CN102188377A - Method for preparing medicine encapsulating liposome - Google Patents
Method for preparing medicine encapsulating liposome Download PDFInfo
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- CN102188377A CN102188377A CN2010101312445A CN201010131244A CN102188377A CN 102188377 A CN102188377 A CN 102188377A CN 2010101312445 A CN2010101312445 A CN 2010101312445A CN 201010131244 A CN201010131244 A CN 201010131244A CN 102188377 A CN102188377 A CN 102188377A
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Abstract
The invention relates to a method for preparing a medicine encapsulating liposome, which comprises: preparing medicine solid dispersion; and uniformly dispersing the medicine solid dispersion and a liposome film-forming material in an organic solvent to prepare the medicine encapsulating liposome. When the method is used, a medicine can be uniformly encapsulated in the liposome, the medicine encapsulating rate is improved, and sudden release of the medicine encapsulating liposome is reduced. The liposome is suitable for encapsulating various medicines and can be used in a wide formulation range.
Description
[technical field]
The invention belongs to the pharmaceutical preparation field, more particularly, the present invention relates to a kind of preparation method of wrapping the medicine carrying composite lipidosome.
[background technology]
Liposome (liposomes) is a kind of by arranging the single or multiple lift microcapsule that orderly lipid bilayer is formed.Liposome belongs to colloid system, has the cytoid structure of class, and is strong with the cell membrane affinity, can increase the ability of encapsulated medicine permeate through cell membranes.The liposome good biocompatibility can realize that targeting is sent in the medicine body, have prolong drug action time, increase medicine inside and outside stability, reduce drug toxicity, strengthen plurality of advantages such as pharmacological action.
The method for preparing liposome is a lot, and film dispersion method, reverse phase evaporation, freeze-drying, injection method, ultrasonic dispersing method etc. are arranged.Directly use at present the liposome entrapment medicine, particularly during water soluble medicament-entrapping, envelop rate is lower usually.Owing to medicine polarity reason, cause medicine skewness in liposome in addition, burst effect is obvious, can not satisfy pharmacopeia and stipulate accordingly.
Active drug delivery technologies such as employing pH gradient method can improve liposome for water soluble drug bag carrying capacity, but initiatively the drug delivery technologies operation is comparatively loaded down with trivial details, and poor reproducibility is difficult to industrial mass and prepares.
The notion of solid dispersion is the earliest in propositions such as Sekiguchi in 1961.The effect characteristics of solid dispersion: the dissolubility and the dissolution rate that 1. increase insoluble drug: after insoluble drug was made solid dispersion, medicine was dispersed in the carrier with molecule, colloid, unformed or microcrystalline state, and specific surface area increases, and dissolution rate is accelerated.2. delay drug release rate: solid dispersions technique has been applied in the product development of slow releasing preparation, by selecting suitable carrier material for use, can obtain the slow-release solid dispersion of different drug release rates.3. improve the bioavailability of insoluble drug: insoluble drug is difficult for being absorbed by body, in clinical practice, be subjected to certain limitation, adopted solid dispersions technique, can make insoluble drug reach the high degree of dispersion homogeneous state, thereby guarantee the absorption and the utilization of its preparation, improve bioavailability.4. improve stability of drug: labile drug can increase stability after making solid dispersion, makes the quality of preparation be easy to control, and can reduce cost.
At present, be to be applied in the solid orally ingestible more than the solid dispersions technique, do not see the report that applies it in the particulate carrier technology of preparing.
[summary of the invention]
The technical problem to be solved in the present invention is at the weak point of existing preparation bag medicine carrying composite lipidosome, and a solution is provided.
