Drug coated balloon catheterTechnical field
The invention belongs to interventional medical equipment field, be specifically related to drug coated balloon catheter.
Background technology
Cardio-vascular interventional therapeutic field from eighties of last century seventies till now, experienced by three and landmark fliesJump.Within 1977, the mankind use balloon expandable coronary stricture pathological changes for the first time, and this is first milestone.Although balloon expandable can eliminate coronary stenosis, but due to the elastical retraction of vascular wall, neointimal hyperplasiaAnd tube wall inner membrance tear etc. can inspire vascular restenosis, target vessel postoperative 3～6 months restenosis rate be up to 30～50%.Bare mental stents in 1986 (being called for short: BMS) come out, it is possible not only to eliminate angiostenosis at once,Greatly reducing the incidence rate of acute reocclusion, it becomes second milestone of interventional therapy simultaneously, but targetThe incidence rate of vascular restenosis is still up to 30%.Calendar year 2001 bracket for eluting medicament (vehicle economy S) comes out, and makesTarget vessel restenosis rate is down to 3% hereinafter referred to as the 3rd milestone.
The invention of support is for solving atherosclerosis and Ink vessel transfusing is narrow provides reasonable solution partyCase, makes therapeutic efficiency greatly improve, but occurs in that Ink vessel transfusing and in-stent restenosis simultaneously, for thin vessels,The shortcomings such as the therapeutic effect of bifurcated vessels and in situ pathological changes etc. is unsatisfactory, owing to accepting patient's number of PCI treatmentAmount rises year by year, and the absolute quantity that the patient of stent restenosis occurs is considerable.Currently for restenosisThe method used includes: the expansion again of simple sacculus, orientation speckle rotary-cut art, turnery art, Ink vessel transfusing are putPenetrating treatment and repeat stenter to implant etc., existing bare ball capsule and drug stent all have some limitations, nakedThe restenosis rate of sacculus is higher, and drug stent is the best for the therapeutic effect of thin vessels and bifurcated vessels,Both fails to show its preferable effectiveness or safety.
The solution restenosis that appears as of medicament elution sacculus (vehicle economy B) brings new hope.Medicine is washedDe-sacculus is similar with DES, substantially comes from the local drug delivery devices theory based on conduit, passes through ballThe Drug inhibition neointimal hyperplasia that capsule carries, mode and the topical remedy of simply carrying medicine are different for action time.
Medicine-coated balloon is by the medicine of anti-proliferate, such as paclitaxel or rapamycin and the combination of additiveThing, coating is in balloon surface.In sacculus is transported to lesion vessels wall softened, expansion and blood vessel wallDuring film contact, by tear blood vessel wall inner membrance pressurization quickly release, diversion medicaments to local vessel wall.Medicine plays the effect of anti-angiogenic neointimal hyperplasia in local, thus prevents the vascular restenosis after vascular procedure.
The core of medicinal balloon play therapeutical effect is medication coat.Due to the anti-proliferate medicine workedFor lipophilic drugs, be insoluble in water, and caking of easily reuniting, form big microgranule, in course of conveying thisThe biggest drug microparticles is easily de-by blood punching.If the particle number come off is many, it is easy to cause distal vesselsThe complication such as obturation, thrombosis, severe patient can cause amputation.
Summary of the invention
For above-mentioned the deficiencies in the prior art, exploitation is needed to meet following condition medicine-coated balloon: the most permissibleIn clinical course or be quickly delivered directly to local tissue area afterwards by active medicine；2. at required targetPosition discharges active medicine rapidly in effective and efficient mode, make it possible to penetrate into rapidly target tissue withTreatment disease；3. medication coat Chinese medicine particle diameter is little, during being delivered to target position and at target positionDuring treatment, drug particles is de-few by blood punching.
The present invention provides a kind of and has quick medicament release coating and the little medicine of medication coat Chinese medicine particle diameterCoating ball ductus bursae.Containing active medicine and carrier in the medication coat of this drug coated balloon catheter, this loadBody, for accelerating active medicine rate of release from sacculus, can make medicine discharge also within the shortest periodRapid osmotic enters the tissue at disease sites, improves ill at vascular system or other body lumens of medicineAbsorbance in tissue, thus realize solving the drug loss in Clinical practice course of conveying and balloon expandableMedicine is to the quick reprinting at target lesion position afterwards.It addition, designed by formula, reach drug particles particle diameterLess, and be delivered to during target position and when treating at target position, drug particles is de-by blood punchingFew.
