CN101502660A - Medicine-carrying polylactic acid microcapsular ultrasound contrast agent and preparation method thereof - Google Patents
Medicine-carrying polylactic acid microcapsular ultrasound contrast agent and preparation method thereof Download PDFInfo
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- CN101502660A CN101502660A CNA2009101111636A CN200910111163A CN101502660A CN 101502660 A CN101502660 A CN 101502660A CN A2009101111636 A CNA2009101111636 A CN A2009101111636A CN 200910111163 A CN200910111163 A CN 200910111163A CN 101502660 A CN101502660 A CN 101502660A
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Abstract
The invention provides a drug-loading polylactic acid microvesicle ultrasound contrast agent and a preparation method thereof, relating to a new preparation of antineoplastic drug. Specifically, the invention provides a drug-loading polylactic acid microvesicle ultrasound contrast agent with noticeable antineoplastic effect and a preparation method thereof. The drug-loading polylactic acid microvesicle ultrasound contrast agent comprises an adventitia material, a main drug and charge gas; wherein, the adventitia material is polylactic acid, the main drug is 10-hydroxycamptothecine and the charge gas is perfluoropropane; wherein, concentration of bulk main drug is 3-5mg/mL; the concentration of the adventitia material is 0.025-0.030g/mL. Under ultra audible sound, internal water phase containing hydroxycamptothecine is added to methylene dichloride containing polylactic acid to prepare initial emulsion; the initial emulsion is dispersed to external water phase containing polyvinyl alcohol by a membrane emulsifier to form diphase emulsion; low velocity stirring by magnetic force at constant temperature is carried out overnight to facilitate oil phase to volatize; the polylactic acid is solidified into envelope; microvesicle precipitation is collected and then is washed, cooled and dried; perfluoropropane is used to charge drug-loading microvesicle samples, thus obtaining the drug-loading microvesicle ultrasound contrast agent.
Description
Technical field
The present invention relates to a kind of antitumor drug novel formulation, particularly relate to a kind of medicine carrying that utilizes ultrasound wave to position and release (10-hydroxycamptothecine is called for short HCPT) polylactic acid microcapsular ultrasound contrast agent and preparation method thereof with targeted drug fortune.
Background technology
Cancer is one of major disease that threatens human health, and the treatment of malignant tumor is to a great extent still based on chemotherapy.Hydroxy camptothecin (10-HCTP) is a kind of broad-spectrum antitumor drug, but this poison of drug side reaction is bigger, mainly shows as bone marrow depression, leukopenia, gastrointestinal reaction, urinary tract stimulation etc.Simultaneously, 10-HCPT is water insoluble, and clinical used water soluble preparation is its sodium salt preparation, has destroyed its anti-topoisomerase I active structure Alpha-hydroxy lactonic ring, has reduced anti-tumor activity.The focus targeting of drugs can carry out targeting of drugs according to the different of tumor type and disease sites, and plays the chemical sproof effect that prevents to damage normal structure and produce medicine.Localization by ultrasonic target drug-carrying microcapsular ultrasound contrast agent is that a kind of ultrasound wave that utilizes positions and the targeted drug of release fortune release system.Localization by ultrasonic target drug-carrying microcapsular ultrasound contrast agent has been started a brand-new research field, can observe the situation that microvesicle runs to target site intuitively by diasonograph, utilize one-level passive target mechanism and ultrasonic cavitation effect to make that microvesicle breaks at target site, release, reach the purpose of target administration.Localization by ultrasonic target drug-carrying microcapsular ultrasound contrast agent can be used for diagnosis and treatment, tumor vessel thromboembolism and the fields such as chemotherapy, gene therapy of thrombosis, and wide application prospect and huge economic benefit are arranged.
At present, the multiple emulsion solvent evaporation method is adopted in common microcapsular ultrasound contrast agent preparation mostly, with filmogen (protein, lipid etc.) and parcel gas (air, fluorocarbon gas etc.) adopt that compound voice shakes, mechanical agitation, emulsifying etc., be difficult to be implemented in the process of microvesicle preparation pharmaceutical pack is entrained in the microbubble, easily cause prepared microvesicle pharmaceutical carrier size and distribution to be difficult to control, the entrained medication amount of microvesicle is limited, poor repeatability etc., all make a big impact for basis and clinical application research, limited application.
