CN111714471A - Polymer microsphere for pulmonary drug delivery and preparation method and application thereof - Google Patents
Polymer microsphere for pulmonary drug delivery and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a polymer microsphere for pulmonary administration and a preparation method and application thereof. The hydrophilic pulmonary disease drug is preliminarily coated by the amphiphilic polymer, the pore structure of the microsphere is regulated, the pore structure on the surface of the microsphere is reduced, and the degradable polymer is coated again, so that the instability of drug release performance caused by agglomeration of the hydrophilic pulmonary disease drug can be prevented, and the effects of controllable release and degradation of the hydrophilic pulmonary disease drug can be achieved.
Description
Technical Field
The invention belongs to the technical field of lung high-molecular drugs, and particularly relates to a high-molecular microsphere for lung drug delivery, and a preparation method and application thereof.
Background
The lung targeting microspheres refer to a particle microsphere system formed by dispersing or adsorbing drugs in various polymer carrier materials, and after the drug-containing microspheres are injected into a vein or inhaled into a human body through a respiratory tract, the drug-containing microspheres can be phagocytized by a reticuloendothelial system distributed in lung tissues or mechanically ingested by pulmonary capillaries when reaching the lung, so that the drugs can be concentrated in the lung tissues, the blood concentration of the lung is increased, the curative effect of the drugs is improved, the drug concentration of the whole body is reduced, and the toxic and side effects are reduced. The materials currently used in such microspheres mainly include inorganic materials, natural polymers and synthetic polymers, and are classified into degradable materials and non-degradable materials according to their degradation properties. Polyesters are the most studied and widely used biodegradable synthetic polymeric materials, such as polylactic acid, polyglycolic acid, poly-caprolactone, poly-beta-hydroxybutyrate, poly-beta-hydroxyvalerate and their copolymers.
At present, the matrix materials of hydrophilic drug-loaded polymer microspheres for treating pulmonary diseases are mainly water-soluble polymers such as chitosan, sodium alginate, hyaluronic acid, gelatin and the like, but the degradation behaviors of the water-soluble polymers are not controllable, so that the problems that the burst release is too high and the drug release is not facilitated are caused; the copolymer of lactic acid-glycolic acid is used as a matrix material to prepare the hydrophilic-loaded microspheres, for example, the drug-loaded microspheres are prepared by adding drugs into an external water phase, or the drug-loaded microspheres are prepared by physically adsorbing the drugs on the surfaces of the copolymer microspheres of lactic acid-glycolic acid, but the obtained microspheres have low drug loading capacity and are not beneficial to long-term administration of lung.
Generally, commercially available hydrophilic drugs for lung diseases cannot be dissolved in an organic solvent, and if the drugs are directly dispersed in the organic solvent to prepare the drug-loaded microspheres, the drug release performance of the microspheres is unstable due to the aggregation of the drugs; if the hydrophilic medicine for lung diseases is dissolved in water and the medicine carrying microspheres are prepared by a multiple emulsion method, the burst release is large due to the large pore structure and specific surface area on the surfaces of the microspheres, which is not beneficial to the stable release of the medicine.
Disclosure of Invention
The invention aims to provide a controllable release and degradation polymer microsphere for pulmonary administration, which can reduce the burst release effect of hydrophilic pulmonary diseases and has high drug loading capacity, and a preparation method and application thereof.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
a high-molecular microball for lung administration is composed of hydrophilic medicine for treating lung diseases, amphiphilic polymer coated on the surface of hydrophilic medicine for treating lung diseases, and degradable polymer coated on the surface of amphiphilic polymer.
Preferably, the mass ratio of the hydrophilic pulmonary disease drug to the amphiphilic polymer is 1 (1-20).
Preferably, the mass ratio of the hydrophilic pulmonary disease drug to the amphiphilic polymer is 1 (5-15).
Preferably, the mass ratio of the amphiphilic polymer to the degradable polymer is 1: (1-8).
