30min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
By pungent for 10g injection tricaprin, 10g injection pungent capric acid diglyceride, 10g injection octanoic acid glycerol three
Ester and the mixing of 10g injection soybean oil, add 0.2g tocopherol, 0.08g enuatrol, 65 DEG C of heating for dissolving, obtain oil phase；
By 9g glycerol, 8g injection soybean phospholipid S-80 joins in 300mL water for injection, and 65 DEG C are heated and use boxshear apparatus
5500rpm shears 5min mixing, obtains aqueous phase.At 60 70 DEG C, oil phase is joined in aqueous phase, and use boxshear apparatus 5500rpm
Shear 20min, obtain colostrum；Colostrum sodium bicarbonate solution and citric acid solution regulation pH are 8.5, through high pressure homogenizer
5000psi homogenizing 1 circulation, 8000psi homogenizing 2 circulation, 15000psi homogenizing 4 circulation, 20000psi homogenizing 10
Individual circulation, water for injection is quantitatively to 400mL, with 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizings of high steam
15min, obtains nanometer lipomul.After measured, the particle diameter of gained nanometer lipomul is 102.8nm, pH7.36.
3. the preparation of teniposide intravenous administration formulation
Draw 4.0mL teniposide solution with syringe, inject in 96mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:24 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 22. prepares a kind of teniposide intravenous administration formulation
1. the preparation of teniposide solution
Specifically comprise the following steps that
250mg teniposide is joined in 50mL PEG400, after dissolving, add 11mg citron acid for adjusting pH
It is 5.5, adds 1.0g needle-use activated carbon, adsorb at 30 DEG C after 30min with the filtering with microporous membrane of 0.45 μm, subpackage,
121 DEG C of sterilizing 15min of high steam, obtain teniposide drug solution.
2. the preparation of nanometer lipomul
Specifically comprise the following steps that
By pungent for 20g injection tricaprin, 10g tricaprin and the mixing of 10g injection Trivent OCG,
Add 4.8g injection phosphotide PL-100M, 95 DEG C of heating for dissolving, add 0.2g tocopherol, 0.08g oleic acid, 95 DEG C
Heating for dissolving, obtains oil phase；Being joined by 9g glycerol in 300mL water for injection, 95 DEG C of heating also use boxshear apparatus 4500rpm
Shear 5min mixing, obtain aqueous phase.At 80 90 DEG C, oil phase is joined in aqueous phase, and shear with boxshear apparatus 7000rpm
10min, obtains colostrum；Colostrum citric acid solution regulation pH is 4.0, through high pressure homogenizer 5000psi homogenizing 1 circulation,
10000psi homogenizing 2 circulation, 15000psi homogenizing 4 circulation, 20000psi homogenizing 4 circulation, water for injection is quantitative
To 400mL, with 0.45 μm filtering with microporous membrane, subpackage, 121 DEG C of sterilizing 15min of high steam, obtain nanometer fat milk
Agent.After measured, the particle diameter of gained nanometer lipomul is 166.3nm, pH6.60.
3. the preparation of teniposide intravenous administration formulation
Draw 3.0mL teniposide solution with syringe, inject in 90mL nanometer lipomul, will teniposide molten
Liquid and nanometer lipomul mix with the volume ratio of 1:30 and shake up, and obtain teniposide intravenous administration formulation.
Embodiment 23. teniposide intravenous administration formulation study on the stability
As a example by the teniposide intravenous administration formulation prepared by embodiment 1, after preparing teniposide intravenous administration formulation, survey
Determine different time medicament contg, the particle diameter of nanometer lipomul and pH value.
Medicine assay method: take appropriate teniposide intravenous administration formulation, through 0.22 micrometer Millipore membrane filtration, removes
Remove the drug crystallization that may separate out, take subsequent filtrate and measure medicament contg, particle diameter and pH value over time in accordance with the law, knot
Fruit is shown in Table 1:
Table 1. teniposide intravenous administration formulation study on the stability result
As can be seen from Table 1, teniposide intravenous administration formulation medicament contg in 10 hours has almost no change, explanation
Teniposide did not separate out in 10 hours；Mean diameter and the pH value of emulsion particles are all not changed in.Measurement result table
Bright teniposide intravenous administration formulation is good at 10 hours internal stabilities, meets clinical application demand.
Below preferred embodiment to the invention is illustrated, but the invention is not limited to described enforcement
Example, those of ordinary skill in the art also can make the modification of all equivalents on the premise of the invention spirit
Or replace, modification or the replacement of these equivalents are all contained in the application claim limited range.
