CN101015702A - Lipid ultrasonic contrast freeze-drying agent and its preparing process - Google Patents
Lipid ultrasonic contrast freeze-drying agent and its preparing process Download PDFInfo
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- CN101015702A CN101015702A CN 200710078164 CN200710078164A CN101015702A CN 101015702 A CN101015702 A CN 101015702A CN 200710078164 CN200710078164 CN 200710078164 CN 200710078164 A CN200710078164 A CN 200710078164A CN 101015702 A CN101015702 A CN 101015702A
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Abstract
The invention relates to a freeze-dried ultrasound contrast agent which is obtained by using film-forming material to encapsulate perfluoropropane. The film-forming material is composed of phospholipids mixture 1.5-3 wt%, glycerol 8-10 wt%, mannitol 4-15 wt%, and distilled water in balance. The preparation method comprises mixing phospholipids mixture, glycerol, mannitol and deionized distilled water; filling perfluoropropane to exchanged the air in the mixture; shaking to obtain perfluoropropane-containing microcapsule; freeze-drying; and filling perfluoropropane again. The inventive ultrasound contrast agent has the advantages of good storage stability, convenient storage and transport, simple preparation, low cost, good developing effect, good safety and reliability, and applicability to industrialized production.
Description
Technical field
The present invention relates to a kind of novel lipid ultrasonic contrast freeze-drying agent and preparation method thereof.
Background technology
Acoustic contrast agent development present situation: at present, with lipid, macromolecule polymer as filmogen the 3rd generation acoustic contrast agent be the focus of research at present, and adipose membrane has good radiography reinforced effects because of its good morphotropism and elasticity.The lipid ultrasonic contrast agent also has natural targeting and good biocompatibility, has demonstrated good prospects for application.The Sonovue of domestic import adopts phospholipid as filmogen, is that difficulty one is applied to clinical acoustic contrast agent by China's Ministry of Public Health approval, but because of it costs an arm and a leg, causes it to be difficult for being used more widely.Present domestic lipid ultrasonic contrast agent research only limits to laboratory, and it is clinical to be difficult to realize that industrialized mass production is applied to, and mainly contains following reason:
1. poor stability, the holding time is short.Liquid contrast agent is preserved, transportation is extremely inconvenient, and its holding time is very limited.And present lyophilized powder lipid contrast agent, the microvesicle suspension vitro stability that forms after redissolving is often also very poor, makes troubles to use.After entering in the body, it is not good that it strengthens imaging results, and the persistent period is too short, is difficult to be applied to clinical.
2. need sound to shake before using or mechanical oscillation could form the microvesicle suspension, need to be equipped with special sound Vibration Meter or mechanical oscillation instrument, it is clinical to be difficult to realize that commercialization is applied to, its preservation, and transportation, use are very inconvenient.
3. the preparation process complexity is wayward, the cost height.Preparation lipid ultrasonic contrast agent at present often needs to carry out repeatedly lyophilization or sound shakes, and parameters, condition are difficult to control in this process, so its cost height, repeatability is often very low, is difficult to realize its commercialization.Also need use organic solvent hydrotropy phospholipid such as chloroform in some preparation method, its removal process can cause cost up, and the residue problem in product is difficult to solve.
4. the preparation condition harshness is unfavorable for medicine carrying or carries gene studies.The present employing sound method of shaking often in the preparation process of acoustic contrast agent, the condition that sound shakes is stable inadequately, and its gnotobiosis also is difficult to realize.And in sound shakes process, can produce a large amount of heats, can influence the activity of lipid and contained medicine or gene, be unfavorable for the research of acoustic contrast agent medicine carrying or year gene therapy aspect.
5. contrast agent filmogen composition complexity is difficult to reach the intravenous injection requirement.
Summary of the invention
The objective of the invention is to improve the contrast agent filmogen, a kind of lipid ultrasonic contrast freeze-drying agent of stable performance is provided; Another object of the present invention is to optimize the preparation technology of contrast agent, and the industrial mass preparation that provides a kind of method for preparing lipid ultrasonic contrast freeze-drying agent to realize ultrasound microbubble contrast agent is preserved with room temperature.
