Medicine eluted cardiovascular frameTechnical field
The present invention relates to a kind of medicinal support, particularly a kind of being used for cardiovascularly can discharge medicine, promote the balloon expandable stent of injured blood vessel wall healing simultaneously.
Background technology
Dotter in 1964 and Judkings (Dotter CT, Jukines MP.Tranaluminal treatmantof arteriosclerotic obstruction, 1964,30:654) notion of percutaneous transluminal angio plasty has been proposed, and hypothesis uses silicone rubber or plastics to come support blood vessels, unobstructed with blood flow in the maintenance lumen of vessels, 1987, Sigwart (Sigwart U, et al.Intravascular stents to prevent occlusionand restenosis after tranaluminal angioplasty.N Engl J Med, 1987; 316:701) grade is used for metal rack in the blood vessel coronary artery first, for treatment blood vessel blockage disease provides good approach.
Ideal support should possess following feature: (1) better biocompatibility: minimum blood coagulation enhancing effect, and implant the back and be difficult for blood coagulation reaction and thrombosis take place, be difficult for causing the inflammatory reaction and the neointimal hyperplasia of blood vessel wall; (2) easy polarization; (3) have pliability preferably, easily shift diseased region onto; (4) easily expansion, support force is strong and mechanical robustness arranged.
Coronary atherosclerotic heart disease is one of major reason of cardiovascular disease death, although emergency treatment reconstructing blood vessel technology [comprises thromboembolism treatment, coronary artery bypass grafting CCABG], percutaneous transluminal coronary angioplasty (PTCA)] saved a large amount of dying patients, but the vascular restenosis incidence rate behind CABG and the PTCA still very high (restenosis rate is 40% behind the PTCA), it mainly comes from inner membrance, middle film hypertrophy and the comprehensive function of blood vessel wall construction geometry reconstruct institute, the appearance of coronary artery bracket and application have obviously reduced the vascular restenosis incidence rate behind the PTCA, yet the clinical practice of support is limited by following Several Factors: 1) subacute stent thrombosis forms (3-10 days); 2) in-stent restenosis in late period (about half a year) (incidence rate about about 20%); 3) tardy property thrombosis.
Patent EP132060 discloses a kind of balloon expandable formula stainless steel stent, and at present, this balloon expandable stainless steel stent can satisfy above-mentioned back three's condition, but subacute stent thrombosis and in-stent restenosis at a specified future date are two big complication of balloon expandable stainless steel stent.For solving an above-mentioned difficult problem, people constantly design and release the biological characteristics that New-support improves support, and drug-eluting stent is exactly wherein a kind of.
Human body drug resistance dosage is too low, is difficult to reach valid density at target site, and this may be the reason that systemic administration does not prove effective.And active drug is transported to the arterial injury place by support, will help the treatment of complication.
United States Patent (USP) U.S.6,231,600 for preventing the in-stent restenosis after support is implanted and the generation of thrombosis, designed a kind of overbrushing layer support technology: ground floor is made up of polymer, anti-restenosis (paclitaxel) and cross-linking agent (aziridine), the second layer is anticoagulant medicine heparin, two-layer between by the cross-linking agent bonding.But the technology of preparing of this Patent publish is comparatively complicated, and has introduced harmful substance (aziridine), is unfavorable for promoting the use of.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of medicine eluted cardiovascular frame, comparatively complicated to overcome subacute stent thrombosis that prior art exists and restenosis at a specified future date and technology of preparing, and introduced harmful substance (aziridine), be unfavorable for the defective promoted the use of, satisfy people's demand.
Technical scheme of the present invention:
Medicine eluted cardiovascular frame of the present invention by support, be coated in the biodegradable layers that the employing Biodegradable material that is coated with medicine on the support makes and constitute.
The preferred balloon expandable stent of said support can be made by rustless steel or biodegradable material.
Biodegradable material comprise Acetic acid, hydroxy-, bimol. cyclic ester (glycolic acid, GA), the L-lactide (L-lactic acid, LLA) or 6-caprolactone (caprolactone, a kind of in homopolymer CL) or the copolymer and with the copolymer of multifunctional amino acid.This preparation methods is a prior art, and its preparation method can be consulted document (Makromol.Chem.1987,188:1809-1814) disclosed method.
The Biodegradable material of coating medicine is a kind of Biodegradable high-molecular grafting heparin, and its preparation method is a prior art, can consult the disclosed method of patent (WO 03/042277A1).
Said medicine is the medicine with anti-restenosis function, comprises in Radix Et Rhizoma Rhei or emodin and rapamycin, dactinomycin, ciclosporin A or the paclitaxel one or more.
