CN103610664A - Method for preparing carbamazepine PLGA (poly lactic-co-glycolic acid) copolymer micro capsule - Google Patents
Method for preparing carbamazepine PLGA (poly lactic-co-glycolic acid) copolymer micro capsule Download PDFInfo
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- CN103610664A CN103610664A CN201310664637.6A CN201310664637A CN103610664A CN 103610664 A CN103610664 A CN 103610664A CN 201310664637 A CN201310664637 A CN 201310664637A CN 103610664 A CN103610664 A CN 103610664A
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- Prior art keywords
- poly
- lactide
- glycolide
- carbamazepine
- carbon dioxide
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- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 229960000623 carbamazepine Drugs 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000003094 microcapsule Substances 0.000 title claims abstract description 28
- 229920001577 copolymer Polymers 0.000 title abstract 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 27
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 27
- 230000008961 swelling Effects 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 9
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 3
- 229960004275 glycolic acid Drugs 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 230000009477 glass transition Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000005192 partition Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 15
- 239000012530 fluid Substances 0.000 abstract description 8
- 238000002347 injection Methods 0.000 abstract description 7
- 239000007924 injection Substances 0.000 abstract description 7
- 238000009826 distribution Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract 2
- 239000003814 drug Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 5
- 238000000935 solvent evaporation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
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Abstract
The invention provides a method for preparing a carbamazepine PLGA (poly lactic-co-glycolic acid) copolymer micro capsule through a supercritical fluid injection method. The method comprises the following steps: firstly dissolving carbamazepine into supercritical carbon dioxide; secondly, feeding the supercritical carbon dioxide which is dissolved with the carbamazepine into a substrate to be maintained for 1 to 5 hours through the plasticization and swelling of PLGA copolymer, and enabling the carbamazepine to be balanced in distribution between the supercritical carbon dioxide and the PLGA copolymer; finally escaping the carbon dioxide, reserving the carbamazepine in the PLGA copolymer substrate, and preparing the carbamazepine PLGA copolymer micro capsule. The carbamazepine PLGA copolymer micro capsule which is prepared through the method is high in solubility and dissolution rate.
Description
Technical field
The present invention relates to a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule.
Background technology
Dissolution and the dissolution rate of crystal habit medicine in aqueous solution is generally all lower, conventionally need to is dispersed in and in polymer support, be improved dissolution by medicine.According to medicine, the dissolution in gastrointestinal tract and permeability are divided into Four types medicine to biopharmaceutics categorizing system, and wherein to show as dissolution low for II type medicine, good penetrability, and the dissolution that therefore increases II type medicine is the important directions of its research.And II type medicine dosage used is when few, in external and body, contacting of experiment can be estimated dissolution, so stripping experiment can provide Useful Information for drug bioavailability.
Traditional method is prepared drug microcapsule and is existed many insoluble problems, as low in emulsifying-solvent evaporation method envelop rate, and slow controlled-release effect is bad, and preparation process is used a large amount of organic solvents and surfactant; Spray drying method is according to solvent boiling point, and the inlet air temperature of selection is higher; Large and wider distribution of the product granularity of ball milling method etc.These problems have caused the shortcomings such as bioavailability separated and that purified product is difficult, preparation condition is unwell to thermal sensitivity medicine and bioactive substance and product is low.Along with the raising that actual production requires pharmaceutical carrier purity, particle size and particle size distribution etc., urgently research and develop these problems of new process improving.
Summary of the invention
The object of the invention is to address the above problem.
The object of the present invention is to provide a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule, having comprised:
First, carbamazepine is dissolved in supercritical carbon dioxide;
Secondly, the supercritical carbon dioxide that is dissolved with carbamazepine passes through the plasticizing of Poly(D,L-lactide-co-glycolide swelling, enter in its matrix and maintain 1-5h, making carbamazepine reach partition equilibrium between supercritical carbon dioxide and Poly(D,L-lactide-co-glycolide;
Finally, carbon dioxide is overflowed, and carbamazepine resides in Poly(D,L-lactide-co-glycolide matrix, makes carbamazepine Poly(D,L-lactide-co-glycolide microcapsule.
In preparation process, carbon dioxide is in supercriticality.For making carbon dioxide in supercriticality, during preparation, temperature is 35-60 ℃, and pressure is 15-35MPa.
According to the present invention, when the supercritical carbon dioxide that is dissolved with carbamazepine enters in Poly(D,L-lactide-co-glycolide matrix, Poly(D,L-lactide-co-glycolide under high pressure absorbs abundant supercritical carbon dioxide, and its glass transition temperature is reduced to below temperature in the kettle.It is liquid that result Poly(D,L-lactide-co-glycolide is converted into elastomeric state by glassy solids, thereby carbamazepine is dispersed in by the Poly(D,L-lactide-co-glycolide of swelling.