We find that in the liposome of preparation bag medicine carrying thing is tested because the medicine polarity difference is big, medicine is difficult to evenly wrap be stated from the liposome.When water soluble drug is made liposome, because of drug distribution in surface of liposome, be easy to generate burst effect; But when fat-soluble medicine was made liposome, because of medicine is embedded in liposome interior fully, medicine was difficult to discharge, thereby did not reach the release concentration of regulation.But some amphipathy macromolecule materials such as Polyethylene Glycol, poloxamer, polyvidone etc. are arranged,, and be easy to be scattered in water, middle polarity even the weakly polar organic solvent with liposome affinity height.Therefore we at first prepare medicine solid dispersion, medicine solid dispersion and liposome filmogen are dispersed in to prepare drug-loaded liposome in the organic solvent then.Found that entrapment efficiency improves, burst effect reduces.
Through test of many times, for improving the preparation method of liposome entrapment medicine, the present invention has adopted following technical scheme:
A kind of preparation method of improving the liposome entrapment medicine of the present invention, be that medicine is scattered in the amphipathy macromolecule material system of dissolving or molten condition, rapid cooling is handled and is obtained medicine solid dispersion, then medicine solid dispersion and liposome filmogen are dispersed in the organic facies system, according to method for preparing lipidosome, make the liposome of bag medicine carrying thing, realize that the even bag of medicine is loaded in liposome, improve the envelop rate of medicine, reduce the burst effect of bag medicine carrying composite lipidosome at liposome.
Above-mentioned medicine is meant middle pharmaceutically active ingredient, chemicals, aminoacid, polypeptide or the protein drug of performance prevention, treatment, health care, cleaning, beautification function.
Above-mentioned amphipathy macromolecule material is meant natural macromolecular material, semi-synthetic macromolecular material and the synthesized polymer material of pharmaceutically generally acknowledging, comprises polyvidone, Polyethylene Glycol, poloxamer and polyvinyl alcohol.
Above-mentioned liposome filmogen comprises hydrogenated phospholipid, synthetic phospholipid, cholesterol and surfactant, and hydrogenated phospholipid comprises: hydrogenation egg yolk lecithin and/or hydrogenated soya phosphatide; Synthetic phospholipid is meant known synthetic phospholipid of pharmacy and polyethyleneglycol modified derivant thereof, comprising: two palmityl PHOSPHATIDYL ETHANOLAMINE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, DOPE, two palmityl phosphatidyl glycerols, two palmityl phosphatidic acid are the polyethyleneglycol modified derivant of one or more and they wherein; Surfactant comprises: tween series, span series, oleic acid, hexadecanol, octadecanol, glycerol, propylene glycol.
Above-mentioned organic facies is meant alcohol, ketone, ester, ether and the alkyl halide of carbon number 10 with interior straight chain, side chain, comprises ethanol, the tert-butyl alcohol, acetone, ethyl acetate, ether, petroleum ether, chloroform, dichloromethane.
Can contain the known surfactant of pharmacy, polyhydric alcohol or saccharide, macromolecular scaffold proppant, antioxidant, stabilizing agent, pH regulator agent in the above-mentioned organic facies system.
The liposome particle diameter of above-mentioned bag medicine carrying thing can be micron order or nanoscale.
The liposome of above-mentioned bag medicine carrying thing can further be removed lipid fragment and unnecessary salt ion by dialysis, processing method centrifugal, chromatography.
Above-mentioned bag medicine carrying composite lipidosome can further be processed, and forms the raw material of oral, mucosa, injection, percutaneous drug delivery preparation, makes the concrete preparation of performance prevention, treatment, health care, cleaning, beautification function.
The preparation method of above-mentioned bag medicine carrying composite lipidosome has the following advantages:
1. the preparation method of bag medicine carrying composite lipidosome of the present invention improves the envelop rate of medicine at liposome, obviously reduces the seepage of bag medicine carrying thing.
2. the preparation method of bag medicine carrying composite lipidosome of the present invention reduces the burst effect of bag medicine carrying composite lipidosome, improves the release behavior of medicine, helps obtaining the drug-loaded liposome of different drug release rates, improves bioavailability of medicament.
3. the preparation method of bag medicine carrying composite lipidosome of the present invention is suitable for wrapping up multiple medicine, is particularly useful for little medicine, water soluble drug and the insoluble drug of medicine, therapeutic dose of Bao Zaiyi oxidation.