This drug coated balloon catheter, including sacculus with cover at the medication coat of sacculus outer surface, described medicineThing coating includes active medicine and carrier；Described active medicine be paclitaxel, rapamycin, paclitaxel deriveThing or rapamycin derivative；Described carrier includes acylate and polyhydric alcohol, the work in described medication coatProperty medicine and carrier mass ratio be 0.5～49, described acylate and the mass ratio of polyhydric alcohol be (3～50)∶1。
Described acylate be acetate, benzoate, maleate, succinate, Ascorbate,Citrate, tartrate, lactate, oxalates, aspartate, nicotinate, gluconate,One or more in stearate, glutamate, Glu, vanillate or Lactobionate；Described polyhydric alcoholFor at least one in Polyethylene Glycol, trometamol, xylitol, sorbitol, mannitol or amino alcohol.
Described active medicine is 0.5～20 μ g/mm at the content of foley's tube outer surface2。
The material of described foley's tube is nylon, nylon elastomer, PET or polyethylene.
Described foley's tube, for active medicine is transported to the target site of blood vessel or tube chamber, treats blood vessel or pipeIntracavity narrow, prevent inner membrance or epithelial proliferation；Described blood vessel is coronary artery, peripheral arterial blood vesselOr cerebral artery vessel；Described tube chamber is esophagus, air flue, intestinal, biliary tract, urinary tract, prostate or nicergolineRoad.
In the medication coat on foley's tube surface of the present invention, carrier is by Lipophilicity material acylate and parentAqueous substance polyhydric alcohol forms, and both all produce synergism during medicine conveying and reprinting the twoAccelerate the eluting release of medicine and absorb and greatly reduce conveying finely divided coming off, reducing coating safety.ToolBody ground, used carrier has the effect that
1, surfactant is made；
First the Lipophilicity material of carrier can be combined with the lipophilic drugs such as rapamycin or paclitaxel, fromAnd reduce coating surface tension, and be conducive to increasing the hydrophilic of coating, the most beneficially medicine is to groupKnit reprinting；
2, make dispersant interval drug crystal grain, contribute to medicament elution and reprinting；
Lipophilic anti-proliferate medicine is the most mutually assembled, and hydrophilelipophile carrier can be fast owing to having lipotropyAfter speed is in combination so that produce interval action between drug molecule, thus greatly reduce and roll into a ball between drug moleculePoly-probability, it is therefore prevented that large-area reunion between drug molecule, and be gathered on apparatus.The most therefore reduceThe size of drug particles and quantity, further decrease size and the quantity of particles from getting loose, greatlyImprove the safety of coating.
3, as cosolvent, there is Premeabilisation of cells effect, beneficially drug absorption.
After Lipophilicity carrier is combined with lipophilic drug molecules, because it has hydrophilic, simultaneously asEvery effect, add the specific surface area of coating thus add medicine dissolubility in intercellular substance, accelerateMedicine arrives the lipid bilayer of target tissue cell membrane, and after medical apparatus and instruments and contact tissue, carrier hydrophilicMaterial is discharged rapidly, promotes that medicine discharges during foley's tube inserts target site the most rapidly,Thus accelerate medicine diffusion in tissue and increase medicine penetrating in tissue, medicine is more easy to be organizedAbsorb.
The present invention compared with prior art, has the following advantages and beneficial effect:
(1) containing acylate and polyhydric alcohol, the two inserting at foley's tube in the medication coat of the present inventionDuring jointly play a role, promote medicine quickly discharge from balloon surface and absorbed by target tissue, simultaneouslyPreventing from discharging too early before medicinal balloon catheter is presented to target site, therefore medicinal balloon catheter can produceEffect reprinted by raw reasonable medicine, reduces size and the quantity of drug particles simultaneously, further subtractsLack size and the quantity of particles from getting loose, be greatly improved the safety of coating.
(2) raw material that the foley's tube of the present invention uses is used equally to intravenous injection, safety and biofaciesCapacitive is preferable.
