CN102697738A - Preparation method of porous microspheres by carbon dioxide fluid anti-solvent method - Google Patents
Preparation method of porous microspheres by carbon dioxide fluid anti-solvent method Download PDFInfo
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- CN102697738A CN102697738A CN2012102208363A CN201210220836A CN102697738A CN 102697738 A CN102697738 A CN 102697738A CN 2012102208363 A CN2012102208363 A CN 2012102208363A CN 201210220836 A CN201210220836 A CN 201210220836A CN 102697738 A CN102697738 A CN 102697738A
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Abstract
The invention provides a preparation method of porous microspheres by carbon dioxide fluid anti-solvent method. The method comprises the steps of sequentially preparing oil phase and water-in-oil emulsion, passing the water-in-oil emulsion through a high-pressure pump, and injecting into a pre-treated high-pressure kettle through a steel needle head, to precipitate out polymer microspheres embedded with ammonium bicarbonate particles; after emulsion injection, maintaining pressure and temperature in the high-pressure kettle, while keeping introduction of carbon dioxide to flush and clear away residual solvent; after flushing, slowly releasing pressure in the high-pressure kettle to atmospheric pressure, and collecting loose powdery product; and performing thermal decomposition on the powdery product at 50 DEG C under vacuum dry condition to obtain the porous microspheres. The method has the advantages of simple operation procedure, low organic solvent residue, large geometrical particle size and small aerodynamic diameter of prepared porous microspheres.
Description
[technical field]
The present invention relates to a kind of preparation of drug carriers method, be specifically related to a kind of method for preparing porous microsphere, especially relate to the method that a kind of CO 2 fluid anti-solvent method prepares porous microsphere.
[background technology]
Compare with solid polymer microsphere with same particle size; Porous microsphere has porous network structure; Not only can be used to adsorb, the fields such as separation and purification of immobilized enzyme, biomacromolecule, and aspect medical carrier, rely on self lower density, irregular configuration of surface; Air dynamic behaviour and pulmonary's settling property have become the first-selection that is suitable for the pulmonary administration dosage form preferably.
Traditional porous microsphere method for preparing mainly contains spray drying method and emulsion process.The former favorable reproducibility simple to operate, but its preparation temperature is when higher, protein-based macromolecular drug or other heat-sensitive substances be degeneration inactivation easily often; The latter relates to more loaded down with trivial details organic solvent and removes step, and organic solvent residual is higher, has higher bio-safety hidden danger.
The supercritical fluid anti-solvent method is a process of utilizing the organic solvent in the characteristic extraction solution of supercritical fluid that solute is separated out; We rely on this ultimate principle successfully to prepare pharmaceutical carriers such as ultra-fine polylactic acid microsphere, magnetic-polylactic acid nano particle; But because how much particle diameters less (being generally less than 1 μ m) of these pharmaceutical carriers, as the pulmonary administration carrier and be not suitable for.Correspondingly; Same principle also is applicable to the water-in-oil emulsion system that contains certain volume water; This water-in-oil emulsion system is an oil phase with the polymeric matrix, is wrapped in the water of being made up of countless tiny ammonium bicarbonate, when the supercritical fluid as anti-solvent contacts with this water-in-oil emulsion; Supercritical fluid is diffused into rapidly in the drop of water-in-oil emulsion; The organic solvent in the drop is walked in extraction, and original dissolved solute composition in the drop is owing to be insoluble to supercritical fluid and then separate out and formed polymer microballoon, and the anti-simultaneously solvent of the ammonium bicarbonate that originally comprises in the drop of water-in-oil emulsion and this polymer microballoon is separated out; And the ammonium bicarbonate of separating out is evenly distributed on the inside (when the water-in-oil emulsion that forms is even, stable system) of this polymer microballoon; Afterwards the sample of collecting is passed through heating and decomposition, will make ammonium bicarbonate be decomposed into nontoxic carbon dioxide, ammonia G&W, and form pore space structure in microsphere inside and surface.Compare with the traditional preparation process method; Supercritical fluid carbon dioxide anti-solvent method advantage is that preparation condition is gentle; Temperature is low; Technology is simple, does not perhaps have organic solvent dissolvent residual, how much particle diameters of product and aerodynamic size to meet the pulmonary administration requirement basically, therefore is especially suitable for use as and makes up the pulmonary administration pharmaceutical carrier.