Preferably, the particle size of the polymeric microspheres for pulmonary administration is 1 μm to 30 μm.
Preferably, the hydrophilic pulmonary disease drug is at least one selected from chloroquine phosphate, isoniazid, cisplatin, adriamycin, aminophylline, curcumin and salbutamol sulfate.
Preferably, the hydrophilic pulmonary disease drug is at least one selected from chloroquine phosphate and isoniazid.
Preferably, the amphiphilic polymer is at least one selected from the group consisting of polyethylene glycol, cyclodextrin, and a copolymer of polyethylene glycol and an amino acid, and has a molecular weight of 1000 to 8000 daltons.
Preferably, the degradable polymer is at least one selected from poly 3-hydroxyalkanoate, polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, poly 3-hydroxybutyrate-co-3-hydroxyvalerate, poly (3-hydroxybutyrate), polybutylene succinate and polytrimethylene carbonate, and the molecular weight of the degradable polymer is 3000-60000 dalton.
In a second aspect of the present invention, there is provided:
a preparation method of polymer microspheres for pulmonary administration comprises the following steps:
(1) dispersing hydrophilic lung disease medicine in an amphiphilic polymer water solution to form a pre-inclusion body;
(2) dispersing the pre-inclusion in a degradable high molecular solution containing an organic solvent to form an inclusion solution;
(3) dispersing the inclusion solution into a solution containing a surfactant, precipitating, cleaning the precipitate, and drying to obtain the polymer microsphere for pulmonary administration.
Preferably, the dispersing speed in the step (1) is 200-20000 rpm, and the dispersing time is +2min-24 h; the dispersing speed in the step (2) is 2000-10000 rpm, and the dispersing time is 2-5 min; the dispersing speed in the step (3) is 500-3000 rpm, and the dispersing time is 4-14 h.
Preferably, the step (1) further comprises: the hydrophilic lung disease medicine is dispersed in an amphiphilic polymer water solution, and is frozen and dried to form a pre-inclusion body, wherein the pre-inclusion body is a nano particle.
Preferably, in the step (1), the mass concentration of the amphiphilic polymer in the amphiphilic polymer aqueous solution is 0.05-0.1 g/mL.
Preferably, the mass concentration of the degradable polymer in the degradable polymer solution containing the organic solvent in the step (2) is 0.05 to 0.1 g/mL.
Preferably, the organic solvent in the step (2) is selected from any one of dichloromethane, chloroform, ethyl acetate and tetrahydrofuran.
Preferably, the volume ratio of the inclusion solution to the surfactant in the step (3) is 1: (15-50).
Preferably, the dispersion temperature in the step (3) is 20 to 80 ℃.
Preferably, in the step (3), the drying is at least one selected from room temperature air drying, heat drying and freeze drying, and the drying time is 12 to 48 hours.
Preferably, the surfactant in the step (3) is at least one selected from polyvinyl alcohol, gelatin, tween, methyl cellulose and span.
Preferably, the surfactant-containing solution in the step (3) has a surfactant content of 0.1 to 5.0% by mass.
Preferably, the surfactant-containing solution in the step (3) is an aqueous solution containing a surfactant or a liquid paraffin solution containing a surfactant.
In a third aspect of the present invention, there is provided:
the polymer microsphere for pulmonary administration is the polymer microsphere for pulmonary administration or prepared by the preparation method of the polymer microsphere for pulmonary administration.
The invention has the beneficial effects that:
1. the hydrophilic pulmonary disease drug is preliminarily coated by the amphiphilic polymer, the pore structure of the microsphere is regulated, the pore structure on the surface of the microsphere is reduced, and the degradable polymer is coated again, so that the instability of drug release performance caused by agglomeration of the hydrophilic pulmonary disease drug can be prevented, and the effects of controllable release and degradation of the hydrophilic pulmonary disease drug can be achieved.
