CN100371032C - Re-stricture preventing medicinal sustained releasing bracket and its preparation - Google Patents
Re-stricture preventing medicinal sustained releasing bracket and its preparation Download PDFInfo
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- CN100371032C CN100371032C CNB2004100139222A CN200410013922A CN100371032C CN 100371032 C CN100371032 C CN 100371032C CN B2004100139222 A CNB2004100139222 A CN B2004100139222A CN 200410013922 A CN200410013922 A CN 200410013922A CN 100371032 C CN100371032 C CN 100371032C
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Abstract
The present invention provides a medicine slow-releasing type blood vessel bracket for preventing restenosis, which relates to a medicine slow-releasing type blood vessel bracket for preventing bracket postoperative blood vessel restenosis and a preparing method thereof. The bracket is composed of a tubular net-shaped blood vessel bracket, a porous ceramic film bottom layer attached on the tubular net-shaped blood vessel bracket and a medicine-carrying degradable surface layer attached on the porous ceramic film bottom layer, wherein the tubular net-shaped blood vessel bracket is made of Ni-Ti memory alloy or stainless steel, the porous ceramic film bottom layer is a calcium-phosphorus bioceramic porous film layer prepared on the surface of the blood vessel bracket, and the medicine-carrying degradable surface layer is formed by compounding biodegradable polymers and specific medicines. The preparing method comprises the following steps: (1) firstly selecting suitable materials to process the blood vessel bracket; (2) carrying out surface activation processing to the blood vessel bracket, and then carrying out two-step bionic deposition; (3) soaking the blood vessel whose surface is provided with a ceramic film bottom layer in mixed solution composed of the specific medicines, biodegradable polymers and solvent.
Description
Technical field
The present invention relates to a kind of medicament slow release type intravascular stent and preparation method thereof, particularly a kind of medicament slow release type intravascular stent that prevents vascular restenosis behind the stenting and preparation method thereof belongs to technical field of medical.
Background technology
At present, intravascular stent has been successfully applied to the interventional therapy cardiovascular and peripheral blood vessel blocks pathological changes, and account for more than 80% of this type of disease treatment, but there is the problem of vascular restenosis behind the stenting in this technology, its restenosis incidence rate is about 15-30%, under the situation of vessel diameter less than 3mm, the incidence rate of restenosis is higher.The generation of vascular restenosis and early stage elastical retraction, the thrombosis in treatment operation back, the smooth muscle migration in mid-term, hypertrophy, it is relevant that the blood vessel in late period such as reinvents at many-sided factor.With the intravascular stent that contains the ray material can be in blood vessel radiation treatment with pre-preventing restenosis of blood vessel, but the pollution of ray, protection and complicated operations formality have limited its popularization.Pass through surface modification treatment, the biocompatibility and the anti-thrombogenic capacity that improve intravascular stent are another new developments of intravascular stent, and can suppress element such as nickel, chromium in the metal rack to be separated out and the inflammatory reaction that causes, but DeGrain, the vascular restenosis in the clinical use does not almost reduce.Studies show that multiple medicine can produce the obvious suppression effect to tunica intima and smooth muscle cell, but the systemic administration poor effect.
Make the medicine carrying of intravascular stent own, can reach the effect of local application, this is effectively prevented that vascular restenosis from bringing dawn.But the medicine that the feeder vessels support is selected to carry can be the medicine of inflammation-inhibiting reaction, as dexamethasone etc.; Can be the medicine that suppresses vascular smooth muscle cells migration, as Ba Dimasitaite (Batimastat) etc.; Also can be to suppress cell proliferation in case the medicine of hemostatic tube neointimal hyperplasia, thunderous handkerchief mycin (Rapamycin), paclitaxel (Taxol) etc.Selected medicine must combine with intravascular stent by certain pharmaceutical carrier, and the effect of carrier has 2 points at least: the one, and drug loading, the 2nd, control release rate of drugs.Except influence factors such as pharmaceutical film form, surface area, thickness, the character of carrier material normally determines the key of drug release behavior.Ideal pharmaceutical carrier should have the behavior of medicine constant release, can make blood drug level continue to maintain best curative effect like this.Be as the problem that carrier exists that with the non-degradable material support medicine a large amount of burst releases in the early stage can occur after implanting, and easily makes blood drug level surpass the poisoning limit, the burst size of later stage medicine does not reach the valid density that prevents restenosis again; In addition, if the compatibility of medicine and non-degradable carrier is poor, the diffusion velocity of medicine in carrier is too slow, does not have drug release in the implantation initial stage, and vascular restenosis is inevitable.The employing degradation material is a pharmaceutical carrier, but medicine constant release in the carrier organism degraded makes blood drug level maintain a stable level in a period of time, and this is ideal.And degradable carrier itself also can be degraded to micromolecule or monomer, is finally absorbed or metabolism by body, need not to take out again.