4. the bag medicine carrying composite lipidosome finished product of the present invention's preparation is solid-state, stability is high, and it is extensive to be suitable for dosage form, can further process, form the raw material of oral, mucosa, injection, percutaneous drug delivery preparation, make the concrete preparation of performance prevention, treatment, health care, cleaning, beautification function.
Annotate: burst effect (dumping or burst effect), drug release at first is the rapid release that sticks to the small amount of drug early period of origination of microparticle surfaces, is called burst effect.Pharmacopoeia of People's Republic of China (2005 editions) regulation, the burst size of medicine carrying microgranules such as liposome in beginning 0.5h should be lower than 40%.
[specific embodiment]
Now further describe the present invention in conjunction with following example.
Embodiment 1: the diclofenac sodium lipidosome
It is the target medicine that first embodiment of the present invention adopts the water soluble drug diclofenac sodium, amphipathy macromolecule material selection polyvidone (PVP), adopt fusion method to prepare diclofenac sodium-polyvidone solid dispersion, the liposome filmogen is selected hydrogenated soya phosphatide, cholesterol, Tween 80 and hexadecanol for use, adopts freeze-drying method preparation bag to carry the liposome of diclofenac sodium.
Experimental group: 30mg polyvidone (PVP) fusion in 65 ℃ of water-baths, add the 8mg diclofenac sodium and be uniformly dispersed, go to quenching processing in 0 ℃ of ice bath, make diclofenac sodium-polyvidone solid dispersion.20mg hydrogenated soya phosphatide, 6mg cholesterol, 2mg Tween 80 and 2mg hexadecanol are dissolved in the 20ml tert-butyl alcohol jointly, in 65 ℃ of water-baths, dissolve, add diclofenac sodium-polyvidone solid dispersion, dissolving fully, add 120mg mannitol (PVP), be uniformly dispersed, be loaded in the cillin bottle-30 ℃ freezing 5 hours, lyophilization (5 * 10
-4Pa 24h) obtains wrapping the solid-state dried frozen aquatic products of liposome that carries diclofenac sodium.
Matched group: 20mg hydrogenated soya phosphatide, 6mg cholesterol, 2mg Tween 80 and 2mg hexadecanol are dissolved in the 20ml tert-butyl alcohol jointly, in 65 ℃ of water-baths, dissolve, adding 8mg diclofenac sodium micropowder (particle diameter is below 15 μ m) is uniformly dispersed, add 120mg mannitol, complete mixing, be loaded in the cillin bottle-30 ℃ freezing 5 hours, lyophilization (5 * 10
-4Pa 24h) obtains wrapping the solid-state dried frozen aquatic products of liposome that carries diclofenac sodium.
Experimental group and matched group inject distilled water 5ml respectively, slightly shake, and promptly obtain wrapping the liposome turbid liquor that carries diclofenac sodium, carry out following mensuration then.
Entrapment efficiency determination: get the diclofenac sodium liposome turbid liquor through the centrifugal 1min of 10000r/min, absorption contains the upper solution 2ml of free diclofenac sodium, survey trap with ultraviolet-visible spectrophotometer in 274nm, substitution diclofenac sodium standard curve utilizes " envelop rate (%)=[(diclofenac sodium total amount-free diclofenac sodium amount)/diclofenac sodium total amount] * 100 " formula to calculate the envelop rate of diclofenac sodium lipidosome.Measure envelop rate once more behind 25 ℃ of placements of diclofenac sodium liposome turbid liquor sample 0.5h.
The diclofenac sodium standard curve: precision takes by weighing the diclofenac sodium standard substance, be mixed with 0.1,0.2 with distilled water, 0.5,1.0,2.5mg/ml series standard solution, survey trap in 274nm, obtain the standard curve of diclofenac na concn and trap, utilize this standard curve to calculate the concentration of diclofenac sodium.
