CN101496813B - Applicance of combination in drug coating of preparing anti-hyperblastosis (vascular restenosis) support - Google Patents
Applicance of combination in drug coating of preparing anti-hyperblastosis (vascular restenosis) support Download PDFInfo
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- CN101496813B CN101496813B CN 200810014140 CN200810014140A CN101496813B CN 101496813 B CN101496813 B CN 101496813B CN 200810014140 CN200810014140 CN 200810014140 CN 200810014140 A CN200810014140 A CN 200810014140A CN 101496813 B CN101496813 B CN 101496813B
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Abstract
The invention belongs to the field of medicine, and in particular relates to a composition for treating reangiostenosis or other hyperblastosis and an application method thereof. The composition comprises Rapamycine, Paclitaxol and Heparin. The application of the composition not only comprises system administration but also comprises slow release of local medicines into pathological tissues. The composition can be coated on a support or a platform in a mode of premixing and/or multilayer spray coating. As proved by experimental data of the invention for the first time, both a mixture of the Rapamycine and the Paclitaxol and a mixture of the Rapamycine, the Paclitaxol and the Heparin have more obvious effect of inhibiting vascular endotheliosis after the implantation of the support compared with a single medicine.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to the compositions and the application process thereof of treatment vascular restenosis or other hamartoplasias.
Background technology
Coronary artery disease
The coronary atherosclerosis disease is that a kind of chronic coronary artery that is caused by tunica intima hamartoplasia stops up or narrows down.From 1900 it become the No.1 disease of harm Western society, in generation in recent years,, although modern medicine has obvious improvement, this disease is not only in western countries, also becomes the common cause of death in China.Have the American near 1,400 ten thousand to suffer from coronary heart disease in the U.S., wherein about 500,000 people die from acute myocardial infarction; The expense that is used in this disease of treatment every year surpasses 1,120 hundred million.Extensive at present coronary risk factor such as the obesity that exists, diabetes and smoking show all that in the quite a long time from now on this disease will continue the serious human beings'health that jeopardizes.
Coronary artery bypass surgery is the common method of treatment coronary heart disease, yet it is than high mortality and post-operative complication, and expensive surgery cost has limited the extensive use of this method.Percutaneous tranluminal coronary angioplasty (PTCA) and coronary stent are implanted these two kinds of Therapeutic Method of (Stenting) art, are the treatment coronary heart disease effective methods that just grows up in nearly 20 years, have obtained significant progress in recent years.
The coronary artery intracavity forming operation is that the conduit that will have expandable balloon is inserted in constitutional coronary artery medicated porridge shape speckle or the insecondary vascular restenosis, thereby improves the unobstructed property of occluding vascular and increase myocardial flow.The subject matter of coronary artery intracavity forming postoperative is the sudden closure of postoperative arteria coronaria.In order to address this problem, clinical heart disease doctor introduced Stent in 1986, and promptly the blood vessel behind balloon expandable is implanted into metal rack, to keep the forever unobstructed of blood vessel.The introducing of Stent is a revolution of getting involved cardiology.In coronary artery stent implantation, the effect of support (tiny metal rack) is the risk of restenosis behind support blood vessels wall and the minimizing angioplasty.The common indication of percutaneous transcoronary angioplasty and/or stenting is that (generation) blocks angina pectoris or the acute myocardial infarction that causes in the blood vessel of diameter greater than 2.5mm.
According to the investigation of american heart medical association, there was 1,300,000 patient do the coronary artery intracavity forming operation approximately in 1997, wherein half needs of patients placing rack.The combination of this Stent and coronary artery intracavity forming operation has become a kind of trend, and especially along with the appearance of drug releasing stent, this trend is with the rate increase in every year 20%.The direct medical cost that spends in this respect every year is above 2,000,000,000 dollars.