Accompanying drawing explanation
Fig. 1 is embodiment 1～6 and the drug release patterns figure of comparative example 1～4.
Fig. 2 is 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle of embodiment 1 preparation.
Fig. 3 is 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle of embodiment 2 preparation.
Fig. 4 is 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle of embodiment 3 preparation.
Fig. 5 is 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle of embodiment 4 preparation.
Fig. 6 is 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle of embodiment 5 preparation.
Fig. 7 is 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle of embodiment 6 preparation.
Fig. 8 is the 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle through comparative example 1 preparation.
Fig. 9 is the 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle through comparative example 2 preparation.
Figure 10 is the 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle through comparative example 3 preparation.
Figure 11 is the 28 days pathological section figures of medicinal balloon catheter far-end skeletal muscle through comparative example 4 preparation.
Detailed description of the invention
Below in conjunction with drawings and Examples, the detailed description of the invention of the present invention is described in further detail, butClaimed content is not limited thereto.
Embodiment 1
By 250mg paclitaxel, 5.0mg citrate, 0.1mg amino alcohol, 10ml ethanol, 4ml purified water is mixedClosing preparation coating solution, wherein the mass ratio of active medicine and carrier is 49；By PTA foley's tube (diameter4mm, long 40mm) in ten thousand grades of clean environments after flap three folding, under hundred grades of clean environments, coating is moltenLiquid precision syringe (being accurate to 2 μ l) drop coating, to the polyester balloon surface after flap, then makes described sacculusIt is dried, repeats drop coating until described balloon surface drug level reaches 20 μ g/mm2, after being dried 24 hours, bagDress, ethylene oxide sterilizing.
Embodiment 2
By 11mg rapamycin, 17mg lactate, 5mg mannitol, 7ml ethanol, the mixing of 3ml purified water is joinedSolution processed, wherein the mass ratio of active medicine and carrier is 0.5；By PTA foley's tube (diameter 4mm, length40mm) in ten thousand grades of clean environments after flap three folding, under hundred grades of clean environments, coating solution is accurateSyringe (being accurate to 2 μ l) drop coating, on the surface of polyester sacculus, then makes described sacculus be dried, and repeats to dripIt is coated with until described balloon surface drug level reaches 3 μ g/mm2, after being dried 24 hours, packaging, oxiraneSterilizing.
Embodiment 3
By 120mg paclitaxel, 36mg sodium benzoate, 12mg Macrogol 2000,10ml ethanol, 4ml is pureChanging water mixed preparing coating solution, wherein the mass ratio of active medicine and carrier is 2.5；By PTA foley's tube(diameter 4mm, long 40mm) after flap three folding, incites somebody to action in ten thousand grades of clean environments under hundred grades of clean environmentsCoating solution spraying equipment sprays to, in the polyester balloon surface after flap, make balloon surface drug level reachTo 3 μ g/mm2, it is dried, packaging, ethylene oxide sterilizing.
Embodiment 4
By 100mg paclitaxel, 50mg sodium benzoate, 5mg Macrogol 2000,10ml ethanol, 4ml purificationWater mixed preparing solution, wherein the mass ratio of active medicine and carrier is 1.82；By PTA foley's tube (diameter4mm, long 40mm) in ten thousand grades of clean environments after flap three folding, under hundred grades of clean environments, coating is moltenLiquid spraying equipment sprays in the polyester balloon surface after flap, makes balloon surface drug level reach 3 μ g/mm2, it is dried, packaging, ethylene oxide sterilizing.
Embodiment 5
By 12mg paclitaxel, 20mg magnesium stearate, 4mg Macrogol 2000,10ml ethanol, 4ml purificationWater mixed preparing solution, wherein the mass ratio of active medicine and carrier is 0.5；By PTA foley's tube (diameter4mm, long 40mm) in ten thousand grades of clean environments after flap three folding, under hundred grades of clean environments, coating is moltenLiquid spraying equipment sprays in the polyester balloon surface after flap, makes balloon surface drug level reach 3 μ g/mm2, it is dried, packaging, ethylene oxide sterilizing.
