CN102058996A - Method for preparing ultrafine drug particles in process of improving supercritical anti-solvent by nonsolvent method - Google Patents
Method for preparing ultrafine drug particles in process of improving supercritical anti-solvent by nonsolvent method Download PDFInfo
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- CN102058996A CN102058996A CN 201010529743 CN201010529743A CN102058996A CN 102058996 A CN102058996 A CN 102058996A CN 201010529743 CN201010529743 CN 201010529743 CN 201010529743 A CN201010529743 A CN 201010529743A CN 102058996 A CN102058996 A CN 102058996A
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Abstract
The invention discloses a method for preparing ultrafine drug particles in process of improving supercritical anti-solvent by a nonsolvent method. The method comprises the following steps: dissolving a material in the mixed solution of an organic solvent and a non solvent to obtain an initial material solution with low concentration and high degree of saturation, wherein the organic solvent is a solvent which can be miscible with the supercritical fluid and the non solvent is another solvent which can be miscible with the organic solvent and can not dissolve the material; and then performing supercritical fluid anti-solvent treatment to obtain the ultrafine particles of the material. Experimental result shows that by adding the non solvent in the drug solution, the concentration can be reduced and the degree of saturation can be increased; then the supercritical carbon dioxide fluid anti-solvent process is performed so as to obviously reduce the particle size of the product and increase the recovery rate; and before the solution is supersaturated, the higher non solvent content is, the smaller drug particles are and the higher recovery rate is.
Description
Technical field
The present invention relates to a kind of preparation method of novel medicament ultrafine dust, promptly adopt non-solvent method to improve the method that overcritical anti-dissolving agent process is prepared the medicine ultrafine dust.Specifically, be in the overcritical anti-solvent method system of routine, non-solvent to be added in the drug solution, reduce its concentration when improving the drug solution saturation degree, thereby separate out sooner when making drug solution and form littler medicine ultrafine dust by the anti-solvent action of supercritical fluid.
Background technology
Drug candidate poorly water-soluble more than 40%, rate of dissolution is slow, is difficult to absorb, and causes bioavilability low, often makes some important drug candidates can not go on the market or make some medicines can not give full play to curative effect.The refinement of drug particles ultra micro is a kind of drug dissolution that improves fast and effectively, improves the technology of bioavilability.After the refinement of drug particles ultra micro and since particle size reduce increase with specific surface, its rate of dissolution is obviously improved, thereby promotes to absorb, improve bioavilability and curative effect.
Traditional miniaturization method comprises methods such as fragmentation, grinding, spray-drying, its shortcoming is that preparation process is relatively fiercer, cause thermal denaturation easily, stability of drug there is higher requirement, be not suitable for polypeptide, protide macromolecular drug or other heat-sensitive substances, and the product particle size distribution is wide, introduce pollutant easily.
The supercritical fluid anti-solvent method is to utilize the characteristic precipitation of supercritical fluid to separate out solute in the solution, makes it to form particulate.Just when the material of desiring nucleation is insoluble to supercritical fluid, can select a kind of this material of dissolution with solvents that can dissolve supercritical fluid.When the supercritical fluid as anti-solvent fully contacted with this solution, supercritical fluid was diffused into rapidly in the solution, and liquor capacity expands, and density descends, and solvability descends, solution supersaturation and nucleation is separated out the solute particulate.Normal at present use supercritical carbon dioxide anti-solvent method is carried out the miniaturization drug particles, compare with traditional method of granulating, supercritical fluid carbon dioxide anti-solvent method advantage is the reaction condition gentleness, temperature is low, technology is simple, do not have or do not have substantially dissolvent residual, little, the controllable size distribution of product cut size, be specially adapted to the especially miniaturization of bio-pharmaceutical of medicine.
