CN101732343A - Nano perfluocarbon liposome particles and preparation method thereof - Google Patents
Nano perfluocarbon liposome particles and preparation method thereof Download PDFInfo
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- CN101732343A CN101732343A CN 200910200608 CN200910200608A CN101732343A CN 101732343 A CN101732343 A CN 101732343A CN 200910200608 CN200910200608 CN 200910200608 CN 200910200608 A CN200910200608 A CN 200910200608A CN 101732343 A CN101732343 A CN 101732343A
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Abstract
The invention relates to nano perfluocarbon liposome particles and a preparation method thereof, belonging to the technical field of biomedicine. The particles have the average particle diameter of 50 to 100nm and comprise the following components in parts by weight: 1 to 20 parts of lecithin, 1 part of cholesterol and 2 to 1000 parts of perfluocarbon liquid. The invention can ensure that the prepared liposome reaches higher entrapment and has uniform particle diameter and batter stability, and guarantees the storage property of the liposome by adopting a freeze-drying process.
Description
Technical field
What the present invention relates to is the material in a kind of biological medicine technology field and preparation method thereof, specifically is a kind of nano perfluocarbon liposome particles and preparation method thereof.
Background technology
Acute lung injury/adult respiratory distress syndrome (ALI/ARDS) is because the pulmonary capillary inflammatory injury that lung serious disease outer or that lung is interior causes, permeability increases, secondary high-permeability pulmonary edema and the anoxia respiratory failure (I type) of carrying out property, chest films showed diffusivity lung soaks into one group of syndrome of shade.Be treatment difficult point and the emphasis in the emergency medicine field, can be secondary in the process of various diseases such as shock, wound, infection that clinical hypoxemia and carrying out property dyspnea with stubbornness is feature, poor prognosis.During treatment, need in time to correct anoxia, to guarantee having enough oxygen to supply in the tissue.(conventional mechanicalventilation, defective CMV) is that it improves the finiteness of oxygenate and overall prognosis to traditional mechanical ventilation, even the complication that might cause (respirator associated pneumonia and injury of lung etc.).In recent years liquid ventilation particularly partial liquid ventilation as if (partial liquid ventilation PLV) has demonstrated good effect.But because traditional liquid ventilation expense is higher and need limit the application during this type of therapy is given treatment at the scene there being the wound respirator to assist the restriction of factors such as carrying out down.
Perfluocarbon (PFC) is that the hydrogen atom in the Hydrocarbon is replaced the compounds that the back forms by fluorine atom, and metabolism does not take place its stable chemical performance in vivo, and is nontoxic, colourless, tasteless, water insoluble; Have high density, low-viscosity, low surface tension and good characteristics such as gas solubility, make it become good breathing gas vehicle medium, be used to blood substitute (PFC Emulsion) the earliest.Simultaneously,, do not need to join type so have because it presents chemistry and biologically inert, the advantage of good biocompatibility, simultaneously, perfluocarbon can be got rid of external by breathing fully.At present, had France, China, Russia, Japan and other countries in 70～eighties of 20th century perfluocarbon emulsion to be carried out comprehensive, detailed research, portioned product also enters clinical trial.But the biocompatibility of this series products also is not fine, and also there are many shortcomings in the preservation aspect.
Liposome (liposome) is as a kind of comparatively widely pharmaceutical carrier of Recent study, and its main feature is to protect encapsulated medicine, increases medicine stability, changes medicine distribution behavior in vivo, and carrying medicaments is passive or initiatively be targeted to diseased region.The research of liposome more and more comes into one's own, and development rapidly, and market prospect that it is tempting and good technical have been penetrated into every field such as pharmacy, biotechnology, immunomodulating, genomic medicine, cosmetics exploitation.Perfluocarbon by liposome can be inserted between the bilayer lipid membrane, can improve its usability preferably, and its side effect of bigger reduction.
Present main means all are that perfluorocarbon compound is prepared into nano level emulsion or it is prepared into water miscible perfluocarbon liquid.Find through retrieval prior art, Chinese patent literature CN101199548A has put down in writing a kind of " perfluocarbon emulsion and preparation method thereof ", the prepared perfluocarbon particle size of emulsion of this method is generally all bigger, and can not well guarantee effective drug loading of perfluocarbon liquid in the prepared emulsion in its preparation process.