Embodiment 6
By 96mg paclitaxel, 40mg sodium stearate, 10mg Macrogol 2000,10ml ethanol, 4ml purificationWater mixed preparing solution, wherein the mass ratio of active medicine and carrier is 1.92；By PTA foley's tube (diameter4mm, long 40mm) in ten thousand grades of clean environments after flap three folding, under hundred grades of clean environments, coating is moltenLiquid spraying equipment sprays in the polyester balloon surface after flap, makes balloon surface drug level reach 3 μ g/mm2, it is dried, packaging, ethylene oxide sterilizing.
Comparative example 1
By 50mg paclitaxel, 20mg Iopromide, 5ml ethanol mixed preparing solution；By PTA foley's tube(diameter 4mm, long 40mm) after flap three folding, incites somebody to action in ten thousand grades of clean environments under hundred grades of clean environmentsCoating solution spraying equipment sprays in the polyester balloon surface after flap, makes the coating drug concentration be3μg/mm2, naturally dry 24 hours, packaging, ethylene oxide sterilizing.
Comparative example 2
By 100mg paclitaxel, 0.5mg sodium benzoate, 0.5mg sorbitol, 10ml ethanol, 4ml purified water is mixedClosing preparation solution, wherein the mass ratio of active medicine and carrier is 100；By PTA foley's tube (diameter 4mm,Long 40mm) after flap three folding, under hundred grades of clean environments, coating solution is sprayed in ten thousand grades of clean environmentsEquipment sprays in the polyester balloon surface after flap, makes balloon surface drug level reach 3 μ g/mm2, dryDry, packaging, ethylene oxide sterilizing.
Comparative example 3
By 75mg paclitaxel, 0.74mg sodium citrate, 0.26mg cetomacrogol 1000,10ml ethanol, 4mlPurified water mixed preparing solution, wherein the mass ratio of active medicine and carrier is 75；PTA foley's tube is (straightFootpath 4mm, long 40mm) in ten thousand grades of clean environments after flap three folding, by coating under hundred grades of clean environmentsSolution spraying equipment sprays to, in the polyester balloon surface after flap, make balloon surface drug level reach3μg/mm2, it is dried, packaging, ethylene oxide sterilizing.
Comparative example 4
By 4.4mg rapamycin, 3.7mg sodium acetate, 18.3mg mannitol, 8ml ethanol, 3ml purified water is mixedClosing preparation solution, wherein the mass ratio of active medicine and carrier is 0.2；By PTA foley's tube (diameter 4mm,Long 40mm) in ten thousand grades of clean environments after flap three folding, under hundred grades of clean environments, by coating solution essenceClose syringe (being accurate to 2 μ l) drop coating, on the surface of polyester sacculus, then makes described sacculus be dried, and repeatsDrop coating is until described balloon surface drug level reaches 3 μ g/mm2, after being dried 24 hours, packaging, epoxy secondAlkane sterilizing.
Course of conveying loss simulation test
Carry out course of conveying loss simulation test with the target vessel of pig arteria coronaria blood vessel simulation coronary artery system, surveyTry before sacculus is full, i.e. foley's tube inserts and moves to the dose loss during target site.
Respectively by embodiment 1～6 and the foley's tube of comparative example 1～4 preparation insert in in-vitro simulated blood vessel model.In simulated blood vessel system, the flotation time is 90 seconds, then takes out conduit.HPLC is utilized to analyze on foley's tubeRemaining medicine, HPLC test condition is: Japan's Shimadzu LC-20A high performance liquid chromatograph, chromatographic column:Aglilent ZOBAX SB-C184.6 × 250mm, 5um, flow phase: methanol: acetonitrile: water=230:360:410,Column temperature: 30 DEG C, UV-detector, detects wavelength 227nm, flow velocity: 1.0ml/min.
HPLC measurement result is as shown in table 1:
Table 1 course of conveying loss simulation test result
Table 1 result shows: compared with the medicine-coated balloon that comparative example 1 is not added with carrier, the medicine of the present inventionSacculus, during moving to Intertherapy site, decreases medicine loss in vascular system, saysCohesive force between foley's tube and the medication coat of the bright present invention is bigger.And compared with comparative example 2～4 medicineLoss amount is the most suitable.
In-vitro simulated test
Make target vessel simulator in vitro with pig arteria coronaria blood vessel and carry out in-vitro simulated test.