Medicine, degradable polymer supported body normally become solution with medicine, degradable carrier material with solvent with the bonded mode of intravascular stent, adopt solution spraying or solution dipping method to obtain the degradable medicaments layer of band medicine on the intravascular stent surface then.Chinese patent ZL00137207.6 " a kind of intravascular stent with anti-restenosis coating layer ", Chinese patent ZL02100011.5 " a kind of coronary artery skeleton medicinal coating of preventing restenosis of blood vessel ", Chinese patent ZL01142641.1 " medicine eluted cardiovascular frame and preparation method thereof " adopt said method to obtain the intravascular stent of band coating of degradable medicaments respectively.Problem is; such coating of degradable medicaments is slick metal or the high molecular polymer rack surface that directly is coated in through polishing; just not ideal enough with the adhesion of support itself; particularly intravascular stent is after implantation; the surface drug carrier begins degraded; it is loose that the structure of carrier can become; water content improves; carrier begins to disintegrate very soon; further reduce the adhesion of carrier and support itself; add the slick surface of pipe network shape intravascular stent to loose carrier without any protection; carrier is easy to come off, and shortens the useful effect life-span of pharmaceutical film.
Summary of the invention
Technical problem: the objective of the invention is deficiency at present medicine carrying intravascular stent, a kind of adhesion that can improve medicine layer and support is provided, can prolongs the cycle of the lasting release of medicine carrying degradable surface layer constant speed and the anti-restenosis medicament slow release type intravascular stent in useful effect life-span and preparation method thereof.
Technical scheme: the present invention is realized by the following technical programs:
Anti-restenosis medicament slow release type intravascular stent of the present invention, by pipe network shape intravascular stent, attached to the porous ceramic film bottom on the pipe network shape intravascular stent, form attached to the medicine carrying degradable surface layer on the porous ceramic film bottom, pipe network shape intravascular stent is made by Ultimum Ti or rustless steel; The porous ceramic film bottom is the calcium phosphate bioceramic porous film layer in the intravascular stent surface preparation; Medicine carrying degradable surface layer is composited by biodegradable polymer and certain drug.
The porous ceramic film bottom of being addressed has double-decker, is made up of calcium phosphate amorphous layer that contacts with intravascular stent and the porous osteolith stone crystalline phase layer that covers on the calcium phosphate amorphous layer, and wherein, calcium phosphate amorphous layer thickness is 1-10 μ m; The osteoid apatite layer thickness is 10-100 μ m.
The biodegradable polymer of being addressed comprises Acetic acid, hydroxy-, bimol. cyclic ester (glycolic acid, GA), L-lactide (L-lactic acid, LLA), 6-caprolactone (caprolactone, a kind of in homopolymer CL) or the copolymer and with the copolymer and the biodegradable heparinization macromolecule (heparinizedpolymer) of multifunctional amino acid.
The certain drug of being addressed comprises one or more the mixture in heparin sodium, rapamycin (Rapamycin), paclitaxel (Taxol), losartan (losartan), dactinomycin, the ciclosporin A.