For achieving the above object, the technical scheme that is adopted is as follows:
1, the filmogen of contrast agent is simplified, improved, all select the safe and reliable material that meets the intravenous injection standard for use, comprise mixture of phospholipids, glycerol and mannitol.It is 1.5～3% that mixture of phospholipids occupies weight ratio, and it is 8～10% that glycerol occupies weight ratio, and it is 4～15% that mannitol occupies weight ratio, and all the other are deionized-distilled water.Various phospholipid often have different phase transition temperatures, by the adipose membrane phase transition temperature unanimity that simple a kind of phospholipid constitutes, less stable.Select for use the phospholipid of multiple different phase transition temperatures to form the adipose membrane structure, its stability is increased greatly by proper proportion.In this contrast agent filmogen, described mixture of phospholipids is selected from 1,2-dipalmitoyl phosphatidyl choline, 1,2 distearoyl phosphatidylcholine, 1,2-DSPE, 1, in the 2-two palmityl PHOSPHATIDYL ETHANOLAMINE, 1,2-G 12S3P, 1, in the 2-two palmityl phosphatidic acid at least two kinds are pressed arbitrary proportion and are formed.
Described mixture of phospholipids can also be selected from 1, in 2-dipalmitoyl phosphatidyl choline (DPPC) and the distearoyl phosphatidylcholine (DSPC) a kind of, 1,2-DSPE (DSPE) and 1, a kind of in the 2-two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE), in addition for reaching the optimum stabilization effect, also can add 1,2-two palmityl phosphatidic acid (DSPA) and 1, a kind of in the 2-two palmityl phosphatidic acid (DPPA), its part by weight is respectively 50%～70%, 15%～30% and 15%～20%.Preferred above several phospholipid are pressed the optimal proportion combination, can make microvesicle have splendid stability.
In experimentation, we find that the miscible formation solvent of glycerol and water has hydrotropy effect preferably to phospholipid.When reaching uniform temperature, can form the lipid suspension.Add the mechanical oscillation effect, phospholipid can be realized disperseing fully and form adipose membrane parcel gas, need not adopt methods such as rotary evaporation or lyophilization to form the lipid suspension, and this process has been saved cost greatly.In addition, in freezing dry process, glycerol also can become freeze drying protectant, strengthens the stability of microcapsule, and the protection microcapsule structure is not destroyed in freeze-drying process.
Mannitol plays skeleton function as good freeze drying protectant in freeze-drying process, prevent that adipose membrane is destructurized, and making lyophilized formulations is that porous loose structure and color are constant substantially, and rehydration is good.Mannitol solution can improve the productive rate of microvesicle and the size that can regulate microvesicle by osmotic pressure, adds its high sepage and can prepare the nano-lipid acoustic contrast agent.
2, above-mentioned raw materials is mixed in tubular container after, place 42 ℃ of water-baths 30～60 minutes to form suspension; Again with perfluoropropane gas displacement air in it, then container is fixed on and vibrated in the mechanical oscillation instrument 30～60 seconds, the operating frequency of mechanical oscillation instrument is 3300～4500 times/minute, obtains containing the microcapsule liquid of perfluoropropane, be transferred in the cillin bottle, put-30 ℃ of pre-freeze half an hour.The sample that pre-freeze is good places freezer dryer, the control lyophilisation condition, and vacuum drying 24～48h charges into perfluoropropane gas again, promptly gets the lipid ultrasonic contrast agent, but long preservation behind the sealing gland.
3, stability and imaging results are observed
This contrast agent is white lyophilized formulations (referring to an accompanying drawing 7), and room temperature sealing is stored in the cillin bottle, in fill perfluoropropane gas.Add 3ml water for injection before using, form milky microvesicle suspension (referring to accompanying drawing 8) with hand even back.Nanoscale microvesicle particle size range 0.3～0.9um (referring to accompanying drawing 1, accompanying drawing 2), mean diameter 0.65um, microbubble concentration 5.3～6.5 * 10
9/ ml; Micron microvesicle particle size range 0.7～1.5um (referring to accompanying drawing 3, accompanying drawing 4), mean diameter 1.2um, microbubble concentration 3.1～4.5 * 10
9/ ml.Respectively at once, 30min, 60min, 2h, 6h, 12h, 24h get the microvesicle suspension in microscopically observe, counting.The microvesicle form is full, homogeneity good.Observe behind the 24h, the microvesicle form does not have significant change, and concentration does not have obvious decline.With contrast agent with
60Co gamma-rays radiation sterilization (radiation dose 1,500,000～1,800,000 rad) is carried out sterility test according to the sampling of pharmacopeia regulation, confirms to have reached sterilization effect.After the redissolution, contrast agent particle diameter, form, each parameter such as concentration has no significant change, more than all prove its good stability.
With the microvesicle suspension with the dosage of 0.05～0.2ml/kg in vein injects Canis familiaris L. or new zealand white rabbit body, observe it down and strengthen the effect that histoorgans such as liver, kidney, heart develop ultrasonic.