According to optimized technical scheme of the present invention, be coated in the biodegradable layers on the support, the weight percent content with medicine of anti-restenosis function is 5～80%; Too high levels, that then generation is filmed breaks, low excessively, then causes restenosis to suppress the decline of ability, will increase coating layer thickness simultaneously, causes the decline of coating quality;
The weight percent content of heparin sodium is 0.002～50%; Too high levels then causes and the conflicting of material and drug compatibility, and is low excessively, then is difficult to suppress the inflammatory reaction that material degradation brings out.
As adopt the L-lactide: Acetic acid, hydroxy-, bimol. cyclic ester: during the homopolymer of 6-caprolactone, its preferred weight ratio is:
L-lactide: Acetic acid, hydroxy-, bimol. cyclic ester: 6-caprolactone=1: 10～90: 5～10.
Emodin is the extraction high-purity composition of Chinese herb rhubarb, belongs to anthraquinone derivatives, is one of activity in vivo composition, has multiple pharmacological effect, and former studies finds that emodin can suppress the propagation of the rabbit aorta SMC of In vitro culture.Jayasuriya etc. find that at first emodin is the strong inhibition agent of tyrosine kinase p56lck, for it further provides experimental basis in clinical practice, we further at cell in vitro experimentation emodin to vascular smooth muscle cell cycle and cyclinD1Influence, find emodin in the process that suppresses smooth muscle cell proliferation by downward modulation cyclin D1Express the process that has blocked cell cycle.Present data shows the cytostatic effect of truly having of emodin, might promote cell death, might promote apoptosis, also might suppress cell in specific period.Experiment finds that the emodin support has the effect that suppresses intimal proliferation in the animal body in our 1,2 and March, but minimum to the regeneration effect of endotheliocyte.
Rapamycin, dactinomycin, ciclosporin A or paclitaxel have confirmed to reduce intimal proliferation at present.
But its endothelialization again that suppresses inner membrance is remarkable equally.
Based on above-mentioned research, we consider the mixing of two or more medicine, can work in coordination with to strengthen cell proliferation, but can significantly reduce existing side effects of pharmaceutical drugs such as rapamycin.Found that " cocktail " drug stent suppresses the restenosis effect in the pig arteria coronaria research in March remarkable, the endothelialization effect is better more simultaneously.
Above-mentioned medicine eluted cardiovascular frame is preparation like this:
(1) at first prepares the balloon expandable stainless steel stent, or prepare the Biodegradable material support according to the technology of United States Patent (USP) U.S.5670161 patent disclosure according to the disclosed technology of patent EP132060;
(2) support be impregnated in the mixed system of the biodegradable layer material of medicine with anti-restenosis function, coating medicine and solvent composition, or adopt and to have the medicine of anti-restenosis function, the biodegradable layer material of coating medicine and the mixed system of solvent composition and spray, said solvent is can dissolved substance and the biodegradable layer material of coating medicine, comprises a kind of and composition thereof in chloroform, ethanol, methanol, dichloroethanes, oxolane, acetone or the DMC dimethyl carbonate;
(3) after the support drying, promptly obtain medicine eluted cardiovascular frame of the present invention.
According to the present invention, support is etching in advance, resurfacing, etching again after also can coating.
Term " etching " refers to the laser clean cut.
After " cocktail " drug stent inserted animal body, all healthy survival of animal; Support immediate postoperative and follow up a case by regular visits to radiography and find that the support vessel lumen is unobstructed.All supports do not have the hemorrhage and attenuation of middle film, unsupported adherent bad and aneurysm formation; Scanning electron microscope finds that the surface of drug stent all has new intima to cover, and lumen of vessels face endothelialization again is complete; The tissue morphology quantitative analysis results of brace sections blood vessel shows that the outer membrane area of bare bracket group and bracket for eluting medicament group does not have significant difference (P=0.556), points out two groups of blood vessel diameters similar.Two groups of damage integration no difference of science of statistics (P=0.148); Inner film thickness is 97.2 ± 43.3um and 64.0 ± 22.0um (P=0.017), and the drug stent group reduces 34.2% than bare bracket; The inner membrance area is 114535.7 ± 50081.8um2With 80292.6 ± 29345.1um2(P=0.036), the medicine group reduces 29.9%; Media area is 94124.8 ± 11510.7um2With 104757.2 ± 28602.6um2(P=0.163), it is remarkable to show that this support suppresses the restenosis effect, and the endothelialization effect is better more simultaneously.Adopt infrared spectrum analysis, compare with the result who implanted two months, the characteristic group of all not finding coating material of support top layer and support top layer conjunctive tissue concludes that thus coating material is degraded fully.