Summary of the invention
The present invention is directed to the prior art above shortcomings, a kind of nano perfluocarbon liposome particles and preparation method thereof is provided, preparation gained nanoscale perfluocarbon liposome can both better controlled aspect particle diameter and drug loading, and experimental repeatability is good, can adapt to the limitation that exists in its use, satisfy the needs of clinical treatment.Simultaneously, the liposome microsphere of this method preparation has to be preserved conveniently, and the bioavailability height, the advantage that side effect is little.
The present invention is achieved by the following technical solutions:
The mean diameter that the present invention relates to nano perfluocarbon liposome particles is 50～100nm, and its component and content are: the cholesterol of the lecithin of 1～20 weight portion, 1～20 weight portion and the perfluorocarbon liquids of 2～1000 weight portions.
Described lecithin is a kind of in hydrogenated soy phosphatidyl choline, soybean lecithin or the Ovum Gallus domesticus Flavus lecithin;
Described cholesterol is a kind of in protein cholesterol, serum cholesterol, yolk cholesterol or the gallbladder cholesterol;
The mass percent concentration of described perfluorocarbon liquids is 95% ~ 100%.
The present invention relates to the preparation method of above-mentioned nano perfluocarbon liposome particles, may further comprise the steps:
The first step, the lecithin with 1～20 weight portion, the cholesterol of 1～20 weight portion and the perfluocarbon of 2～1000 weight portions are dissolved in the reaction bulb that fills organic solvent, make liposome solutions behind the ultra-sonic dispersion;
Described lecithin is a kind of in hydrogenated soy phosphatidyl choline, soybean lecithin or the Ovum Gallus domesticus Flavus lecithin;
Described cholesterol is a kind of in protein cholesterol, serum cholesterol, yolk cholesterol or the gallbladder cholesterol;
Described organic solvent is meant: chloroform, methanol, ethanol, normal hexane, dichloromethane, acetic acid third fat, trichloroethylene, toluene, 1, a kind of in 2-dichloroethanes, xylol, acetic acid penta fat, tetrachloroethylene, n-amyl alcohol or the hexone.
Second step, the liposome solutions in the reaction bulb is carried out reduced pressure treatment and heat drying successively handle, obtain the liposome solute;
Described vacuum decompression is handled and is meant: the environment that liposome solutions is placed 20～60 ℃ and 0～1MPa decompression is down flung to organic solvent, obtains the liposome solute;
Described heat drying is meant: carry out vacuum drying under 10～70 ℃.
The 3rd step, use buffer solution dissolve the thin film on the bottle wall that is formed on reaction bulb, obtain the lipoid suspension through the swelling water bath processing;
The component of described buffer solution and content thereof are: the soft agent of 0.01～20mg/mL surfactant and 0.01～20mg/mL, the pH of this buffer solution are 6.0～8.5;
Described surfactant is a kind of in span, tween, cetyl trimethyl ammonium bromide, Polyethylene Glycol, polyethenoxy ether sulphonate or the polycyclic aromatic hydrocarbon sulfonate condensation substance.
The 4th step, add freeze drying protectant after adopting high speed shear method or high pressure homogenization method with lipoid suspension homogenizing, drying obtains nano perfluocarbon liposome particles after handling.
Described high speed shear method is meant: place high-speed shearing machine to carry out mechanical agitation the lipoid suspension.
Described high pressure homogenization method is meant: adopt high pressure homogenizer the lipoid suspension to be placed under the pressure of 60～100MPa the circulation homogenizing 0.5～2 hour;
Described dried is meant lyophilization or vacuum drying;
Described freeze drying protectant is a kind of in mannitol, trehalose, fructose, trehalose, glucose, lactose, sorbitol or the sucrose, and its consumption is 0～80% of a liposome solutions gross mass.
The prescription and the technology of nano perfluocarbon of the present invention (FC-77) liposome can make liposome reach higher entrapment, and prepared liposome uniform particle diameter, and stability is also better.And make the storage of liposome obtain guarantee by freeze-dry process.
Description of drawings
Fig. 1 is an embodiment field transmission Electronic Speculum picture.
Fig. 2 is embodiment particle size distribution figure.