It is less that the supercritical carbon dioxide anti-solvent legal system is equipped with the report of porous microsphere, and based on the report of having seen, the practitioner sums up and finds to exist following problem: the hole on porous microsphere surface is under the surface sweeping ultramicroscope and not obvious, and need can be discerned by instrument; Or even the problem that porous microsphere surface atresia, inner hollow or hole do not connect mutually appears.These problems are disadvantageous for carrying out for the pulmonary administration as pharmaceutical carrier.
[summary of the invention]
Technical problem to be solved by this invention is to provide a kind of CO 2 fluid anti-solvent method to prepare the method for porous microsphere, makes the porous microsphere that makes have the characteristic that how much particle diameter is big, aerodynamic diameter is little.
The present invention solves the problems of the technologies described above through following technical scheme: a kind of CO 2 fluid anti-solvent method prepares the method for porous microsphere, and its concrete steps are following:
(1) preparation oil phase: by mass ratio is to take by weighing polymer and surfactant in 1: 1～3: 1 and be dissolved in mixing in an amount of organic solvent that then to obtain mass concentration be 1.5%～2.5% oil phase; Wherein polymer is dissolved in organic solvent and is insoluble to CO 2 fluid;
(2) preparation water-in-oil emulsion: to configure mass concentration is that the ammonium bicarbonate aqueous solution of 100mg/mL～300mg/mL is a water; The oil phase that afterwards step (1) is obtained and this water are to mix to form mixed liquor in 10: 1.0 or 10: 1.5 by volume, then this mixed liquor are placed and carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion;
(3) autoclave pretreatment: carbon dioxide is liquefied through refrigeration system; Carbon dioxide pressurization after then will being liquefied by high-pressure plunger pump also pumps in the autoclave; During the temperature and pressure treating to reach predetermined in the autoclave; Wherein this temperature is that 28 ℃, pressure are 8MPa～12MPa, keeps the speed that pumps into of carbon dioxide, and the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave;
(4) water-in-oil emulsion that step (2) is made is that the steel syringe needle of 25G～27G sprays in the autoclave of step (3) through high-pressure pump and via internal diameter; Make to be embedded with the particulate polymer microballoon of ammonium bicarbonate and to separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min～2.0mL/min to water-in-oil emulsion;
(5) after water-in-oil emulsion has sprayed, keep the autoclave internal pressure of step (3) and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 15～30min; Drip washing finishes the back this autoclave is carried out slow release, when treating that the interior pressure of this autoclave is reduced to normal pressure, collects and obtains fluffy powdery product;
(6) powdery product of step (5) being collected places under 50 ℃ of vacuum drying conditions and carries out heating and decomposition, obtains porous microsphere.
Further, the ultrasound condition in the said step (2) during ultrasonic emulsification is: ultrasonicly last 3min altogether, and every ultrasonic 3s stops 3s; Ultrasonic power is 200W～400W.
Further, said polymer is a kind of in PLLA, polylactic acid and Polyethylene Glycol acid block copolymer, polymethyl methacrylate, polyvinyl methyl ethermaleic anhydride, the alcohol soluble protein.
Further, said organic solvent is a kind of in dichloromethane, acetone, the ethanol.
Further, said surfactant is any of class of department class, Tweens, poloxamer class (like PF-127) or alkyl polyglucoside class.
The beneficial effect that CO 2 fluid anti-solvent method of the present invention prepares the method for porous microsphere is: can make the big and aerodynamic of how much particle diameters directly through less porous microsphere; And this porous microsphere not only the surface hole bigger; Under the surface sweeping ultramicroscope, can significantly show, and its inside and outside aperture connects each other; Thereby make this porous microsphere meet requirement as the pulmonary administration pharmaceutical carrier.
[description of drawings]
Combine embodiment that the present invention is done further description with reference to the accompanying drawings.
Fig. 1 is the SEM shape appearance figure of embodiment one gained porous microsphere among the present invention.
Fig. 2 is the SEM shape appearance figure of embodiment two gained porous microspheres among the present invention.
Fig. 3 is the SEM shape appearance figure of embodiment three gained porous microspheres among the present invention.
Fig. 4 is the SEM shape appearance figure of embodiment four gained porous microspheres among the present invention.
Fig. 5 is the SEM shape appearance figure of embodiment five gained porous microspheres among the present invention.