Vascular restenosis
Vascular restenosis is meant the vascular restenosis of Stent or coronary artery intracavity forming postoperative, is because one deck blood vessel proliferation of cells reaction of being made up of connective tissue and smooth muscle cell in the tunica intima is caused.In the patient of vascular restenosis, the hypertrophy of tunica intima causes obstruction of artery and heart oxygen supply deficiency, and causes arrhythmia or asystole.Before coating stent of medicine occurred, restenosis was a problem maximum in the interventional therapy always behind the angioplasty.For percutaneous transcoronary angioplasty, 6 months restenosis relapse rates of menophania balloon expandable are up to 50%; Stent is reduced to 20-30% with this numeral; And sirolimus (CYPHER
TM, Cordis Inc, Miami Lakes, Florida) and paclitaxel (TAXUS
TM, Boston Scientific Inc, Natick, MA) drug releasing stent can significantly reduce the restenosis relapse rate extremely less than 5%.Yet for the patient who suffers from little blood vessel or diabetes and diffusivity vascular lesion, the risk of operation back restenosis is still quite high.(bare metal stent is 30%-60%, and coating stent of medicine is 6%-18%) in-stent restenosis is many-sided, an incremental process.Although the structure of arteries tissue for the reaction mechanism of neo-implanted support still under study for action, it has been generally acknowledged that this process comprises three phases: 1) the thrombosis stage (support insert 0-3 days after): this stage is the initial reaction of arteries tissue to neo-implanted support, it is characterized by the quick active of platelet and neutrophil granule cell, stick, cohesion and deposition are to form thrombosis in injured position.Antithrombotic therapy is running through this stage, its objective is the thrombosis problem that causes after the prevention support is implanted.2) the recovery stage: this stage is 3-8 days after surgery, it is characterized in that progressive inflammatory cell infiltration.This stage comprises that inflammatory cells such as granulocyte, mononuclear cell and macrophage are activated, and and then soaks into injured blood vessel wall.Subsequently, the newly-generated inflammatory cell of damaged vessel walls stimulates and has caused smooth muscle cell proliferation, transfer.Yet cytokine, chemokines and somatomedin that those inflammatory cells discharge have further promoted the damage location inflammatory reaction again, cause the hypertrophy of neointima.3) proliferative phase: this stage continues 1-3 month, and it depends on the thickness and the speed of growth of residue thrombosis.In this stage, inflammatory cell is transferred to remaining thrombosis, forms one " cap-like structure " on mural thrombus.The gradual propagation of cell absorbs remaining thrombosis, and is finally substituted by cambium.The neointima growth course is very similar to the growth course of tumor tissues.This similarity has caused the invention of present antitumor drug paclitaxel and rapamycin drug stent.
Drug releasing stent comprises three basic ingredients: metal rack, polymer and bioactivator.Metal rack is the pharmaceutical carrier of drug releasing stent.Polymer then is to be used for storage of pharmaceutical.Whether successful the compatibility of metal rack, polymer, medicine and blood vessel wall be drug releasing stent key factor.
Metal rack is a device from medicine to the tremulous pulse of pathological changes that carry, and ideal delivery device should have bigger surface area, certain support force and flexibility.At present the obtainable or bracket for eluting medicament just under study for action of all commercial sources all is as carrier with traditional support.Although the traditional crown support that uses today has stronger suppleness than the support before 10 years, bendability, easier arrival branch vessel, littler advantages such as metal covering, it still has circumscribed as the instrument of medicament transport.
The long-chain molecule that polymer is made up of a lot of little repetitives.They form the medicine accumulator tank and help the conveying of prolong drug.Usually, the polymer that is used for drug releasing stent can be divided into organic, inorganic, degradable, nondegradable, synthetic, crude.Coated substrate comprises polymer and anti-restenosis material, is the important component part of drug conveying support.Medicine is stored in the coating, and drug release rate is regulated by polymer.The medication coat material must keep its physicochemical properties constant after sterilization, and can stretch rather than come off after the support expansion, separates.In 4 weeks after support is inserted, drug slow discharges to stop the hypertrophy or the transplanting of smooth muscle cell.Being connected of medicine and rack surface can be covalent bond (e.g., C-C bonds, sulfur bridges) or non-covalent bond (e.g., ionic, hydrogen bonds).
