CN102078624B - Efficient Gd-loaded liposome preparation and preparation method thereof - Google Patents
Efficient Gd-loaded liposome preparation and preparation method thereof Download PDFInfo
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- CN102078624B CN102078624B CN2010106075785A CN201010607578A CN102078624B CN 102078624 B CN102078624 B CN 102078624B CN 2010106075785 A CN2010106075785 A CN 2010106075785A CN 201010607578 A CN201010607578 A CN 201010607578A CN 102078624 B CN102078624 B CN 102078624B
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Abstract
The invention relates to a composite for diagnosing a human body or an animal body, namely, an efficient Gd-loaded liposome preparation and a preparation method thereof. The liposome preparation is prepared from the following components in parts by weight: 30-80 parts of paramagnetic Gd contrast agent, 250-500 parts of lecithin, 50-200 parts of liposome stabilizer and 200-600 parts of buffer solution, based on the weight of metal Gd. The Gd-loaded liposome is prepared by using a phospholipid gel method, and the Gd-loaded amount of the liposome prepared by the method is high, thereby effectively delaying the retention period of the contrast agent in the body; and the liposome is good in storage stability.
Description
Technical field
The present invention relates to a kind of Liposomal formulation of diagnosing with paramagnetism gadolinium contrast agent, it has the efficient characteristics such as gadolinium, slow release of carrying, and can be used as contrast medium, is used for diagnosing image form such as MRI, CT, scintigraphy, and then is used for the early diagnosis of tumor.
Background technology
Human beings'health and life in the tumor serious threat, and every year is made a definite diagnosis about 1,000 ten thousand people because of dead about 6,000,000 people of malignant tumor in the whole world.The key issue that oncotherapy faces is how early discovery, diagnosis and treatment.Iconography has the kinds of tumors diagnostic techniques at present, like nuclear magnetic resonance, and X-radial imaging, ultrasonic imaging and nuclear medicine etc.Wherein contrast agent is used to strengthen the intensity of image, through changing tissue local magnetic field intensity or relaxation time, or comes the difference of Enhanced Imaging factor through contrast agent physiology, biochemical characteristic, reaches the radiography purpose.
What magnetic resonance contrast agent was used is exactly the chelate of paramagnetic metal gadolinium ion the most widely, these hydrophilic chelates, and like Gd-DTPA, Gd-DOTA, Gd-DO3A-HP and Gd-DTPA-BMA are distributed in outside the born of the same parents, and are eliminated by kidney.Free gadolinium has high toxicity, is distributed in skeleton and liver in vivo, and can cause hepatic necrosis rapidly.All gadolinium contrast agent that contain all are chelates, can change intravital distribution behind the chelating to improve picture contrast, improve its toxic and side effects simultaneously.
Liposome is as a kind of targeted drug carrier; Can be with distributing in the body that changes medicine in drug powder or the cyto-architectural microgranule of solution type of being embedded in; Reduce the therapeutic dose and the toxic and side effects that reduces medicine of medicine, and can produce persistent therapeutical effect as drug-reservoir.After liposome injects in the body; Can from blood flow, be removed fast by the reticuloendothelial system picked-up; And nanometer liposome be because its small-size effect, skin effect can make its picked-up of escaping reticuloendothelial system and the prolong drug time of staying in vivo, and then reaches diseased region.
