CN1159071C - Preparation method of biodegradable medicine composite macromolecular scaffold material - Google Patents
Preparation method of biodegradable medicine composite macromolecular scaffold material Download PDFInfo
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Abstract
The present invention relates to a preparation method of biodegradable medicine composite high molecular support material, which belongs to the technical field of biological engineering. The present invention is characterized in that high molecular polylactic acid, polycaprolactone and anti-restenosis medicines are dissolved in solvent to obtain solution which is poured into a container for film forming to produce filaments; the filament is dipped in mixed solution prepared from L-lactic acid, glycolide copolymer, solvent and anti-restenosis medicines, and dried or frozen and dried, and then, soaked in anticoagulated blood solution and dried; the filament is wound around a mould for thermoset molding to obtain high molecular support material; the solvent is prepared from chloroform, 1, 4 dioxane and dimethyl sulfoxide, the anti-restenosis medicines are paclitaxel, taxotere, arotinoic acid ethyl ester, probucol, dexamethasone and sirolimus, and the anticoagulated blood solution is prepared from carboxylation sulfuric ester chitosan water solution or miscible solvent of heparin sodium water solution and propanone. The support material prepared by the present invention has good biocompatibility and blood vessel restenosis and blood coagulation embolism are effectively avoided.
Description
Technical field
The present invention relates to a kind of preparation method of biodegradable medicine composite macromolecular scaffold material, belong to technical field of bioengineering.
Background technology
Through the conduit interventional therapy is one of the most frequently used treatment means of vascular obstruction disease, and especially percutaneous puncture transluminal coronary angioplasty art (PTCA) is the very effective Therapeutic Method of coronary occlusion disease.The metal rack of present clinical use is a kind of foreign body to human body, and making us has doubt to its secular safety.And metal rack also can cause damage to ductus arteriosus wall, and reaction and restenosis cause inflammation.
The degradable macromolecule support has better biocompatibility, and finally degradation in vivo disappears, and avoids the The Long-term Effect to human body.Macromolecular material can carry slow releasing pharmaceutical by means such as absorption grafting easily, reaches the purpose of anti-hemostasis-coagulation and restenosis.This support also can be used for other positions of human body, is used to guarantee the unobstructed of various pipelines, and as urethra, bile duct etc.TamaiH etc. have reported that on the CIRCULATION magazine (CIRCULATION102 (4): 399-404 JUL 25 2000), this is the report that the degradable macromolecule support is applied to human body for the first time for experimental result in the polylactic acid bracket implant into body six months.In order better to prevent restenosis, research worker explore always various prevent restenosis method.Commonly used have radiation method, gene therapy, a medicament slow release method etc.Datta A etc. has described a kind of band medicine degradable macromolecule support in patent EP1110561-A2, two-layer inside and outside being divided into, and can carry different medicines, to regulate the slow release speed of medicine.The medicine of common anti-restenosis has taxol etc.
The preparation of support is first filamentation, and is Wrapping formed again.Canesh R. makes the polylactic acid film forming with the method for spraying, and then is rolled into silk, but this silk is thick excessively, can not satisfy the demand (ASAIO Journal, M584,1994) of implant into body.L.Fambri etc. have obtained acid fiber by polylactic with melt spinning, but have serious signs of degradation, cause polymer molecular weight about 2/3 (Polymer Vol.38 NO.1 pp79-85,1997) that descend.Before this, L.Fambri etc. must be the fiber of polylactic acid with dry spinning, signs of degradation is also not serious, but there is the very poor problem of operability, be difficult to obtain long even filament (Journalof materials science:materials in medicine 679-683,5,1994), and be not easy to pore-creating on fiber.
Summary of the invention
The objective of the invention is to propose a kind of good biocompatibility, can effectively prevent the preparation method of the biodegradable medicine composite macromolecular scaffold material that vascular restenosis and blood coagulation thromboembolism occur.