In the process of supercritical carbon dioxide anti-solvent method miniaturization drug particles, the present drug concentrations of discovering has the significant effects effect.What have studies show that, concentration is big more, and the drug particles of preparing is big more; The result of study that has is then just opposite.Analyze and find, when concentration increased, on the one hand, the solute of unit volume increased, and the growth time of crystal increases in anti-dissolving agent process, and the grain diameter of formation is also big more; And on the other hand, concentration increases makes the saturation degree of solution increase, in anti-dissolving agent process the formation of nucleus fast more, help forming smaller particles.Therefore, concentration depends on the equilibrium relation of crystal growth time and the speed of growth in the anti-dissolving agent process to the influence of grain diameter.
Therefore, the present invention is based on the few and saturate initial feed liquid of solute of a kind of unit volume of imagination acquisition, be the initial feed liquid of low concentration, high saturation, adopt the supercritical carbon dioxide fluid anti-solvent method to handle this initial feed liquid then, to obtain the ultrafine dust of solute.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of novel medicament ultrafine dust, promptly adopt non-solvent method to improve the method that overcritical anti-dissolving agent process is prepared the medicine ultrafine dust, with particle diameter, the raising rate of recovery that reduces product.
The objective of the invention is to be achieved through the following technical solutions:
Non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust, with material dissolution in organic solvent and non-solvent, organic solvent be with supercritical fluid can miscible mutually solvent, non-solvent is can be miscible mutually with this organic solvent but can not dissolve the another kind of solvent of this material, obtain the initial material solution of low concentration, high saturation thus, carry out the anti-solvent of supercritical fluid then and handle, obtain the ultrafine dust of material.
Described supercritical fluid includes but not limited to CO 2 fluid, can also be other pure fluid.
Described supercritical fluid anti-solvent method comprises that all are based on carbon dioxide all technologies as the principle of anti-solvent, be the technology that the basis derives promptly, comprise the gas anti-solvent method, compress anti-solvent precipitation, the aerosol solvent extraction, strengthen that quality is transmitted overcritical anti-solvent method, supercritical fluid is forced dispersion method etc. with the supercritical carbon dioxide anti-solvent method.
Described material includes but not limited to medicine, can also be anyly to dissolve in organic solvent and be insoluble to the material of supercritical carbon dioxide fluid.
The course of dissolution of described material is: earlier with material dissolution in supercritical fluid can miscible mutually organic solvent in, under agitation slowly add then with this organic solvent can miscible mutually another kind of solvent, promptly can not dissolve the non-solvent of this material, obtain the initial material solution of low concentration, high saturation; Perhaps earlier with material dissolution in can be miscible mutually with organic solvent but can not dissolve in the non-solvent of this material, under agitation slowly add then and supercritical fluid can miscible mutually organic solvent, obtain the initial material solution of low concentration, high saturation; Perhaps material is dissolved in simultaneously in the mixed liquor or other mixed liquors of organic solvent and non-solvent, obtains the initial material solution of low concentration, high saturation.
The addition of described non-solvent requires to be lower than the critical quantity that the feed liquid supersaturation is separated out.
After adopting such scheme, the present invention utilizes the supercritical carbon dioxide anti-solvent method to handle the initial feed liquid of low concentration, high saturation again: the carbon dioxide in the steel cylinder is after refrigeration system liquefaction, pressurize by high-pressure plunger pump, after heating up by the water bath with thermostatic control in the pipeline again, pump in the autoclave, treat to meet the requirements of in the still pressure, keep carbon dioxide and pump into speed, opening vent valve exits with given pace, and regulate outside drying box of autoclave and pipeline bath temperature, to keep still internal pressure, temperature constant; Reach experiment temperature required after, supercritical carbon dioxide is by the coaxial two streaming nozzle outer passage in autoclave top, the initial feed liquid of low concentration, high saturation by the nozzle inner channel, pumps into autoclave by high-pressure pump simultaneously; After finishing the pump sample, keep pressure and temperature-resistant, continue to feed carbon dioxide drip washing a period of time, slowly release when treating that the still internal pressure is reduced to normal pressure, can be collected ultra-fine grain product.
