CN102697738B - 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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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 method of pharmaceutical carrier, be specifically related to a kind of method of preparing porous microsphere, especially relate to a kind of method that CO 2 fluid anti-solvent method is prepared porous microsphere.
[background technology]
Compare with the solid polymer microsphere with same particle size, porous microsphere has porous network structure, not only can be for the fields such as separation and purification of absorption, immobilized enzyme, biomacromolecule, and aspect medical carrier, rely on self lower density, irregular configuration of surface, air dynamic behaviour and pulmonary's settling property, become the first-selection that is suitable for pulmonary administration dosage form preferably.
Traditional porous microsphere preparation method 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 easy deactivation 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.
Supercritical fluid anti-solvent method is the 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 the pharmaceutical carriers such as ultra-fine polylactic acid microsphere, magnetic-polylactic acid nano particle, but how much particle diameters less (being generally less than 1 μ m) due to these pharmaceutical carriers, are used as pulmonary administration carrier and are not suitable for.Correspondingly, same principle is also applicable to the water-in-oil emulsion system that contains certain volume water, this water-in-oil emulsion system be take polymeric matrix as oil phase, be wrapped in the water being formed by 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 drop is walked in extraction, the original solute composition dissolving is separated out and has been formed polymer microballoon owing to being insoluble to supercritical fluid in drop, the ammonium bicarbonate originally comprising in the drop of water-in-oil emulsion and this polymer microballoon simultaneously anti-solvent are separated out, and the ammonium bicarbonate of separating out is evenly distributed on the inside of this polymer microballoon (when the water-in-oil emulsion forming is even, during stable system), afterwards by the sample of collecting by adding thermal decomposition, will make ammonium bicarbonate be decomposed into nontoxic carbon dioxide, ammonia G&W, and formed pore space structure in microsphere inside and surface.Compare with traditional preparation method, supercritical fluid carbon dioxide anti-solvent method advantage is that preparation condition is gentle, temperature is low, technique is simple, do not have or substantially do not have organic solvent dissolvent residual, how much particle diameters of product and aerodynamic size to meet pulmonary administration requirement, be therefore especially suitable for use as and build pulmonary administration pharmaceutical carrier.
Supercritical carbon dioxide anti-solvent legal system is less for the report of porous microsphere, the report based on having seen, and practitioner sums up and finds to exist following problem: the hole on porous microsphere surface is also not obvious under surface sweeping ultramicroscope, need can identify by instrument; Or even there is the problem that porous microsphere surface atresia, inner hollow or hole do not connect mutually.These problems are disadvantageous for carrying out for 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 making have the characteristic that geometry particle diameter is large, aerodynamic diameter is little.
The present invention solves the problems of the technologies described above by the following technical programs: a kind of CO 2 fluid anti-solvent method is prepared the method for porous microsphere, and its concrete steps are as follows:
(1) prepare oil phase: be within 1: 1～3: 1, take polymer and surfactant and be dissolved in and in appropriate organic solvent, mix that to obtain mass concentration be 1.5%～2.5% oil phase in mass ratio; Wherein polymer is dissolved in organic solvent and is insoluble to CO 2 fluid;
(2) prepare water-in-oil emulsion: take that to configure the ammonium bicarbonate aqueous solution that mass concentration is 100mg/mL～300mg/mL be water, the oil phase afterwards step (1) being obtained is within 10: 1.0 or 10: 1.5, to mix to form mixed liquor with this water by volume, then this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion;
(3) autoclave pretreatment: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa～12MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave;
(4) water-in-oil emulsion step (2) being made is by high-pressure pump and via internal diameter, be 25G～27G steel syringe needle sprays in the autoclave of step (3), the polymer microballoon that is embedded with ammonium bicarbonate granule is separated out, and 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, maintain the autoclave internal pressure of step (3) and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 15～30min; Drip washing finishes rear this autoclave to be carried out to slow release, and the Pressure Drop in this autoclave during to normal pressure, is collected and obtained fluffy powdery product;
(6) powdery product of step (5) being collected is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtains porous microsphere.
Further, the ultrasound condition in described step (2) during ultrasonic emulsification is: ultrasonicly altogether last 3min, and every ultrasonic 3s stops 3s; Ultrasonic power is 200W～400W.
Further, described polymer is a kind of in Poly-L-lactic acid, polylactic acid and polyglycolic acid block copolymer, polymethyl methacrylate, polyvinyl methyl ethermaleic anhydride, alcohol soluble protein.