For achieving the above object, the preparation method of a kind of biodegradable medicine composite macromolecular scaffold material that the present invention proposes is characterized in that this method may further comprise the steps successively:
(1) degradable macromolecule polylactic acid and polycaprolactone are joined in the organic solvent chloroform for (100%: 0%)～(0%: 100%) by mass percentage, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
(2) in above-mentioned solution, add anti-restenosis medicaments, fully stir, and leave standstill and remove bubble;
(3) solution of above-mentioned preparation is poured in the container into volatilization, film forming;
(4) film is made filament;
(5) with mol ratio L-lactic acid: the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) places container, adds chloroform solvent, and being configured to the quality volumetric concentration is the solution of 0.01%～15%g/ml; Add anti-restenosis medicaments, fully stir and leave standstill and remove bubble;
(6) filament of step (4) preparation is dipped solvent flashing, airing in the solution of step (5);
(7) filament of airing being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soak, and takes out airing, is the macromolecule filament;
(8) the macromolecule filament is wound on the mould, thermoset forming is biodegradable medicine composite macromolecular scaffold material.
A kind of preparation method of biodegradable medicine composite macromolecular scaffold material is characterized in that: this method may further comprise the steps successively:
(1) degradable macromolecule polylactic acid and polycaprolactone are joined organic solvent 1 for (100%: 0%)～(0%: 100%) by mass percentage, in 4 dioxane, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
(2) in above-mentioned solution, add anti-restenosis medicaments, fully stir, and leave standstill and remove bubble;
(3) solution of above-mentioned preparation is poured into lyophilizing behind the container, film forming;
(4) film is made filament;
(5) with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) copolymer places container, adds 1,4 dioxane solvent, is configured to the solution that the quality volumetric concentration is 0.01%～15%g/ml; Add anti-restenosis medicaments, fully stir and leave standstill and remove bubble;
(6) filament of step (4) preparation is dipped lyophilizing then in the solution of step (5);
(7) freeze dried filament being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soak, and takes out airing, is the macromolecule filament;
(8) the macromolecule filament is wound on the mould, thermoset forming is the biodegradable medicine composite macromolecular scaffold material.
A kind of preparation method of biodegradable medicine composite macromolecular scaffold material is characterized in that: this method may further comprise the steps successively:
(1) degradable macromolecule polylactic acid and polycaprolactone are joined in the organic solvent dimethyl sulfoxide for (100%: 0%)～(0%: 100%) by mass percentage, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
(2) in above-mentioned solution, add anti-restenosis medicaments, fully stir, and leave standstill and remove bubble;
(3) mixed solution of above-mentioned preparation is poured into lyophilizing behind the container, film forming;
(4) film is made filament;
(5) with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) copolymer places container, adds dimethyl sulfoxide solvent, and being configured to the quality volumetric concentration is the solution of 0.01%～15%g/ml; Add anti-restenosis medicaments, fully stir and leave standstill and remove bubble;
(6) filament of step (4) preparation is dipped lyophilizing then in the solution of step (5);
(7) freeze dried filament is put into the aqueous solution of carboxylated Sulfation chitosan and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 and soaked, take out airing, be the macromolecule filament;
(8) the macromolecule filament is wound on the mould, thermoset forming is the compound Biodegradable high-molecular timbering material of medicine.
In above-mentioned preparation method, described anti-restenosis medicaments is any in paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, Sai Misong, the sirolimus.
In above-mentioned preparation method, the solution of step (2) preparation can be poured in the container, volatilization is extruded into filament.
In above-mentioned preparation method, also available heparin sodium aqueous solution of the described anticoagulation solution of step (7) and the miscible preparation of acetone; Also available carboxylated Sulfation chitosan mixes by mass ratio (0%: 100%)～(100%: 0%) with heparin sodium, is configured to aqueous solution again, then with the miscible preparation of acetone.
Because the present invention is with good biocompatibility, multiple macromolecular material that degradation rate is controlled and anticoagulation, prevent that the medicine of restenosis from combining, and by unique process means and freeze-drying, on support or the pore-creating of support top layer, excellent operability can be obtained having, the intravascular stent that vascular restenosis and blood coagulation thromboembolism occur can be effectively prevented.