4, freeze-drying is applicable to commercial production, and reaches aseptic requirement easily, for condition has been created in contrast agent application clinically.Suitability for industrialized production can prepare by the following method: (1) is joined according to the above ratio and is got various raw materials, preparation lipid suspension, and the lipid suspension carried out sterilization treatment, divide the cast container of packing into then.(2) with air in the perfluoropropane gas displacement cast container, in the mechanical oscillation instrument, vibrate then, frequency 3300～4500 times/minute, amplitude 10～20mm, duration of oscillation 30～60s makes microcapsule liquid.(3) microcapsule liquid is shifted branch and be filled in the 5ml cillin bottle, send in the freezer dryer, the control lyophilisation condition, vacuum drying, all processes all can be realized the sterile working.(4) after drying finishes, feed the fluorocarbon gas of degerming after filtration again in the freezer dryer, gland seal then.This course of industrialization, preparation technology is easy, is easy to control, has guaranteed the realization of product ommercialization.
The invention effect
1. by having a process for preparing a kind of lipid ultrasonic microvesicle contrast freeze-drying agent of stable performance.All raw material is safe and reliable, meet the intravenous injection standard.
2. Zhi Bei contrast agent is a lyophilized formulations, in per unit (bottle) lyophilized formulations, and the about 80mg of solid weight, gas 40～70mg.Room temperature is preserved, transportation, easy to use.Solubility property is good, only needs to add 3ml water for injection before using, and gets final product so that the have gentle hands jog is even.The microvesicle suspension of formation has splendid stability after redissolving, and room temperature is placed above 24h does not have obvious change (be no more than 6 hours standing time after the lyophilized powder contrast agent of the bibliographical information redissolution at present), can preserve about 7 days under 4 ℃ of conditions.
3. preparation technology is easy, easy to operate, and cost is low, can implement industrialized mass production.
The preparation condition gentleness, be easy to control, and can prepare nanoscale lipid microbubble contrast agent, help medicine carrying or carry a gene combining ultrasonic treating research (not influencing the activity of contained medicine or gene).
5. zoopery confirms that this contrast agent enhanced imaging results is good.Behind the radiography, the Hepar Leporis seu Oryctolagi vessel branch can clearly show (referring to accompanying drawing 5), and excess of the kidney matter is developed and evenly strengthened (referring to accompanying drawing 6), and the single injection persistent period reaches 20min, satisfies the clinical diagnosis needs fully.In the experimentation, obvious adverse reaction does not appear in animal, and after experiment finished, animal was in good condition.Dissect internal organs pathologic findings such as animal liver, kidney, heart and do not find damage, prove that it is safe and reliable.
Description of drawings
Accompanying drawing 2 is nanoscale microvesicle particle size distribution figure of the present invention
Accompanying drawing 3 is observed micron order microbubble contrast agent of the present invention (* 400) down for optical microscope;
Accompanying drawing 4 is micron order microvesicle particle size distribution figure of the present invention;
Accompanying drawing 5 develops for microvesicle of the present invention strengthens the Hepar Leporis seu Oryctolagi blood vessel;
Wherein: before A is radiography; After B is radiography.Liver blood vessel does not show that liver blood vessel branch is high-visible behind the radiography before the radiography
Accompanying drawing 6 strengthens the rabbit kidney parenchymal bluss for microvesicle of the present invention;
Wherein: A is a radiography pronephridiostome essence; B is a radiography metanephros essence, and radiography metanephros essence evenly strengthens
Accompanying drawing 7 is lipid contrast freeze-drying agent sample of the present invention;
The microvesicle suspension that accompanying drawing 8 forms for lipid contrast freeze-drying agent redissolution of the present invention back.
The specific embodiment
Example 1
Filmogen: mixture of phospholipids is 1,2-dipalmitoyl phosphatidyl choline (DPPC), 1,2-DSPE (DSPE) and 1, three kinds of 2-two palmityl phosphatidic acid (DSPA), mannitol, glycerol, perfluoropropane (C3F8);
Equipment: electronic balance, constant water bath box, mechanical oscillation instrument, freezer dryer etc.;
Method: take by weighing earlier DPPC5mg, DSPE2mg, DSPA1mg, mannitol 22.5mg mixing respectively, add glycerol 50ul, deionized-distilled water 450ul, pack in the tubular hermetic container of a 1.5ml, replace air in it with perfluoropropane.Place 42 ℃ of water-bath 30min,, must contain the microcapsule liquid of perfluoropropane, change in the cillin bottle, put-30 ℃ of pre-freeze half an hour with mechanical oscillation instrument vibration 60s.The sample that pre-freeze is good places freezer dryer, the control lyophilisation condition, and vacuum drying 24h charges into perfluoropropane gas again, promptly gets the lipid ultrasonic contrast agent, and sealing is added a cover back room temperature and is preserved.
