CN104096245A - Ultrasound lipid microbubble wrapping drug-carrying albumin nanoparticles and preparation method thereof - Google Patents
Ultrasound lipid microbubble wrapping drug-carrying albumin nanoparticles and preparation method thereof Download PDFInfo
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- CN104096245A CN104096245A CN201410342322.4A CN201410342322A CN104096245A CN 104096245 A CN104096245 A CN 104096245A CN 201410342322 A CN201410342322 A CN 201410342322A CN 104096245 A CN104096245 A CN 104096245A
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Abstract
The invention discloses an ultrasound lipid microbubble wrapping drug-carrying albumin nanoparticles and a preparation method thereof. The drug-carrying albumin nanoparticles comprise drugs and albumin. An ultrasound lipid microbubble membrane material mainly comprises phospholipid components and can wrap gas and the drug-carrying albumin nanoparticles simultaneously to form a composite structure with the gas and the nanoparticles in the middle. According to the ultrasound lipid microbubble wrapping the drug-carrying albumin nanoparticles and the preparation method thereof, the drug-carrying capacity of the microbubble is high, the preparation technology is simple, the production cost is low, and the ultrasound lipid microbubble is prone to industrial production, not only can be taken as an ultrasound developer for disease diagnosis, but also can be taken as a drug-carrying preparation for disease treatment.
Description
[technical field]
Relate to lipid microbubble of a kind of middle parcel medicine carrying albumin nano granular and gas and preparation method thereof herein.
[background technology]
Along with the development of ultrasonic development technology, it is found that microvesicle can significantly improve ultrasonoscopy to specific mass, in the middle of developing thus, the ultrasonic microbubble of gassiness is as acoustic contrast agent.Acoustic contrast agent can strengthen the organa parenchymatosums' such as cardiac muscle, liver, brain two-dimensional ultrasonic image and blood flow Doppler effect, can obviously improve the ultrasonic resolution capability for diseased region form.
Nano-medicament carrier is the focus in current pharmaceutical preparation research.Nanoparticle has the following advantages aspect drug delivery: have relatively high drug loading and envelop rate, can improve the blood drug level of target position, prolong drug is in the action time of target position, reduce drug degradation, improve medicine stability, and nanoparticle has EPR effect, be beneficial to transmission medicine and enter the pathological tissues such as tumor.But the development of targeted nano granule runs into some problems, as still not ideal enough in targeting efficiency, the joint efficiency of targeted molecular and nano-carrier is lower.
Medicine carrying ultrasonic microbubble drug-supplying system is a kind of Novel Drug Delivery Systems that has potentiality.The method is made up of medicine-carrying microvesicle system and ultrasonically controlled-release system.Its principle be by medicine-carrying microvesicle after intravenous injection, body surface adopt ultrasonic radiation, make microvesicle directional blasting, in vivo target site discharge medicine.The explosion of microvesicle simultaneously can cause " acoustic horn effect ", strengthens local blood capillary and permeability of cell membrane, promotes drug osmotic, thereby realizes the target administration of medicine.But still there is at present technical barrier: microvesicle is as pharmaceutical carrier, and microvesicle center is gas, and shell is lipid film, thereby its drug loading is lower, cause that to be transported to the drug level of target position lower, concerning most drug, be not enough to produce effective pharmacological action.Medicine-carrying microvesicle is only applicable to the medicine that a small amount of drug effect is stronger at present.
[summary of the invention]
This law improving eyesight be for lipid microbubble entrapment efficiency and drug loading is low and the inefficient problem of nanoparticle targeting, provide a kind of new centre to wrap up the preparation method of the lipid microbubble of medicine carrying albumin nano granular and gas simultaneously.The microvesicle of this novel parcel medicine carrying albumin nano granular can improve the drug loading of microvesicle greatly, and this microvesicle broken up under localization by ultrasonic irradiation in vitro, discharges medicine carrying albumin nano granular in target position, greatly improves target administration efficiency.
Object of the present invention realizes by following technical solution:
Step 1; the albumin aqueous solution of preparation 0.5%～6%; the alcoholic solution of another compounding pharmaceutical; the alcoholic solution of medicine is added drop-wise in albumin aqueous solution with the speed of 0.1～5mL/min; add a certain amount of glutaraldehyde; stir and solidify, rotary evaporation is removed ethanol, obtains medicine carrying albumin nano granular suspension.