The result: experimental group diclofenac sodium liposome encapsulation meansigma methods is 85%, and matched group envelop rate meansigma methods is 51%.Experimental group diclofenac sodium liposome encapsulation meansigma methods is 72% behind 25 ℃ of placement 0.5h, and the burst size in the 0.5h is lower than 40%, has avoided the burst effect of liposome.And the envelop rate meansigma methods reduces to 28% behind 25 ℃ of placements of matched group 0.5h, and the burst size in the 0.5h surpasses 40%, and there is burst effect in liposome.The result shows that diclofenac sodium lipidosome that the present invention prepares has effectively improved the envelop rate of diclofenac sodium, has avoided the burst effect of liposome, thereby has prolonged the release action of diclofenac sodium lipidosome.
Embodiment 2: Paclitaxel liposome
It is the target medicine that second embodiment of the present invention adopts the fat-soluble medicine paclitaxel, amphipathy macromolecule material Polyethylene Glycol (PEG 2000), adopt solvent-fusion method to prepare paclitaxel-Polyethylene Glycol solid dispersion, the liposome filmogen is selected dipalmitoyl phosphatidyl choline (DPPC), the grafted DSPE of Macrogol 2000 (DSPE-PEG2000) and Tween 80 for use, adopts injection method preparation bag to carry the liposome of paclitaxel.
Experimental group: 30mg Polyethylene Glycol (PEG 2000) adds in the 0.5ml dehydrated alcohol, and fusion in 65 ℃ of water-baths adds the 5mg paclitaxel and is uniformly dispersed, and goes to quenching processing in 0 ℃ of ice bath, makes paclitaxel-Polyethylene Glycol solid dispersion.5mg dipalmitoyl phosphatidyl choline (DPPC), the grafted DSPE of 1mg Macrogol 2000 (DSPE-PEG2000) add the 20ml chloroform: methanol (3: 1, V/V) dissolve in the mixed solvent, add paclitaxel-Polyethylene Glycol solid dispersion and be uniformly dispersed, constitute organic facies.Get in the 20ml 0.02mol/L phosphate buffer (PBS) of 10mg Tween 80 adding pH=7, mixing constitutes water.Organic facies is injected the aqueous phase of (25 ± 2) that 1000r/min stirs ℃, and 1000r/min stirs 10min, forms liposome turbid liquor, and 25 ℃ of rotary evaporations of water-bath eliminate organic solvent, obtain wrapping the liposome of year paclitaxel.
Matched group: 5mg dipalmitoyl phosphatidyl choline (DPPC), the grafted DSPE of 1mg Macrogol 2000 (DSPE-PEG2000) add the 20ml chloroform: methanol (3: 1, V/V) dissolve in the mixed solvent, add the 5mg paclitaxel, constitute organic facies.Get in the 20ml 0.02mol/L phosphate buffer (PBS) of 10mg Tween 80 adding pH=7, mixing constitutes water.Organic facies is injected the aqueous phase of (25 ± 2) that 1000r/min stirs ℃, and 1000r/min stirs 10min, forms liposome turbid liquor, and 25 ℃ of rotary evaporations of water-bath eliminate organic solvent, obtain wrapping the liposome of year paclitaxel.
Entrapment efficiency determination: get the Paclitaxel liposome suspension through the centrifugal 1min of 10000r/min, draw the upper solution that 0.5ml contains free paclitaxel, survey trap with ultraviolet-visible spectrophotometer in 480nm, substitution paclitaxel standard curve utilizes " envelop rate (%)=[(paclitaxel total amount-free paclitaxel amount)/paclitaxel total amount] * 100 " formula to calculate the envelop rate of Paclitaxel liposome.Measure envelop rate once more behind 25 ℃ of placements of Paclitaxel liposome suspension sample 0.5h.
The paclitaxel standard curve: precision takes by weighing the paclitaxel standard substance, is mixed with 0.25,0.5,1.0 with distilled water, 2.0 the series standard solution of 5.0mg/ml is surveyed trap in 480nm, obtain the standard curve of paclitaxel concentration and trap, utilize this standard curve to calculate the concentration of paclitaxel.