Further, described organic solvent is a kind of in dichloromethane, acetone, ethanol.
Further, described surfactant is any of class of department class, Tweens, poloxamer class (as PF-127) or alkyl polyglucoside class.
The beneficial effect that CO 2 fluid anti-solvent method of the present invention is prepared the method for porous microsphere is: can make the large and aerodynamic of how much particle diameters directly through less porous microsphere, and this porous microsphere not only surface hole larger, under surface sweeping ultramicroscope, can significantly show, and its inside and outside aperture connects mutually; Thereby make this porous microsphere meet the requirement as pulmonary administration pharmaceutical carrier.
[accompanying drawing explanation]
The invention will be further described in conjunction with the embodiments with reference to the accompanying drawings.
Fig. 1 is the SEM shape appearance figure of embodiment mono-gained porous microsphere in the present invention.
Fig. 2 is the SEM shape appearance figure of embodiment bis-gained porous microspheres in the present invention.
Fig. 3 is the SEM shape appearance figure of embodiment tri-gained porous microspheres in the present invention.
Fig. 4 is the SEM shape appearance figure of embodiment tetra-gained porous microspheres in the present invention.
Fig. 5 is the SEM shape appearance figure of embodiment five gained porous microspheres in the present invention.
Fig. 6 is the SEM shape appearance figure of embodiment six gained porous microspheres in the present invention.
Fig. 7 is the SEM shape appearance figure of embodiment seven gained porous microspheres in the present invention.
Fig. 8 is the SEM shape appearance figure of embodiment eight gained porous microspheres in the present invention.
Fig. 9 is the SEM shape appearance figure of embodiment nine gained porous microspheres in the present invention.
Figure 10 is the SEM shape appearance figure of embodiment ten gained porous microspheres in the present invention.
Figure 11 is the SEM shape appearance figure of embodiment 11 gained porous microspheres in the present invention
Figure 12 is the SEM shape appearance figure of embodiment 12 gained load methotrexate porous microspheres in the present invention.
Figure 13 is the SEM shape appearance figure of embodiment 13 gained load ftorafur porous microspheres in the present invention.
Figure 14 is the SEM shape appearance figure after embodiment mono-gained porous microsphere amplification in the present invention.
Figure 15 is the SEM shape appearance figure after embodiment seven gained porous microspheres amplifications in the present invention.
[specific embodiment]
A kind of CO 2 fluid anti-solvent method of the present invention is prepared the method for porous microsphere, and its concrete steps are as follows: (1) prepares oil phase: be within 1: 1～3: 1, take polymer and surfactant and be dissolved in and in appropriate organic solvent, mix that to obtain mass concentration be 1.5%～2.5% oil phase in mass ratio; Wherein polymer is dissolved in organic solvent and is insoluble to supercritical carbon dioxide fluid; (2) prepare water-in-oil emulsion: take that to configure the ammonium bicarbonate aqueous solution that mass concentration is 100mg/mL～300mg/mL be water, the oil phase afterwards step (1) being obtained is within 10: 1.0 or 10: 1.5, to mix to form mixed liquor with this water by volume, then this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; (3) autoclave pretreatment: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa～12MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; (4) water-in-oil emulsion step (2) being made is by high-pressure pump and via internal diameter, be 25G-27G steel syringe needle sprays in the autoclave of step (3), the polymer microballoon that is embedded with ammonium bicarbonate granule is separated out, and 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, maintain the autoclave internal pressure of step (3) and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 15～30min; Drip washing finishes rear this autoclave to be carried out to slow release, and the Pressure Drop in this autoclave during to normal pressure, is collected and obtained fluffy powdery product; (6) powdery product of step (5) being collected is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtains porous microsphere.
Wherein, polymer is a kind of in Poly-L-lactic acid, polylactic acid and polyglycolic acid block copolymer, polymethylacrylic acid, polyvinyl methyl ethermaleic anhydride, alcohol soluble protein; Organic solvent is a kind of in dichloromethane, acetone, ethanol; Surfactant is, class of department class, Tweens, poloxamer class (as PF-127) or alkyl polyglucoside class any; Ultrasound condition when the middle ultrasonic emulsification of step (2) is: ultrasonic 3min and the every ultrasonic 3s stop 3s of altogether lasting, when ultrasonic power is 200W～400W, the uniformity of prepared water-in-oil emulsion and stability are optimum.