Polymeric material should be the biologically inert material, should not cause the inflammatory reaction of tissue behind the implant into body.Also can satisfy similar requirement in the market without any polymer.Up to the present, test the most successful drug releasing stent rapamycin and taxol drug and discharge support, all adopting nondegradable biomaterial is the polymer of medicine: the rapamycin drug stent is to adopt polybutyl methacrylate and polyethylene vinyl acetate (polyethylene-co-vinyl acetate (PEVA)/poly n-butyl methacrylate (PBMA) copolymer bag carries sirolimus, and the taxol drug carriage support adopts (styrene-b-isobutylene-b-styrene) polymer bag to carry paclitaxel.
Bioactive substance.Seeking a medicine that effectively suppresses neointimal hyperplasia is the key of bracket for eluting medicament success.The regeneration of the medicine reply tissue of ideal anti-restenosis has the inhibitory action of height, not only the not murder by poisoning of its pair cell, and should be able to allow support to implant back blood vessel endothelialization once more.
The taxol drug coating bracket
The mechanism of action: paclitaxel, the extract in the bark of Pacific Ramulus et folium taxi cuspidatae and yewtree is the antitumor drug that is generally used for treating breast carcinoma and ovarian cancer.The anti-hypertrophy performance of paclitaxel embody concentration dependent and with the bonded alternative of microtubule, especially to the beta group of the tubulin of N-terminal.This combination needed tubulin critical concentration when reducing polymerization and stoping depolymerization promotes the polymerization of tubulin to form stable microtubule.The structure of microtubule is stablized by the binding and the quantity that is multiplied.
Paclitaxel reveals tangible dosage in intracellular and relies on effect: low dosage makes interphase in cell division rest on the G1 stage by inducing P53 and P21 tumor suppressor gene, thereby causes apoptosis.The G2 that high dose is considered to influence cell cycle is to the M phase: the transformation from the G2 phase to the M phase requires microtubule depolymerization, and the structure that paclitaxel can stabilize microtubules causes mitosis to stop.On the other hand, the high dose paclitaxel influences M to G1 phase process, causes to stop behind the mitosis even might be apoptosis.In addition, some protease all follows the final result of microcosmic relevant with the serine stretch protein phosphorylation, thereby these effects also can be suppressed by paclitaxel.
The effect of paclitaxel coating bracket: the paclitaxel coating bracket is to coat paclitaxel (1ug/mm on metal rack
2) and non-degradable polymer (styrene-b-isobutylene-b-styrene).(＜2 years) paclitaxel coating bracket (TAXUS I, TAXUS II and TAXUS IV) is compared with naked metal rack in a short time, has the effect of obvious suppression vascular restenosis.But its long-term effect remains to be observed.
The rapamycin coating stent of medicine
The mechanism of action.Rapamycin is a kind of novel macrolide immunosuppressants, obtains checking and approving of U.S. FDA in 1999 as the anti-rejection drugs after the organ transplantation.Thereby its basis that is applied to the cardiovascular drugs support is the vascular restenosis after implanting by its mechanism control support that suppresses hamartoplasia.The biological agent mechanism of rapamycin is: at first enter histiocyte, combine with immune rabphilin Rab FK-12 in the histiocyte, form RAPA-FK 12 complex, this complex can stop the signal conduction, thereby optionally stops protein synthesis.With after immune rabphilin Rab FK-12 combines, rapamycin is by suppressing activity and the cell cycle dependant kinase (cdk) and the kinase whose activity of cyclin (cyclin) complex of mammiferous RAPA target protein (mTOR), and the proteinic phosphorylation of cancer eye (having genetic), thereby stop the conversion of cell cycle from the G1 phase to the S phase.
The effect of rapamycin drug releasing stent and points for attention: the composition of rapamycin coating stent of medicine comprises a metal rack, rapamycin (1.40 μ g/mm
2) and the polymer formed of the mixture of the polyethylene cellulose acetate of 50% polybutyl methacrylate and 50%.Medicine layer surface coverage one deck covering layer, with control medicine release several times.After support was implanted, medicine went by polymer being discharged in the blood slowly in about 30 days.Rapamycins coating support (CYPHER
TM) be first drug stent that is gone on the market by drugs approved by FDA, be used widely in 50 countries at present.With taxanes seemingly, the effect that its short-term suppresses restenosis is obvious, but long-term effect remains further to be observed.