Respectively by embodiment 1～6 and the PTA foley's tube of comparative example 1～4 preparation insert in simulation target blood vessel, rightSacculus liquid is charged to about 12atm.Transition percentage of elongation (that is: the ratio of balloon diameter and blood vessel diameter) be about 1.10～1.20.Medicine is transported in target tissue in the liquid of 30～60 seconds fills the time, is then exitted by foley's tubeAnd take out from in-vitro simulated test system, collect target vessel tissue.By tissue extraction and HPLC, analyzeThe remaining dose retained on medicament contg in molecular target tissue and sacculus, ibid, result is such as test conditionShown in table 2.
The in-vitro simulated test result of table 2
As shown in Table 2: compared with the medicine-coated balloon that comparative example 1 is not added with carrier, the medicine ball of the present inventionCapsule is during ductal ectasia, and the absorbance of medicine is increased by vascular tissue, compared with comparative example 2～4,The absorbance of medicine is also increased by vascular tissue, and absorbance is relevant with the mass ratio of carrier with active medicine.
Particles from getting loose is tested
In vitro under simulation test (purified water, 37 DEG C, 300ml/min) environment, simulation conveying, expand ballCapsule, eluting balloon surface, the detection microgranule that comes off of medication coat, by particulate instrument detection come off micro-Grain size and number.And by the specific size of microscopic method Observe and measure large scale microgranule (＞ 100 μm)And pattern.
Table 3 in-vitro simulated particles from getting loose test result
As shown in Table 3: compared with the medicine-coated balloon of comparative example 1～4, the medicinal balloon of the present invention is at conduitIn simulaed path process of expansion, particles from getting loose level to get well far away (maximum particle diameter chi compared to comparative example 1～4Very little smaller, each size range particle number is fewer than it).It is hereby understood that the size of particles from getting loose and quantity withThe mass ratio of active medicine and carrier, and the mass ratio between carrier also has significant relationship, implements in the present inventionLess drug particle size and less particles from getting loose quantity can be obtained in the range of example.
Drug release test
Test the loss amount of medicine during sacculus is full.
By embodiment 1～6 and the foley's tube of comparative example 1～4 preparation in healthy miniature pig body, peripheral arterialVasodilation, respectively at 30min, 24h, 7 day, follows up a case by regular visits to after 28 days, takes ball and expands section blood vessel, cleans up,Medicament contg is measured: drug release patterns is as shown in Figure 1 in HPLC.
Fig. 1 result shows: compared with the drug coated balloon catheter (comparative example 1～4) not having carrier,Effect reprinted by the medicinal balloon catheter medicine of the present invention and bioavailability substantially to be got well.FurtherlyBright, the present invention prepares medicinal balloon catheter drug release effect relatively comparative example and substantially to get well.
Safety research is tested
On the femoral artery,superficial of healthy miniature pig left and right, use the medicinal balloon catheter of embodiment 1～6 preparation respectivelyCarry out 1:(1.1～1.2 with the medicinal balloon catheter of comparative example 1～4 preparation) vasodilation, take out remote after 28 daysEnd skeletal muscle tissue, paraffin section prepares (RM2235 type paraffin slicing machine, Leica company of Germany), applicationOptical microscope (DM2500 type micrometering system, Leica company of Germany) and image analysis software are carried outGraphical analysis, observes vascular thrombosis in skeletal muscle, occlusion condition and ischemia, and Skeletal Muscle Cell is downright badEtc. complication.
Result shows: through the medicinal balloon catheter of the present invention after vasodilation, its far-end skeletal muscle groupKnit and do not find any change (Fig. 2～Fig. 7), the most do not find thrombosis, ischemia and necrocytosis etc. alsoSend out disease；The medicinal balloon catheter of comparative example 2～4 is after vasodilation, and ball expands section blood vessel, far-end skeletal muscleTissue does not finds any change (Fig. 9～11), does not finds thrombosis, ischemia and necrocytosis etc. also yetSend out disease；And after vasodilation, it is found that partial occlusion (Fig. 8) through the medicinal balloon catheter of comparative example 1,And periinfarct tissue cell necrosis phenomenon.Illustrating further, it is micro-that the present invention prepares medicinal balloon catheterAbscission is less, safer.