CN102451160A - Preparation method of long-circulating nanoparticle - Google Patents
Preparation method of long-circulating nanoparticle Download PDFInfo
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- CN102451160A CN102451160A CN2010105160032A CN201010516003A CN102451160A CN 102451160 A CN102451160 A CN 102451160A CN 2010105160032 A CN2010105160032 A CN 2010105160032A CN 201010516003 A CN201010516003 A CN 201010516003A CN 102451160 A CN102451160 A CN 102451160A
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Abstract
The invention which belongs to the medicine processing field concretely relates to a preparation method of a long-circulating nanoparticle. The preparation method of the long-circulating nanoparticle provided in the invention has the advantages of simple operation, and good targeting and good in vitro release of products. The method comprises the following steps: 1, dissolving 5-Fu (5-fluorouracil), PEG-PHDCA (polyethylene glycol-poly(hexadecyl cyanoacrylate)) and a phosphatide in a mixed organic solvent of tetrahydrofuran and ethanol to form an organic phase; 2, slowly adding the organic phase to a water phase of a surfactant in a dropwise manner under magnetic stirring, and fully diffusing the organic phase by continuously stirring for 1h after finishing the dropwise addition; 3, carrying out reduced pressure evaporation to remove the organic solvent to obtain a nanoparticle colloidal suspension with a blue opalescence; 4, carrying out ultracentrifugation separation deposition on the nanoparticle, and washing; and 5, carrying out ultrasonic dispersion with a 4% mannitol solution, and freeze-drying.
Description
Technical field:
The invention belongs to the medicine manufacture field, in particular, relate to a kind of method for preparing of long-circulating nanoparticles.
Background technology:
As everyone knows, the defense function of human body is very strong, and it is very strong to the identification ability of external foreign body that its powerful RE is engulfed system.Many discovering behind the quiet notes of nanoparticle, mainly concentrates on the abundant organ of mononuclear phagocyte (MPS); Especially in liver, spleen, the bone marrow, for the medicine of these organs of targeting, that yes is desirable for this; But for other medicines, nanoparticle is concentrated in these organs, makes that the circulation time of medicine in blood is very short; Arrive not target organ, can not produce the long-acting slow-release effect.For addressing the above problem, developed long-circulating nanoparticles.
Long-circulating nanoparticles mainly is the surface nature that changes microgranule through finishing, to reach long circulating effect.Through improve the nanoparticle surface hydrophilicity, increase sterically hindered, reduce Zeta potential, control particle diameter can reduce or avoid within the specific limits MPS to the identification of nanoparticle and combination subsequently, engulf, thereby reach macrocyclic purpose.
Long-circulating nanoparticles can be used for sustained-release preparation, and clinical angiographic diagnosis is for the nanoparticle of PEG coating; Can connect albumen, antibody, gene etc. through proper method; Be used for the targeting specified tissue, gene therapy, with its outstanding advantage and widely range of application receive the attention of Producer day by day.
5-fluorouracil can be singly with or drug combination treat various types of malignant tumor, but major defect is fat-soluble little, oral absorption not exclusively and be difficult to prediction; Behind vein or the artery administration, drug half-life short (being merely 10min in vivo) is unfavorable for continuous chemotherapy, and has the toxicity such as local excitation reaction, gastrointestinal reaction and bone marrow depression of dose dependent; Synthetic fluorouracil derivant anti-tumor activity is not high, and these deficiencies have limited 5-Fu application clinically to a certain extent.
Summary of the invention:
The present invention is exactly to the problems referred to above, provides a kind of simple to operate, product to have the method for preparing of the long-circulating nanoparticles of better targeting property, release in vitro property.
In order to realize above-mentioned purpose of the present invention, preparation process of the present invention is: get 5-Fu, PEG-PHDCA and phospholipid are dissolved in it in oxolane and the alcoholic acid mixed organic solvents; Constitute organic facies, under magnetic agitation, this organic facies slowly is added drop-wise to the aqueous phase of surfactant; After dropwising, continue to stir 1h, organic facies is fully spread; Reduction vaporization is removed organic solvent then; Obtain the opalescent nanoparticle colloidal state of blueing color suspension, this nanoparticle through the ultracentrifugation precipitation separation, is washed; With 4% mannitol solution ultra-sonic dispersion, lyophilization.