Clinically, get involved the cardiovascular doctor and often be difficult to decision when selecting drug releasing stent, because present only rapamycin and taxol drug support, though the mechanism of action difference, clinical effectiveness is on a par.Under a lot of situations, the doctor promptly implants the rapamycin support and implants the paclitaxel support again in same patient's blood vessel., this can be regarded as the prelude of the two drug combination treatment restenosis.Up-to-date clinical research shows that also intravascular stent (rapamycin and the paclitaxel) end that is implanted into different pharmaceutical in same patient's blood vessel sees that any side effect is arranged.
It is a big inducement that causes restenosis to take place that early stage thrombosis is assembled, and controlling early stage thrombotic main method clinically is to implant posterior vein or oral a large amount of anticoagulation medicines such as heparin, the aspirin etc. of awarding at support.But it is cause after the medication hemorrhage that system awards the greatest problem of antithrombotic reagent.
Definition
" cell hyperplasiaing state " is meant and arteriosclerosis, restenosis, the diseased cells growth that proliferative vitreoretinopathy is relevant with psoriasis.This speech does not mean the hyperplasia relevant with the cancer state.
" diseased cells hypertrophy " is meant the improper division of smooth muscle cell or fibril cell." inhibition of diseased cells hypertrophy " then is meant the morbid state growth that suppresses this type of cell.
" compositions " is meant all medicinal mixtures that are used to suppress restenosis, such as the compositions that comprises paclitaxel and rapamycin.
" administration " comprises route of administration at this, it comprises play a role all approach of (effectively inhibition of cell proliferation) of compositions that can allow. comprises by being administered systemically (as: intravenous injection) and partial or privileged sites administration, as subcutaneous, parenteral route, intraperitoneal etc.), oral, transdermal, or by the medicament transport conduit or implant the medicine carrying device.
" effective dose " is meant and can brings into play abundant inhibiting drug dose to the diseased cells hypertrophy.Effective dose is looked concrete condition and is changed, such as the type of cell growth, and administering mode and position, patient's body weight, the degree of cell growth etc.
Summary of the invention
The purpose of this invention is to provide a kind of compositions that can effectively suppress vascular restenosis or arteriosclerosis formation, wherein restenosis is to occur in tube chamber class tissues such as blood vessel, bile duct, esophagus and trachea.The compositions that is used for inhibition of cell proliferation mainly comprises microtubule stabilizer and immunosuppressant, also comprises anticoagulant.Wherein microtubule stabilizer is the paclitaxel or derivatives thereof, and immunosuppressant is the rapamycin or derivatives thereof, and anticoagulant is the heparin or derivatives thereof.The using method of compositions is that whole body is administered systemically, and it is by drug delivery catheter, and seal wire or support are transported to the part.On the one hand, application process is local the use.Medication comprises on the one hand and adopts the conduit topical, on the other hand, slowly discharges by support.Wherein said support is coated with the effective ingredient of compositions.Support is the support that is coated with compositions-be coating stent of medicine, and further, the mode of medication coat comprises that multilamellar sprays step by step; Or be sprayed on the rack surface again after pharmaceutical premixed.The kind of support including, but not limited to: be on the one hand the degradable medicaments support--the present composition is joined on the degradable polymer support.On the other hand, metal rack promptly is covered with said composition at metal support surface.
On the other hand, the present invention includes inhibition restenosis effective dose.
Experimental result shows, during the topical thing, and the pharmaceutical formulation group among the present invention and more can effectively suppress the generation that support is implanted the back vascular restenosis than any single drug group.Another one finds it is that compositions of the present invention is lower than the toxicity of single drug pair cell under same dosage situation.
Compositions of the present invention is used for blood vessel, bile duct, histogenetic hamartoplasia of body lumens such as esophagus and bronchus or restenosis.
Biomechanism of the present invention and clinical basis
The mechanism of vascular restenosis and tumor growth machine-processed similar all is to be feature with the neointimal hyperplasia.Drug combination is a kind of effective, well-known method in the clinical treatment of daily tumor.