Experimental result proves: the adding non-solvent reduces concentration, improves saturation degree in drug solution, carries out the supercritical carbon dioxide fluid anti-solvent method again, but conspicuousness ground reduces particle diameter, the raising rate of recovery of product; Before solution reached supersaturation, non-solvent content was big more, and the drug particles particle diameter is more little, the rate of recovery is high more.
Description of drawings
Fig. 1 is the SEM shape appearance figure of the Puerarin particle prepared under the different condition among the embodiment 1;
Fig. 2 is the SEM shape appearance figure of methotrexate (MTX) ultrafine dust among the embodiment 2.
Concrete implementation content
Embodiment 1
Adopt the total divisor experimental design, investigate of the influence of factors such as solvent/non-solvent ratio, concentration and flow velocity at supercritical carbon dioxide anti-solvent method miniaturization Puerarin particle.As a) .2 of Fig. 1 a experiment condition: 1,1.0%, the implementation process of 1.0ml/min is as follows: the Puerarin of 300mg is dissolved in the absolute ethyl alcohol of 20ml, adds non-solvent-carrene of 10ml then, obtaining the solvent/non-solvent ratio is 2: 1, and concentration is 1.0% Puerarin solution.Carbon dioxide in the steel cylinder is after refrigeration system liquefaction, pressurize by high-pressure plunger pump, after heating up by the water bath with thermostatic control in the pipeline again, pump in the autoclave, treat to meet the requirements of pressure in the still, keep carbon dioxide and pump into speed, open vent valve and exit with given pace, and regulate outside drying box of autoclave and pipeline bath temperature, to keep still internal pressure, temperature constant.Reach experiment temperature required after, supercritical carbon dioxide is by the coaxial two streaming nozzle outer passage in autoclave top, the initial feed liquid of low concentration, high saturation by the nozzle inner channel, pumps into autoclave by high-pressure pump simultaneously.System pressure is that 12MPa, temperature are that 306K, carbon dioxide flow velocity are 25NL/h, and the feed liquid flow velocity is 1.0ml/min.After finishing the pump sample, keep pressure and temperature-resistant, continue to feed carbon dioxide drip washing 30 minutes, slowly release when treating that the still internal pressure is reduced to normal pressure, is collected the Puerarin ultra-fine grain product.Preparation process among Fig. 1 under other experiment conditions is the same.
The rate of recovery, particle diameter and the size distribution of the Puerarin ultrafine dust of preparing under table 1. different technical parameters
The analysis result of Minitab software shows, the solvent/non-solvent ratio is remarkable influence factor, and solvent/non-solvent is than more little, and the particle diameter of Puerarin is more little.From found that of Fig. 1 and table 1, when other technological parameters were constant, solvent/non-solvent was than more little, and the granularity of Puerarin is more little, and it is narrow more to distribute, and the rate of recovery is high more.Experimental result proves: the adding non-solvent reduces concentration, improves saturation degree in feed liquid, but carries out particle diameter, the raising rate of recovery that supercritical carbon dioxide fluid anti-solvent method conspicuousness ground reduces product again.
Embodiment 2
Methotrexate (MTX) is dissolved in the methyl-sulfoxide, add non-solvent acetone then, obtaining methyl-sulfoxide/acetone is 1: 2 and 1: 4, and concentration is 0.5% methotrexate (MTX) solution, and flow velocity is that 0.5ml/min handles with the supercritical carbon dioxide anti-solvent procedure parameter among the embodiment 1.The pattern of the methotrexate (MTX) ultrafine dust that obtains as shown in Figure 2, average grain diameter is respectively 1243nm and 446nm.
Claims (8)
1. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust, it is characterized in that: with material dissolution in organic solvent and non-solvent, organic solvent be with supercritical fluid can miscible mutually solvent, non-solvent is can be miscible mutually with this organic solvent but can not dissolve the another kind of solvent of this material, obtain the initial material solution of low concentration, high saturation thus, carry out the anti-solvent of supercritical fluid then and handle, obtain the ultrafine dust of material.
2. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: described supercritical fluid is pure fluid, includes but not limited to CO 2 fluid.
3. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: described supercritical fluid anti-solvent method comprises that all are based on carbon dioxide all technologies as the principle of anti-solvent, be the technology that the basis derives promptly, comprise the gas anti-solvent method, compress anti-solvent precipitation, the aerosol solvent extraction, strengthen that quality is transmitted overcritical anti-solvent method, supercritical fluid is forced dispersion method with the supercritical carbon dioxide anti-solvent method.
4. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: described material is to dissolve in organic solvent and the material that is insoluble to supercritical carbon dioxide fluid, includes but not limited to medicine.
5. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: the course of dissolution of described material is: earlier with material dissolution in supercritical fluid can miscible mutually organic solvent in, under agitation slowly add then with this organic solvent can miscible mutually another kind of solvent, promptly can not dissolve the non-solvent of this material, obtain the initial material solution of low concentration, high saturation.
6. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: the course of dissolution of described material is: earlier with material dissolution in can be miscible mutually with organic solvent but can not dissolve in the non-solvent of this material, under agitation slowly adding then can miscible mutually organic solvent with supercritical fluid, obtains the initial material solution of low concentration, high saturation.
7. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: the course of dissolution of described material is: material is dissolved in the mixed liquor of organic solvent and non-solvent simultaneously, obtains the initial material solution of low concentration, high saturation.
8. non-solvent method improves the method that overcritical anti-dissolving agent process prepares the medicine ultrafine dust according to claim 1, it is characterized in that: the addition of described non-solvent requires to be lower than the critical quantity that the feed liquid supersaturation is separated out.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107986922A (en) * | 2017-11-17 | 2018-05-04 | 李国庆 | A kind of supercritical gas anti-solvent method carries out ammonium perchlorate modified technique |
| CN108853498A (en) * | 2018-07-05 | 2018-11-23 | 华侨大学 | A kind of preparation method and applications of indocyanine green polymer nano granules |
Citations (5)
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| CN1066874A (en) * | 1991-05-23 | 1992-12-09 | 中国科学院广州化学研究所 | Overcritical (or liquid) carbon dioxide abstraction and refined wheat germ oil technology |
| CN1220906A (en) * | 1998-10-23 | 1999-06-30 | 潘见 | Separation method for material composition by supercritical fluid crystallization |
| US20020142049A1 (en) * | 2001-03-30 | 2002-10-03 | Lee David Soong-Hua | Generation of pharmaceutical agent particles using focused acoustic energy |
| US20040258756A1 (en) * | 2001-10-25 | 2004-12-23 | Mcloughlin Martin John | Novel process |
| CN101185868A (en) * | 2006-12-15 | 2008-05-28 | 国家纳米技术与工程研究院 | Technique for preparing lomoxicam ultra-fine particles using by supercritical fluid crystallization technology |
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- 2010-10-29 CN CN 201010529743 patent/CN102058996A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1066874A (en) * | 1991-05-23 | 1992-12-09 | 中国科学院广州化学研究所 | Overcritical (or liquid) carbon dioxide abstraction and refined wheat germ oil technology |
| CN1220906A (en) * | 1998-10-23 | 1999-06-30 | 潘见 | Separation method for material composition by supercritical fluid crystallization |
| US20020142049A1 (en) * | 2001-03-30 | 2002-10-03 | Lee David Soong-Hua | Generation of pharmaceutical agent particles using focused acoustic energy |
| US20040258756A1 (en) * | 2001-10-25 | 2004-12-23 | Mcloughlin Martin John | Novel process |
| CN101185868A (en) * | 2006-12-15 | 2008-05-28 | 国家纳米技术与工程研究院 | Technique for preparing lomoxicam ultra-fine particles using by supercritical fluid crystallization technology |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107986922A (en) * | 2017-11-17 | 2018-05-04 | 李国庆 | A kind of supercritical gas anti-solvent method carries out ammonium perchlorate modified technique |
| CN108853498A (en) * | 2018-07-05 | 2018-11-23 | 华侨大学 | A kind of preparation method and applications of indocyanine green polymer nano granules |
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Application publication date: 20110518 |