The preparation method of anti-restenosis medicament slow release type intravascular stent of the present invention is:
1) at first selects the good intravascular stent of suitable materials processing for use;
2) intravascular stent is carried out surface activation process, go on foot bionical deposition processes by two then, obtain the porous ceramic film bottom of forming successively by fine and close calcium phosphate amorphous layer and porous osteolith stone crystalline phase layer on the intravascular stent surface;
3) surface is had the intravascular stent of porous ceramic film bottom be immersed in to have certain drug, in the mixed solution of biodegradable polymer and solvent composition, soak time is 0.5-2 minute, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 1-100 μ m;
4) take out support at last, under the room temperature vacuum dry 24-72 hour, can get anti-restenosis medicament slow release type intravascular stent of the present invention.
The intravascular stent that reaches described in the above-mentioned preparation method is mainly used in the obstruction pathological changes of coronary artery, cerebral arteries, pulmonary artery, renal artery, ventral aorta, thoracic aorta and other blood vessels, its version can be any or form that other is new of the prior art, and the present invention repeats no more.
Usually the calcium phosphate bioceramic coating adopts the plasma spraying method preparation, but this method is not suitable for the thin pipe network shape intravascular stent of complex-shaped, little and wall, and its pyroprocess is easy to change the performance of intravascular stent, particularly can change the memory effect and the super-elasticity of recalled nitinol alloy stent.The present invention's preparation has the bionic method of above-mentioned special double-deck porous ceramic film bottom to be finished under lower temperature, and the intravascular stent substrate performance is not had influence, is specially adapted to the Ultimum Ti intravascular stent, and need not special equipment.
It is the ebullient H of 10-60% that described surface activation process adopts concentration
2O
2Aqueous solution, the processing time is 10-90 minute, take out flushing after, be immersed in temperature again and be 30-80 ℃, concentration and be in the NaOH aqueous solution of 1-10M 6-48 hour.
Described bionical deposition processes of two steps comprises the steps:
1) the bionical calcifying solution A of preparation: bionical calcifying solution A presses the active constituent content of ionometer:
Sodium ion 500-850mM, magnesium ion 4.5-6.0mM, calcium ion 10.0-13.5mM, chloride ion 500-800mM, phosphoric acid hydrogen radical ion 4.0-6.0mM, bicarbonate ion 15.0-30.0mM;
2) the bionical calcifying solution B of preparation: bionical calcifying solution B presses the active constituent content of ionometer:
Sodium ion 100.0-180.0mM, potassium ion 4.0-5.5mM, magnesium ion 3.0-4.5mM, calcium ion 2.0-3.5mM, chloride ion 80.0-150.0mM, phosphoric acid hydrogen radical ion 0.5-1.5mM, bicarbonate ion 6.5-12.0mM, sulfate ion 0.5-1.0mM;
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is among the 10-30 ℃ of bionical calcifying solution A, under stirring condition, take out after bionical deposition processes 12-36 hour, clean, drying, the intravascular stent surface obtains the calcium phosphate amorphous layer of thickness 1-10 μ m;
4) the bionical deposition processes of porous osteolith stone crystalline phase layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is among the 30-50 ℃ of bionical calcifying solution B, took out in bionical deposition processes 12-144 hour, clean, drying, further deposit thickness is 10-100 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous layer.
The solvent that the preparation of medicine carrying degradable surface layer is adopted can be acetone, dichloromethane, chloroform, oxolane etc.In order to allow the mixed liquor of medicine, degradation material and solvent fully permeate in the surface micropore of porous ceramic film bottom, medication coat adopts dipping method.Support Chinese medicine content can be controlled by the concentration of mixed liquor Chinese medicine and the coating number of times of coating.
Beneficial effect: different with traditional medicine carrying intravascular stent is, anti-restenosis medicament slow release type intravascular stent of the present invention has increased one deck and has had special double-deck porous ceramic film bottom between intravascular stent and degradable medicaments layer, this porous ceramic film bottom can suppress that element such as nickel, chromium in the metal rack is separated out and the inflammatory reaction that causes, improves the biocompatibility and the corrosion resistance of support; Simultaneously again can and medicine carrying degradable surface layer between form firm mechanical snap, improved the adhesion of medicine layer and support, can prolong the cycle and the useful effect life-span of the lasting release of medicine carrying degradable surface layer constant speed.Anti-restenosis medicament slow release type intravascular stent can effectively slow down even eliminate the generation of vascular restenosis by the biodegradation of surface drug carrier and stable lasting release of anti-restenosis function medicament.