According to the present invention, by release, be depressurized to ambient pressure, thereby carbon dioxide dissolubility in Poly(D,L-lactide-co-glycolide declines and overflows, Poly(D,L-lactide-co-glycolide is returned to glassy state by elastomeric state, and that carbamazepine and Poly(D,L-lactide-co-glycolide are had an effect and overflowed is slower, finally reside in Poly(D,L-lactide-co-glycolide.
Preferably, the time of liberation of carbon dioxide is 0.5-3h.
The carbamazepine medicine microcapsule dissolution and the dissolution rate that by supercritical fluid injection method of the present invention, make improve a lot.
Accompanying drawing explanation
Fig. 1 is the equipment drawing that uses the inventive method:
01-carbon dioxide storage tank;
02-low temperature thermostat bath;
03-high-pressure pump;
04-preheater;
05-inlet valve;
06-autoclave;
07-middle level sintered plate;
08-low layer sintered plate;
09-choke valve.
Fig. 2 is that the carbamazepine Poly(D,L-lactide-co-glycolide microcapsule that supercritical fluid injection method of the present invention makes makes the dissolution curve comparison diagram of the carbamazepine Poly(D,L-lactide-co-glycolide microcapsule of same drug loading with respect to emulsifying-solvent evaporation method.
The specific embodiment
Embodiment 1
Fig. 1 is the equipment drawing of implementing the inventive method, and this device mainly comprises carbon dioxide induction system and autoclave, and main implementation process is: carbamazepine and Poly(D,L-lactide-co-glycolide are placed in respectively on the low layer and middle level sintered plate that injects still; Start to inject kettle heater, after temperature in the kettle reaches preset value, by the low temperature thermostat bath liquefaction of flowing through of the carbon dioxide in steel cylinder, by high-pressure pump, compressed and after preheater preheating, from passing at the bottom of still, inject in still; Rising still internal pressure, after temperature and pressure is all stable, maintains certain hour; Closing carbon dioxide inlet valve, in still, carbon dioxide is discharged through choke valve, unloads and is depressed into normal pressure, obtains carbamazepine Poly(D,L-lactide-co-glycolide microcapsule.
Poly(D,L-lactide-co-glycolide and carbamazepine ratio, its mass ratio can be 1: 4,1: 5,1: 6.
Lactic acid and hydroxyacetic acid ratio in Poly(D,L-lactide-co-glycolide, its mol ratio can be 50: 50,75: 25,100: 0
Embodiment 2
It is 28.1% carbamazepine Poly(D,L-lactide-co-glycolide microcapsule that supercritical fluid injection method of the present invention makes drug loading, its preparation condition is: Poly(D,L-lactide-co-glycolide and carbamazepine mass ratio are 1: 5, in Poly(D,L-lactide-co-glycolide, the mol ratio of lactic acid and hydroxyacetic acid is 50: 50, pressure 30MPa, 40 ℃ of temperature, time 1h in still, carbon dioxide time of liberation 1h.
Comparative example
It is 28.3% carbamazepine Poly(D,L-lactide-co-glycolide microcapsule that emulsifying-solvent evaporation method makes drug loading, its preparation process is: will be dissolved with the dichloromethane solution (oil phase of Poly(D,L-lactide-co-glycolide, O), in 5ml, add interior water (W
1) alcoholic solution of carbamazepine, ultrasonic emulsification makes colostric fluid.Then be added dropwise to outer water (W
2) magnetic agitation emulsion in the ultra-pure water solution of polyvinyl alcohol, pour double emulsion into 300ml ultra-pure water solution for continuous and stir, after organic solvent volatilization, after filtration, cleaning, drying under reduced pressure both carbamazepine Poly(D,L-lactide-co-glycolide microcapsule.
Dissolution method: with reference to 2010 editions Chinese Pharmacopoeias, adopt and turn the vitro release that basket method is measured carbamazepine Poly(D,L-lactide-co-glycolide microcapsule.Precision takes quantitative carbamazepine microcapsule, is placed in and turns basket, and the PBS buffer of 500ml of take is release medium, rotating speed 100r/min, and operation in accordance with the law at (37 ± 0.5) ℃, respectively at scheduled time sampling 5.0ml, and adds the blank PBS of 5.0ml.Above-mentioned sampling, after 0.22 μ m membrane filtration, is measured trap in 285nm place with ultraviolet spectrophotometer, be converted into the accumulation stripping percentage rate of different time, the stripping curve figure of m-preparation during drafting.