At present, existing many paramagnetic metal ion and chelate thereof are encapsulated the report in liposome both at home and abroad, prior art mainly can be divided two types: the first kind is to utilize liposome that needed diagnostic agent is wrapped in center aqueous intracavity; Because of these chelates all are hydrophilic; Seepage from lipid film very easily, envelop rate is lower (referring to Inter J Pharm, 2006; 312:105-112.UyenM Le; And some take to be fit to the multilamelar liposome of method such as multi-emulsion method preparation of liposome water soluble drug (referring to Acad J Sec Mil Med Univ.2007 Zhengrong Cui, et al.Long-circulating gadolinium-encapsulated liposomes for potentialapplication in tumor neutron capture therapy); 28 (1): 87-90.ZHANG Wei; GENG Fang, et al.Preparation and characterization of pulmonary targeting DepoFoam loaded MRcontrast media:gadopentetate dimeglumine), though envelop rate improves; But its particle diameter is bigger, in the micron order scope; Second type is that needed chelate and hydrophobicity " anchor " base is combined, and chelate is limited on the liposome membrane, and the DTPA-distearyl amide that this type conjugate has been reported has people such as Hnatowich is (referring to J Nucl Med; 1981; 22:810-814.Hnatowich D J, Friedman B, Clancy B; And Novak M.Labeling of Preformed Liposomes with Gd-67and Tc-99m by Chelation); People's such as Kabalka DTPA-distearyl ester (referring to Magn Reson Med1991,19:406-415.Kabalka G W, Davis M A; Et al.Gadolinium-labeled liposomes containingamphiphilic Gd-DTPA derivatives of varying chain length:targeted MRI contrast enhancementagents for the liver) and people's such as Volkmar the many chelate polymers of DTPA-PLL-NGPE (referring to Colloids andSurfaces B:Biointerfaces; 2000,18,293-299.Weissig V; Babich J; Torchilin V.Long-circulatinggadolinium-loaded liposomes:potential use for magnetic resonance imaging of the blood pool), the liposome stability of this class methods preparation is better, and gadolinium chelate compound or complex are difficult for leaking out from lipid film; But preparation process more complicated; Some compositions are also expensive, and some water-insoluble materials can't eliminate from liver, and permanent the reservation wherein.
Although the report of the Liposomal agents of many paramagnetism gadolinium contrast agent is arranged, its performance still is difficult to satisfy the clinical practice requirement.This mainly is because its low envelop rate, is difficult to remove free trivalent gadolinium ion chelate in the liposome, and contrast agent is prone to that reason such as leakage causes during storage.
In general; Fat-soluble medicine is easy to parcel and advances in the liposome, on the other hand, and for water soluble drug; Through medicine electrically charged with the electrostatic interaction between charged lipid or lean in the liposome initiatively medicine carrying of outside gradient, water soluble drug also can high envelop rate wraps into aqueous phase in the liposome.Yet for a kind of water miscible neutral medicine, height is sealed wraps into the liposome not a duck soup.For effectively with this water miscible medicine a large amount of encapsulate aqueous phase in liposome; People such as Brandl M (referring to ChemPhys Lipids, 1997,87; 65-72.Brandl M; Drechsler M, Bachmann D, and Bauer K H.Morphologyof semisolid aqueous phosphatidylcholine dispersions; A freeze fracture electron microscopy study.) proposed the notion of a kind of vesicle type phospholipid gel (VPG), it is a kind of spawn that goes out to have unique vesicle form that when lipid concentration is higher than 250mg/g or 325mmol/L far away, prepares.The ratio of aqueous medium and vesicle are compared highlyer outward in the VPG vesicle, and the ability of promptly sealing aqueous pharmaceutical is stronger; In the vesicle core and there is not Concentraton gradient on every side, still can guarantee the constant of the inner drug loading of VPG under the long preservation; Before application, add excessive aqueous medium, and gentle agitation, can make VPG change small liposome (SUV) dispersion into.
The present invention uses for reference the preparation principle of vesicle phospholipid gel, improves method for preparing, through the novel method of thin film dispersion-high pressure homogenize-vacuum concentration, has prepared the high Liposomal formulation that carries gadolinium.Its preparation technology is simple, and liposome is higher to the gadolinium amount of carrying of gadolinium chelate compound, and particle diameter is less, stable performance, and have the good slow release effect, but the efficient diagnosis infantile tumour.