In mixture of the present invention, rapamycin or paclitaxel all are fat-soluble, has identical release profiles, and the two can independently effectively suppress the hypertrophy of endotheliocyte by different approach, therefore, in theory, two kinds of medicines should have cooperative effect to the generation that prevents restenosis when the use in conjunction of coating stent of medicine.Simultaneously because the cooperative effect of the two, its required dosage that suppresses restenosis is low during also than single drug.Rapamycin and paclitaxel mainly act on the second, three phase that restenosis takes place.Rapamycin and paclitaxel drug combination are used for the treatment of the mechanism of action of vascular restenosis: rapamycin is by acting on the hypertrophy that the cell cycle S phase stops endotheliocyte, and paclitaxel then is to reach same inhibition effect by the M phase of optionally blocking cell growth cycle.Among the present invention,,, thereby improve therapeutic effect from the multi-faceted blocking-up proliferation of cells of different cell growth cycles by with the two associating.
As previously mentioned, restenosis-principal element is brought out in early stage hematoblastic cohesion.Controlling early stage thrombotic main method clinically is to implant posterior vein or oral a large amount of anticoagulation medicines such as heparin, the aspirin etc. of awarding at support.But it is cause after the medication hemorrhage that system awards the greatest problem of antithrombotic reagent.Heparin in this mixture can solve this problem during by topical.As with mixture with the polymer overlay film on the intravascular stent surface because heparin is soluble in water, can in a few hours to a couple of days after support is implanted, discharge (first phase that restenosis takes place, thus can greatly suppress the formation of early stage thrombosis.And that rapamycin and paclitaxel are is fat-soluble, discharges slow (having discharged the moon 80% in 28 days) (the second, three phase of restenosis generation) in blood vessel.Thereby, in case the mixture medicines among the present invention can be from different angles after discharging the support implant into body, different periods, the generation of multi-faceted blocking-up restenosis.
Experimental data among the present invention confirms rapamycin+paclitaxel mixture first, blood vessel endothelium hypertrophy after rapamycin+paclitaxel+heparin mixture is implanted support during than any single drug all has more significant inhibition effect, and this has sufficient digital proof in accompanying drawing in the back.
Using method
(use) of the present invention method, the pharmaceutical composition among the present invention is mainly used in the patient who might or just suffer from proliferative disease, gives and effective dosage through certain route of administration.
Used choice drug is paclitaxel and rapamycin and heparin or their derivant in inventive compositions.All medicines in the present composition all are available on the market.
In the present invention, foregoing description compositions (rapamycin+paclitaxel or rapamycin+paclitaxel+heparin) is used to suppress the formation of vascular restenosis." inhibition " comprises reduction at this, postpones or eliminate the hyperplasia of morbid state." reduction " means the vascellum tunica interna incrassation that smooth muscle cell proliferation caused that reduces the vascularization postoperative." delay " meaning is at postangioplasty, the time of the vascellum endometrial hyperplasia outbreak of postponement." elimination " means reduction fully or postpones neointimal hyperplasia fully so that enough blood flows are arranged in the blood vessel and do not need operating intervention.
The present invention's compositions can award by any valid approach.These approach comprise but are not limited to and be administered systemically, as discontinuously or the intravenous injection that continues, and subcutaneous tissue, muscle, the intramuscular injection of peritoneum etc.
Wherein an ideal medication is a catheter drug delivery, and conduit has a soft pole usually, and an air bag is arranged at the top of pole.Be equipped with a plurality of micropores on the air bag, air bag is transported to diseased region after, again the pressurization and medicine is injected in the tissue of pathological changes.Also medicine can be used in the polymer, form hydrogel, spread on balloon surface then, again sacculus is poured in the diseased region.
Another ideal administering mode is to use infusion catheter or drug conveying seal wire.With the terminal pathological changes place of inserting of infusion catheter, conduit is connected with syringe pump, the end of conduit has path usually, medicine is injected into the tissue of pathological changes by this path.Drug conveying seal wire, seal wire are empty, and for the inculcating of medicine, and at its end an openning are arranged.
Another selection of administering mode is that medicine is covered in the medical apparatus and instruments such as intravascular stent, implants in the diseased region then.The endovascular stent that is used for blood vessel sacculus plasty has been the technology of comparative maturity.