The specific embodiment
The used macromolecular material of the present invention comprises polylactic acid (PLLA), polycaprolactone (PCL), L-lactic acid/glycolide copolymer (PLGA), and these materials all are the high-molecular biologic degradation materials that can be used for human body through the medical practice proof.PLLA has good hardness strength character, adds the elasticity that a certain amount of PCL then can improve support, so use the mixture of PLLA and PCL in the skeleton of support.If add medicine in support, along with high molecular degraded, medicine just can be released in the blood.The local sustained release of this medicine both can be brought into play long curative effect, saved repeatedly external injection, also can make medicine that the side effect of other parts of health is dropped to minimum.In order to control the speed of medicament slow release, can add at rack surface and be coated with the medicine controlled-release coating.Used PLGA is the copolymer of L-lactic acid and Acetic acid, hydroxy-, bimol. cyclic ester among the present invention.Because the different in kind of L-lactic acid and Acetic acid, hydroxy-, bimol. cyclic ester by adjusting their ratio in copolymer, can be adjusted the degradation rate of polymer, thereby the speed of control drug release.
The present invention can produce micropore with freeze-drying on support, can suitably accelerate scaffold degradation speed, is controlled at intravital life period, also the may command release rate of drugs.Carboxylated Sulfation chitosan and heparin sodium have good anticoagulation function, infiltrate in the polymeric stent by infusion method, and the micropore size by on control solution concentration, soak time and the polymeric stent can reach different drug treating times.
The preparation method of a kind of biodegradable medicine composite macromolecular scaffold material that the present invention proposes, this method may further comprise the steps successively:
A. degradable macromolecule polylactic acid (molecular weight is 100,000～300,000) and polycaprolactone (molecular weight is 100,000～300,000) are joined in the organic solvent chloroform for (100%: 0%)～(0%: 100%) by mass percentage, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
B. in above-mentioned solution, add any in anti-restenosis medicaments paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus, the molal volume concentration of medicine is 0.0001～10 (mol/ml), fully stir, and leave standstill and remove bubble;
C. the solution of above-mentioned preparation is poured in the container, under 0～30 ℃, allowed solution evaporation, film forming, the thickness of the amount controlling diaphragm by control cast solution, film forming thickness is 0.1～0.6mm;
D. film is made the filament that width is 0.1～0.6mm, also the solution of step (b) preparation can be poured in the container, volatilization is extruded into filament;
E. with mol ratio L-lactic acid: the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) (molecular weight is 50,000～150,000) places container, adds chloroform solvent, is configured to the solution that the quality volumetric concentration is 0.01%～15%g/ml; Add any in anti-restenosis medicaments paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus, making medicine molal volume concentration is 0.01～10mol/ml, fully stirs and leaves standstill and remove bubble;
F. the filament of step (d) preparation is dipped in the solution of step (e), under 0～30 ℃, allowed solvent evaporates then, airing;
G. the filament of airing being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soaked 1～48 hour; Also the available quality volumetric concentration is heparin sodium aqueous solution and 1: 1 (volume ratio) miscible preparation anticoagulation of the acetone solution of 0.1%～20% (g/ml); Also available carboxylated Sulfation chitosan mixes by mass ratio (0%: 100%)～(100%: 0%) with heparin sodium, be configured to the aqueous solution that the quality volumetric concentration is 0.1%～20% (g/ml) again, with 1: 1 (volume ratio) miscible preparation anticoagulation of acetone solution; Take out airing, be the macromolecule filament;
H. the macromolecule filament is wound on the mould,, is the biodegradable medicine composite macromolecular scaffold material at 40～100 ℃ of following thermoset formings.The formed thereby shape is two kinds, and a kind of is helical form, and a kind of is Z-shaped configuration.