For method of the present invention is further elaborated explanation, applicant has exemplified following embodiment.
Embodiment mono-
Take 112.5mg Poly-L-lactic acid and 37.5mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 1.5%; The ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL of take is water, getting this water 1.0mL, dropwise to drop to described mass concentration be to mix to form mixed liquor in 1.5% oil phase, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 26G (i.e. 0.24 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, the anti-solvent of Poly-L-lactic acid microsphere that includes porogen ammonium bicarbonate is separated out, and 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 15min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope (SEM) as shown in Figure 1.
Embodiment bis-
The flow velocity that water-in-oil emulsion sprays into autoclave becomes 1.0mL/min, and other condition is with operation with embodiment mono-, and the pattern that resulting porous microsphere is observed under scanning electron microscope as shown in Figure 2.
Embodiment tri-
Take 157.5mg Poly-L-lactic acid and 52.5mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.1%; The ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL of take is water, getting this water 1.0mL, dropwise to drop to described mass concentration be to form mixed liquor in 2.1% oil phase, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 26G (i.e. 0.24 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in Figure 3.
Embodiment tetra-
The flow velocity that water-in-oil emulsion sprays into autoclave becomes 1.0mL/min, and other condition is with operation with embodiment tri-, and the pattern that resulting porous microsphere is observed under scanning electron microscope as shown in Figure 4.
Embodiment five
Take 153.4mg Poly-L-lactic acid and 76.7mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.3%; The ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL of take is water, getting this water 1.0mL, dropwise to drop to described mass concentration be to form mixed liquor in 2.3% oil phase, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be that 26G (i.e. 0.24 μ m) steel syringe needle sprays in pretreated autoclave via internal diameter, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope 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 is with operation with embodiment five, and the pattern that resulting porous microsphere is observed under scanning electron microscope as shown in Figure 6.
Embodiment seven
The water volume dropwise dropping in oil phase becomes 1.5mL, and the internal diameter of steel syringe needle becomes 27G (i.e. 0.21 μ m), and other condition is with operation with embodiment five, and the pattern that resulting porous microsphere is observed under scanning electron microscope as shown in Figure 7.
Embodiment eight
Take 150.0mg Poly-L-lactic acid and 100.0mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.5%; The ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL of take is water, getting this water 1.0mL, dropwise to drop to described mass concentration be to form mixed liquor in 2.5% oil phase, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 12MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 27G (i.e. 0.21 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in Figure 8.
Embodiment nine
Take 125.0mg Poly-L-lactic acid and 125.0mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.5%; The ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL of take is water, getting this water 1.5mL, dropwise to drop to described mass concentration be to form mixed liquor in 2.5% oil phase, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 12MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 25G (i.e. 0.26 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in Figure 9.
Embodiment ten
Take 138.0mg Poly-L-lactic acid and 92.0mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.3%; The ammonium bicarbonate aqueous solution that configures mass concentration 300mg/mL of take is water, getting this water 1.5mL, dropwise to drop to described mass concentration be to form mixed liquor in 2.3% oil phase, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 26G (i.e. 0.24 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in figure 10.
Embodiment 11
Take 133.3mg Poly-L-lactic acid and 66.7mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.0%; Configure the ammonium bicarbonate aqueous solution 1.0mL of mass concentration 200mg/mL, dropwise drop to described mass concentration and be in 2.0% oil phase and form mixed liquor, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 10MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 26G (i.e. 0.24 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 20min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in figure 11.
Embodiment 12
Take 138.0mg Poly-L-lactic acid and 92.0mg surfactant PF-127 and the two is dissolved in and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.3%; Configure the ammonium bicarbonate aqueous solution 1.0mL of mass concentration 300mg/mL, and 51.8mg methotrexate is dissolved in to this solution mixes rear as water, dropwise drop to described mass concentration and be in 2.3% oil phase and form mixed liquor, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; The water-in-oil emulsion making is sprayed in pretreated autoclave by high-pressure pump and via 26G (0.24 μ m) steel syringe needle, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in figure 12.