Fig. 6 is the SEM shape appearance figure of embodiment six gained porous microspheres among the present invention.
Fig. 7 is the SEM shape appearance figure of embodiment seven gained porous microspheres among the present invention.
Fig. 8 is the SEM shape appearance figure of embodiment eight gained porous microspheres among the present invention.
Fig. 9 is the SEM shape appearance figure of embodiment nine gained porous microspheres among the present invention.
Figure 10 is the SEM shape appearance figure of embodiment ten gained porous microspheres among the present invention.
Figure 11 is the SEM shape appearance figure of embodiment 11 gained porous microspheres among the present invention
Figure 12 is the SEM shape appearance figure of embodiment 12 gained load methotrexate porous microspheres among the present invention.
Figure 13 is the SEM shape appearance figure of embodiment 13 gained load ftorafur porous microspheres among the present invention.
Figure 14 is the SEM shape appearance figure after embodiment one gained porous microsphere amplifies among the present invention.
Figure 15 is the SEM shape appearance figure after embodiment seven gained porous microspheres amplify among the present invention.
[specific embodiment]
A kind of CO 2 fluid anti-solvent method of the present invention prepares the method for porous microsphere, and its concrete steps are following: (1) preparation oil phase: by mass ratio is to take by weighing polymer and surfactant in 1: 1～3: 1 and be dissolved in mixing in an amount of organic solvent that then to obtain mass concentration be 1.5%～2.5% oil phase; Wherein polymer is dissolved in organic solvent and is insoluble to supercritical carbon dioxide fluid; (2) preparation water-in-oil emulsion: to configure mass concentration is that the ammonium bicarbonate aqueous solution of 100mg/mL～300mg/mL is a water; The oil phase that afterwards step (1) is obtained and this water are to mix to form mixed liquor in 10: 1.0 or 10: 1.5 by volume, then this mixed liquor are placed and carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion; (3) autoclave pretreatment: carbon dioxide is liquefied through refrigeration system; Carbon dioxide pressurization after then will being liquefied by high-pressure plunger pump also pumps in the autoclave; During the temperature and pressure treating to reach predetermined in the autoclave; Wherein this temperature is that 28 ℃, pressure are 8MPa～12MPa, keeps the speed that pumps into of carbon dioxide, and the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; (4) water-in-oil emulsion that step (2) is made is that the steel syringe needle of 25G-27G sprays in the autoclave of step (3) through high-pressure pump and via internal diameter; Make to be embedded with the particulate polymer microballoon of ammonium bicarbonate and to separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min～2.0mL/min to water-in-oil emulsion; (5) after water-in-oil emulsion has sprayed, keep the autoclave internal pressure of step (3) and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 15～30min; Drip washing finishes the back this autoclave is carried out slow release, when treating that the interior pressure of this autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; (6) powdery product of step (5) being collected places under 50 ℃ of vacuum drying conditions and carries out heating and decomposition, obtains porous microsphere.
Wherein, polymer is a kind of in PLLA, polylactic acid and Polyethylene Glycol acid block copolymer, polymethylacrylic acid, polyvinyl methyl ethermaleic anhydride, the alcohol soluble protein; Organic solvent is a kind of in dichloromethane, acetone, the ethanol; Surfactant is, class of department class, Tweens, poloxamer class (like PF-127) or alkyl polyglucoside class any; Ultrasound condition in the step (2) during ultrasonic emulsification is: ultrasonicly last 3min altogether and every ultrasonic 3s stops 3s, when ultrasonic power was 200W～400W, the uniformity of prepared water-in-oil emulsion and stability were optimum.
For method of the present invention is further set forth explanation, the applicant following embodiment that given an example.
Embodiment one
Take by weighing 112.5mg PLLA and 37.5mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 1.5% oil phase; With the ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL is water; Getting this water 1.0mL, dropwise to drop to said mass concentration be to mix to form mixed liquor in 1.5% the oil phase, this mixed liquor placed carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion afterwards; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 26G (i.e. 0.24 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make the anti-solvent of PLLA microsphere include the porogen ammonium bicarbonate separate out, wherein to spray into the flow velocity of autoclave be 2.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 15min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, observed pattern is as shown in Figure 1 down in scanning electron microscope (SEM) for this porous microsphere.