The specific embodiment:
Preparation process of the present invention is: get 5-Fu, PEG-PHDCA and phospholipid are dissolved in it in oxolane and the alcoholic acid mixed organic solvents, constitute organic facies; Under magnetic agitation, this organic facies slowly is added drop-wise to the aqueous phase of surfactant, after dropwising; Continue to stir 1h, organic facies is fully spread, reduction vaporization is removed organic solvent then; Obtain the opalescent nanoparticle colloidal state of blueing color suspension, this nanoparticle through the ultracentrifugation precipitation separation, is washed; With 4% mannitol solution ultra-sonic dispersion, lyophilization.
The present invention selects mixing speed, preparation temperature, V
Water: V
Organic, the phospholipid consumption is as the influence factor of nanoparticle quality, visible table 1, table 2, table 3, table 4.
Table 1 mixing speed is to the influence of nanoparticle quality
| Rotating speed/rmin -1 | Particle diameter/nm | Envelop rate/% |
| 200 | 605 | 38.36 |
| 500 | 321 | 35.18 |
| 800 | 143 | 33.34 |
| 1200 | 87 | 23.21 |
Table 2V
Water: V
OrganicInfluence to the nanoparticle quality
| V Water∶V Organic | Particle diameter/nm | Envelop rate/% |
| 1.5∶1 | 246 | 35.03 |
| 2.5∶1 | 131 | 33.45 |
| 3.5∶1 | 125 | 27.76 |
| 5.5∶1 | 103 | 20.20 |
Table 3 preparation temperature is to the influence of nanoparticle quality
| Preparation temperature/℃ | 20 | 25 | 30 | 40 | 50 |
| Envelop rate/% | 32.68 | 35.84 | 35.53 | 34.51 | 29.35 |
Table 4 phospholipid consumption is to the influence of nanoparticle quality
| Phospholipid consumption/mg | Particle diameter/nm | Envelop rate/% |
| 0 | 145 | 30.31 |
| 10 | 126 | 37.89 |
| 20 | 134 | 39.37 |
| 40 | 295 | 40.56 |
| 80 | 441 | 41.54 |
As a kind of preferred version, preparation process of the present invention is: mixing speed 200rmin
-1, 25 ℃ of preparation temperatures, V
Water: V
OrganicBe that 1.5: 1, phospholipid consumption are 80mg.
Claims (2)
1. the method for preparing of a long-circulating nanoparticles is characterized in that, preparation process of the present invention is: get 5-Fu; PEG-PHDCA and phospholipid are dissolved in it in oxolane and the alcoholic acid mixed organic solvents, constitute organic facies, under magnetic agitation; This organic facies slowly is added drop-wise to the aqueous phase of surfactant, after dropwising, continues to stir 1h; Organic facies is fully spread, and reduction vaporization is removed organic solvent then, obtains the opalescent nanoparticle colloidal state of blueing color suspension; This nanoparticle through the ultracentrifugation precipitation separation, is washed; With 4% mannitol solution ultra-sonic dispersion, lyophilization.
2. the method for preparing of a kind of long-circulating nanoparticles according to claim 1 is characterized in that, preparation process of the present invention is: mixing speed 200rmin
-1, 25 ℃ of preparation temperatures, V
Water: V
OrganicBe 1.5: 1, the phospholipid consumption is 80mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105160032A CN102451160A (en) | 2010-10-22 | 2010-10-22 | Preparation method of long-circulating nanoparticle |
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| CN2010105160032A CN102451160A (en) | 2010-10-22 | 2010-10-22 | Preparation method of long-circulating nanoparticle |
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| CN102451160A true CN102451160A (en) | 2012-05-16 |
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| CN2010105160032A Pending CN102451160A (en) | 2010-10-22 | 2010-10-22 | Preparation method of long-circulating nanoparticle |
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| US9741754B2 (en) | 2013-03-06 | 2017-08-22 | Apple Inc. | Charge transfer circuit with storage nodes in image sensors |
| US9912883B1 (en) | 2016-05-10 | 2018-03-06 | Apple Inc. | Image sensor with calibrated column analog-to-digital converters |