Another steps in sequence of preparation method of a kind of biodegradable medicine composite macromolecular scaffold material that the present invention proposes may further comprise the steps:
A. degradable macromolecule polylactic acid (molecular weight is 100,000～300,000) and polycaprolactone (molecular weight is 100,000～300,000) are joined organic solvent 1 for (100%: 0%)～(0%: 100%) by mass percentage, in 4 dioxane, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
B. in above-mentioned solution, add any in anti-restenosis medicaments paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus, the molal volume concentration of medicine is 0.0001～10 (mol/ml), fully stir, and leave standstill and remove bubble;
C. the solution of above-mentioned preparation is poured into behind the container-20～4 ℃ freezing down, put into the freezer dryer lyophilizing then, the thickness of the amount controlling diaphragm by control cast solution, film forming thickness is 0.1～0.6mm;
D. film is made the filament that width is 0.1～0.6mm, also the solution of step (b) preparation can be poured in the container, volatilization is extruded into filament;
E. with mol ratio L-lactic acid: (molecular weight is 50 in Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%), 000～150,000) copolymer places container, adds 1,4 dioxane solvents are configured to the solution that the quality volumetric concentration is 0.01%～15%g/ml; Add any in anti-restenosis medicaments paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus, making medicine molal volume concentration is 0.01～10mol/ml, fully stirs and leaves standstill and remove bubble;
F. the filament of step (d) preparation is dipped in the solution of step (e), freezing under-20～4 ℃ then, put into the freezer dryer lyophilizing again;
G. freeze dried filament being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soaked 1～48 hour; Also the available quality volumetric concentration is heparin sodium aqueous solution and 1: 1 (volume ratio) miscible preparation anticoagulation of the acetone solution of 0.1%～20% (g/ml); Also available carboxylated Sulfation chitosan mixes by mass ratio (0%: 100%)～(100%: 0%) with heparin sodium, be configured to the aqueous solution that the quality volumetric concentration is 0.1%～20% (g/ml) again, with 1: 1 (volume ratio) miscible preparation anticoagulation of acetone solution; Take out airing, be the macromolecule filament;
H. the macromolecule filament is wound on the mould,, is biodegradable medicine composite macromolecular scaffold material at 40～100 ℃ of following thermoset formings.The formed thereby shape is two kinds, and a kind of is helical form, and a kind of is Z-shaped configuration.
Another steps in sequence of preparation method of a kind of biodegradable medicine composite macromolecular scaffold material that the present invention proposes may further comprise the steps:
A. degradable macromolecule polylactic acid (molecular weight is 100,000～300,000) and polycaprolactone (molecular weight is 100,000～300,000) are joined in the organic solvent dimethyl sulfoxide for (100%: 0%)～(0%: 100%) by mass percentage, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
B. in above-mentioned solution, add any in anti-restenosis medicaments paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus, the molal volume concentration of medicine is 0.0001～10 (mol/ml), fully stir, and leave standstill and remove bubble;
C. the mixed solution of above-mentioned preparation is poured into behind the container-20～20 ℃ freezing down, put into the freezer dryer lyophilizing then, the thickness of the amount controlling diaphragm by control cast solution, film forming thickness is 0.1～0.6mm;
D. film is made the filament that width is 0.1～0.6mm, also the solution of step (b) preparation can be poured in the container, volatilization is extruded into filament;
E. with mol ratio L-lactic acid: (molecular weight is 50 in Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%), 000～150,000) copolymer places container, adds dimethyl sulfoxide solvent, is configured to the solution that the quality volumetric concentration is 0.01%～15%g/ml; Add any in anti-restenosis medicaments paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus, making medicine molal volume concentration is 0.01～10mol/ml, fully stirs and leaves standstill and remove bubble;
F. the filament of step (d) preparation is dipped in the solution of step (e), freezing under-20～20 ℃ then, put into the freezer dryer lyophilizing again;
G. freeze dried filament being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soaked 1～48 hour; Also the available quality volumetric concentration is heparin sodium aqueous solution and 1: 1 (volume ratio) miscible preparation anticoagulation of the acetone solution of 0.1%～20% (g/ml); Also available carboxylated Sulfation chitosan mixes by mass ratio (0%: 100%)～(100%: 0%) with heparin sodium, be configured to the aqueous solution that the quality volumetric concentration is 0.1%～20% (g/ml) again, with 1: 1 (volume ratio) miscible preparation anticoagulation of acetone solution; Take out airing, be the macromolecule filament;
H. the macromolecule filament is wound on the mould,, is the compound Biodegradable high-molecular timbering material of medicine at 40～100 ℃ of following thermoset formings.The formed thereby shape is two kinds, and a kind of is helical form, and a kind of is Z-shaped configuration.
Embodiment 1:
A. add PLLA in the organic solution chloroform, be configured to the solution that the quality volumetric concentration is 1% (g/ml), stir, fully dissolving.Used PLLA molecular weight is 100,000.
B. add paclitaxel in the solution, making medicine molal volume concentration is 0.0001 (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution is poured in the bar shaped mould, under 0 ℃, allows solution evaporation, film forming.By controlling the thickness of the amount controlling diaphragm of pouring into a mould solution, film forming thickness is 0.1mm.Make the filament that width is 0.1mm.
D. dispose anticoagulative substance solution.With the quality volumetric concentration is the aqueous solution of the carboxylated Sulfation chitosan of 0.1% (g/ml), miscible with acetone 1: 1 (volume ratio).
E. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (d) prepared soaked 1 hour.Take out airing.
F. the macromolecule filament being wound on the fixed mold, is helical form at 40 ℃ of following thermoset formings.
Embodiment 2:
A. add PCL in organic solution 1,4 dioxane, be configured to the solution that the quality volumetric concentration is 20% (g/ml), stir, fully dissolving.Used PCL molecular weight is 300,000.
B. add taxotere (Docetaxel) in the solution, making medicine molal volume concentration is 1 (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution pour into behind the mould-20 ℃ freezing down, put into the freezer dryer lyophilizing then.By controlling the thickness of the amount controlling diaphragm of pouring into a mould solution, film forming thickness is 0.4mm.Make the filament that width is 0.4mm.
D. dispose anticoagulative substance solution.With the quality volumetric concentration is the aqueous solution of the carboxylated Sulfation chitosan of 20% (g/ml), miscible with acetone 1: 1 (volume ratio).
E. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (d) prepared soaked 48 hours.Take out airing.
F. the macromolecule filament is wound on the fixed mold, at 100 ℃ of following thermoset formings.The formed thereby shape is a helical form.
Embodiment 3:
A. add PLLA: PCL=50% in the organic solution dimethyl sulfoxide: the degradable macromolecule of 50% (mass ratio), be configured to the solution that the quality volumetric concentration is 10% (g/ml), stir, fully dissolving.Used PLLA molecular weight is 200,000, and the PCL molecular weight is 200,000.
B. add aryltretinoin ethylester (Arotinoind ethylester) in the solution, making medicine molal volume concentration is 0.001 (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution pour into behind the mould-20 ℃ freezing down, put into the freezer dryer lyophilizing then.By controlling the thickness of the amount controlling diaphragm of pouring into a mould solution, film forming thickness is 0.6mm.Make the filament that width is 0.6mm.
D. with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=100%: 0%, molecular weight are that 50,000 PLGA (PLLA just) places container, add chloroform, are configured to the solution that the quality volumetric concentration is 0.01%g/ml.Add taxotere (Docetaxel), making medicine molal volume concentration is 0.01mol/ml.Fully stir and leave standstill and remove bubble.The filament of preparation in the step (3) is dipped in solution.Under 0 ℃, allow solvent evaporates, airing.
E. dispose anticoagulative substance solution.With the quality volumetric concentration is the heparin sodium aqueous solution of 0.1% (g/ml), miscible with acetone 1: 1 (volume ratio).
F. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (e) prepared soaked 3 hours.Take out airing.
G. the macromolecule filament is wound on the fixed mold, at 100 ℃ of following thermoset formings.The formed thereby shape is Z-shaped configuration.
Embodiment 4:
A. add PLLA: PCL=25% in the organic solution chloroform: the degradable macromolecule of 75% (mass ratio), be configured to the solution that the quality volumetric concentration is 10% (g/ml), stir, fully dissolving.Used PLLA molecular weight is 300,000, and the PCL molecular weight is 100,000.
B. add probucol (Probucol) in the solution, making medicine molal volume concentration is 0.01 (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution is poured in the bar shaped mould, under 30 ℃, allows solution evaporation, film forming.By controlling the thickness of the amount controlling diaphragm of pouring into a mould solution, film forming thickness is 0.6mm.Make the filament that width is 0.6mm.
D. with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=50%: 50%, molecular weight are that 150,000 PLGA places container, add 1,4 dioxane, are configured to the solution that the quality volumetric concentration is 15%g/ml.Add aryltretinoin ethylester (Arotinoindethylester), making medicine molal volume concentration is 0.1mol/ml.Fully stir and leave standstill and remove bubble.The filament of preparation in the step (3) is dipped in solution.Filament is freezing under-20 ℃, puts into the freezer dryer lyophilizing then.
E. dispose anticoagulative substance solution.With the quality volumetric concentration is the heparin sodium aqueous solution of 20% (g/ml), miscible with acetone 1: 1 (volume ratio).
F. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (e) prepared soaked 24 hours.Take out airing.
G. the macromolecule filament is wound on the fixed mold, at 100 ℃ of following thermoset formings.The formed thereby shape is Z-shaped configuration.