Different with at present common medicine carrying intravascular stent is, this anti-restenosis medicament slow release type intravascular stent has increased one deck and has had special double-deck porous ceramic film bottom between intravascular stent and degradable medicaments layer, this porous ceramic film bottom itself is that the good calcium phosphate bioceramic of biocompatibility is formed, with support bond strength height, and stable performance in physiological environment.In the porous ceramic film bottom, the fine and close calcium phosphate amorphous layer that contacts with intravascular stent can suppress that element such as nickel, chromium in the metal rack is separated out and the inflammatory reaction that causes, improves the biocompatibility and the corrosion resistance of support; The osteoid apatite crystalline phase layer porous that contacts with medicine carrying degradable surface layer, with solution spraying or solution dipping method when this porous ceramic film bottom surface prepares medicine carrying degradable surface layer, the solution that contains medicine and degradable medicaments carrier material deeply is penetrated in the porous osteoid apatite crystalline phase layer by capillarity, the result makes the firm mechanical snap of formation between medicine carrying degradable surface layer and the porous ceramic film bottom, improve the adhesion of medicine layer and support, can prolong cycle and useful effect life-span that medicine carrying degradable surface layer constant speed continues release.Its medicine carrying degradable surface layer is composited as one or more medicines in heparin sodium, rapamycin (Rapamycin), paclitaxel (Taxol), losartan (losartan), dactinomycin, the ciclosporin A by the medicine of biodegradable polymer carrier and anti-restenosis function.Biodegradation by pharmaceutical carrier and anti-restenosis function medicament stablize persistent release, can effectively slow down even eliminate the generation of vascular restenosis, be mainly used in the obstruction pathological changes of coronary artery, cerebral arteries, pulmonary artery, renal artery, ventral aorta, thoracic aorta and other blood vessels
The instantiation mode
Embodiment 1
Anti-restenosis medicament slow release type Ultimum Ti intravascular stent is by pipe network shape intravascular stent, attached to the porous ceramic film bottom on the pipe network shape intravascular stent, form attached to the medicine carrying degradable surface layer on the porous ceramic film bottom, and pipe network shape intravascular stent is made by Ultimum Ti or rustless steel; The porous ceramic film bottom is the calcium phosphate bioceramic porous film layer in the intravascular stent surface preparation; Medicine carrying degradable surface layer is composited by biodegradable polymer and certain drug.
The porous ceramic film bottom is that 1.5-2.0 μ m, fine and close calcium phosphate amorphous layer and thickness are that 15-20 μ m, porous osteolith stone crystalline phase layer are formed by thickness; Medicine carrying degradable surface layer is made up of biodegradable heparinization macromolecule and anti-restenosis medicaments paclitaxel, this support is after operation is implanted, and heparin and paclitaxel discharge continually and steadily, can prevent the generation of tampon, promote the healing of injured blood vessel wall, effectively eliminate the generation of vascular restenosis.Its preparation process is as follows:
1) at first processes intravascular stent by the laser scoring method with Ultimum Ti tubing;
2) intravascular stent surface activation process: after the Ultimum Ti intravascular stent used acetone, 70% ethanol, distilled water ultrasonic cleaning successively, adopting concentration was 20% ebullient H
2O
2Aqueous solution is handled, and the processing time is 45 minutes, take out flushing after, be immersed in temperature again and be in 30-50 ℃, the NaOH aqueous solution of 4M after 24-36 hour, take out distilled water flushing, 70 ℃ of dryings.