Summary of the invention
The objective of the invention is to prepare the Liposomal formulation of a kind of efficient year gadolinium, nanometer particle size, be intended to a large amount of gadoliniums are wrapped in the liposome,, delay its circulation time in vivo, improve the radiography effect through the nanometer liposomeization of gadolinium contrast agent.
Disclosed by the invention is the efficient gadolinium liposome that carries that is prepared by phospholipid gel, has studied a kind of method of effective raising water soluble drug liposome dosage form envelop rate, is particularly useful for wrapping up gadolinium chelate compound.
The object of the invention is realized through following measure:
A kind of efficient year gadolinium Liposomal formulation; It is characterized in that forming: with 30～80 parts of the paramagnetism gadolinium contrast agent of the weight of metal gadolinium in following weight proportion raw material and adjuvant; 250～500 parts in lecithin, 50～200 parts of liposome stabilizing agents, 200～600 parts in buffer solution; Described paramagnetism gadolinium contrast agent is the chelate of the trivalent ion of metal gadolinium, and its consumption is that the weight with the metal gadolinium serves as to calculate benchmark.The lecithin, the liposome stabilizing agent that take by weighing corresponding weight in proportion are dissolved in the quantitative organic solvent, and the evaporated under reduced pressure solvent obtains the lipid thin film; Add buffer solution and carry out hydration eluting thin film, hydration temperature is 30～50 ℃, and hydration time is 2～4 hours, obtains the blank liposome suspension; With gained blank liposome suspension high pressure homogenize, pressure is 40～90MPa, and cycle-index is 6～15 times, and the control particle diameter is at 20～200nm; And then change over to revolve and carry out reduced vacuum in the steaming and concentrate, remove moisture and reach more than the 250mg/ml until phospholipid concentration, obtain phospholipid gel; In proportion phospholipid gel and contrast agent are mixed, 45 ℃ are incubated 5 hours down, obtain the efficient gadolinium Liposomal formulation that carries.
Further; Preferably; Described efficient year gadolinium Liposomal formulation is characterized in that forming in following weight proportion raw material and adjuvant: with 40～60 parts of the paramagnetism gadolinium contrast agent of the weight of metal gadolinium, 300～400 parts in lecithin; 100～200 parts of liposome stabilizing agents, 200～600 parts in buffer solution.
Above-mentioned paramagnetism gadolinium contrast agent is the trivalent ion of metal gadolinium and the chelate of chelating agen, and its consumption is that the weight with the metal gadolinium serves as to calculate benchmark, down with; Said paramagnetism gadolinium contrast agent is selected from one of Gd-DTPA, Gd-DTPA-BMA, Gd-DO3A-HP, Gd-DOTA.
Said paramagnetism gadolinium contrast agent can adopt the commercially available prod; Like the Magnevist Solution injection of German Bayer Schering Pharma company or the gadodiamide product of Amersham Health company; Perhaps adopt people such as Li Tie good fortune (" synthesizing of MRI paramagnetic contrast agent Gd-DTPA "; Chemical reagent; 2004,26 (3), pp190-191) or Tatjana; The method of people such as N (" Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging ", Eur Biophys J (2006) 35:136-144) bibliographical information prepares;
Described lecithin is selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline or hydrogenated yolk lecithin.
Said liposome stabilizing agent is selected from cholesterol, vitamin E.
It is 6.8 or 7.4 PBS, injection normal saline that said buffer solution is selected from pH.
According to above-mentioned method for preparing, phospholipid concentration can change the envelop rate and a year gadolinium amount of liposome to gadolinium chelate compound in the phospholipid gel through changing.(said year gadolinium amount is meant year gadolinium concentration of liposome, takes advantage of envelop rate to calculate by the total gadolinium concentration that adds.)
The used organic solvent of the present invention is that chloroform, volume ratio are wherein a kind of of chloroform and methanol mixed solvent, ethanol of 1: 1～3: 1.It is 6.8 or the PBS of pH7.4 that used buffer solution is selected from pH, the injection normal saline.