Example 2
Filmogen: mixture of phospholipids is 1,2-dipalmitoyl phosphatidyl choline (DPPC), 1, two kinds of 2-DSPE (DSPE), mannitol, glycerol, perfluoropropane (C3F8);
Equipment: electronic balance, constant water bath box, mechanical oscillation instrument, freezer dryer etc.
Method: take by weighing earlier DPPC7mg, DSPE2mg, mannitol 22.5mg mixing respectively, add glycerol 50ul, deionized-distilled water 450ul, pack in the tubular hermetic container of a 1.5ml, replace air in it with perfluoropropane.Place 42 ℃ of water-bath 30min,, must contain the microcapsule liquid of perfluoropropane, change in the cillin bottle, put-30 ℃ of pre-freeze half an hour with mechanical oscillation instrument vibration 30s.The sample that pre-freeze is good places freezer dryer, the control lyophilisation condition, and vacuum drying 36h charges into perfluoropropane gas again, promptly gets the lipid ultrasonic contrast agent, and sealing is added a cover back room temperature and is preserved.
Example 3
Filmogen: mixture of phospholipids is 1,2-dipalmitoyl phosphatidyl choline (DPPC), 1,2-DSPE (DSPE), 1, three kinds of 2-two palmityl phosphatidic acid (DSPA), mannitol, glycerol, perfluoropropane (C3F8);
Equipment: electronic balance, constant water bath box, mechanical oscillation instrument, freezer dryer etc.;
Method: take by weighing earlier DPPC5mg, DSPE2mg, DSPA1mg, mannitol 22.5mg mixing respectively, add glycerol 50ul, deionized-distilled water 450ul, pack in the tubular hermetic container of a 1.5ml, replace air in it with perfluoropropane.Place 42 ℃ of water-bath 30min,, must contain the microcapsule liquid of perfluoropropane, change in the cillin bottle, put-30 ℃ of pre-freeze half an hour with mechanical oscillation instrument vibration 60s.The sample that pre-freeze is good places freezer dryer, the control lyophilisation condition, and vacuum drying 24h charges into perfluoropropane gas again, promptly gets the lipid ultrasonic contrast agent, and sealing is added a cover back room temperature and is preserved.
Example 4
Filmogen: mixture of phospholipids is 1 distearoyl phosphatidylcholine (DSPC), 1,2-two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE) and 1, three kinds of 2-two palmityl phosphatidic acid (DPPA), mannitol, glycerol, perfluoropropane (C3F8);
Equipment: electronic balance, constant water bath box, mechanical oscillation instrument, freezer dryer etc.;
Method: take by weighing earlier DSPC5mg, DPPE2mg, DPPA1mg, mannitol 22.5mg mixing respectively, add glycerol 50ul, deionized-distilled water 450ul, pack in the tubular hermetic container of a 1.5ml, replace air in it with perfluoropropane.Place 42 ℃ of water-bath 30min,, must contain the microcapsule liquid of perfluoropropane, change in the cillin bottle, put-30 ℃ of pre-freeze half an hour with mechanical oscillation instrument vibration 60s.The sample that pre-freeze is good places freezer dryer, the control lyophilisation condition, and vacuum drying 24h charges into perfluoropropane gas again, promptly gets the lipid ultrasonic contrast agent, and sealing is added a cover back room temperature and is preserved.
Example 5
Filmogen: mixture of phospholipids is 1,2-dipalmitoyl phosphatidyl choline (DPPC), distearoyl phosphatidylcholine (DSPC), 1,2-DSPE (DSPE), 1,2-two palmityl phosphatidic acid (DSPA), 1, five kinds of 2-two palmityl phosphatidic acid (DPPA), mannitol, glycerol, perfluoropropane (C3F8);
Equipment: electronic balance, constant water bath box, mechanical oscillation instrument, freezer dryer etc.;
Method: take by weighing earlier each 1mg of DPPC3mg, DSPC4mg, DSPE2mg, DSPA and DPPA, mannitol 22.5mg respectively and mix, add glycerol 50ul, deionized-distilled water 450ul, pack in the tubular hermetic container of a 1.5ml, replace air in it with perfluoropropane.Place 42 ℃ of water-bath 30min,, must contain the microcapsule liquid of perfluoropropane, change in the cillin bottle, put-30 ℃ of pre-freeze half an hour with mechanical oscillation instrument vibration 60s.The sample that pre-freeze is good places freezer dryer, the control lyophilisation condition, and vacuum drying 24h charges into perfluoropropane gas again, promptly gets the lipid ultrasonic contrast agent, and sealing is added a cover back room temperature and is preserved.