The support that is used for administration can be a metal rack.Usually metal rack should have excellent biological compatibility.Timbering material commonly used comprises Nitinol and rustless steel.During concrete the use, medicine can be loaded into and be sprayed at rack surface again after being dissolved in polymer in the cutting of rack surface or with medicine.
The another kind of situation of metal rack is that metal rack as platform, at metal support surface covering one deck fiber polymer or other biological material, is dissolved in medicine in the polymer.Serve as the platform of polymer transport medicine at this metal rack, for blood vessel provides a mechanical support, polymer is then controlled the release of medicine.
Support is a biodegradable stent as other situation of planting of pharmaceutical carrier, and biodegradable stent promptly can be a Biodegradable material such as polylactic acid or metal degradation material such as magnesium alloy bracket.In polylactic acid bracket, can directly medicine be joined in the support, medicine discharges with the explanation of support.In magnesium alloy bracket, medicine can then need to be sprayed at rack surface, and then slowly releases.
In order to confirm this invention, we are sprayed at metal support surface with the medicine prescription composite of invention, are implanted into then in the femoral artery of rat carotid artery and rabbit.To discuss to these research situation later on.
Used metal rack is the stainless steel metal support in the research.
The support of drug loading compound composition is inserted in the rat carotid artery blood vessel shown in example 3.Simultaneously in contrast, will not have medicine to load (bare bracket), and paclitaxel only will be housed and rapamycin three pack supports only are housed and implant in the rat carotid artery in the lump yet.
Implant rat carotid artery after one month at all supports, rat is put to death,, carefully from tissue, measure the degree of restenosis behind the separating support again at microscopically with formalin high pressure pouring carotid artery.Calculate the formula of restenosis: (normal inner membrance area-residual inner membrance area)/normal inner membrance area * 100 calculate.
Its stenosis rate of support of the present invention's pharmaceutical formulation parcel is 5.8%.The stenosis rate of bare metal stent is 16%.Only being loaded with the paclitaxel stenosis rate is 12%, and its stenosis rate of support that only is loaded with rapamycin is 11.9%.It in the accompanying drawing 5 summary of experiment.
The result shows: rapamycin and paclitaxel drug combination are having more significant curative effect than any single drug aspect the generation that suppresses vascular restenosis.
In another research, rack surface is coated with pharmaceutical composition of the present invention.Wherein ground floor is wrapped in paclitaxel, and the second layer is wrapped in rapamycin, and outermost layer scribbles heparin.
During test, with three bare metal stents, three polymer overlay film frames, three paclitaxel overlay film frames, three rapamycin overlay film frames, three heparin overlay film frames and three hybrid medicine coated stents are implanted in the femoral artery of rabbit.Implant in back one month, after rabbit euthanasia, trip out support by above-mentioned method row pathology section examination analysis.
Its stenosis rate of support of compositions B parcel is 5.3%.The stenosis rate of bare metal stent is 18%.The polymer group is 21%, and only being loaded with the paclitaxel stenosis rate is 12%, and its stenosis rate of support that only is loaded with rapamycin is 11.9%.Heparin wraps up to such an extent that support is to be the summary of experiment in 21%. accompanying drawings 6.
Description of drawings
The result shows that medicinal mixture B (rapamycin+paclitaxel+heparin) coated stent is having more significant curative effect than any single drug aspect the generation that suppresses vascular restenosis.Do not see thrombosis in any blood vessel in the test in the mixture.
Fig. 1 illustrates the metal net shaped metal rack that is applicable to each embodiment.
Fig. 2 illustrates the process and the method for multilayer medicine coating, and wherein 1 is paclitaxel, and 2 is rapamycin, and 3 is polymer.
Fig. 3 illustrates the process and the method for premix coating medicine.
Fig. 4 support was implanted back one month, the percentage ratio of the present invention's coating stent of medicine and the caused vascular restenosis of single medicine coating bracket.
Fig. 5 support was implanted back one month, and the rapamycin of premix medicine of the present invention, paclitaxel and its composition coating support are at the percentage ratio of the caused restenosis of rabbit femoral artery.