Embodiment 13
Taking 106.9mg Poly-L-lactic acid and 71.3mg surfactant PF-127 and 51.8mg ftorafur is dissolved in three altogether and in 10mL dichloromethane, mixes to obtain the mass concentration oil phase that is 2.3%; Configure the ammonium bicarbonate aqueous solution 1.0mL of mass concentration 300mg/mL, dropwise drop to described mass concentration and be in 2.3% oil phase and form mixed liquor, afterwards this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion; Autoclave is carried out to pretreatment, particularly: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave; By the water-in-oil emulsion making by high-pressure pump and be 26G (i.e. 0.24 μ m) via internal diameter steel syringe needle sprays in pretreated autoclave, make Poly-L-lactic acid microsphere that in water-in-oil emulsion, ammonium bicarbonate and Poly-L-lactic acid form simultaneously anti-solvent 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, maintain autoclave internal pressure and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 30min; Drip washing finishes rear autoclave to be carried out to slow release, and the Pressure Drop in autoclave during to normal pressure, is collected and obtained fluffy powdery product; The powdery product of collecting is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtain porous microsphere, the pattern that this porous microsphere is observed under scanning electron microscope as shown in figure 13.
In addition, applicant has also carried out particle diameter to the resulting porous microsphere of the various embodiments described above 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
Pattern and the table 1 by the various embodiments described above gained porous microsphere, under scanning electron microscope, observed are known, the large and aerodynamic of how much particle diameters of the porous microsphere tool that makes via the inventive method is directly through the feature of less porous microsphere, and porous microsphere not only surface hole larger, under surface sweeping ultramicroscope, can significantly show, and its inside and outside aperture connects mutually; Therefore the porous microsphere that, the inventive method makes meets the requirement as pulmonary administration pharmaceutical carrier.
Claims (2)
1. CO 2 fluid anti-solvent method is prepared a method for porous microsphere, it is characterized in that: concrete steps are as follows:
(1) prepare oil phase: in mass ratio for 1:1～3:1 takes polymer and surfactant and be dissolved in appropriate organic solvent and mix and obtain the oil phase that mass concentration is 1.5 ﹪～2.5 ﹪; Wherein polymer is dissolved in organic solvent and is insoluble to supercritical carbon dioxide fluid;
(2) prepare water-in-oil emulsion: take that to configure the ammonium bicarbonate aqueous solution that mass concentration is 100 mg/mL～300 mg/mL be water, the oil phase afterwards step (1) being obtained is within 10: 1.0 or 10: 1.5, to mix to form mixed liquor with this water by volume, then this mixed liquor is placed under condition of ice bath and carries out ultrasonic emulsification to make water-in-oil emulsion;
(3) autoclave pretreatment: carbon dioxide is liquefied through refrigeration system, then by high-pressure plunger pump, the carbon dioxide after liquefaction is pressurizeed and pumped in autoclave, while reaching predetermined temperature and pressure in autoclave, wherein this temperature is that 28 ℃, pressure are 8 MPa～12 MPa, maintain the speed that pumps into of carbon dioxide, open the vent valve of autoclave with 1.8 m
3the speed of/h is exitted, and regulates the outside drying baker of autoclave and pipeline bath temperature to keep pressure, the temperature constant in autoclave;
(4) water-in-oil emulsion step (2) being made is by high-pressure pump and via internal diameter, be 25G～27G steel syringe needle sprays in the autoclave of step (3), the polymer microballoon that is embedded with ammonium bicarbonate granule is separated out, and wherein to spray into the flow velocity of autoclave be 1.0 mL/min～2.0 mL/min to water-in-oil emulsion;
(5) after water-in-oil emulsion has sprayed, maintain the autoclave internal pressure of step (3) and temperature-resistant, continue to pass into carbon dioxide drip washing to remove residual solvent, the drip washing time is 15～30 min; Drip washing finishes rear this autoclave to be carried out to slow release, and the Pressure Drop in this autoclave during to normal pressure, is collected and obtained fluffy powdery product;
(6) powdery product of step (5) being collected is placed under 50 ℃ of vacuum drying conditions and adds thermal decomposition, obtains porous microsphere;
Described polymer is Poly-L-lactic acid; Described organic solvent is dichloromethane; Described surfactant is poloxamer class.
2. CO 2 fluid anti-solvent method according to claim 1 is prepared the method for porous microsphere, it is characterized in that: ultrasound condition during the middle ultrasonic emulsification of described step (2) is: ultrasonic 3 min that altogether last, and every ultrasonic 3 s stop 3 s; Ultrasonic power is 200 W～400 W.
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