(Ran Haitao such as Ran Haitao, appoint red, Wang Zhi is firm etc. a kind of preparation of novel high polymer polymeric material microcapsular ultrasound contrast agent and external development experiment .[J]. Chinese ultrasonic image is learned magazine .2005,10:774-776) has reported a kind of preparation and external development experiment of novel high polymer polymeric material microcapsular ultrasound contrast agent.
Summary of the invention
The object of the present invention is to provide a kind of medicine-carrying polylactic acid microcapsular ultrasound contrast agent and preparation method thereof with remarkable antitumous effect.
Technical scheme of the present invention is to adopt supersound method in conjunction with SPG film emulsion process and Freeze Drying Technique, with polylactic acid as membrane material, interior parcel hydroxy camptothecin and perfluoropropane.
Medicine-carrying polylactic acid microcapsular ultrasound contrast agent of the present invention comprises outer membrane material, principal agent and fills gas carrier, and outer membrane material is a polylactic acid, and principal agent is 10-hydroxycamptothecine (HCPT), and filling gas carrier is perfluoropropane (C
3F
8).
Described 10-hydroxycamptothecine is preferably 3～5mg/mL by the concentration of mass/volume ratio; Described polylactic acid is preferably 0.025～0.030g/mL by the concentration of mass/volume ratio.Described polylactic acid is preferably PDLLA (PDLLA).
The preparation method of medicine-carrying polylactic acid microcapsular ultrasound contrast agent of the present invention may further comprise the steps:
1) the HCPT crude drug is dissolved in the NaOH solution, being prepared into HCPT concentration is the interior water of 3～5mg/mL;
2) with dichloromethane dissolving PDLLA powder, by mass percentage, add the emulsifying agent of system total amount 1.0%～2.0%, mix homogeneously, making PDLLA concentration is the outer oil phase of 0.025g～0.030g/mL;
3) by interior water: outer oil phase volume ratio is 1: (8～10), interior water is joined in the outer oil phase, under the ultrasonication, be prepared into the W/O colostric fluid;
4) polyvinyl alcohol (PVA) is dissolved in the distilled water, makes PVA concentration and be 1.0%～4.0% outer water;
5) colostric fluid is changed in the SPG mocromembrane emulsator barochamber, select 1.1 μ m～2 μ mSPG films, the adjusting nitrogen pressure is 40～45kpa, and by colostrum: outer water volume ratio is 1: (8～10), and colostric fluid is crossed the SPG film enter the W/O/W emulsion that outer aqueous phase must be stable;
6) magnetic agitation is volatilized oil phase fully, and PDLLA is solidified into peplos, centrifugal collection microvesicle precipitation, and washing, lyophilization obtains white powder medicine carrying microvesicle sample;
7) use C
3F
8To the inflation of medicine carrying microvesicle sample, 3～5 times repeatedly, get medicine-carrying polylactic acid microcapsular ultrasound contrast agent.
In step 1), the pH value of NaOH solution is preferably 9.0.In step 2) in, described emulsifying agent is preferably Arlacel-80 or Arlacel-60.In step 3), described ultrasonic being preferably (80～100) W10S (8～10) is inferior.
The present invention is a material with biodegradable high molecular polymer PDLLA, adopts the medicine carrying microcapsular ultrasound contrast agent of supersound method in conjunction with parcel hydroxy camptothecin and perfluoropropane gas in SPG film emulsifying technology and the Freeze Drying Technique preparation.After intravenous injection is arrived in the body, can determine microvesicle position in vivo by ultra sonic imaging, utilize the ultrasonic cavitation effect can make microvesicle fragmentation of fixed place and time, targeting drug release, cumulative release is 64.14% after one week, have the good slow release effect, increase targeting moiety blood drug level, reduce the purpose of dosage, reduction whole body toxic and side effects and target administration thereby reach.Prepared emulsion droplet uniform particle diameter is controlled, emulsion-stabilizing, mild condition, favorable reproducibility.HCPT keeps and suppresses topoisomerase I active group, stable in properties; The envelop rate of microvesicle reaches 56.48 ± 5.40%, carrying drug ratio 1.13 ± 0.19%.In addition, the emulsive equipment of SPG film and simple for process is easy to scale; Simultaneously, the SPG film makes energy to be used effectively, and power consumption is few, is easy to industry and promotes, and is that a kind of application is extremely wide and the emulsification method of bright prospects arranged.