The result: Paclitaxel liposome envelop rate meansigma methods is 84%, and matched group envelop rate meansigma methods is 85%, no significant difference.Experimental group Paclitaxel liposome envelop rate meansigma methods is 72% behind 25 ℃ of placement 0.5h, discharges certain medicine and does not show burst effect.The envelop rate meansigma methods is 82% behind 25 ℃ of placements of matched group 0.5h, and drug release is very slow.The result shows that the Paclitaxel liposome that the present invention prepares does not have the burst effect of liposome, and has release behavior preferably, improves the effectiveness of its treatment.
Embodiment 3: the irinotecan hydrochloride liposome
It is the target medicine that the 3rd embodiment of the present invention adopts irinotecan hydrochloride, amphipathy macromolecule material selection poloxamer (Poloxamer 188), adopt fusion method to prepare irinotecan hydrochloride-poloxamer solid dispersion, the liposome filmogen is selected hydrogenation egg yolk lecithin, cholesterol, Tween 80 and glycerol for use, adopts the even method preparation of high pressure breast bag to carry the nanometer liposome of irinotecan hydrochloride.
Experimental group: 55mg poloxamer (Poloxamer 188) fusion in 65 ℃ of water-baths, add the 5mg irinotecan hydrochloride and be uniformly dispersed, obtain irinotecan hydrochloride-poloxamer solid dispersion.20mg hydrogenation egg yolk lecithin, 6mg cholesterol, 2mg Tween 80,6mg glycerol join in 80 ℃ of water of 10ml, add irinotecan hydrochloride-poloxamer solid dispersion, with high pressure dispersing emulsification machine emulsifying four times, microporous filter membrane by 0.22 μ m carries out granulate, obtains wrapping the nanometer liposome that carries irinotecan hydrochloride.
Matched group: 20mg hydrogenation egg yolk lecithin, 6mg cholesterol, 2mg Tween 80,6mg glycerol join in 80 ℃ of water of 10ml, add the 5mg irinotecan hydrochloride, with high pressure dispersing emulsification machine emulsifying four times, microporous filter membrane by 0.22 μ m carries out granulate, obtains wrapping the nanometer liposome that carries irinotecan hydrochloride.
Entrapment efficiency determination: get the irinotecan hydrochloride liposome turbid liquor through the centrifugal 1min of 10000r/min, draw the upper solution that 2ml contains the free hydrochloric acid irinotecan, survey trap with ultraviolet-visible spectrophotometer in 370nm, substitution irinotecan hydrochloride standard curve utilizes " envelop rate (%)=[(irinotecan hydrochloride total amount-free hydrochloric acid irinotecan amount)/irinotecan hydrochloride total amount] * 100 " formula to calculate the envelop rate of irinotecan hydrochloride liposome.Measure envelop rate once more behind 25 ℃ of placements of irinotecan hydrochloride liposome turbid liquor sample 0.5h.
The irinotecan hydrochloride standard curve: precision takes by weighing the irinotecan hydrochloride standard substance, be mixed with 0.25,0.5 with distilled water, 1.0,2.0,5.0mg/ml series standard solution, survey trap in 370nm, obtain the standard curve of irinotecan hydrochloride concentration and trap, utilize this standard curve to calculate the concentration of irinotecan hydrochloride.
The result: irinotecan hydrochloride liposome encapsulation meansigma methods is 84%, and matched group envelop rate meansigma methods is 30%.Irinotecan hydrochloride liposome encapsulation meansigma methods is 67% behind 25 ℃ of placement 0.5h, does not show burst effect.And the envelop rate meansigma methods reduces to 14% behind 25 ℃ of placements of matched group 0.5h, has obvious burst effect.The result shows that irinotecan hydrochloride liposome that the present invention prepares effectively improves the envelop rate of medicine, has avoided the burst effect of liposome.
Embodiment 4: the irinotecan hydrochloride lipidosome injection
The 4th embodiment of the present invention adopts the further processing and preparing irinotecan hydrochloride of the irinotecan hydrochloride liposome lipidosome injection of embodiment 3 preparations.