Embodiment two
The flow velocity that water-in-oil emulsion sprays into autoclave becomes 1.0mL/min, and other condition and operation are with embodiment one, and resulting porous microsphere observed pattern under scanning electron microscope is as shown in Figure 2.
Embodiment three
Take by weighing 157.5mg PLLA and 52.5mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.1% oil phase; With the ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL is water; Getting this water 1.0mL, dropwise to drop to said mass concentration be to form mixed liquor in 2.1% the oil phase, this mixed liquor placed carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion afterwards; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 26G (i.e. 0.24 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 2.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is as shown in Figure 3.
Embodiment four
The flow velocity that water-in-oil emulsion sprays into autoclave becomes 1.0mL/min, and other condition and operation are with embodiment three, and resulting porous microsphere observed pattern under scanning electron microscope is as shown in Figure 4.
Embodiment five
Take by weighing 153.4mg PLLA and 76.7mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.3% oil phase; With the ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL is water; Getting this water 1.0mL, dropwise to drop to said mass concentration be to form mixed liquor in 2.3% the oil phase, this mixed liquor placed carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion afterwards; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that 26G (i.e. 0.24 μ m) steel syringe needle sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.5mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is as shown in Figure 5.
Embodiment six
The internal diameter of steel syringe needle becomes 27G (i.e. 0.21 μ m), and other condition and operation are with embodiment five, and resulting porous microsphere observed pattern under scanning electron microscope is as shown in Figure 6.
Embodiment seven
The water volume that dropwise drops in the oil phase becomes 1.5mL, and the internal diameter of steel syringe needle becomes 27G (i.e. 0.21 μ m), and other condition and operation are with embodiment five, and resulting porous microsphere observed pattern under scanning electron microscope is as shown in Figure 7.
Embodiment eight
Take by weighing 150.0mg PLLA and 100.0mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.5% oil phase; With the ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL is water; Getting this water 1.0mL, dropwise to drop to said mass concentration be to form mixed liquor in 2.5% the oil phase, this mixed liquor placed carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion afterwards; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 12MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 27G (i.e. 0.21 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is as shown in Figure 8.
Embodiment nine
Take by weighing 125.0mg PLLA and 125.0mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.5% oil phase; With the ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL is water; Getting this water 1.5mL, dropwise to drop to said mass concentration be to form mixed liquor in 2.5% the oil phase, this mixed liquor placed carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion afterwards; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 12MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 25G (i.e. 0.26 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is as shown in Figure 9.
Embodiment ten
Take by weighing 138.0mg PLLA and 92.0mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.3% oil phase; With the ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL is water; Getting this water 1.5mL, dropwise to drop to said mass concentration be to form mixed liquor in 2.3% the oil phase, this mixed liquor placed carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion afterwards; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 26G (i.e. 0.24 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is shown in figure 10.
Embodiment 11
Take by weighing 133.3mg PLLA and 66.7mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.0% oil phase; Configure the ammonium bicarbonate aqueous solution 1.0mL of mass concentration 200mg/mL, dropwise drop to said mass concentration and be in 2.0% the oil phase and form mixed liquor, this mixed liquor is placed carry out ultrasonic emulsification under the condition of ice bath afterwards to make water-in-oil emulsion; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 10MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 26G (i.e. 0.24 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.5mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 20min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is shown in figure 11.
Embodiment 12
Take by weighing 138.0mg PLLA and 92.0mg surfactant PF-127 and the two be dissolved in mixing in the 10mL dichloromethane that to get mass concentration be 2.3% oil phase; Configure the ammonium bicarbonate aqueous solution 1.0mL of mass concentration 300mg/mL; And the 51.8mg methotrexate is dissolved in behind this solution mixing as water; Dropwise drop to said mass concentration and be in 2.3% the oil phase and form mixed liquor, this mixed liquor is placed carry out ultrasonic emulsification under the condition of ice bath afterwards to make water-in-oil emulsion; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; The water-in-oil emulsion that makes is sprayed in the pretreated autoclave through high-pressure pump and via 26G (0.24 μ m) steel syringe needle; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is shown in figure 12.