Description of drawings
Fig. 1 is the sem photograph of embodiment 1 gained medicine carrying microvesicle.
Fig. 2 is embodiment 1 gained medicine carrying microvesicle nature drug release time/release accumulative perception curve chart.In Fig. 2, abscissa is sample time (h), and vertical coordinate is release accumulative perception (%).
Fig. 3 is that hydroxy camptothecin sample time among the embodiment 1/(blood drug level in the table is come according to serum hydroxy-camptothecin alkali concn/A414nm absworption peak area regression equation calculation by the HPLC eluting peak peak area of hydroxy camptothecin the blood drug level change curve.Matched group: the pH9.0 NaOH injection of aqueous solution group of hydroxy camptothecin.Microvesicle group: the normal saline suspension injection group of carrying hydroxy camptothecin PDLLA microvesicle).In Fig. 3, abscissa is sample time (min), and vertical coordinate is blood drug level (ng/ml); ◆ be matched group blood drug level (ng/ml) that ■ is a microvesicle group blood drug level (ng/ml).
The specific embodiment
The invention will be further described below by embodiment.
Embodiment 1
With hydroxy camptothecin powder 40mg, be dissolved in the NaOH solution of 10mLpH9.0, make the HCPT solution of concentration 4mg/mL, as interior water, standby; The 250mgPDLLA powder after the dissolving of 10mL dichloromethane, adds the 0.1mL Arlacel-80, and mixing is as outer oil phase; Get 1gPVA with fully dissolving of distilled water heating, be settled to 100mL, make the PVA aqueous solution of concentration 1.0%, as outer water, standby; (100W10S10) is inferior under the ultrasonication, gets the interior water of 1mL and at the uniform velocity joins in the outer oil phase of 10mL with syringe, is prepared into stable colostric fluid.
Colostric fluid is changed in the SPG mocromembrane emulsator barochamber, select 1.1 μ m aperture SPG films, regulate high pure nitrogen pressure, this colostric fluid is crossed the SPG mocromembrane enter the stable W/O/W emulsion of outer aqueous phase acquisition that 100mL contains 1.0%PVA to 40kPa; Room temperature continues the low speed magnetic agitation spends the night, and oil phase is volatilized fully, and PDLLA is solidified into peplos, and the centrifugal about 10min of 3000g collects the microvesicle precipitation, and after pure water washed three times, lyophilization obtained white powder microvesicle sample; The microvesicle sample is loaded in the 15mL glue cover glass bottle seals, insert No. 6 injection needles on the lid and pass through with supplied gas, vial is positioned in two neck triangular flasks, two neck triangular flasks connect vacuum pump and C respectively
3F
8, vacuum pump is taken out in the bottle behind the air, opens C is housed
3F
8The air valve of container to the microvesicle inflation, is full of C three times repeatedly fully
3F
8The medicine carrying microvesicle of gas.After measured, the envelop rate of microvesicle is 56.48%, carrying drug ratio 1.13%.Fig. 1 is prepared microvesicle sem photograph, microvesicle form rule, evenly big or small, smooth surface rounding.Fig. 2 is release under the microvesicle natural conditions, and cumulative release reaches 64.14% after the week.Fig. 3 is mixed with the medicine carrying microvesicle normal saline suspension injection that concentration is 0.02g/ml for microvesicle is dissolved in normal saline, behind the intravenous injection new zealand white rabbit, compare with matched group, keep constant relatively blood drug level in the long period, have tangible sustained drug release effect.From the experiment of new zealand white rabbit contrast echocardiography, show, new zealand rabbit is carried out cardiac ultrasonic not injecting under the acoustic contrast agent condition, because blood echo is lower, ventricle develops light, left atrium and arteries can't present in ultrasonoscopy substantially, and this makes the heart change ultrasonic diagnosis be difficult to carry out.Behind the injection acoustic contrast agent, because contrast agent has stronger echo under ultrasonication, ventricle is developed become clear, be the effective means of heart change ultrasonic diagnosis.