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is that bionical calcifying solution A is among 20 ℃ of bionical calcifying solution A by the active constituent content of ionometer: sodium ion 610mM, magnesium ion 4.5mM, calcium ion 12.5mM, chloride ion 610.0mM, phosphoric acid hydrogen radical ion 5.0mM, bicarbonate ion 18.0mM.Bionical calcifying solution A employing magnetic stirring apparatus stirs, takes out after bionical deposition processes 12-24 hour, and the distilled water ultrasonic cleaning, drying at room temperature, the intravascular stent surface obtains the calcium phosphate amorphous layer of thickness 1.5-2.0 μ m, densification.
4) the bionical deposition processes of osteoid apatite crystalline phase layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is that bionical calcifying solution B presses the active constituent content of ionometer among 30 ℃ of bionical calcifying solution B: sodium ion 120.0mM, potassium ion 5.0mM, magnesium ion 3.5mM, calcium ion 2.5mM, chloride ion 120.0mM, phosphoric acid hydrogen radical ion 1.0mM, bicarbonate ion 11.0mM, sulfate ion 0.5mM.Took out in bionical deposition processes 12-36 hour, the distilled water ultrasonic cleaning, drying at room temperature, further deposit thickness is 15-20 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous underlayer.
5) 4 gram degradable heparinizations poly-(lactic-co-glycolic acid-aminoacid) and the anti-restenosis medicaments paclitaxel of 10 grams are dissolved in the acetone of 20ml, again the surface there is the Ultimum Ti intravascular stent of porous ceramic film bottom to be immersed in this solution, soak time is 1.5 minutes, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 30-50 μ m;
6) take out support at last, under the room temperature vacuum dry 24-72 hour, standby.
Embodiment 2
Anti-restenosis medicament slow release type Ultimum Ti intravascular stent, form by Ultimum Ti intravascular stent, porous ceramic film bottom and medicine carrying degradable surface layer, promptly by pipe network shape intravascular stent, attached to the porous ceramic film bottom on the pipe network shape intravascular stent, form attached to the medicine carrying degradable surface layer on the porous ceramic film bottom, pipe network shape intravascular stent is made by Ultimum Ti or rustless steel; The porous ceramic film bottom is the calcium phosphate bioceramic porous film layer in the intravascular stent surface preparation; Medicine carrying degradable surface layer is composited by biodegradable polymer and certain drug.
The porous ceramic film bottom is that 1.5-2.0 μ m, fine and close calcium phosphate amorphous layer and thickness are that 15-20 μ m, porous osteolith stone crystalline phase layer are formed by thickness; Medicine carrying degradable surface layer is made up of poly-L-lactide and anti-restenosis medicaments rapamycin, and this support is after operation is implanted, and rapamycin discharges continually and steadily, can promote the healing of injured blood vessel wall, effectively eliminates the generation of vascular restenosis.Its preparation process is as follows:
1) at first processes intravascular stent by the laser scoring method with Ultimum Ti tubing;
2) intravascular stent surface activation process: after the Ultimum Ti intravascular stent used acetone, 70% ethanol, distilled water ultrasonic cleaning successively, adopting concentration was 20% ebullient H
2O
2Aqueous solution is handled, and the processing time is 45 minutes, take out flushing after, be immersed in temperature again and be in 30-50 ℃, the NaOH aqueous solution of 4M after 24-36 hour, take out distilled water flushing, 70 ℃ of dryings.
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is that bionical calcifying solution A is among 20 ℃ of bionical calcifying solution A by the active constituent content of ionometer: sodium ion 610mM, magnesium ion 4.5mM, calcium ion 12.5mM, chloride ion 610.0mM, phosphoric acid hydrogen radical ion 5.0mM, bicarbonate ion 18.0mM.Bionical calcifying solution A employing magnetic stirring apparatus stirs, takes out after bionical deposition processes 12-24 hour, and the distilled water ultrasonic cleaning, drying at room temperature, the intravascular stent surface obtains the calcium phosphate amorphous layer of thickness 1.5-2.0 μ m, densification.
