CN1869106A - Method of preparing polymer nanometerl micron ball assisted by ultrasonic wave - Google Patents
Method of preparing polymer nanometerl micron ball assisted by ultrasonic wave Download PDFInfo
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- CN1869106A CN1869106A CNA2006100194657A CN200610019465A CN1869106A CN 1869106 A CN1869106 A CN 1869106A CN A2006100194657 A CNA2006100194657 A CN A2006100194657A CN 200610019465 A CN200610019465 A CN 200610019465A CN 1869106 A CN1869106 A CN 1869106A
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Abstract
An ultrasonic aided process for preparing the polymer nano-ball (or micron-balls) used for the release controllable system of medicine includes such steps as mixing polymer with disperser, ultrasonic dispersing and removing disperser to obtain target product.
Description
Technical field
The present invention relates to a kind of method of utilizing ultrasonic supplementary means to prepare polymer nanocomposite, micron ball, belong to polymeric material field.
Background technology
Up to now, the nanometer, the micron particle material that are used for the medicine sustained release mainly are polymkeric substance, can be divided into natural macromolecular material and synthesized polymer material by synthetic method; Be divided into biodegradable polymer and non-biodegradation macromolecular material by degradation property.Developing rapidly of nanotechnology makes the research of pharmaceutical dosage form enter a new phase, and in the research of all polymeric medicine Controlled Release System, nanometer, micron particle controlled release drug delivery system have accounted for significant proportion at present.
At present, the preparation method commonly used of Nano/micron ball has methods such as dialysis, emulsion polymerization, emulsified solvent volatilization, spraying drying and fusion.In this several method, dialysis method only is applicable to amphipathic nature polyalcohol usually, is not suitable for hydrophobic polymer.And the microspherulite diameter narrow range that scorification makes, but need temperature higher, only be applicable to the medicine that thermostability is high.
Summary of the invention
The objective of the invention is in order to overcome the defective that methods such as existing dialysis, emulsion polymerization, emulsified solvent volatilization, spraying drying and fusion exist when preparing the Nano/micron ball, the novel method of a kind of ultrasonic aid preparation polymer nanocomposite/micron ball is provided, this method can be implemented in room temperature, and simple to operate.
Technical scheme provided by the invention is to carry out supersound process add dispersion agent in polymkeric substance after, polymkeric substance promptly is dispersed in the dispersion agent with the form of nanometer or micron ball, eliminate dispersion agent promptly get dispersity evenly, size distribution is at the nanometer or micron ball of 100-5000 nanometer.
Its concrete preparation process is as follows: molecular weight be add in the polymkeric substance of 1000-500000 with the polymer quality ratio be 1000: 1-1: 1 dispersion agent, again with the mixture that obtains under 0 ℃-40 ℃ and normal pressure, with power is that the ultrasonic wave of 50-500W is carried out supersound process, eliminate at last dispersion agent promptly get size distribution in 100-5000 nanometer, dispersity less than 1 nanometer or micron ball.
Used polymkeric substance comprises poly-glycollide (PGA), polylactide (PLA), polycaprolactone (PCL), poly-2 in the aforesaid method, 2-dimethyl trimethylene carbonate (PDTC), PTMC (PTMC), poly-5-benzyloxy-trimethylene carbonate (PBTMC), and their mixture, their multipolymer, their polymkeric substance, their polymkeric substance of cholic acid functionalization and/or the polymkeric substance of their tree type polymer PAMAM-OH functionalization of cholesterol functionalization, polymericular weight is between 1000-500000.Used dispersion agent comprises water, methyl alcohol, ethanol, ether, normal hexane, sherwood oil, acetone, methylene dichloride, trichloromethane, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, toluene or their mixture.
The time of supersound process is 1-10 minute in the aforesaid method.The method of removing dispersion agent comprises the method for directly draining, water dialysis lyophilization, removes the method for dispersion agent accordingly according to the different choice of used dispersion agent, directly drains method, water dialysis lyophilization is a routine techniques.The pressure that removes dispersion agent is pressed onto 1 normal atmosphere from 0.0001 atmosphere, and the temperature of removing dispersion agent is between 10 ℃-100 ℃.