In the foregoing description, in per unit (bottle) lyophilized formulations, solid weight is 70～90mg, perfluoropropane gas 40-70mg.
Claims (5)
1. lipid ultrasonic contrast freeze-drying agent, form by filmogen parcel fluorocarbon gas, it is characterized in that: filmogen comprises mixture of phospholipids, glycerol, mannitol, wherein, it is 1.5-3% that phospholipid occupies weight ratio, it is 8-10% that glycerol occupies weight ratio, and it is 4-15% that mannitol occupies weight ratio, and all the other are distilled water; Described mixture of phospholipids is selected from 1,2-dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, 1,2-DSPE, 1, in the 2-two palmityl PHOSPHATIDYL ETHANOLAMINE, 1,2-two palmityl phosphatidic acid, 1 are pressed arbitrary proportion and are formed at least two kinds in the 2-two palmityl phosphatidic acid.
2, lipid ultrasonic contrast freeze-drying agent according to claim 1, it is characterized in that: mixture of phospholipids is selected from 1, a kind of in 2-dipalmitoyl phosphatidyl choline and the distearoyl phosphatidylcholine, 1,2-DSPE and 1, a kind of in the 2-two palmityl PHOSPHATIDYL ETHANOLAMINE, 1,2-two palmityl phosphatidic acid and 1, a kind of in the 2-two palmityl phosphatidic acid, its part by weight is respectively 50%～70%, 15%～30% and 15%～20%.
3, a kind of method for preparing lipid ultrasonic contrast freeze-drying agent, carry out according to the following steps:
(1) mixture of phospholipids, glycerol, mannitol are mixed in container in proportion with aqueous solution, 42 ℃ of waters bath with thermostatic control 30～60 minutes form the lipid suspension;
(2) with perfluoropropane gas displacement vessel head air, be fixed in then and carry out 3300～4500 times/minute vibration in the mechanical oscillation instrument, vibrate 30-60 second, obtain containing the microcapsule liquid of perfluoropropane gas, it is transferred in the cillin bottle, puts-30 ℃ of pre-freeze half an hour;
(3) pre-freeze is good sample is put in the freezer dryer, and vacuum drying 24-48 hour, charge into perfluoropropane gas at last again, sealing gland, room temperature is preserved.
4, lipid ultrasonic contrast freeze-drying agent according to claim 1 is characterized in that: in the per unit lyophilized formulations, and solid weight 70～90mg, perfluoropropane gas 40-70mg.
5, lipid ultrasonic contrast freeze-drying agent according to claim 2 is characterized in that: in the per unit lyophilized formulations, and solid weight 70～90mg, perfluoropropane gas 40-70mg.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822640A (en) * | 2010-04-23 | 2010-09-08 | 王明 | Sulbenicillin sodium liposome injection |
| CN103638534A (en) * | 2013-12-02 | 2014-03-19 | 东南大学 | Nanometer lipid ultrasonic contrast agent and preparation method thereof |
| WO2019051752A1 (en) * | 2017-09-14 | 2019-03-21 | 吴金凤 | Method for preparing lipidosome nano-bubble ultrasound contrast agent |
| CN110251693A (en) * | 2019-06-14 | 2019-09-20 | 东南大学 | A kind of preparation method of lipid ultrasonic contrast agent |
-
2007
- 2007-02-02 CN CN 200710078164 patent/CN101015702A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822640A (en) * | 2010-04-23 | 2010-09-08 | 王明 | Sulbenicillin sodium liposome injection |
| CN103638534A (en) * | 2013-12-02 | 2014-03-19 | 东南大学 | Nanometer lipid ultrasonic contrast agent and preparation method thereof |
| CN103638534B (en) * | 2013-12-02 | 2016-03-30 | 东南大学 | A kind of nano-lipid acoustic contrast agent and preparation method |
| WO2019051752A1 (en) * | 2017-09-14 | 2019-03-21 | 吴金凤 | Method for preparing lipidosome nano-bubble ultrasound contrast agent |
| CN110251693A (en) * | 2019-06-14 | 2019-09-20 | 东南大学 | A kind of preparation method of lipid ultrasonic contrast agent |
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