Fig. 6: compositions and single medicine support to suppress restenosis in the body experimentation
Fig. 7: in the mixture, the rapamycin of different proportion and paclitaxel are to the inhibitory action of vascular restenosis
Taxol, the premixing coating test of rapamycin and heparin and composition thereof mixture in the PBMA/PEVA polymer.
In order to determine that can mix dosage form spread upon on the metal rack, we soak into 40 supports in four kinds of different block copolymer drug dosage forms: single polymer, single rapamycin, single taxol, single heparin group, rapamycin+taxol compositions, rapamycin+paclitaxel+heparin compostions, every group has ten supports.Macromolecular coating is by 50% polybutyl methacrylate and and 50% polyethylene vinyl acetate.Form 1 is the summary of medicine grouping and every group of medicine.
The multilayer film test in the PLA polymer of rapamycin, paclitaxel and heparin and compositions A thereof and B
PLA (polylactic acid) is dissolved in chloroform by the concentration of 6.7mg/ml makes polymer solution.Solution is equally divided into three parts, each part 2ml.Add the 5mg rapamycin and in first's polymer solution, make rapamycin-copolymer solution (2.5mg/ml).Add the 5mg paclitaxel and in the second portion polymer solution, make paclitaxel-copolymer solution (2.5mg/ml).Adding 5 milligrams of heparin and make heparin-polymer solution in the polymer solution in the third part. the rapamycins coating solution that at first naked metal rack is immersed first makes the ground floor coating in 30 seconds, behind the natural drying, again it was immersed second portion solution (taxol coating solution) 30 seconds, under the room temperature after the drying, support was immersed third part heparin coating solution 30 seconds more at last, after drying fully, the weighing weight support frame calculates medicine/copolymer coated gross weight according to drug solution concentration then.Form 2 is the summaries of total quantity that are wrapped in the medicine of support by every kind of the method.
Table two: rapamycin, paclitaxel and heparin and composition medicine thereof layered coating in polylactic acid polymer is made summary
| Group | Polymer | Rapamycin | Paclitaxel | Heparin | Compositions A | Compositions B |
| Rapamycin+paclitaxel | Rapamycin+paclitaxel+heparin | ? | ? | ? | ? | ? |
| Number of holders (individual) | 10 | 10 | 10 | 10 | ?10 | 10 |
| Spraying weight (milligram) | 10 | 14 | 15 | 15 | ?7.1/7.1 | 4.9/5.1/5.1 |
Rapamycin and taxol drug discharge test.
In order to determine rapamycin, the stability of paclitaxel, we have further implemented organism outside medicament elution and have studied on three supports that scribble mixture.In the experiment each support is placed in the 2.5ml normal saline, what the speed of changeing with per minute 200 in 37 ℃ of bain-maries was not stopped then rocks.Change normal saline solution every day and be in release conditions all the time to keep support.During 1,2,4 weeks after experiment beginning, take out a support respectively, be placed in 1 milliliter 100% ethanol, measure the content of rapamycin and paclitaxel in the ethanol then with high pressure liquid chromatograph.Experimental result, rapamycin and paclitaxel all can be detected three time periods, showed that two kinds of medicines are stable in the entire bracket drug release process.
Example executes 4
The mixture medicines support is implanted the rat carotid artery test
In order to determine that whether rapamycin/paclitaxel mixed coating (mixture A) is suppressing in-stent restenosis than single rapamycin or paclitaxel coating bracket better effects if, we further implant rat carotid artery with 12 supports describing in the example 1.Wherein copolymer coated support (3 supports), rapamycin (3 supports), paclitaxel (3 supports), rapamycin/paclitaxel mixture (3 supports).Support is inserted 4 weeks of back, and the rat of all experiments is peaceful and comfortable deadly.Remove support then and carry out pathological analysis.
Accompanying drawing 5 has been described the difference that 4 pack supports are implanted restenosis rate incidence rate in the blood vessel of back.With the polymer phase ratio, rapamycin and paclitaxel coating bracket can significantly reduce in-stent restenosis rate (being respectively 11.9% and 12.1%vs.16.5%, P＜0.05).But in paclitaxel single coating and rapamycin single coating group, not significantly difference (11.9%vs.12.1%, p＞0.05), this result is identical with paclitaxel single coating support clinical experiment data with all relevant rapamycins of publishing.The most significant discovery is: rapamycin/paclitaxel mixed coating can further reduce restenosis rate to 5.8% in the blood vessel, compares with single paclitaxel coating bracket with single rapamycin, and restenosis rate has reduced near 50%.