The method of ultrasonic aid preparation polymer nanocomposite provided by the invention/micron ball has following beneficial effect:
The main method of the uniform Nano/micron ball of original preparation dispersity is dialysis method and scorification.Dialysis method is applicable to amphipathic nature polyalcohol usually, is not suitable for hydrophobic polymer.Scorification needs comparatively high temps, so can only be used for the high medicine of thermostability, should not be extensive use of.The method that the present invention proposes both had been applicable to amphipathic nature polyalcohol, also was applicable to hydrophobic polymer; Can at room temperature implement, the thermostability of medicine is not had particular requirement, and enforcement easy and simple to handle, easy, the nanometer of gained or a micron spherolite directly are distributed in the 100-5000 nanometer, and dispersity can be used for the preparation of multiple controlled release drug delivery system less than 1.Therefore, the method that the present invention proposes is the multiple controlled release drug delivery system of carrier applicable to preparation with the multiple polymers, in the preparation of the controlled release drug delivery system of polymkeric substance, have important application prospects, be with a wide range of applications in the bio-medical field.
Description of drawings
Fig. 1 is the form of poly-(L-rac-Lactide) Nano microsphere of embodiment 1 preparation;
Fig. 2 is the form of the BTMC-GA copolymer nanometer microsphere of embodiment 5 preparations;
Fig. 3 is the size distribution of the BTMC-GA copolymer nanometer microsphere of embodiment 5 preparations;
Fig. 4 is the form of Nano microsphere of the end capped LA-GA multipolymer of cholesterol of embodiment 6 preparation;
Fig. 5 embodiment 7 preparation be the form of Nano microsphere of the polylactide of cholic acid functionalization;
Fig. 6 is the form of Nano microsphere of polycaprolactone (PAMAM-PCL) of the tree type polymer PAMAM-OH functionalization of embodiment 8 preparation;
Embodiment
Embodiment 1:
In 1 part of (in mass) molecular weight is 100000 poly-(L-rac-Lactide), add 180 parts of tetrahydrofuran (THF)s in 25 ℃ with normal pressure under, in the ultrasonoscope of 100W, after ultrasonic 5 minutes, under normal temperature, 1 normal atmosphere, tetrahydrofuran (THF) is taken out the most Nano microsphere that gathers (L-rac-Lactide) that promptly gets with water pump.This Nano microsphere form is measured by scanning electron microscope (SEM), (see figure 1), and size distribution is measured by particle diameter instrument (ZetaSizer).Median size: 660.2 nanometers, dispersity: 0.349.
Embodiment 2:
At 1 part of (in mass) molecular weight 150000 poly-(D, the L-rac-Lactide) adds 180 parts of tetrahydrofuran (THF)s under 40 ℃ and normal pressure, in the ultrasonoscope of 50W after ultrasonic 3 minutes, under 10 ℃, 1 normal atmosphere, tetrahydrofuran (THF) is taken out and promptly got the microballoon that gathers (D, L-rac-Lactide) to the greatest extent with water pump.The size distribution of this microballoon is measured by particle diameter instrument (ZetaSizer).Median size: 3236 nanometers, dispersity: 0.332.
Embodiment 3:
At 1 part of (in mass) molecular weight is to add 130 parts of tetrahydrofuran (THF)s and 50 parts of ultrapure waters in 30000 the polycaprolactone (PCL) under 25 ℃ and normal pressure, in the ultrasonoscope of 50W after ultrasonic 5 minutes, the molecular weight cut-off of packing into is in the dialysis tubing of 8000-12000, after tetrahydrofuran (THF) is removed in dialysis in ultrapure water, under 20 ℃, normal pressure, remove again and anhydrate, obtain the microballoon of polycaprolactone (PCL) with Freeze Drying Equipment.The size distribution of this microballoon is measured by particle diameter instrument (ZetaSizer).Median size: 1941 nanometers, dispersity: 0.371.