Step 2, is mixed in proportion phospholipid, glycerol and phosphate buffer heat.The albumin nano granular suspension making added appropriate step 1 before heating is cultivated in.Be filled with fluorine carbon gas vibration 2-200s, make the lipid microbubble of parcel medicine carrying albumin nano granular.
The microvesicle making by mechanical oscillation method in step 2, inner air inclusion and medicine carrying albumin nano granular, its diameter Distribution scope is 4 to 6 microns.
The microvesicle of gained of the present invention can quiet note for clinical, or adopt art-recognized method to be prepared into powder or lyophilized preparation administration.
With by nanoparticle absorption or be connected in compared with the system on microvesicle surface, the present invention prepares the lipid microbubble of parcel medicine carrying albumin nano granular first, and medicine carrying albumin nano granular is wrapped in to microvesicle adipose membrane inside.Preparation technology is simple, is easy to industrialization, and preparation process does not relate to chemical reaction, does not adopt the organic solvent that toxicity is large.
The lipid microbubble of the parcel medicine carrying albumin nano granular that this patent is prepared first can accurately be located in vivo explosion under transabdominal ultrasonography irradiation, discharges the albumin nano granular of its parcel, thereby improves the target administration efficiency of nanoparticle.Adopt the method for microvesicle parcel drug-carrying nanometer particle can significantly improve the drug loading of microvesicle, reduce the degraded of medicine, realize the slow release of medicine at target position, prolong drug action time, increased the curative effect of medicine.
Brief description of the drawings:
Fig. 1 is 100 times of lower light microscopic photos of the prepared lipid microbubble that carries fluorine carbon gas of example 1 of the present invention
Fig. 2 is the image under the prepared optical microscope (400 times) that carries curcumin albumin nano granular lipid microbubble of the embodiment of the present invention 1.
Fig. 3 is the schematic diagram of the lipid microbubble that carries curcumin albumin nano granular and fluorine carbon gas prepared of the present invention
Fig. 4 is the granularmetric analysis figure that bag prepared by the present invention carries the lipid microbubble of curcumin albumin nano granular and fluorine carbon gas
Fig. 5 is the external development figure that bag prepared by the present invention carries the lipid microbubble of curcumin albumin nano granular and fluorine carbon gas
Fig. 6 is the rabbit liver development figure that bag prepared by the present invention carries the lipid microbubble of curcumin albumin nano granular and fluorine carbon gas
Fig. 7 is that bag prepared by the present invention carries the lipid microbubble of curcumin albumin nano granular and fluorine carbon gas in the release in vitro situation of ultrasonic front and back.
Detailed description of the invention:
Describe the present invention by the following examples, but the present invention is not limited in following embodiment.
Embodiment 1
1, carry the preparation of the lecithin microvesicle of fluorine carbon gas
Lecithin, glycerol and phosphate buffer are mixed and heated, and the mass volume ratio of glycerol and phosphate buffer is 58.1%.The mass volume ratio of lecithin and phosphate buffer is 6.1%.Be filled with fluorine carbon gas vibration 40-50s, make blank lipid microbubble.
2, prepare curcumin albumin nano granular based on Nanoparticle albumin-bound technology
Precision takes recipe quantity curcumin and is dissolved in 1ml ethyl acetate and forms oil phase, separately getting 40mg albumin is dissolved in 4mL distilled water and forms water, both mix, magnetic stirrer 5min forms colostrum, under condition of ice bath, colostrum is placed in to cell pulverization machine Probe Ultrasonic Searching (85W, 1min) and obtains emulsion, by emulsion be transferred to Rotary Evaporators revolve steam remove ethyl acetate, obtain curcumin nano suspension.
3, carry the preparation of curcumin albumin nano granular lipid microbubble
Lecithin, glycerol and phosphate buffer are mixed and heated, and the mass ratio of glycerol and phosphate buffer is 58.1%.The mass ratio of lecithin and phosphate buffer is 6.1%.The curcumin nano suspension making added the step 2 of 400 μ l before heating is cultivated in.Heating was cultivated after 2 hours, was filled with fluorine carbon gas shock and swung 40-50s, made the lipid microbubble that carries albumin nano granular.
Embodiment 2
1, carry the preparation of the lecithin microvesicle of fluorine carbon gas
Lecithin, glycerol and phosphate buffer are mixed and heated, and the mass volume ratio of glycerol and phosphate buffer is 58.1%.The mass volume ratio of lecithin and phosphate buffer is 6.1%.Be filled with fluorine carbon gas vibration 40-50s, make blank lipid microbubble.