2. The amphiphilic polymer is used for wrapping water-soluble medicine for treating lung diseases, and is combined with the medicine in non-covalent bond forms such as electrostatic force, hydrogen bond, hydrophilic and hydrophobic acting force and the like to obtain the polymer microsphere which has better affinity to the water-soluble medicine and does not obviously influence the degradation performance of degradable polymer.
3. In the polymer microsphere for pulmonary administration prepared by the invention, the release rate of the hydrophilic pulmonary disease drug is 0.5-35%/day, and the long-term pulmonary administration is realized.
4. The mass ratio of hydrophilic lung disease medication to amphiphilic macromolecules in the macromolecular microspheres for pulmonary administration is controlled within 1 (1-20), and the mass ratio of the amphiphilic macromolecules to degradable macromolecules is controlled within 1: (1-8), the microspheres can realize large drug-loading rate and controllable release of hydrophilic lung disease medication; the slow release performance of the microspheres can be further improved; otherwise, too large an amount of hydrophilic pulmonary disease medication may result in an increased burst effect.
Drawings
FIG. 1 is a graph of in vitro solute release for microspheres of examples 1-5 and comparative examples 1-3.
Detailed Description
In order to make the objects, technical solutions and technical effects of the present invention more clear, the present invention will be described in further detail with reference to specific embodiments. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. Those in examples or comparative examples or test examples, for which no specific conditions are indicated, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) mixing 40mg of aminophylline with 10mL of aqueous solution containing 8% polyethylene glycol 4000, stirring at 5000rpm for 30min to obtain aqueous solution of polyethylene glycol 4000 containing aminophylline, and freeze-drying for 48h to obtain polyethylene glycol 4000 granules containing aminophylline;
(2) dissolving 0.8g of polylactic acid (with a molecular weight of about 3.5 ten thousand daltons) in 10mL of dichloromethane to obtain a polylactic acid solution; adding 300mg of polyethylene glycol 4000 granules containing aminophylline, and stirring at 25 ℃ and 6000rpm for 3min to obtain polylactic acid solution containing aminophylline;
(3) pouring the polylactic acid solution containing the aminophylline into 300mL of aqueous solution containing 0.7% of methyl cellulose, and continuously stirring at 1200rpm for 10h at 45 ℃; the product is washed by water and centrifuged for three times (each time the centrifugation condition is 10000rpm, 20min, 10 ℃), the precipitated product is collected, and the polylactic acid microspheres loaded with aminophylline are obtained after freeze drying for 36 h.
Example 2: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) mixing 500mg curcumin with 10mL aqueous solution containing 5% cyclodextrin, stirring at 20000rpm for 2min to obtain cyclodextrin aqueous solution containing curcumin;
(2) dissolving 0.5g of polylactic acid-glycolic acid copolymer (with the molecular weight of about 6.0 ten thousand daltons) in 10mL of tetrahydrofuran to obtain polylactic acid-glycolic acid copolymer solution; then adding 5mL of cyclodextrin water solution containing curcumin, stirring at 10 ℃ and 8000rpm for 4min to obtain polylactic acid-glycolic acid copolymer solution containing curcumin;
(3) pouring the polylactic acid-glycolic acid copolymer solution containing curcumin into 400mL of aqueous solution containing 3.0% 1788 type polyvinyl alcohol, and continuously stirring at 1000rpm for 14h at 50 ℃; washing the product with water and centrifuging for three times (each time centrifuging at 8000rpm, 30min, 4 deg.C), collecting precipitate, and freeze drying for 48h to obtain curcumin-loaded polylactic acid-glycolic acid copolymer microsphere.