Embodiment 4:
1 part of (in mass) molecular weight be 11000 poly-(2,2-dimethyl trimethylene carbonate) adds 130 parts of tetrahydrofuran (THF)s and 50 parts of ultrapure waters in (PDTC) under 25 ℃ and normal pressure, in the ultrasonoscope of 50W after ultrasonic 3 minutes, the molecular weight cut-off of packing into is in 3500 the dialysis tubing, after tetrahydrofuran (THF) is removed in dialysis in ultrapure water, remove with Freeze Drying Equipment again and anhydrate, gathered (2,2-dimethyl trimethylene carbonate) microballoon (PDTC).The size distribution of this microballoon is measured by particle diameter instrument (ZetaSizer).Median size: 3064 nanometers, dispersity: 0.228.
Embodiment 5:
At 1 part of (in mass) molecular weight is to add 40 parts of acetone and 40 parts of ultrapure waters in 20000 the BTMC-GA multipolymer under 20 ℃ and normal pressure, in the ultrasonoscope of 100W after ultrasonic 5 minutes, the molecular weight cut-off of packing into is in the dialysis tubing of 8000-12000, after tetrahydrofuran (THF) is removed in dialysis in ultrapure water, under normal temperature, 0.0001 normal atmosphere, remove again and anhydrate, obtain the Nano microsphere of BTMC-GA multipolymer with Freeze Drying Equipment.This Nano microsphere form is measured by scanning electron microscope (SEM), (see figure 2), and size distribution is measured (see figure 3) by particle diameter instrument (ZetaSizer).Median size: 638.1 nanometers, dispersity: 0.325.
Embodiment 6:
At 1 part of (in mass) molecular weight is to add 180 parts of tetrahydrofuran (THF)s in 2300 the end capped LA-GA multipolymer of cholesterol under 5 ℃ and normal pressure, in the ultrasonoscope of 100W, after ultrasonic 3 minutes, tetrahydrofuran (THF) is taken out the Nano microsphere that promptly gets the end capped LA-GA multipolymer of cholesterol to the greatest extent with water pump.This Nano microsphere form is measured by scanning electron microscope (SEM), (see figure 4), and size distribution is measured by particle diameter instrument (ZetaSizer).Median size: 616.7 nanometers, dispersity: 0.557.The structural formula of the end capped LA-GA multipolymer of cholesterol is as follows:
Embodiment 7:
In being the polylactide (structural formula is seen Fig. 6) of 6000 cholic acid functionalization, 1 part of (in mass) molecular weight adds 250 parts of dehydrated alcohols under 10 ℃ and normal pressure, in the ultrasonoscope of 100W, after ultrasonic 5 minutes, ethanol is taken out the Nano microsphere that promptly gets cholic acid functional poly rac-Lactide to the greatest extent with water pump.This Nano microsphere form is measured by scanning electron microscope (SEM), (see figure 5), and size distribution is measured by particle diameter instrument (ZetaSizer).Median size: 287.3 nanometers, dispersity: O.0846.The structural formula of the polylactide of cholic acid functionalization is as follows:
Embodiment 8:
In being the polycaprolactone (PAMAM-PCL) of 85800 tree type polymer PAMAM-OH functionalization, 1 part of (in mass) molecular weight adds 90 parts of tetrahydrofuran (THF)s and 90 parts of ultrapure waters under 10 ℃ and normal pressure, in the ultrasonoscope of 100W after ultrasonic 5 minutes, the molecular weight cut-off of packing into is in the dialysis tubing of 8000-12000, after tetrahydrofuran (THF) is removed in dialysis in ultrapure water, remove with Freeze Drying Equipment again and anhydrate, obtain the Nano microsphere of the polycaprolactone (PAMAM-PCL) of tree type polymer PAMAM-OH functionalization.This Nano microsphere form is measured by scanning electron microscope (SEM), (see figure 6), and size distribution is measured by particle diameter instrument (ZetaSizer).Median size: 285.2 nanometers, dispersity: 0.014.
Claims (8)
1. the method for ultrasonic aid preparation polymer nanocomposite/micron ball, it is characterized in that: carry out supersound process after in polymkeric substance, adding dispersion agent, polymkeric substance promptly is dispersed in the dispersion agent with the form of nanometer or micron ball, eliminate dispersion agent promptly get dispersity evenly, size distribution is at the nanometer or micron ball of 100-5000 nanometer.
2. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1/micron ball, it is characterized in that adopting following concrete steps: molecular weight be add in the polymkeric substance of 1000-500000 with the polymer quality ratio be 1000: 1-1: 1 dispersion agent, again with the mixture that obtains under 0 ℃-40 ℃ and normal pressure, with power is that the ultrasonic wave of 50-500W is carried out supersound process, eliminate at last dispersion agent promptly get size distribution in 100-5000 nanometer, dispersity less than 1 nanometer or micron ball.
3. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1 and 2/micron ball, it is characterized in that: used polymkeric substance comprises poly-glycollide (PGA), polylactide (PLA), polycaprolactone (PCL), poly-2,2-dimethyl trimethylene carbonate (PDTC), PTMC (PTMC), poly-5-benzyloxy-trimethylene carbonate (PBTMC), and their mixture, their multipolymer, the polymkeric substance of their cholesterol functionalization, the polymkeric substance of the polymkeric substance of their cholic acid functionalization and/or their tree type polymer PAMAM-OH functionalization, polymericular weight is between 1000-500000.
4. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1 and 2/micron ball, it is characterized in that: used dispersion agent comprises water, methyl alcohol, ethanol, ether, normal hexane, sherwood oil, acetone, methylene dichloride, trichloromethane, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, toluene or their mixture.
5. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1 and 2/micron ball, it is characterized in that: the time of supersound process is 1-10 minute.
6. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1 and 2/micron ball is characterized in that: the method for removing dispersion agent comprises the method for directly draining, water dialysis lyophilization.
7. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1 and 2/micron ball is characterized in that: the pressure that removes dispersion agent is pressed onto 1 normal atmosphere from 0.0001 atmosphere.
8. the method for ultrasonic aid preparation polymer nanocomposite according to claim 1 and 2/micron ball is characterized in that: the temperature of removing dispersion agent is between 10 ℃-100 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012063381A (en) * | 2010-09-14 | 2012-03-29 | Ricoh Co Ltd | Toner and developer, image forming method using the same, and thermoplastic resin for toner |
| CN105709232A (en) * | 2016-01-26 | 2016-06-29 | 湖北大学 | Core-shell sustained release nanosphere and preparation method thereof |
| CN108684688A (en) * | 2018-06-14 | 2018-10-23 | 国家纳米科学中心 | A kind of nano pesticide composition and preparation method thereof |
| EP4257126A3 (en) * | 2015-09-04 | 2023-12-06 | Yale University | Polymeric bile acid nanocompositions targeting the pancreas and colon |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037272C (en) * | 1991-08-27 | 1998-02-04 | 福建师范大学 | Technology of preparation for polyethylene and polypropylene powder |
| CN1460468A (en) * | 2003-06-05 | 2003-12-10 | 浙江大学 | Improved preparation method of high-molecular microsphere embedding protein medicine and vaccine |
| CN1257708C (en) * | 2004-01-17 | 2006-05-31 | 浙江大学 | Modified water-soluble medicine and vaccine embedded macromolecule microsphere preparation method |
| CN1309779C (en) * | 2004-09-16 | 2007-04-11 | 同济大学 | Process for preparing biological degradable polymer magnetic composite nano particle |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012063381A (en) * | 2010-09-14 | 2012-03-29 | Ricoh Co Ltd | Toner and developer, image forming method using the same, and thermoplastic resin for toner |
| EP4257126A3 (en) * | 2015-09-04 | 2023-12-06 | Yale University | Polymeric bile acid nanocompositions targeting the pancreas and colon |
| CN105709232A (en) * | 2016-01-26 | 2016-06-29 | 湖北大学 | Core-shell sustained release nanosphere and preparation method thereof |
| CN105709232B (en) * | 2016-01-26 | 2020-11-06 | 湖北大学 | Core-shell type slow-release nanosphere and preparation method thereof |
| CN108684688A (en) * | 2018-06-14 | 2018-10-23 | 国家纳米科学中心 | A kind of nano pesticide composition and preparation method thereof |
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Granted publication date: 20081119 |