The pressure parameter of employing high pressure homogenizer of the present invention optimization is 60～80MPa, and cycle-index is 8～12 times.
The gadolinium Liposomal formulation was the gel preparation in efficient year according to the invention.
The invention provides a kind of efficient year gadolinium Liposomal formulation, this liposome is prepared from as component with gadolinium contrast agent, lecithin, liposome stabilizing agent diagnosis.Liposome provided by the invention has following characteristics: gadolinium amount height is carried in (1); (2) particle diameter is little; (3) the good slow release effect is arranged; (4) good stability stores several no medicines leakages in March.
Description of drawings
Fig. 1 is for carrying the transmission electron microscope photo of gadolinium Liposomal formulation.
Fig. 2 is for carrying gadolinium Liposomal formulation particle size distribution figure.
Fig. 3 for the external elution profiles of carrying the gadolinium Liposomal formulation (▲: the Magnevist Solution injection; ■: carry the gadolinium liposome).
The specific embodiment
Through following embodiment the specific embodiment of the present invention is described, but protection scope of the present invention is not limited to this.
Embodiment 1
Take by weighing soybean lecithin 10g, cholesterol 2.5g, vitamin E 0.2g raw material and be dissolved in the 300ml chloroform, 45 ℃ of constant temperature decompressions rotation evaporative removal solvents down form lipid membranes; Add 1000ml phosphate buffer (pH7.4) and carry out hydration eluting thin film 3.5h, make blank liposome; Blank liposome is carried out high pressure homogenize, and homogenizing is 15 times under the 50MPa, after 0.22 micron membrane filtration degerming, carries out vacuum concentration under the room temperature to 20ml, promptly gets phospholipid gel.Get the 1ml phospholipid gel and mix with the Gd-DTPA of 1ml0.8mmol/ml, 45 ℃ are incubated 5 hours.Packing, seal.
Use the dynamic light scattering laser particle size analyzer to measure its volume average particle size and be 107.0nm; Its transmission electron microscope picture and particle size distribution figure see Fig. 1 and Fig. 2; Its external elution profiles in PBS (pH=7.4) is seen Fig. 3, and the envelop rate that change lecithin concentration records in this example is seen table 1 with a year gadolinium amount result.
Table 1 phospholipid concentration is to liposome encapsulation and the influence of carrying the gadolinium amount
| Phospholipid concentration (mg/ml) | Envelop rate (%) | Carry gadolinium amount (mg/ml) |
| 250 | 30.9 | 19.4 |
| 300 | 37.7 | 23.7 |
| 350 | 45.6 | 28.6 |
| 400 | 51.7 | 32.5 |
Take by weighing egg yolk lecithin 24g, cholesterol 4g, vitamin E 0.6g raw material and be dissolved in 300ml chloroform and the methanol (volume ratio 1: 1), 35 ℃ of constant temperature decompressions rotation evaporative removal solvents down form lipid membranes; Add the 1500ml normal saline and carry out hydration eluting thin film 3h, make blank liposome; Blank liposome is carried out high pressure homogenize, and homogenizing is 10 times under the 80MPa, after 0.22 micron membrane filtration degerming, carries out vacuum concentration under the room temperature to 20ml, promptly gets phospholipid gel.Get the 1ml phospholipid gel and mix with the Gd-DTPA-BMA of 1ml0.6mmol/ml, 45 ℃ are incubated 5 hours.Packing, seal.
Embodiment 3
Take by weighing hydrogenated soya phosphatide 15g, cholesterol 2g, vitamin E 0.4g raw material and be dissolved in the 300ml dehydrated alcohol, 40 ℃ of constant temperature decompressions rotation evaporative removal solvents down form lipid membranes; Add 1000ml phosphate buffer (pH6.8) and carry out hydration eluting thin film 3h, make blank liposome; Blank liposome is carried out high pressure homogenize, and homogenizing is 6 times under the 90MPa, after 0.22 micron membrane filtration degerming, carries out vacuum concentration under the room temperature to 20ml, promptly gets phospholipid gel.Get the 1ml phospholipid gel and mix with the Gd-DTPA of 1ml0.4mmol/ml, 45 ℃ are incubated 5 hours.Packing, seal.