Claims (10)
1. a teniposide intravenous administration formulation, is made up of teniposide solution and nanometer lipomul two parts, and its feature exists
As follows with the component of nanometer lipomul and proportioning in teniposide solution:
(A) teniposide solution
(B) nanometer lipomul
Teniposide solution mixes with the volume ratio of 1:10 1:100 before Clinical practice with nanometer lipomul and shakes up.
2. the teniposide intravenous administration formulation as described in claim 1, it is characterised in that in described teniposide solution,
Teniposide content is 1 25%；PH adjusting agent is selected from citric acid, malic acid, acetic acid, hydrochloric acid, sodium bicarbonate, carbonic acid
One or more in sodium, sodium hydroxide；Solvent for injection be selected from polyethylene glycol 200, Liquid Macrogol, Polyethylene Glycol
400, one or more in Macrogol 600, propylene glycol, dehydrated alcohol, glycerol.
3. the teniposide intravenous administration formulation as described in claim 1, it is characterised in that in described nanometer lipomul,
Oil for injection is selected from pungent tricaprin, pungent capric acid diglyceride, pungent capric acid monoglyceride, octanoic acid monoglyceride, octanoic acid
In diglyceride, Trivent OCG, capric acid monoglyceride, capric acid diglyceride, tricaprin, soybean oil one
Plant or multiple；One or more in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, poloxamer of emulsifying agent；Antioxidant is fertility
Phenol；One or more in oleic acid, enuatrol of stabilizer；Isoosmotic adjusting agent selected from glycerol, sorbitol, mannitol,
One or more in glucose, sodium chloride；PH adjusting agent selected from citric acid, malic acid, hydrochloric acid, acetic acid, sodium carbonate,
One or more in sodium bicarbonate, sodium hydroxide.
4. the teniposide intravenous administration formulation as described in claim 1, it is characterised in that in teniposide intravenous administration formulation,
Teniposide solution is 1:10 1:50 with the volume ratio of nanometer lipomul.
5. the teniposide intravenous administration formulation as described in claim 1, it is characterised in that in described teniposide solution, pH
Regulator is selected from citric acid or malic acid, and regulation pH is 4.0 7.0；Solvent for injection is PEG400.
6. the teniposide intravenous administration formulation as described in claim 1, it is characterised in that in described nanometer lipomul
Oil for injection is selected from the mixed liquor of soybean oil, pungent tricaprin or soybean oil with pungent tricaprin, and content is
5% 30%；Emulsifying agent is selected from soybean phospholipid or Ovum Gallus domesticus Flavus lecithin, and content is 1.2% 5%；Isoosmotic adjusting agent is glycerol,
Regulation is to isotonic with human body；Stabilizer is selected from oleic acid or enuatrol, and content is 0.03%；PH adjusting agent is selected from hydrochloric acid or carbonic acid
Hydrogen sodium, regulation pH is 6.0 9.0；The Average Particle Diameters of nanometer lipomul is 50 300nm.
7. the preparation method of a kind of teniposide intravenous administration formulation as described in as arbitrary in claim 16, step is as follows:
A) preparation of teniposide solution: by proportioning, teniposide is dissolved completely in solvent for injection, regulates by pH adjusting agent
PH is 4.0 7.0, adds proper amount of active carbon, adsorb, filter, subpackage, sterilizing, obtain teniposide solution；
B) preparation of nanometer lipomul: by prescription, emulsifying agent, stabilizer are dissolved in injection oil, obtain oil phase；By stabilizer,
Emulsifying agent, isoosmotic adjusting agent add in water for injection, and heating also shears mixing with boxshear apparatus, obtains aqueous phase；At 50 100 DEG C
Lower that oil phase is mixed with water, and shear 2 30min with boxshear apparatus, rotating speed is 300 8000rpm, obtains colostrum；Colostrum
It is 4.0 9.0 with pH adjusting agent regulation pH, after further emulsifying, uses water for injection constant volume, filter, subpackage, sterilizing,
Obtain nanometer lipomul.
8. the preparation method as described in claim 7, it is characterised in that: the defecator used during filtration, filter including micropore
Film, sand stick, sintered filter funnel or bag type filter；During the further emulsifying of colostrum, high pressure homogenizer emulsifying, machinery can be used
Stirring and emulsifying, ultrasonic emulsification or colloid mill emulsifying.
9. the preparation method as described in claim 7, it is characterised in that: the method for described sterilizing includes rotating type high-pressure steam
Sterilization Kettle, flowing steam or filtering with microporous membrane are degerming.
10. the preparation method as described in claim 7, it is characterised in that: the Average Particle Diameters of nanometer lipomul before and after sterilizing
It is 50 300nm.
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