4) the bionical deposition processes of osteoid apatite crystalline phase surface layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is that bionical calcifying solution B presses the active constituent content of ionometer among 30 ℃ of bionical calcifying solution B: sodium ion 120.0mM, potassium ion 5.0mM, magnesium ion 3.5mM, calcium ion 2.5mM, chloride ion 120.0mM, phosphoric acid hydrogen radical ion 1.0mM, bicarbonate ion 11.0mM, sulfate ion 0.5mM.Took out in bionical deposition processes 12-36 hour, the distilled water ultrasonic cleaning, drying at room temperature, further deposit thickness is 15-20 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous underlayer.
5) 10 gram degradable poly L-lactides and the anti-restenosis medicaments rapamycin of 5 grams are dissolved in the chloroform of 20ml, again the surface there is the Ultimum Ti intravascular stent of porous ceramic film bottom to be immersed in this solution, soak time is 1.5 minutes, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 30-50 μ m;
6) take out support at last, under the room temperature vacuum dry 24-72 hour, standby.
Embodiment 3
A kind of anti-restenosis medicament slow release type rustless steel intravascular stent is made up of rustless steel intravascular stent, porous ceramic film bottom and medicine carrying degradable surface layer.The porous ceramic film bottom is that 7.5-9.0 μ m, fine and close calcium phosphate amorphous layer and thickness are that 40-50 μ m, porous osteolith stone crystalline phase layer are formed by thickness; Medicine carrying degradable surface layer is made up of biodegradable heparinization macromolecule and anti-restenosis medicaments paclitaxel, this support is after operation is implanted, and heparin and paclitaxel discharge continually and steadily, can prevent the generation of tampon, promote the healing of injured blood vessel wall, effectively eliminate the generation of vascular restenosis.Its preparation process is as follows:
1) at first processes intravascular stent by the laser scoring method with stainless steel pipe;
2) intravascular stent surface activation process: after the rustless steel intravascular stent used acetone, 70% ethanol, distilled water ultrasonic cleaning successively, adopting concentration was 50% ebullient H
2O
2Aqueous solution is handled, and the processing time is 60 minutes, take out flushing after, be immersed in temperature again and be 30-40 ℃, concentration and be in the NaOH aqueous solution of 2M 12-24 hour.
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is that bionical calcifying solution A is among 30 ℃ of bionical calcifying solution A by the active constituent content of ionometer: sodium ion 610mM, magnesium ion 4.5mM, calcium ion 12.5mM, chloride ion 610.0mM, phosphoric acid hydrogen radical ion 5.0mM, bicarbonate ion 18.0mM.Bionical calcifying solution A employing magnetic stirring apparatus stirs, takes out after bionical deposition processes 30-36 hour, and the distilled water ultrasonic cleaning, drying at room temperature, the intravascular stent surface obtains the calcium phosphate amorphous layer of thickness 7.5-9.0 μ m, densification.
4) the bionical deposition processes of osteoid apatite crystalline phase layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is that bionical calcifying solution B presses the active constituent content of ionometer among 50 ℃ of molten B of bionical calcification: sodium ion 120.0mM, potassium ion 5.0mM, magnesium ion 3.5mM, calcium ion 2.5mM, chloride ion 120.0mM, phosphoric acid hydrogen radical ion 1.0mM, bicarbonate ion 11.0mM, sulfate ion 0.5mM.Took out in bionical deposition processes 64-72 hour, the distilled water ultrasonic cleaning, drying at room temperature, further deposit thickness is 40-50 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous layer.
5) 4 gram degradable heparinizations poly-(lactic-co-glycolic acid-aminoacid) and the anti-restenosis medicaments paclitaxel of 10 grams are dissolved in the acetone of 20ml, again the surface there is the rustless steel intravascular stent of porous ceramic film bottom to be immersed in this solution, soak time is 1.5 minutes, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 30-50 μ m;
6) take out support at last, under the room temperature vacuum dry 24-72 hour, standby.