Compare with emulsifying-solvent evaporation method, dissolution and the dissolution rate of the carbamazepine Poly(D,L-lactide-co-glycolide microcapsule that supercritical fluid injection method of the present invention makes all significantly increase.As shown in Figure 2, supercritical fluid injection method carbamazepine preparation within 15 day time reaches 89%, and emulsifying-solvent evaporation method only has 43.1%.The increase of dissolution and dissolution rate can make in carbamazepine Poly(D,L-lactide-co-glycolide microcapsule and exist without crystal type carbamazepine owing to supercritical fluid injection method.
Claims (7)
1. a method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule, is characterized in that:
First, carbamazepine is dissolved in supercritical carbon dioxide;
Secondly, the supercritical carbon dioxide that is dissolved with carbamazepine passes through the plasticizing of Poly(D,L-lactide-co-glycolide swelling, enter in its matrix and maintain 1-5h, making carbamazepine reach partition equilibrium between supercritical carbon dioxide and Poly(D,L-lactide-co-glycolide; Finally, carbon dioxide is overflowed, and carbamazepine resides in Poly(D,L-lactide-co-glycolide matrix, makes carbamazepine Poly(D,L-lactide-co-glycolide microcapsule.
2. a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule as claimed in claim 1, is characterized in that: preparation process temperature is 35-60 ℃, and pressure is 15-35MPa.
3. a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule as claimed in claim 1, it is characterized in that: when the supercritical carbon dioxide that is dissolved with carbamazepine enters in Poly(D,L-lactide-co-glycolide matrix, Poly(D,L-lactide-co-glycolide under high pressure absorbs abundant supercritical carbon dioxide, and its glass transition temperature is reduced to below temperature in the kettle.It is liquid that result Poly(D,L-lactide-co-glycolide is converted into elastomeric state by glassy solids, thereby carbamazepine is dispersed in by the Poly(D,L-lactide-co-glycolide of swelling.
4. a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule as claimed in claim 1, it is characterized in that: by release, be depressurized to ambient pressure, thereby carbon dioxide dissolubility in Poly(D,L-lactide-co-glycolide declines and overflows, Poly(D,L-lactide-co-glycolide is returned to glassy state by elastomeric state, and that carbamazepine and Poly(D,L-lactide-co-glycolide are had an effect and overflowed is slower, finally reside in Poly(D,L-lactide-co-glycolide.
5. a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule as claimed in claim 4, is characterized in that, the release time is 0.5-3h.
6. a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule as described in any one in claim 1-4, is characterized in that Poly(D,L-lactide-co-glycolide and carbamazepine mass ratio are 1: 4-1: 6.
7. a kind of method of preparing carbamazepine Poly(D,L-lactide-co-glycolide microcapsule as described in any one in claim 1-4, its feature is in Poly(D,L-lactide-co-glycolide that lactic acid and hydroxyacetic acid mol ratio are 50: 50-100: 0.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012270A (en) * | 2015-07-28 | 2015-11-04 | 大连大学 | Method for preparing drug-loaded PLA/Fe3O4 microparticles through supercritical penetration process |
| CN105055371A (en) * | 2015-07-15 | 2015-11-18 | 江苏阿尔法药业有限公司 | Oral pregabalin preparation |
| EP3220955A4 (en) * | 2014-11-18 | 2018-07-25 | Pixarbio Corporation | Compositions for treating acute, post-operative, or chronic pain and methods of using the same |
| CN109897205A (en) * | 2017-12-11 | 2019-06-18 | 上海中医药大学 | A kind of preparation method of the controllable PLGA microballoon of volume |
| CN110585172A (en) * | 2019-10-21 | 2019-12-20 | 安徽工业大学 | Preparation method and anti-tumor application of double-targeting nanocapsule |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3220955A4 (en) * | 2014-11-18 | 2018-07-25 | Pixarbio Corporation | Compositions for treating acute, post-operative, or chronic pain and methods of using the same |
| EP3220917A4 (en) * | 2014-11-18 | 2018-07-25 | Pixarbio Corporation | Compositions for treating acute, post-operative, or chronic pain and methods of using the same |
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| CN105012270A (en) * | 2015-07-28 | 2015-11-04 | 大连大学 | Method for preparing drug-loaded PLA/Fe3O4 microparticles through supercritical penetration process |
| CN105012270B (en) * | 2015-07-28 | 2018-07-13 | 大连大学 | A kind of overcritical process of osmosis preparation PLA/Fe of application3O4The method of drug-carried fine particle |
| CN109897205A (en) * | 2017-12-11 | 2019-06-18 | 上海中医药大学 | A kind of preparation method of the controllable PLGA microballoon of volume |
| CN109897205B (en) * | 2017-12-11 | 2021-10-01 | 上海中医药大学 | Preparation method of PLGA microspheres with controllable volume |
| CN110585172A (en) * | 2019-10-21 | 2019-12-20 | 安徽工业大学 | Preparation method and anti-tumor application of double-targeting nanocapsule |
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