The irinotecan hydrochloride liposome turbid liquor that embodiment 3 experimental grouies are made is through the sephadex column eluting, and the liposome that free irinotecan hydrochloride and bag is carried irinotecan hydrochloride separates.Bag is carried the irinotecan hydrochloride liposome is packaged in the ampoule of 5ml,
60The irinotecan hydrochloride lipidosome injection is made in Co radiation sterilization (RAD=150～1,800,000).The electron microscopic morphology observation is carried out in the sampling of irinotecan hydrochloride lipidosome injection, and bag carries the liposome form rounding of irinotecan hydrochloride, evenly, does not have the group of gathering, particle size distribution 100-250nm.The result shows that wrapping the liposome that carries irinotecan hydrochloride can make concrete preparations such as injection, and form keeps better, and is stable higher.
In the above-described embodiments, only the present invention has been carried out exemplary description, but those skilled in the art can carry out various modifications to the present invention after reading present patent application under the situation that does not break away from the spirit and scope of the present invention.
Claims (9)
1. preparation method of wrapping the medicine carrying composite lipidosome, it is characterized in that: medicine is scattered in the amphipathy macromolecule material system of dissolving or molten condition, rapid cooling is handled and is obtained medicine solid dispersion, then medicine solid dispersion and liposome filmogen are dispersed in the organic facies system, according to method for preparing lipidosome, make the liposome of bag medicine carrying thing, realize that the even bag of medicine is loaded in liposome.
2. preparation method according to claim 1 is characterized in that: described medicine is meant middle pharmaceutically active ingredient, chemicals, aminoacid, polypeptide or the protein drug of performance prevention, treatment, health care, cleaning, beautification function.
3. preparation method according to claim 1, it is characterized in that: described amphipathy macromolecule material is meant natural macromolecular material, semi-synthetic macromolecular material and the synthesized polymer material of pharmaceutically generally acknowledging, comprises polyvidone, Polyethylene Glycol, poloxamer and polyvinyl alcohol.
4. preparation method according to claim 1 is characterized in that: described liposome filmogen comprises hydrogenated phospholipid, synthetic phospholipid, cholesterol and surfactant, and hydrogenated phospholipid comprises: hydrogenation egg yolk lecithin and hydrogenated soya phosphatide; Synthetic phospholipid is meant known synthetic phospholipid of pharmacy and polyethyleneglycol modified derivant thereof, comprising: two palmityl PHOSPHATIDYL ETHANOLAMINE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, DOPE, two palmityl phosphatidyl glycerols, two palmityl phosphatidic acid are the polyethyleneglycol modified derivant of one or more and they wherein; Surfactant comprises: tween series, span series, oleic acid, hexadecanol, octadecanol, glycerol, propylene glycol.
5. preparation method according to claim 1, it is characterized in that: described organic facies is meant alcohol, ketone, ester, ether and the alkyl halide of carbon number 10 with interior straight chain, side chain, comprises ethanol, the tert-butyl alcohol, acetone, ethyl acetate, ether, petroleum ether, chloroform, dichloromethane.
6. preparation method according to claim 1 is characterized in that: also contain in the known surfactant of pharmacy, polyhydric alcohol or saccharide, macromolecular scaffold proppant, antioxidant, stabilizing agent, the pH regulator agent one or more in the described organic facies system.
7. preparation method according to claim 1 is characterized in that: the liposome particle diameter of described bag medicine carrying thing is micron order or nanoscale.
8. preparation method according to claim 1 is characterized in that: the liposome of described bag medicine carrying thing is further removed lipid fragment and unnecessary salt ion by dialysis, processing method centrifugal, chromatography.
9. preparation method according to claim 1, it is characterized in that: described bag medicine carrying composite lipidosome is further processed, form the raw material of oral, mucosa, injection, percutaneous drug delivery preparation, make the concrete preparation of performance prevention, treatment, health care, cleaning, beautification function.
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| CN111419827A (en) * | 2018-12-21 | 2020-07-17 | 宜昌人福药业有限责任公司 | Pharmaceutical composition for alfentanil transdermal administration and preparation method and application thereof |
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