Embodiment 5:
A. add PLLA: PCL=75% in organic solution 1,4 dioxane: the degradable macromolecule of 25% (mass ratio), be configured to the solution that the quality volumetric concentration is 20% (g/ml), stir, fully dissolving.Used PLLA molecular weight is 100,000, and the PCL molecular weight is 100,000.
B. add dexamethasone (Dexamethasone) in the solution, making medicine molal volume concentration is 0.1 (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution pour into behind the mould 4 ℃ freezing down, put into the freezer dryer lyophilizing then.By controlling the thickness of the amount controlling diaphragm of pouring into a mould solution, film forming thickness is 0.4mm.Make the filament that width is 0.4mm.
D. with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=25%: 75%, molecular weight are that 10,000 PLGA places container, add dimethyl sulfoxide, are configured to the solution that the quality volumetric concentration is 10%g/ml.Add probucol (Probucol), making medicine molal volume concentration is 10mol/ml.Fully stir and leave standstill and remove bubble.The filament of preparation in the step (3) is dipped in solution.Filament is freezing under-20 ℃, puts into the freezer dryer lyophilizing then.
E. dispose anticoagulative substance solution.Carboxylated Sulfation chitosan and heparin sodium are pressed mass ratio mixing in 50%: 50%, be configured to the aqueous solution that the quality volumetric concentration is 0.1% (g/ml) again, miscible with acetone 1: 1 (volume ratio).
F. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (e) prepared soaked 12 hours.Take out airing.
G. the macromolecule filament is wound on the fixed mold, at 40 ℃ of following thermoset formings.The formed thereby shape is Z-shaped configuration.
Embodiment 6:
A. add PLLA in the organic solution dimethyl sulfoxide, be configured to the solution that the quality volumetric concentration is 20% (g/ml), stir, fully dissolving.Used PLLA molecular weight is 300,000.
B. add sirolimus (Sirolimus) in the solution, making medicine molal volume concentration is 10% (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution pour into behind the mould 20 ℃ freezing down, put into the freezer dryer lyophilizing then.By controlling the thickness of the amount controlling diaphragm of pouring into a mould solution, film forming thickness is 0.1mm.Be cut into the filament that width is 0.1mm.
D. with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=75%: 25%, molecular weight are that 50,000 PLGA places container, add chloroform, are configured to the solution that the quality volumetric concentration is 0.1%g/ml.Add dexamethasone (Dexamethasone), making medicine molal volume concentration is 1mol/ml.Fully stir and leave standstill and remove bubble.The filament of preparation in the step (3) is dipped in solution.Filament allows solvent evaporates under 30 ℃, airing.
E. dispose anticoagulative substance solution.Carboxylated Sulfation chitosan and two kinds of anticoagulative substances of heparin sodium are pressed mass ratio mixing in 25%: 75%, be configured to the aqueous solution that the quality volumetric concentration is 10% (g/ml) again, miscible with acetone 1: 1 (volume ratio).
F.. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (e) prepared soaked 36 hours.Take out airing.
G. the macromolecule filament is wound on the fixed mold, at 100 ℃ of following thermoset formings.The formed thereby shape is Z-shaped configuration.
Embodiment 7:
A. add PCL in the organic solution chloroform, be configured to the solution that the quality volumetric concentration is 1% (g/ml), stir, fully dissolving.Used PCL molecular weight is 100,000.
B. solution is poured in certain container, in air, evaporate into to a certain degree after, from aperture, extrude.Control rate of extrusion and aperture, thus the control filament diameter is 0.1mm.
C. with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=0%: 100%, molecular weight are that 150,000 PLGA (just poly-Acetic acid, hydroxy-, bimol. cyclic ester) places container, add 1,4 dioxane, are configured to the solution that the quality volumetric concentration is 15%g/ml.Add sirolimus (Sirolimus), making medicine molal volume concentration is 0.01mol/ml.Fully stir and leave standstill and remove bubble.The filament of preparation in the step (2) is dipped in solution.Filament is freezing under 4 ℃, puts into the freezer dryer lyophilizing then.
D. dispose anticoagulative substance solution.Carboxylated Sulfation chitosan and two kinds of anticoagulative substances of heparin sodium are pressed mass ratio mixing in 75%: 25%, be configured to the aqueous solution that the quality volumetric concentration is 10% (g/ml) again, miscible with acetone 1: 1 (volume ratio).
E. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (d) prepared soaked 48 hours.Take out airing.
F. the macromolecule filament is wound on the fixed mold thermoset forming under 40C.The formed thereby shape is a helical form.
Embodiment 8:
A. add PLLA: PCL=50% in organic solution 1,4 dioxane: the degradable macromolecule of 50% (mass ratio), be configured to the solution that the quality volumetric concentration is 20% (g/ml), stir, fully dissolving.Used PLLA molecular weight is 300,000, and the PCL molecular weight is 300,000.
B. add paclitaxel in the solution, making medicine molal volume concentration is 0.0001 (mol/ml).Fully stir and leave standstill and remove bubble.
C. solution is poured in certain container, in air, evaporate into to a certain degree after, from aperture, extrude.Control rate of extrusion and aperture, thus the control filament diameter is 0.6mm.
D. with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=50%: 50%, molecular weight are that 50,000 PLGA places container, add dimethyl sulfoxide, are configured to the solution that the quality volumetric concentration is 1%g/ml.Add paclitaxel, making medicine molal volume concentration is 0.01mol/ml.Fully stir and leave standstill and remove bubble.The filament of preparation in the step (c) is dipped in solution.Filament is freezing under 20 ℃, puts into the freezer dryer lyophilizing then.
E. dispose anticoagulative substance solution.Carboxylated Sulfation chitosan and two kinds of anticoagulative substances of heparin sodium are pressed mass ratio mixing in 90%: 10%, be configured to the aqueous solution that the quality volumetric concentration is 0.1% (g/ml) again, miscible with acetone 1: 1 (volume ratio).
F. make the macromolecule filament carry one deck anticoagulative substance.Filament being put into the solution that (e) prepared soaked 24 hours.Take out airing.
G. the macromolecule filament is wound on the fixed mold, at 100 ℃ of following thermoset formings.The formed thereby shape is Z-shaped configuration.
Claims (7)
1, a kind of preparation method of biodegradable medicine composite macromolecular scaffold material is characterized in that this method may further comprise the steps successively:
(1) degradable macromolecule polylactic acid and polycaprolactone are joined in the organic solvent chloroform for (100%: 0%)～(0%: 100%) by mass percentage, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
(2) in above-mentioned solution, add anti-restenosis medicaments, fully stir, and leave standstill and remove bubble;
(3) solution of above-mentioned preparation is poured in the container into volatilization, film forming;
(4) film is made filament;
(5) with mol ratio L-lactic acid: the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) places container, adds chloroform solvent, and being configured to the quality volumetric concentration is the solution of 0.01%～15%g/ml; Add anti-restenosis medicaments, fully stir and leave standstill and remove bubble;
(6) filament of step (4) preparation is dipped solvent flashing, airing in the solution of step (5);
(7) filament of airing being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soak, and takes out airing, is the macromolecule filament;
(8) the macromolecule filament is wound on the mould, thermoset forming is biodegradable medicine composite macromolecular scaffold material.
2, a kind of preparation method of biodegradable medicine composite macromolecular scaffold material is characterized in that this method may further comprise the steps successively:
(1) degradable macromolecule polylactic acid and polycaprolactone are joined organic solvent 1 for (100%: 0%)～(0%: 100%) by mass percentage, in 4 dioxane, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
(2) in above-mentioned solution, add anti-restenosis medicaments, fully stir, and leave standstill and remove bubble;
(3) solution of above-mentioned preparation is poured into lyophilizing behind the container, film forming;
(4) film is made filament;
(5) with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) copolymer places container, adds 1,4 dioxane solvent, is configured to the solution that the quality volumetric concentration is 0.01%～15%g/ml; Add anti-restenosis medicaments, fully stir and leave standstill and remove bubble;
(6) filament of step (4) preparation is dipped lyophilizing then in the solution of step (5);
(7) freeze dried filament being put into the quality volumetric concentration is that the aqueous solution of carboxylated Sulfation chitosan of 0.1%～20% (g/ml) and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 soak, and takes out airing, is the macromolecule filament;
(8) the macromolecule filament is wound on the mould, thermoset forming is the biodegradable medicine composite macromolecular scaffold material.