Example 5: mixture medicines B support is implanted the experimental study of rabbit femoral artery
With the polylactic acid-medicine overlay film frame that makes in the example 2, bare bracket (3) wherein, copolymer coated support (3 supports), rapamycin (3 supports), paclitaxel (3 supports), heparin (3), rapamycin/paclitaxel/heparin mixture (3 supports).Implant the rabbit femoral artery, after 4 weeks, that the rabbit of all experiments is peaceful and comfortable deadly.Take out support then and carry out pathological analysis.
Accompanying drawing 6 has been described the difference that 6 pack supports are implanted restenosis rate incidence rate in the blood vessel of back.With the polymer phase ratio, rapamycin and paclitaxel coating bracket can significantly reduce the in-stent restenosis rate.But in paclitaxel single coating and rapamycin single coating group, not significantly difference. heparin coating stent of medicine and bare bracket or polymer support do not have significant difference, show that the heparin drug stent itself does not have the effect of significant anti-restenosis, but can prevent the formation of tampon.Rapamycin/paclitaxel/heparin mixed coating can further reduce restenosis rate to 5.5% in the blood vessel, compares with single paclitaxel coating bracket with single rapamycin, and restenosis rate has reduced near 50%.
Embodiment 6: among the mixture medicines B, the rapamycin of different proportion and paclitaxel are to the influence of vascular restenosis.
In order to determine the optimal proportion of different pharmaceutical in mixture, we further make the different proportion mixture of ingredients as stated above, comprising rapamycin: paclitaxel=50: 50, three groups of 60: 40 and 70: 30.Get in the mixture in the ownership, heparin concentration is constant.The mixture of the different proportion that makes is sprayed at rack surface, after the drying, implants as mentioned above in the rat carotid artery, 28 days taking-up supports carry out the pathological section analysis.The result shows: the compositions of three kinds of different proportions all has inhibitory action to vascular restenosis, but becomes the grouping effect best with the ratio at 50: 50.See Fig. 7.
Embodiment 7: among the mixture B, the heparin of different proportion is to thrombotic influence in the blood vessel.
In order to determine that different heparin concentrations are to thrombotic influence in the mixture, we further make the mixture of different heparin ratios, wherein rapamycin as stated above: paclitaxel=immobilize at 50: 50, and the ratio of heparin in total composition is divided into 10%, 20% and 30% 3 group.The mixture of the different proportion that makes is sprayed at rack surface, after the drying, implants as mentioned above in the rat carotid artery, 28 days taking-up supports carry out the pathological section analysis.The result shows: heparin concentration accounted in compositions 30% o'clock, did not almost have the formation of thrombosis in the blood vessel.
Claims (5)
1. a compositions is used for the application of the medication coat of inhibition of cell proliferation intravascular stent in preparation, it is characterized in that described compositions comprises microtubule stabilizer paclitaxel and immunosuppressant rapamycin, and its usage ratio scope is from 50: 50 to 70: 30.
2. compositions as claimed in claim 1 is used for the application of the medication coat of inhibition of cell proliferation intravascular stent in preparation, and the usage ratio scope that it is characterized in that described rapamycin and paclitaxel is 50: 50.
3. compositions as claimed in claim 1 is used for the application of the medication coat of inhibition of cell proliferation intravascular stent in preparation, it is characterized in that also comprising the anticoagulant heparin, and the ratio of its consumption in total composition is 30%.
4. the compositions described in claim 3 is used for the application of the medication coat of inhibition of cell proliferation intravascular stent in preparation, it is characterized in that said medication coat is that multilamellar sprays step by step, and outermost layer scribbles heparin.
5. the compositions described in claim 1 is used for the application of the medication coat of inhibition of cell proliferation intravascular stent in preparation, it is characterized in that said medication coat is premixed compositions.
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