CN1367023A - 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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- CN1367023A CN1367023A CN 02104071 CN02104071A CN1367023A CN 1367023 A CN1367023 A CN 1367023A CN 02104071 CN02104071 CN 02104071 CN 02104071 A CN02104071 A CN 02104071A CN 1367023 A CN1367023 A CN 1367023A
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- 239000003814 drug Substances 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 70
- 239000000463 material Substances 0.000 title claims abstract description 30
- 239000002131 composite material Substances 0.000 title claims description 19
- 239000000243 solution Substances 0.000 claims abstract description 142
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 56
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims abstract description 38
- 208000037803 restenosis Diseases 0.000 claims abstract description 31
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 29
- 239000004626 polylactic acid Substances 0.000 claims abstract description 29
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 26
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 21
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 21
- 229920000669 heparin Polymers 0.000 claims abstract description 18
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims abstract description 18
- 229960001008 heparin sodium Drugs 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 14
- 229920001577 copolymer Polymers 0.000 claims abstract description 13
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960003912 probucol Drugs 0.000 claims abstract description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011259 mixed solution Substances 0.000 claims abstract description 4
- 229920002521 macromolecule Polymers 0.000 claims description 50
- 238000003756 stirring Methods 0.000 claims description 48
- 239000007864 aqueous solution Substances 0.000 claims description 27
- 229920001661 Chitosan Polymers 0.000 claims description 21
- 230000019635 sulfation Effects 0.000 claims description 21
- 238000005670 sulfation reaction Methods 0.000 claims description 21
- 230000010100 anticoagulation Effects 0.000 claims description 20
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 20
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 18
- 238000010105 thermoset forming Methods 0.000 claims description 17
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 12
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 12
- 229960002930 sirolimus Drugs 0.000 claims description 12
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 12
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 11
- 229960003957 dexamethasone Drugs 0.000 claims description 11
- 125000004494 ethyl ester group Chemical group 0.000 claims description 11
- 229940063683 taxotere Drugs 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000003118 drug derivative Substances 0.000 claims description 8
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000002429 anti-coagulating effect Effects 0.000 abstract description 21
- 238000002156 mixing Methods 0.000 abstract description 5
- 238000004108 freeze drying Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 238000001035 drying Methods 0.000 abstract 2
- 229920002101 Chitin Polymers 0.000 abstract 1
- AKUJBENLRBOFTD-RPRRAYFGSA-N Dexamethasone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O AKUJBENLRBOFTD-RPRRAYFGSA-N 0.000 abstract 1
- 238000007605 air drying Methods 0.000 abstract 1
- 238000007598 dipping method Methods 0.000 abstract 1
- NULUAKSYPPSJCO-FBMGVBCBSA-N ethyl 4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1\C=C(/C)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 NULUAKSYPPSJCO-FBMGVBCBSA-N 0.000 abstract 1
- 238000002791 soaking Methods 0.000 abstract 1
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- 125000002456 taxol group Chemical group 0.000 abstract 1
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- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 8
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- 229960003668 docetaxel Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
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- 238000010521 absorption reaction Methods 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
A preparation method of biodegradable medicine-compounded macromolecular scaffolding material includes the following steps: dissolving macromolecular polylactic acid, polycaprolactone and restenosis-resisting medicine in the solvent, pouring the prepared solution into a container for film-forming, making the said film into filament, dipping the said filament in the mixed solution prepared with L-lactic acid and diglycolide copolymer, solvent and restenosis-resisting medicine and drying in the air or freeze-drying, then soaking the said filament in anticoagulative solution, drying in the air, making filament wind round the mould, thermosetting and forming so as to obtain the invented product. The described solvent is chloroform, 1,4-dioxane and dimethyl sulfoxide, the restenosis-resisting medicine is taxol, taxadter, arotinoid ethylester, probucol, dectan and cilomosi, and the anticoagulative solution is prepared with carboxylated sulfurnic aid esterified chitin aqueos solution or heparin sodium aqueos solution and acetone through the process of mixing and solvation reaction.
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, at 40 ℃ of following thermoset formings.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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