2, the preparation of curcumin albumin nano granular
Adopt desolvation to prepare curcumin albumin nano granular; precision takes 10mg bovine serum albumin and is dissolved in 1mL water; separately taking 4mg curcumin is dissolved in 6mL dehydrated alcohol; volume flow with 1mL/min is added drop-wise to curcumin alcoholic solution in albumin aqueous solution; add a certain amount of 0.25% glutaraldehyde; lucifuge stirs 4h solidifies, and removes ethanol in 35 DEG C of rotary evaporations, obtains curcumin albumin nano granular suspension.Recording its envelop rate is 85.48%.
3, carry the preparation of curcumin albumin nano granular lipid microbubble
Lecithin, glycerol and phosphate buffer are mixed and heated, and the mass ratio of glycerol and phosphate buffer is 58.1%.The mass ratio of lecithin and phosphate buffer is 6.1%.The nanoparticle suspension making added the step 2 of 400 microlitres before heating is cultivated in.Heating was cultivated after 2 hours, was filled with fluorine carbon gas shock and swung 40-50s, made the lipid microbubble that carries albumin nano granular.Gained microvesicle, in optical microphotograph Microscopic observation, be the results are shown in Figure to 1 and Fig. 2.The particle size distribution figure of gained microvesicle is shown in Fig. 4.
4, external water pocket develops
The lipid microbubble water pocket that carries fluorine carbon gas and curcumin albumin nano granular making is wrapped up, measure its development effect.Result shows that microvesicle prepared by the present invention has good external development effect (Fig. 5).
5, new zealand white rabbit liver develops
Taking new zealand white rabbit (new zealand white rabbit derives from Medical University Of Chongqing's Experimental Animal Center) as experimental subject, application speed is slept after new II type (1mL/Kg) intramuscular anesthesia White Rabbit, dorsal position solid, adopt the method for self cross-reference, before radiography, by the phospholipid microvesicle that carries fluorine carbon gas and curcumin albumin nano granular of 1mL, in rabbit auricular vein injects rabbit body, observe the development effect at rabbit liver position.Result shows that microvesicle prepared by the present invention has development effect (seeing Fig. 6) in good body.
6, external supersonic discharges
Application Bag filter method, investigates lipid microbubble that the bag that makes carries curcumin albumin nano granular and fluorine carbon gas ultrasonic or do not add the curcumin accumulative total release rate (seeing Fig. 7) of different time points in ultrasonic situation.Result shows that, under ultrasonication, the rate of releasing drug of microvesicle improves greatly, proves that this microvesicle has good ultrasonic response, and under ultrasonication, adipose membrane breaks, and discharges the curcumin albumin nano granular of its parcel, and rate of releasing drug improves greatly.
Claims (7)
1. one kind carries the lipid microbubble of albumin nano granular, its feature is as in membrane structure that this lipid microbubble is made up of phospholipid composition, in described membrane structure, be enclosed with the albumin nano granular of gas and medicine carrying simultaneously, wherein phospholipid composition is selected from phospholipid material, and albumin is selected from albumin class material.
2. the lipid microbubble of as claimed in claim 1 year albumin nano granular, is characterized in that: described phospholipid includes but not limited to Ovum Gallus domesticus Flavus lecithin, soybean lecithin, phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE, and other matrix material.
3. the lipid microbubble that carries as claimed in claim 1 albumin nano granular, is characterized in that: described albumin class material includes but not limited to human serum albumin, bovine serum albumin, albumin rabbit serum, porcine hemoglobin, sheep blood serum albumin, donkey serum albumin or horse serum albumin and other kind albumin.
4. the lipid microbubble that carries as claimed in claim 1 albumin nano granular, is characterized in that: described albumin nano granular is wrapped in lipid microbubble inside.
5. the lipid microbubble that carries as claimed in claim 1 albumin nano granular, is characterized in that: described gas is selected from the gas of fluorocarbon gas, air, oxygen, nitrogen and carbon dioxide one or more mixing wherein.
6. a preparation method of wrapping up the lipid microbubble of albumin nano granular, is characterized in that, comprises the steps:
Step (a): adopt desolvation, the albumin nano granular that emulsion process or Nanoparticle albumin-bound legal system are main material for the albumin of carrier band medicine.
Step (b): phospholipid composition adds in the mixed solution of hot glycerol and phosphate buffer and dissolves;
Step (c): the medicine carrying albumin nano granular suspension making in step (a) is added in the phospholipid mixed solution making in step (b).