Claims (7)
1. efficient gel Liposomal formulation that carries gadolinium; It is characterized in that forming: with 30～80 parts of the paramagnetism gadolinium contrast agent of the weight of metal gadolinium in following weight proportion raw material and adjuvant; 250～500 parts in lecithin, 50～200 parts of liposome stabilizing agents, 200～600 parts in buffer solution; Described paramagnetism gadolinium contrast agent is the chelate of the trivalent ion of metal gadolinium; Its consumption is that the weight with the metal gadolinium serves as to calculate benchmark; Said liposome stabilizing agent is selected from cholesterol, vitamin E; The lecithin, the liposome stabilizing agent that take by weighing corresponding weight in proportion are dissolved in the quantitative organic solvent, and the evaporated under reduced pressure solvent obtains the lipid thin film; Add buffer solution and carry out hydration eluting thin film, hydration temperature is 30～50 ℃, and hydration time is 2～4 hours, obtains the blank liposome suspension; With gained blank liposome suspension high pressure homogenize, pressure is 40～90MPa, and cycle-index is 6～15 times, and the control particle diameter is at 20～200nm; And then change over to revolve and carry out reduced vacuum in the steaming and concentrate, remove moisture and reach more than the 250mg/ml until phospholipid concentration, obtain phospholipid gel; In proportion phospholipid gel and contrast agent are mixed, 45 ℃ are incubated 5 hours down, obtain the efficient gadolinium Liposomal formulation that carries.
2. efficient year according to claim 1 gadolinium Liposomal formulation; It is characterized in that forming: with 40～60 parts of the paramagnetism gadolinium contrast agent of the weight of metal gadolinium in following weight proportion raw material and adjuvant; 300～400 parts in lecithin, 100～200 parts of liposome stabilizing agents, 200～600 parts in buffer solution.
3. according to described efficient year gadolinium Liposomal formulation of one of claim 1～2, it is characterized in that: said paramagnetism gadolinium contrast agent is selected from one of Gd-DTPA, Gd-DTPA-BMA, Gd-DO3A-HP, Gd-DOTA.
4. according to described efficient year gadolinium Liposomal formulation of one of claim 1～2, it is characterized in that: said lecithin is selected from wherein one or more of Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin.
5. according to described efficient year gadolinium Liposomal formulation of one of claim 1～2, it is characterized in that: it is 6.8 or 7.4 PBS, injection normal saline that said buffer solution is selected from pH.
6. efficient year according to claim 1 gadolinium Liposomal formulation is characterized in that: said organic solvent is that chloroform, volume ratio are wherein a kind of of chloroform and methanol mixed solvent, ethanol of 1: 1～3: 1.
7. efficient year according to claim 1 gadolinium Liposomal formulation is characterized in that: it adopts the high pressure homogenizer pressure parameter is 60～80MPa, and cycle-index is 8～12 times.
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| CN102626392B (en) * | 2012-04-19 | 2013-05-29 | 海南永田药物研究院有限公司 | Solid preparation of doxycycline ambroxol medicine compound |
| CN102631330B (en) * | 2012-04-19 | 2013-05-29 | 海南美大制药有限公司 | Lansoprazole vesicle type phospholipid gel slow release solid preparation |
| CN106692992B (en) * | 2015-09-10 | 2019-08-23 | 浙江大学 | Solid lipid magnetic resonance nano particle and its preparation method and application |
| CN115364246A (en) * | 2021-05-18 | 2022-11-22 | 上海交通大学医学院附属第九人民医院 | Targeted contrast agent and preparation method and application thereof |
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