Example 3: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) mixing 100mg of chloroquine phosphate with 10mL of aqueous solution containing 10% of cyclodextrin, and stirring at 200rpm for 24h to obtain a chloroquine phosphate-containing polyethylene glycol 2000 aqueous solution;
(2) dissolving 1.0g of polylactic acid-glycolic acid copolymer (with the molecular weight of about 3.0 ten thousand daltons) in 10mL of dichloromethane to obtain polylactic acid-glycolic acid copolymer solution; then adding 5mL of chloroquine-containing polyethylene glycol 2000 aqueous solution, and stirring at 10000rpm for 1.5min at 0 ℃ to obtain chloroquine-containing polylactic acid-glycolic acid copolymer solution;
(3) pouring the chloroquine phosphate-containing polylactic acid-glycolic acid copolymer solution into 150mL of aqueous solution containing 0.1% 1788 type polyvinyl alcohol, and continuously stirring at 1000rpm for 14h at 60 ℃; the product is washed by water and centrifuged for three times (the centrifugation conditions are 20000rpm, 30min and 4 ℃) and the precipitated product is collected and freeze-dried for 24 hours to obtain the chloroquine phosphate-loaded polylactic acid-glycolic acid copolymer microspheres.
Example 4: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) mixing 60mg of adriamycin with 10ml of aqueous solution containing 6% of cyclodextrin, and stirring at 1000rpm for 10 hours to obtain polyethylene glycol 6000 aqueous solution containing the adriamycin;
(2) dissolving 0.8g of polycaprolactone (molecular weight of about 4.0 ten thousand daltons) in 10mL of chloroform to obtain a polycaprolactone solution; then adding 0.15mL of polyethylene glycol 6000 aqueous solution containing the adriamycin, and stirring for 2min at 5000rpm at 40 ℃ to obtain polycaprolactone solution containing the adriamycin;
(3) pouring the polycaprolactone solution containing the adriamycin into 500mL of aqueous solution containing 5.0% of gelatin, and continuously stirring at 2000rpm for 8h at 30 ℃; washing the product with water and centrifuging for three times (the centrifugation conditions are 5000rpm, 20min and 10 ℃) at each time, collecting the precipitate, and freeze-drying for 12 hours to obtain the polycaprolactone microsphere loaded with the adriamycin.
Example 5: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) mixing 40mg of isoniazid with 10mL of aqueous solution containing 8% of cyclodextrin, stirring at 10000rpm for 3min to obtain the aqueous solution of cyclodextrin containing isoniazid, and freeze-drying for 24h to obtain cyclodextrin particles containing isoniazid;
(2) dissolving 0.6g of poly 3-hydroxybutyrate-co-3-hydroxyvalerate (molecular weight about 4.5 kilodaltons) in 10mL of ethyl acetate to obtain a poly 3-hydroxybutyrate-co-3-hydroxyvalerate solution; adding 200mg of cyclodextrin granules containing isoniazid, and stirring at 2000rpm at 35 ℃ for 5min to obtain poly (3-hydroxybutyrate-co-3-hydroxyvalerate) solution containing isoniazid;
(3) pouring the isoniazid-containing poly 3-hydroxybutyrate-co-3-hydroxyvalerate solution into 350mL of 1.0% gelatin-containing aqueous solution, and continuously stirring at 3000rpm for 4h at 20 ℃; washing the product with water, centrifuging for three times (each time centrifuging at 10000rpm, 30min and 10 ℃), collecting the precipitate, and freeze-drying for 24h to obtain the isoniazid-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) microspheres.
Comparative example 1: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) dissolving 1.0g of polylactic acid-glycolic acid copolymer (with the molecular weight of about 3.0 ten thousand daltons) in 10mL of dichloromethane to obtain polylactic acid-glycolic acid copolymer solution; then adding 50mg chloroquine phosphate, and stirring at 10000rpm for 1.5min at 0 ℃ to obtain chloroquine phosphate-containing polylactic acid-glycolic acid copolymer solution;
(2) pouring the chloroquine phosphate-containing polylactic acid-glycolic acid copolymer solution into 150mL of aqueous solution containing 0.1% 1788 type polyvinyl alcohol, and continuously stirring at 1000rpm for 14h at 60 ℃; the product is washed by water and centrifuged for three times (the centrifugation conditions are 20000rpm, 30min and 4 ℃) and the precipitated product is collected and freeze-dried for 24 hours to obtain the chloroquine phosphate-loaded polylactic acid-glycolic acid copolymer microspheres.