Step (d): after cultivation, specific gas is filled with in medicine carrying container, utilizes the mode dissolution liquid such as ultrasonic, stirring, concussion to form the emulsion that particle diameter is even and physical property is stable.In the middle of obtaining, contain the lipid microbubble of gas and albumin nano granular.
7. the lipid microbubble that carries as claimed in claim 1 albumin nano granular, is characterized in that: after pharmaceutical pack is wrapped in to albumin nano granular, wrap up in microvesicle, nanoparticle is present in microvesicle adipose membrane again.
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| CN105999314A (en) * | 2016-07-11 | 2016-10-12 | 四川省人民医院 | Ultrasonic contrast agent and preparing method thereof |
| CN106267248A (en) * | 2016-09-08 | 2017-01-04 | 重庆医科大学 | A kind of lipid ultrasonic microvesicle carrying modified with folic acid mesoporous silicon dioxide nano particle and preparation method thereof |
| CN108114273A (en) * | 2018-02-02 | 2018-06-05 | 南京大学 | A kind of perfluocarbon albumin nano granular and preparation method and application |
| KR20200034631A (en) * | 2018-09-21 | 2020-03-31 | 삼육대학교산학협력단 | Ultrasound-Assisted Delivery System using Microcapsule Platform Containing Nanobubbles and Drugs |
| CN113876737A (en) * | 2021-10-22 | 2022-01-04 | 复旦大学附属金山医院(上海市金山区核化伤害应急救治中心、上海市金山区眼病防治所) | Lipid-coated albumin-bound chemotherapeutic drug nanoparticle and preparation method and application thereof |
| CN115590986A (en) * | 2022-11-08 | 2023-01-13 | 杭州师范大学附属医院（杭州市第二人民医院）（Cn） | Preparation method and application of lipid nano microbubble ultrasound contrast agent carrying tanshinone IIA |
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| CN101711736A (en) * | 2009-12-17 | 2010-05-26 | 重庆医科大学 | Method for preparing medicine-carrying microvesicle |
| CN101850124A (en) * | 2010-04-13 | 2010-10-06 | 姬尚义 | Albumin nanometer-ultrasonic microbubble carrier tissue type plasminogen activator gene target system and preparation method thereof |
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| CN105999314A (en) * | 2016-07-11 | 2016-10-12 | 四川省人民医院 | Ultrasonic contrast agent and preparing method thereof |
| CN105999314B (en) * | 2016-07-11 | 2018-12-18 | 四川省人民医院 | A kind of acoustic contrast agent and preparation method thereof |
| CN106267248A (en) * | 2016-09-08 | 2017-01-04 | 重庆医科大学 | A kind of lipid ultrasonic microvesicle carrying modified with folic acid mesoporous silicon dioxide nano particle and preparation method thereof |
| CN106267248B (en) * | 2016-09-08 | 2020-02-07 | 重庆医科大学 | Lipid ultrasonic microbubble carrying folic acid modified mesoporous silica nanoparticles and preparation method thereof |
| CN108114273A (en) * | 2018-02-02 | 2018-06-05 | 南京大学 | A kind of perfluocarbon albumin nano granular and preparation method and application |
| KR20200034631A (en) * | 2018-09-21 | 2020-03-31 | 삼육대학교산학협력단 | Ultrasound-Assisted Delivery System using Microcapsule Platform Containing Nanobubbles and Drugs |
| KR102216549B1 (en) | 2018-09-21 | 2021-02-17 | 삼육대학교산학협력단 | Ultrasound-Assisted Delivery System using Microcapsule Platform Containing Nanobubbles and Drugs |
| US11890370B2 (en) | 2018-09-21 | 2024-02-06 | Sahmyook University Industry-Academic Cooperation Foundation | Ultrasound-induced drug delivery system using drug carrier comprising nanobubbles and drug |
| CN113876737A (en) * | 2021-10-22 | 2022-01-04 | 复旦大学附属金山医院(上海市金山区核化伤害应急救治中心、上海市金山区眼病防治所) | Lipid-coated albumin-bound chemotherapeutic drug nanoparticle and preparation method and application thereof |
| CN115590986A (en) * | 2022-11-08 | 2023-01-13 | 杭州师范大学附属医院（杭州市第二人民医院）（Cn） | Preparation method and application of lipid nano microbubble ultrasound contrast agent carrying tanshinone IIA |
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