With hydroxy camptothecin powder 50mg, be dissolved in the NaOH solution of 10mLpH9.0, make the HCPT solution of concentration 5mg/mL, as interior water, standby; The 25OmgPDLLA powder after the dissolving of 10mL dichloromethane, adds the 0.2mL Arlacel-80, and mixing is as outer oil phase; 2gPVA, fully dissolving of distilled water heating is settled to 100mL, makes the PVA aqueous solution of concentration 2.0%; As outer water, standby; (100W10S8) is inferior under the ultrasonication, gets the interior water of 1mL and at the uniform velocity joins in the outer oil phase of 10mL with syringe, is prepared into stable colostric fluid.
Colostric fluid is changed in the SPG mocromembrane emulsator barochamber, select 1.3 μ m aperture SPG films, regulate high pure nitrogen pressure, this colostric fluid is crossed the SPG mocromembrane enter the stable W/O/W emulsion of outer aqueous phase acquisition that 100mL contains 2.0%PVA to 40kPa; Room temperature continues the low speed magnetic agitation spends the night, and oil phase is volatilized fully, and PDLLA is solidified into peplos, and the centrifugal about 10min of 3000g collects the microvesicle precipitation, wash three times after, lyophilization, acquisition white powder microvesicle sample; The microvesicle sample is loaded in the 15mL glue cover glass bottle seals, insert No. 6 injection needles on the lid and pass through with supplied gas, vial is positioned in two neck triangular flasks, two neck triangular flasks connect vacuum pump and C respectively
3F
8, vacuum pump is taken out in the bottle behind the air, opens C is housed
3F
8The air valve of container to the microvesicle inflation, is full of C three times repeatedly fully
3F
8The medicine carrying microvesicle of gas is preserved.The envelop rate of microvesicle is 56.70%, carrying drug ratio 1.04%.
With hydroxy camptothecin powder 40mg, be dissolved in the NaOH solution of 10mLpH9.0, make the HCPT solution of concentration 4mg/ml, as interior water, standby; The 300mgPDLLA powder after the dissolving of 10mL dichloromethane, adds 0.2mLSpan-60, and mixing is as outer oil phase; 3.6gPVA fully dissolving of distilled water heating is settled to 90mL, makes the PVA aqueous solution of concentration 4.0%; As outer water, standby; (80W10S10) is inferior under the ultrasonication, gets the interior water of 1mL and at the uniform velocity joins in the outer oil phase of 10mL with syringe, is prepared into stable colostric fluid.
Colostric fluid is changed in the SPG mocromembrane emulsator barochamber, select 1.1 μ m aperture SPG films, regulate high pure nitrogen pressure, this colostric fluid is crossed the SPG mocromembrane enter the stable W/O/W emulsion of outer aqueous phase acquisition that 90mL contains 4.0%PVA to 45kPa; Room temperature continues the low speed magnetic agitation spends the night, and oil phase is volatilized fully, and PDLLA is solidified into peplos, and the centrifugal about 10min of 3000g collects the microvesicle precipitation, wash three times after, lyophilization, acquisition white powder microvesicle sample; The microvesicle sample is loaded in the 15mL glue cover glass bottle seals, insert No. 6 injection needles on the lid and pass through with supplied gas, vial is positioned in two neck triangular flasks, two neck triangular flasks connect vacuum pump and C respectively
3F
8, vacuum pump is taken out in the bottle behind the air, opens C is housed
3F
8The air valve of container to the microvesicle inflation, is full of C three times repeatedly fully
3F
8The medicine carrying microvesicle of gas is preserved.The envelop rate of microvesicle is 55.30%, carrying drug ratio 1.23%.