Embodiment 13
Taking by weighing 106.9mg PLLA and 71.3mg surfactant PF-127 and 51.8mg ftorafur is dissolved in mixing in the 10mL dichloromethane altogether with the three to get mass concentration is 2.3% oil phase; Configure the ammonium bicarbonate aqueous solution 1.0mL of mass concentration 300mg/mL, dropwise drop to said mass concentration and be in 2.3% the oil phase and form mixed liquor, this mixed liquor is placed carry out ultrasonic emulsification under the condition of ice bath afterwards to make water-in-oil emulsion; Autoclave is carried out pretreatment; Particularly: carbon dioxide is liquefied through refrigeration system; Carbon dioxide after then will liquefy by high-pressure plunger pump pressurizes and also pumps in the autoclave, and during the temperature and pressure treating to reach predetermined in the autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa; Keep the speed that pumps into of carbon dioxide, the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave; Is that the steel syringe needle of 26G (i.e. 0.24 μ m) sprays in the pretreated autoclave with the water-in-oil emulsion that makes through high-pressure pump and via internal diameter; Make ammonium bicarbonate in the water-in-oil emulsion, and the anti-simultaneously solvent of PLLA microsphere that forms of PLLA separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min to water-in-oil emulsion; After water-in-oil emulsion has sprayed, keep autoclave internal pressure and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes the back autoclave is carried out slow release, when treating that the interior pressure of autoclave is reduced to normal pressure, collects and obtains fluffy powdery product; The powdery product of collecting placed under 50 ℃ of vacuum drying conditions carry out heating and decomposition, obtain porous microsphere, this porous microsphere observed pattern under scanning electron microscope is shown in figure 13.
In addition, the applicant has also carried out particle diameter to the resulting porous microsphere of above-mentioned each embodiment and has detected and statistics, and its statistical result is as shown in table 1 below.
The particle diameter statistical result of each embodiment gained porous microsphere of table 1
Through above-mentioned each embodiment gained porous microsphere under scanning electron microscope observed pattern, and table 1 can know; The big and aerodynamic of how much particle diameters of the porous microsphere tool that makes via the inventive method is directly through the characteristics of less porous microsphere; And porous microsphere not only the surface hole bigger; Under the surface sweeping ultramicroscope, can significantly show, and its inside and outside aperture connects each other; Therefore, the porous microsphere that makes of the inventive method meets the requirement as the pulmonary administration pharmaceutical carrier.
Claims (5)
1. a CO 2 fluid anti-solvent method prepares the method for porous microsphere, and it is characterized in that: concrete steps are following:
(1) preparation oil phase: by mass ratio is to take by weighing polymer and surfactant in 1: 1～3: 1 and be dissolved in mixing in an amount of organic solvent that then to obtain mass concentration be 1.5%～2.5% oil phase; Wherein polymer is dissolved in organic solvent and is insoluble to supercritical carbon dioxide fluid;
(2) preparation water-in-oil emulsion: to configure mass concentration is that the ammonium bicarbonate aqueous solution of 100mg/mL～300mg/mL is a water; The oil phase that afterwards step (1) is obtained and this water are to mix to form mixed liquor in 10: 1.0 or 10: 1.5 by volume, then this mixed liquor are placed and carry out ultrasonic emulsification under the condition of ice bath to make water-in-oil emulsion;
(3) autoclave pretreatment: carbon dioxide is liquefied through refrigeration system; Carbon dioxide pressurization after then will being liquefied by high-pressure plunger pump also pumps in the autoclave; During the temperature and pressure treating to reach predetermined in the autoclave; Wherein this temperature is that 28 ℃, pressure are 8MPa～12MPa, keeps the speed that pumps into of carbon dioxide, and the vent valve of opening autoclave is with 1.8m
3The speed of/h is exitted, and outside drying baker and the pipeline bath temperature of regulating autoclave are to keep pressure, the temperature constant in the autoclave;
(4) water-in-oil emulsion that step (2) is made is that the steel syringe needle of 25G～27G sprays in the autoclave of step (3) through high-pressure pump and via internal diameter; Make to be embedded with the particulate polymer microballoon of ammonium bicarbonate and to separate out, wherein to spray into the flow velocity of autoclave be 1.0mL/min～2.0mL/min to water-in-oil emulsion;
(5) after water-in-oil emulsion has sprayed, keep the autoclave internal pressure of step (3) and temperature-resistant, continue to feed carbon dioxide drip washing to remove residual solvent, the drip washing time is 15～30min; Drip washing finishes the back this autoclave is carried out slow release, when treating that the interior pressure of this autoclave is reduced to normal pressure, collects and obtains fluffy powdery product;
(6) powdery product of step (5) being collected places under 50 ℃ of vacuum drying conditions and carries out heating and decomposition, obtains porous microsphere.