3, a kind of preparation method of biodegradable medicine composite macromolecular scaffold material is characterized in that this method may further comprise the steps successively:
(1) degradable macromolecule polylactic acid and polycaprolactone are joined in the organic solvent dimethyl sulfoxide for (100%: 0%)～(0%: 100%) by mass percentage, be configured to the solution that the quality volumetric concentration is 1%～20% (g/ml), stir, fully dissolving;
(2) in above-mentioned solution, add anti-restenosis medicaments, fully stir, and leave standstill and remove bubble;
(3) mixed solution of above-mentioned preparation is poured into lyophilizing behind the container, film forming;
(4) film is made filament;
(5) with mol ratio L-lactic acid: Acetic acid, hydroxy-, bimol. cyclic ester=(0%: 100%)～(100%: 0%) copolymer places container, adds dimethyl sulfoxide solvent, and being configured to the quality volumetric concentration is the solution of 0.01%～15%g/ml; Add anti-restenosis medicaments, fully stir and leave standstill and remove bubble;
(6) filament of step (4) preparation is dipped lyophilizing then in the solution of step (5);
(7) freeze dried filament is put into the aqueous solution of carboxylated Sulfation chitosan and the anticoagulation solution of acetone (volume ratio) preparation in 1: 1 and soaked, take out airing, be the macromolecule filament;
(8) the macromolecule filament is wound on the mould, thermoset forming is the compound Biodegradable high-molecular timbering material of medicine.
4,, it is characterized in that described anti-restenosis medicaments is any in paclitaxel, paclitaxel drug derivative taxotere, aryltretinoin ethylester, probucol, dexamethasone, the sirolimus according to claim 1,2 or 3 described preparation methoies.
5, according to claim 1,2 or 3 described preparation methoies, it is characterized in that also the solution of above-mentioned steps (2) preparation to be poured in the container, volatilization is extruded into filament.
6,, it is characterized in that also available heparin sodium aqueous solution of the described anticoagulation solution of above-mentioned steps (7) and the miscible preparation of acetone according to claim 1,2 or 3 described preparation methoies.
7, according to claim 1,2 or 3 described preparation methoies, it is characterized in that the also available carboxylated Sulfation chitosan of the described anticoagulation solution of step (7) mixes by mass ratio (0%: 100%)～(100%: 0%) with heparin sodium, be configured to aqueous solution again, then with the miscible preparation of acetone.
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| CN100346850C (en) * | 2003-05-28 | 2007-11-07 | 微创医疗器械(上海)有限公司 | Medicine coating rack |
| DE10244847A1 (en) * | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medical device for drug delivery |
| CN100462070C (en) * | 2003-06-30 | 2009-02-18 | 于美丽 | Retinoic acid release control nanomicrosphere and its preparation method |
| CN1321705C (en) * | 2004-07-02 | 2007-06-20 | 清华大学 | Method for preparing multilayer medicine composite degradable biliary tract rack visible under X-ray |
| CN100464789C (en) * | 2005-12-22 | 2009-03-04 | 上海交通大学 | Digestive tract stent with anti-cancer medicinal particles |
| CN1799650B (en) * | 2005-12-30 | 2010-07-14 | 李文涛 | Method for preparing biodegradable drug-carried high molecular material stent |
| CN101007187B (en) * | 2007-01-26 | 2014-01-01 | 复旦大学附属华山医院 | Preparation method of composite drug-eluting stent and its drug coated layer |
| CN101947333B (en) * | 2010-08-27 | 2014-06-25 | 安泰科技股份有限公司 | Biodegradable medicament-loaded polymer scaffold and preparation method thereof |
| CN107261867B (en) * | 2017-08-10 | 2019-09-24 | 武汉纺织大学 | A kind of preparation method of super water-purifying filter film |
| US11925728B2 (en) | 2018-01-09 | 2024-03-12 | Shandong Huaan Biotechnology Co., Ltd. | Degradable vascular stent capable of avoiding late restenosis |
| CN108641074B (en) * | 2018-05-23 | 2021-01-29 | 重庆大学 | Biodegradable material and preparation method and application thereof |
| CN112546306A (en) * | 2020-12-25 | 2021-03-26 | 常州大学 | Multilayer medicine-carrying PLGA wire material, preparation method and application |
| CN114259607B (en) * | 2021-12-28 | 2023-01-24 | 宇航 | Preparation method of stent |
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