The specific embodiment
Below embodiments of the invention are elaborated, present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Taking by weighing 60mg perfluocarbon (FC-77), 400mg hydrolecithin and 150mg protein cholesterol is dissolved in the 20ml chloroform altogether, ultrasonic making it dissolved fully, be transferred in the round-bottomed flask, under 45 ℃ water-bath, rotating speed is 200r/min, reduction vaporization falls organic solvent makes it film forming on the bottle wall, and vacuum drying is 24 hours under the room temperature.Adding tween 80, the 9mg/ml that 60ml concentration is 8mg/ml then goes to support in the phosphate buffered solution of sodium cholate, abundant swelling, again through the ultrasonic 10min of water-bath, this the suspension that obtains was joined in the high pressure homogenizer under the pressure of 80Mpa the circulation homogenizing 1 hour, and this moment is for being with white opalescent perfluocarbon (FC-77) liposome solutions.This solution is added 800mg mannitol lyophilization 48 hours, both obtained white liposome powder.
Taking by weighing 8mg perfluocarbon (FC-77), 200mg soybean lecithin and 50mg protein cholesterol is dissolved in the 20ml methanol altogether, ultrasonic making it dissolved fully, be transferred in the round-bottomed flask, under 25 ℃ water-bath, rotating speed is 300r/min, reduction vaporization falls organic solvent makes it film forming on the bottle wall, and vacuum drying is 8 hours under the room temperature.Adding Arlacel-80, the 6mg/ml that 20ml concentration is 4mg/ml then goes to support in the phosphate buffered solution of sodium cholate, abundant swelling, again through the ultrasonic 30min of water-bath, this the suspension that obtains was joined in the high pressure homogenizer under the pressure of 60Mpa the circulation homogenizing 0.5 hour, and this moment is for being with white opalescent perfluocarbon (FC-77) liposome solutions.This solution is added 300mg mannitol lyophilization 24 hours,, both obtained white liposome powder.
Embodiment 3
Taking by weighing 168mg perfluocarbon (FC-77), 400mg Ovum Gallus domesticus Flavus lecithin and 250mg serum cholesterol is dissolved in 80ml acetic acid penta fat altogether, ultrasonic making it dissolved fully, be transferred in the round-bottomed flask, under 45 ℃ water-bath, rotating speed is 100r/min, reduction vaporization falls organic solvent makes it film forming on the bottle wall, and vacuum drying is 12 hours under the room temperature.Adding Polyethylene Glycol, the 20mg/ml that 40ml concentration is 12mg/ml then goes to support in the phosphate buffered solution of sodium cholate, abundant swelling, again through the ultrasonic 60min of water-bath, this the suspension that obtains was joined in the high pressure homogenizer under the pressure of 100Mpa the circulation homogenizing 2 hours, and this moment is for being with white opalescent perfluocarbon (FC-77) liposome solutions.This solution is added 800mg mannitol lyophilization 48 hours, both obtained white liposome powder.
Embodiment 4
Taking by weighing 80mg perfluocarbon (FC-77), 600mg Ovum Gallus domesticus Flavus lecithin and 350mg serum cholesterol is dissolved in the 60ml ethanol altogether, ultrasonic making it dissolved fully, be transferred in the round-bottomed flask, under 30 ℃ water-bath, rotating speed is 200r/min, reduction vaporization falls organic solvent makes it film forming on the bottle wall, and vacuum drying is 24 hours under the room temperature.Adding polyethenoxy ether sulphonate, the 8mg/ml that 80ml concentration is 6mg/ml then goes to support in the phosphate buffered solution of sodium cholate, abundant swelling, again through the ultrasonic 20min of water-bath, this the suspension that obtains was joined in the high pressure homogenizer under the pressure of 60Mpa the circulation homogenizing 1.5 hours, and this moment is for being with white opalescent perfluocarbon (FC-77) liposome solutions.This solution is added 450mg mannitol lyophilization 24 hours, both obtained white liposome powder.
Claims (10)
1. nano perfluocarbon liposome particles, it is characterized in that: its component and content are: the cholesterol of the lecithin of 1～20 weight portion, 1 weight portion and the perfluorocarbon liquids of 2～1000 weight portions;
Described granule mean diameter is 50～100nm.
2. nano perfluocarbon liposome particles according to claim 1 is characterized in that, described lecithin is a kind of in hydrogenated soy phosphatidyl choline, soybean lecithin or the Ovum Gallus domesticus Flavus lecithin.
3. nano perfluocarbon liposome particles according to claim 1 is characterized in that, described cholesterol is a kind of in protein cholesterol, serum cholesterol, yolk cholesterol or the gallbladder cholesterol.