2. CO 2 fluid anti-solvent method according to claim 1 prepares the method for porous microsphere, it is characterized in that: the ultrasound condition in the said step (2) during ultrasonic emulsification is: ultrasonicly last 3min altogether, and every ultrasonic 3s stops 3s; Ultrasonic power is 200W～400W.
3. CO 2 fluid anti-solvent method according to claim 1 prepares the method for porous microsphere, it is characterized in that: said polymer is a kind of in PLLA, polylactic acid and Polyethylene Glycol acid block copolymer, polymethyl methacrylate, polyvinyl methyl ethermaleic anhydride, the alcohol soluble protein.
4. CO 2 fluid anti-solvent method according to claim 1 prepares the method for porous microsphere, it is characterized in that: said organic solvent is a kind of in dichloromethane, acetone, the ethanol.
5. CO 2 fluid anti-solvent method according to claim 1 prepares the method for porous microsphere, it is characterized in that: said surfactant is any of class of department class, Tweens, poloxamer class or alkyl polyglucoside class.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102941043A (en) * | 2012-10-12 | 2013-02-27 | 华侨大学 | Method of preparing porous polymer microspheres by high voltage electrostatic anti-solvent process |
| CN104001219A (en) * | 2014-06-13 | 2014-08-27 | 华侨大学 | Method for sintering co-loading cell porous microsphere scaffold through subcritical carbon dioxide |
| CN105963714A (en) * | 2016-06-16 | 2016-09-28 | 华侨大学 | Method for preparing micro nano porous microspheres carrying gene and polypeptide drugs through supercritical fluid technology |
| CN107929263A (en) * | 2017-11-22 | 2018-04-20 | 福建医科大学 | Novel biodegradable controlled release preparation of Pin1 inhibitor ATRA and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050147687A1 (en) * | 2003-07-18 | 2005-07-07 | Julia Rashba-Step | Methods for fabrication, uses and compositions of small spherical particles of AAT prepared by controlled phase separation |
| CN101036870A (en) * | 2007-02-06 | 2007-09-19 | 四川大学 | Polylactide microsphere preparation by using supercritical CO2 antisolvent technology |
-
2012
- 2012-06-28 CN CN201210220836.3A patent/CN102697738B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050147687A1 (en) * | 2003-07-18 | 2005-07-07 | Julia Rashba-Step | Methods for fabrication, uses and compositions of small spherical particles of AAT prepared by controlled phase separation |
| CN101036870A (en) * | 2007-02-06 | 2007-09-19 | 四川大学 | Polylactide microsphere preparation by using supercritical CO2 antisolvent technology |
Non-Patent Citations (2)
| Title |
|---|
| 王长鸣等: "在超临界二氧化碳中制备超高分子量聚乙烯多孔微球", 《高等学校化学学报》 * |
| 蒲曦鸣: "超临界CO_2抗溶剂法制备聚乳酸药物缓释微球", 《功能材料》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102941043A (en) * | 2012-10-12 | 2013-02-27 | 华侨大学 | Method of preparing porous polymer microspheres by high voltage electrostatic anti-solvent process |
| CN102941043B (en) * | 2012-10-12 | 2015-08-05 | 华侨大学 | High-pressure electrostatic anti-dissolving agent process prepares the method for porous polymer bead |
| CN104001219A (en) * | 2014-06-13 | 2014-08-27 | 华侨大学 | Method for sintering co-loading cell porous microsphere scaffold through subcritical carbon dioxide |
| CN104001219B (en) * | 2014-06-13 | 2016-01-20 | 华侨大学 | Subcritical carbon dioxide sintering carries the method for cell porous microsphere support altogether |
| CN105963714A (en) * | 2016-06-16 | 2016-09-28 | 华侨大学 | Method for preparing micro nano porous microspheres carrying gene and polypeptide drugs through supercritical fluid technology |
| CN105963714B (en) * | 2016-06-16 | 2019-12-13 | 华侨大学 | Method for preparing gene and polypeptide drug-loaded micro-nano porous microspheres by supercritical fluid technology |
| CN107929263A (en) * | 2017-11-22 | 2018-04-20 | 福建医科大学 | Novel biodegradable controlled release preparation of Pin1 inhibitor ATRA and its preparation method and application |
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