Comparative example 2: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) dissolving 50mg of chloroquine phosphate in 10mL of aqueous solution to obtain the chloroquine phosphate-containing aqueous solution;
(2) dissolving 1.0g of polylactic acid-glycolic acid copolymer (with the molecular weight of about 3.0 ten thousand daltons) in 10mL of dichloromethane to obtain polylactic acid-glycolic acid copolymer solution; then adding 5ml of chloroquine phosphate-containing aqueous solution, and stirring at 10000rpm for 1.5min at 0 ℃ to obtain chloroquine phosphate-containing polylactic acid-glycolic acid copolymer solution;
(3) pouring the chloroquine phosphate-containing polylactic acid-glycolic acid copolymer solution into 150mL of aqueous solution containing 0.1% 1788 type polyvinyl alcohol, and continuously stirring at 1000rpm for 14h at 60 ℃; the product is washed by water and centrifuged for three times (the centrifugation conditions are 20000rpm, 30min and 4 ℃) and the precipitated product is collected and freeze-dried for 24 hours to obtain the chloroquine phosphate-loaded polylactic acid-glycolic acid copolymer microspheres.
Comparative example 3: a high molecular microsphere for pulmonary administration and a preparation method thereof are disclosed:
(1) mixing 200mg of chloroquine phosphate with 10mL of aqueous solution containing 10% of cyclodextrin, and stirring at 200rpm for 24 hours to obtain a chloroquine phosphate-containing polyethylene glycol 2000 aqueous solution;
(2) dissolving 1.0g of polylactic acid-glycolic acid copolymer (with the molecular weight of about 3.0 ten thousand daltons) in 10mL of dichloromethane to obtain polylactic acid-glycolic acid copolymer solution; then adding 5mL of chloroquine-containing polyethylene glycol 2000 aqueous solution, and stirring at 10000rpm for 1.5min at 0 ℃ to obtain chloroquine-containing polylactic acid-glycolic acid copolymer solution;
pouring the chloroquine phosphate-containing polylactic acid-glycolic acid copolymer solution into 150mL of aqueous solution containing 0.1% 1788 type polyvinyl alcohol, and continuously stirring at 1000rpm for 14h at 60 ℃; the product is washed by water and centrifuged for three times (the centrifugation conditions are 20000rpm, 30min and 4 ℃) and the precipitated product is collected and freeze-dried for 24 hours to obtain the chloroquine phosphate-loaded polylactic acid-glycolic acid copolymer microspheres.
Test example:
the microspheres prepared in examples 1 to 5 and comparative examples 1 to 3 were subjected to in vitro solute release evaluation, and the results are shown in fig. 1.
The evaluation method comprises the following steps: in vitro solute release experiments were performed in a constant temperature shaker at 37 ℃ with a stirring speed of 60 rpm. 50mg of the microspheres were immersed in 20ml of PBS (pH 7.4), and the test solution was periodically collected and supplemented with an equal amount of PBS, and the solute content of the collected test solution was measured by High Performance Liquid Chromatography (HPLC). And substituting the absorbance of the solute at a certain time point into a standard curve of the solute to obtain the actual released amount of the solute at the time point. The cumulative amount of solute released at this time point is determined by dividing the actual amount by the total amount of solute loaded in the microspheres.