4. the preparation method of a nano perfluocarbon liposome particles according to claim 1 is characterized in that, may further comprise the steps:
The first step, the lecithin with 1～20 weight portion, the cholesterol of 1 weight portion and the perfluocarbon of 2～1000 weight portions are dissolved in the reaction bulb that fills organic solvent, make liposome solutions behind the ultra-sonic dispersion;
Second step, the liposome solutions in the reaction bulb carried out successively vacuum decompression is handled and heat drying is handled, obtain the liposome solute;
The 3rd step, use buffer solution dissolve the thin film on the bottle wall that is formed on reaction bulb, obtain the lipoid suspension through the swelling water bath processing;
The 4th step, add freeze drying protectant after adopting high speed shear method or high pressure homogenization method with lipoid suspension homogenizing, drying obtains nano perfluocarbon liposome particles after handling.
5. the preparation method of nano perfluocarbon liposome particles according to claim 4, it is characterized in that, described organic solvent is meant: chloroform, methanol, ethanol, normal hexane, dichloromethane, acetic acid third fat, trichloroethylene, toluene, 1, a kind of in 2-dichloroethanes, xylol, acetic acid penta fat, tetrachloroethylene, n-amyl alcohol or the hexone.
6. the preparation method of nano perfluocarbon liposome particles according to claim 4, it is characterized in that, described vacuum decompression is handled and is meant: with liposome solutions place 20～60 ℃ and less than the environment of 1MPa down decompression fling to organic solvent, obtain the liposome solute.
7. the preparation method of nano perfluocarbon liposome particles according to claim 4, it is characterized in that, the component of described buffer solution and content thereof are: the soft agent of 0.01～20mg/mL surfactant and 0.01～20mg/mL, the pH of this buffer solution are 6.0～8.5.
8. the preparation method of nano perfluocarbon liposome particles according to claim 4 is characterized in that, described high speed shear method is meant: place high-speed shearing machine to carry out mechanical agitation the lipoid suspension.
9. the preparation method of nano perfluocarbon liposome particles according to claim 4 is characterized in that, described high pressure homogenization method is meant: adopt high pressure homogenizer the lipoid suspension to be placed under the pressure of 60～100MPa the circulation homogenizing 0.5～2 hour.
10. the preparation method of nano perfluocarbon liposome particles according to claim 4 is characterized in that, described freeze drying protectant is a kind of in mannitol, trehalose, fructose, trehalose, glucose, lactose, sorbitol or the sucrose.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988294A (en) * | 2012-12-13 | 2013-03-27 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of fluorocarbon compound liposome |
| CN111617267A (en) * | 2020-07-07 | 2020-09-04 | 南京大学 | Nano-scale ultrasonic contrast agent coated with perfluorocarbon |
| CN113101269A (en) * | 2021-04-15 | 2021-07-13 | 四川大学华西医院 | Delivery system based on nano-liposome, preparation method and application |
| CN115969790A (en) * | 2022-05-27 | 2023-04-18 | 哈尔滨医科大学 | Pneumonia treatment drug PFC @4-OI and preparation method and application thereof |
-
2009
- 2009-12-24 CN CN 200910200608 patent/CN101732343A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988294A (en) * | 2012-12-13 | 2013-03-27 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of fluorocarbon compound liposome |
| CN102988294B (en) * | 2012-12-13 | 2015-03-11 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of fluorocarbon compound liposome |
| CN111617267A (en) * | 2020-07-07 | 2020-09-04 | 南京大学 | Nano-scale ultrasonic contrast agent coated with perfluorocarbon |
| CN113101269A (en) * | 2021-04-15 | 2021-07-13 | 四川大学华西医院 | Delivery system based on nano-liposome, preparation method and application |
| CN113101269B (en) * | 2021-04-15 | 2022-04-29 | 四川大学华西医院 | Delivery system based on nano-liposome, preparation method and application |
| CN115969790A (en) * | 2022-05-27 | 2023-04-18 | 哈尔滨医科大学 | Pneumonia treatment drug PFC @4-OI and preparation method and application thereof |
| CN115969790B (en) * | 2022-05-27 | 2024-09-06 | 哈尔滨医科大学 | Medicine PFC@4-OI for treating pneumonia and preparation method and application thereof |
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Open date: 20100616 |