| US10263032B2 (en) | 2013-03-04 | 2019-04-16 | Apple, Inc. | Photodiode with different electric potential regions for image sensors |
| US10285626B1 (en) | 2014-02-14 | 2019-05-14 | Apple Inc. | Activity identification using an optical heart rate monitor |
| US10440301B2 (en) | 2017-09-08 | 2019-10-08 | Apple Inc. | Image capture device, pixel, and method providing improved phase detection auto-focus performance |
| US10438987B2 (en) | 2016-09-23 | 2019-10-08 | Apple Inc. | Stacked backside illuminated SPAD array |
| US10609348B2 (en) | 2014-05-30 | 2020-03-31 | Apple Inc. | Pixel binning in an image sensor |
| US10622538B2 (en) | 2017-07-18 | 2020-04-14 | Apple Inc. | Techniques for providing a haptic output and sensing a haptic input using a piezoelectric body |
| US10656251B1 (en) | 2017-01-25 | 2020-05-19 | Apple Inc. | Signal acquisition in a SPAD detector |
| US10801886B2 (en) | 2017-01-25 | 2020-10-13 | Apple Inc. | SPAD detector having modulated sensitivity |
| US10848693B2 (en) | 2018-07-18 | 2020-11-24 | Apple Inc. | Image flare detection using asymmetric pixels |
| US10962628B1 (en) | 2017-01-26 | 2021-03-30 | Apple Inc. | Spatial temporal weighting in a SPAD detector |
| US11019294B2 (en) | 2018-07-18 | 2021-05-25 | Apple Inc. | Seamless readout mode transitions in image sensors |
| US11546532B1 (en) | 2021-03-16 | 2023-01-03 | Apple Inc. | Dynamic correlated double sampling for noise rejection in image sensors |
| US11563910B2 (en) | 2020-08-04 | 2023-01-24 | Apple Inc. | Image capture devices having phase detection auto-focus pixels |
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2010
- 2010-10-22 CN CN2010105160032A patent/CN102451160A/en active Pending
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10263032B2 (en) | 2013-03-04 | 2019-04-16 | Apple, Inc. | Photodiode with different electric potential regions for image sensors |
| US9741754B2 (en) | 2013-03-06 | 2017-08-22 | Apple Inc. | Charge transfer circuit with storage nodes in image sensors |
| US10943935B2 (en) | 2013-03-06 | 2021-03-09 | Apple Inc. | Methods for transferring charge in an image sensor |
| US10285626B1 (en) | 2014-02-14 | 2019-05-14 | Apple Inc. | Activity identification using an optical heart rate monitor |
| US10609348B2 (en) | 2014-05-30 | 2020-03-31 | Apple Inc. | Pixel binning in an image sensor |
| US9912883B1 (en) | 2016-05-10 | 2018-03-06 | Apple Inc. | Image sensor with calibrated column analog-to-digital converters |
| US10438987B2 (en) | 2016-09-23 | 2019-10-08 | Apple Inc. | Stacked backside illuminated SPAD array |
| US10658419B2 (en) | 2016-09-23 | 2020-05-19 | Apple Inc. | Stacked backside illuminated SPAD array |
| US10656251B1 (en) | 2017-01-25 | 2020-05-19 | Apple Inc. | Signal acquisition in a SPAD detector |
| US10801886B2 (en) | 2017-01-25 | 2020-10-13 | Apple Inc. | SPAD detector having modulated sensitivity |
| US10962628B1 (en) | 2017-01-26 | 2021-03-30 | Apple Inc. | Spatial temporal weighting in a SPAD detector |
| US10622538B2 (en) | 2017-07-18 | 2020-04-14 | Apple Inc. | Techniques for providing a haptic output and sensing a haptic input using a piezoelectric body |
| US10440301B2 (en) | 2017-09-08 | 2019-10-08 | Apple Inc. | Image capture device, pixel, and method providing improved phase detection auto-focus performance |
| US10848693B2 (en) | 2018-07-18 | 2020-11-24 | Apple Inc. | Image flare detection using asymmetric pixels |
| US11019294B2 (en) | 2018-07-18 | 2021-05-25 | Apple Inc. | Seamless readout mode transitions in image sensors |
| US11659298B2 (en) | 2018-07-18 | 2023-05-23 | Apple Inc. | Seamless readout mode transitions in image sensors |
| US11563910B2 (en) | 2020-08-04 | 2023-01-24 | Apple Inc. | Image capture devices having phase detection auto-focus pixels |
| US11546532B1 (en) | 2021-03-16 | 2023-01-03 | Apple Inc. | Dynamic correlated double sampling for noise rejection in image sensors |
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Application publication date: 20120516 |