As can be seen from FIG. 1, no obvious burst action exists in examples 1 to 5, and the burst effect of example 3 is smaller compared with comparative examples 1 to 3, which proves that the microspheres pre-coated with amphiphilic polymer for treating lung diseases prepared by the method of the present invention have obvious regulation and control effects on the slow release effect of solute, and the release rate of the hydrophilic drugs for treating lung diseases can be 0.5 to 35% per day. Compared with the embodiment 3, the comparative example 1 directly disperses chloroquine phosphate in the polylactic acid-glycolic acid copolymer solution, does not adopt amphiphilic polymer to wrap the medicine for the hydrophilic lung diseases, lacks the effective and uniform dispersion of the chloroquine phosphate in the embodiment 3, accelerates the early solute release rate and generates burst release phenomenon; compared with the embodiment 3, the comparison example 2 dissolves chloroquine phosphate in the water solution, and the hydrophilic lung disease medicine is not wrapped by the amphiphilic polymer to obtain the conventional porous microsphere, so that the specific surface area of the microsphere is greatly increased, the number of the protein binding solutes embedded on the surface of the microsphere is greatly increased, and the burst release phenomenon is more obvious.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A polymeric microsphere for pulmonary delivery, comprising: comprises hydrophilic lung disease medicine, amphiphilic polymer coated on the surface of the hydrophilic lung disease medicine and degradable polymer coated on the surface of the amphiphilic polymer.
2. The polymeric microsphere for pulmonary administration according to claim 1, wherein: the mass ratio of the hydrophilic lung disease medicine to the amphiphilic polymer is 1 (1-20).
3. The polymeric microsphere for pulmonary administration according to claim 1, wherein: the mass ratio of the amphiphilic polymer to the degradable polymer is 1: (1-8).
4. The polymeric microsphere for pulmonary administration according to claim 1, wherein: the particle size of the polymer microsphere for pulmonary administration is 1-30 μm.
5. The polymeric microsphere for pulmonary administration according to claim 1 or 2, wherein: the hydrophilic medicine for treating lung diseases is at least one selected from chloroquine phosphate, isoniazid, cisplatin, adriamycin, aminophylline, curcumin and salbutamol sulfate.
6. The polymeric microsphere for pulmonary administration according to any one of claims 1 to 3, wherein: the amphiphilic polymer is at least one selected from polyethylene glycol, cyclodextrin and a copolymer of polyethylene glycol and amino acid, and the molecular weight of the amphiphilic polymer is 1000-8000 daltons.
7. The polymeric microsphere for pulmonary administration according to claim 1 or 3, wherein: the degradable macromolecule is at least one selected from poly-3-hydroxyalkanoate, polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, poly-3-hydroxybutyrate-co-3-hydroxyvalerate, poly (3-hydroxybutyrate), polybutylene succinate and polytrimethylene carbonate, and the molecular weight of the degradable macromolecule is 3000-60000 dalton.
8. A preparation method of polymer microspheres for pulmonary administration is characterized by comprising the following steps: the method comprises the following steps:
(1) dispersing hydrophilic lung disease medicine in an amphiphilic polymer water solution to form a pre-inclusion body;
(2) dispersing the pre-inclusion in a degradable high molecular solution containing an organic solvent to form an inclusion solution;
(3) dispersing the inclusion solution into an aqueous solution containing a surfactant, precipitating, cleaning the precipitate, and drying to obtain the polymer microsphere for pulmonary administration.
9. The method of claim 8, wherein the polymeric microspheres are prepared by a method comprising: the dispersing speed in the step (1) is 200-20000 rpm, and the dispersing time is 2min-24 h; preferably, the dispersing speed in the step (2) is 2000-10000 rpm, and the dispersing time is 2-5 min; preferably, the dispersing speed in the step (3) is 500-3000 rpm, and the dispersing time is 4-14 h.
10. The application of the polymer microsphere for pulmonary administration in preparing the medicine for treating pulmonary diseases is characterized in that: the polymer microsphere for pulmonary administration is the polymer microsphere for pulmonary administration in any one of claims 1 to 7, or is prepared by the preparation method of the polymer microsphere for pulmonary administration in claim 8 or 9.
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