By above-mentioned disclosed technical scheme as seen, the present invention has applied the Biodegradable high-molecular grafting heparin that one deck has anti-restenosis function on this support, make the medicine with inhibition restenosis function be able to slow release, the sustained release material will degraded fully in 1～7 month.After support is implanted, anti-restenosis medicaments discharges, adopt degradable macromolecule grafting heparin as the sustained release material, fully suppress neointimal hyperplasia, the continual and steady existence of heparin, can prevent generation acute, subacute stent thrombosis, can promote simultaneously the healing of injured blood vessel wall, prevent the generation of advanced thrombus, compare with traditional heparin support, overcome the not anti-body fluid of heparin and washed away (heparin is a water soluble drug), and the defective of introducing noxious substance in the chemical bond process.
The specific embodiment
Embodiment 1
The preparation of Biodegradable material:
Take by weighing 70 parts of L-lactides, 5 parts of Acetic acid, hydroxy-, bimol. cyclic esters and 25 parts of 6-caprolactones in exsiccant, as to have stirrer polymerization bottle, use N2Replace 3 times, place 160 ℃ of oil baths, after waiting to melt, add the 0.02g/ml stannous octoate chloroformic solution (catalytic amount is the 0.02wt% of monomer mass) of certain volume, chloroform is removed in decompression, stirs reaction 5h down, and polymer dissolves with chloroform, ethanol precipitation.(gel permeation chromatography GPC) characterizes the molecular weight of resulting polymers, and molecular weight is greater than 100,000 with gel permeation chromatography.
Embodiment 2
The preparation of heparinization poly-(lactic-co-glycolic acid-aminoacid):
Take by weighing morpholine diketone derivatives monomer that 0.1molL-lactide and 0.05mol contain benzyloxy protection glutamic acid in exsiccant, as to have stirrer polymerization bottle, use N2Replace 3 times, place 160 ℃ of oil baths, after waiting to melt, add the 0.02g/ml stannous octoate chloroformic solution of certain volume, chloroform is removed in decompression, stirs reaction 5h down, and polymer dissolves with chloroform, ethanol precipitation.Resulting polymers is with the Pd/C catalyst, and hydrogen bubbling 40 is sloughed benzyloxy, is promptly gathered (lactic-co-glycolic acid-glutamic acid).
Contain amino, carboxyl in the heparin, will gather in the mixed solvent that (lactic-co-glycolic acid-aspartic acid) be dissolved in oxolane and water, heparin sodium is dissolved in the low amounts of water, regulating pH with diluted acid is about 4.Both are mixed, Dcci (the dicyclohexylcarbodiimide that adds equivalent, DCC), stir 24h down at 4 ℃, removal of solvent under reduced pressure adds an amount of chloroform again, the elimination insoluble matter, gained solution petroleum ether precipitation, dry 24h under the room temperature promptly obtains heparinization macromolecule (heparinizedpolymer).
Embodiment 3
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the 0.1 anti-restenosis medicaments Radix Et Rhizoma Rhei of gram and 0.1 Cray handkerchief mycin (Rampamycin) are dissolved in the 5ml chloroform, again balloon expandable stent are dipped in this solution about 30s, dry up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 4
0.1 gram heparinization is gathered (lactic-co-glycolic acid-aminoacid) and the 0.15 anti-restenosis medicaments emodin of gram and 0.1 gram dactinomycin (Actonimycin) to be dissolved in the 5ml chloroform, again balloon expandable stent is dipped in this solution about 30s, dries up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 5
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the 0.1 anti-restenosis medicaments emodin of gram and 0.08 gram paclitaxel (Taxol) are dissolved in the 5ml chloroform, again balloon expandable stent are dipped in this solution about 30s, dry up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 6
Get a medical stainless steel tubing, coat heparinization poly-(lactic-co-glycolic acid-aminoacid) at internal layer, outer is the mixture that coating material coats Radix Et Rhizoma Rhei and paclitaxel with heparinization poly-(lactic-co-glycolic acid-aminoacid), again pipe is become balloon expandable stent with laser ablation.This rack inner wall contacts with blood, owing to there is heparin coating to have the anticoagulation function, can prevent the formation of tampon; Skin slowly releases paclitaxel, and paclitaxel can suppress neointimal hyperplasia, thereby alleviates in-stent restenosis, and heparinization poly-(lactic-co-glycolic acid-aminoacid) can promote the healing of blood vessel wound simultaneously.