Claims (8)
1. medicine-carrying polylactic acid microcapsular ultrasound contrast agent is characterized in that comprising outer membrane material, principal agent and fills gas carrier, and outer membrane material is a polylactic acid, and principal agent is a 10-hydroxycamptothecine, and filling gas carrier is perfluoropropane.
2. medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 1 is characterized in that described 10-hydroxycamptothecine is 3～5mg/mL by the concentration of mass/volume ratio.
3. medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 1 is characterized in that described polylactic acid is 0.025～0.030g/mL by the concentration of mass/volume ratio.
4. medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 1 is characterized in that described polylactic acid is a PDLLA.
5. the preparation method of medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 1 is characterized in that may further comprise the steps:
1) the HCPT crude drug is dissolved in the NaOH solution, being prepared into HCPT concentration is the interior water of 3～5mg/mL;
2) with dichloromethane dissolving PDLLA powder, by mass percentage, add the emulsifying agent of system total amount 1.0%～2.0%, mix homogeneously, making PDLLA concentration is the outer oil phase of 0.025g～0.030g/mL;
3) by interior water: outer oil phase volume ratio is 1: 8～10, and interior water is joined in the outer oil phase, under the ultrasonication, is prepared into the W/O colostric fluid;
4) polyvinyl alcohol is dissolved in the distilled water, makes PVA concentration and be 1.0%～4.0% outer water;
5) colostric fluid is changed in the SPG mocromembrane emulsator barochamber, select 1.1 μ m～2 μ mSPG films, the adjusting nitrogen pressure is 40～45kpa, and by colostrum: outer water volume ratio is 1: 8～10, colostric fluid is crossed the SPG film enter the W/O/W emulsion that outer aqueous phase must be stable;
6) magnetic agitation is volatilized oil phase fully, and PDLLA is solidified into peplos, centrifugal collection microvesicle precipitation, and washing, lyophilization obtains white powder medicine carrying microvesicle sample;
7) use C
3F
8To the inflation of medicine carrying microvesicle sample, 3～5 times repeatedly, get medicine-carrying polylactic acid microcapsular ultrasound contrast agent.
6. medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 5 is characterized in that in step 1), and the pH value of NaOH solution is 9.0.
7. medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 5 is characterized in that in step 2) in, described emulsifying agent is Arlacel-80 or Arlacel-60.
8. medicine-carrying polylactic acid microcapsular ultrasound contrast agent as claimed in claim 5 is characterized in that in step 3), described ultrasonic be that (80～100) W10S (8～10) is inferior.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861345A (en) * | 2012-10-22 | 2013-01-09 | 南京林业大学 | Preparation method of polymer microvesicle ultrasonic contrast agent |
| CN103432602A (en) * | 2013-08-27 | 2013-12-11 | 中国科学院化学研究所 | Micro-capsule ultrasonic contrast agent and preparation method thereof |
| CN112402631A (en) * | 2020-10-15 | 2021-02-26 | 佳木斯大学 | Composite Fe3O4PLA microbubble of-GO-ASA and preparation method thereof |
-
2009
- 2009-02-27 CN CNA2009101111636A patent/CN101502660A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861345A (en) * | 2012-10-22 | 2013-01-09 | 南京林业大学 | Preparation method of polymer microvesicle ultrasonic contrast agent |
| CN103432602A (en) * | 2013-08-27 | 2013-12-11 | 中国科学院化学研究所 | Micro-capsule ultrasonic contrast agent and preparation method thereof |
| CN103432602B (en) * | 2013-08-27 | 2015-09-30 | 中国科学院化学研究所 | A kind of micro-capsule ultrasonic contrast agent and preparation method thereof |
| CN112402631A (en) * | 2020-10-15 | 2021-02-26 | 佳木斯大学 | Composite Fe3O4PLA microbubble of-GO-ASA and preparation method thereof |
| CN112402631B (en) * | 2020-10-15 | 2022-11-25 | 佳木斯大学 | Composite Fe 3 O 4 PLA microbubble of-GO-ASA and preparation method thereof |
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Open date: 20090812 |