Embodiment 4
Anti-restenosis medicament slow release type Ultimum Ti intravascular stent is made up of Ultimum Ti intravascular stent, porous ceramic film bottom and medicine carrying degradable surface layer.The porous ceramic film bottom is that 7.5-9.0 μ m, fine and close calcium phosphate amorphous layer and thickness are that 60-80 μ m, porous osteolith stone crystalline phase layer are formed by thickness; Medicine carrying degradable surface layer is made up of biodegradable heparinization macromolecule and anti-restenosis medicaments paclitaxel, this support is after operation is implanted, and heparin and paclitaxel discharge continually and steadily, can prevent the generation of tampon, promote the healing of injured blood vessel wall, effectively eliminate the generation of vascular restenosis.Its preparation process is as follows:
1) at first processes intravascular stent by the laser scoring method with Ultimum Ti tubing;
2) intravascular stent surface activation process: after the Ultimum Ti intravascular stent used acetone, 70% ethanol, distilled water ultrasonic cleaning successively, adopting concentration was 30% ebullient H
2O
2Aqueous solution is handled, and the processing time is 90 minutes, take out flushing after, be immersed in temperature again and be 60-70 ℃, concentration and be in the NaOH aqueous solution of 8M 24-36 hour, take out distilled water flushing, 70 ℃ of dryings.
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is that bionical calcifying solution A is among 30 ℃ of bionical calcifying solution A by the active constituent content of ionometer: sodium ion 610mM, magnesium ion 4.5mM, calcium ion 12.5mM, chloride ion 610.0mM, phosphoric acid hydrogen radical ion 5.0mM, bicarbonate ion 18.0mM.Bionical calcifying solution A employing magnetic stirring apparatus stirs, takes out after bionical deposition processes 24-36 hour, and the distilled water ultrasonic cleaning, drying at room temperature, the tubular bone internal fixator surface obtains the calcium phosphate amorphous layer of thickness 7.5-9.0 μ m, densification.
4) the bionical deposition processes of osteoid apatite crystalline phase layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is that bionical calcifying solution B presses the active constituent content of ionometer among 50 ℃ of molten B of bionical calcification: sodium ion 120.0mM, potassium ion 5.0mM, magnesium ion 3.5mM, calcium ion 2.5mM, chloride ion 120.0mM, phosphoric acid hydrogen radical ion 1.0mM, bicarbonate ion 11.0mM, sulfate ion 0.5mM.Took out in bionical deposition processes 72-144 hour, the distilled water ultrasonic cleaning, drying at room temperature, further deposit thickness is 60-80 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous layer.
5) 4 gram degradable heparinizations poly-(lactic-co-glycolic acid-aminoacid) and the anti-restenosis medicaments paclitaxel of 10 grams are dissolved in the acetone of 20ml, again the surface there is the Ultimum Ti intravascular stent of porous ceramic film bottom to be immersed in this solution, soak time is 1.5 minutes, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 20-30 μ m;
6) take out support at last, under the room temperature vacuum dry 24-72 hour, standby.
Embodiment 5
Anti-restenosis medicament slow release type Ultimum Ti intravascular stent is made up of Ultimum Ti intravascular stent, porous ceramic film bottom and medicine carrying degradable surface layer.The porous ceramic film bottom is that 7.5-9.0 μ m, fine and close calcium phosphate amorphous layer and thickness are that 60-80 μ m, porous osteolith stone crystalline phase layer are formed by thickness; Medicine carrying degradable surface layer is made up of poly-L-lactide and anti-restenosis medicaments rapamycin, and this support is after operation is implanted, and rapamycin discharges continually and steadily, can promote the healing of injured blood vessel wall, effectively eliminates the generation of vascular restenosis.Its preparation process is as follows:
1) at first processes intravascular stent by the laser scoring method with Ultimum Ti tubing;
2) intravascular stent surface activation process: after the Ultimum Ti intravascular stent used acetone, 70% ethanol, distilled water ultrasonic cleaning successively, adopting concentration was 30% ebullient H
2O
2Aqueous solution is handled, and the processing time is 90 minutes, take out flushing after, be immersed in temperature again and be 60-70 ℃, concentration and be in the NaOH aqueous solution of 8M 24-36 hour, take out distilled water flushing, 70 ℃ of dryings.
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is that bionical calcifying solution A is among 30 ℃ of bionical calcifying solution A by the active constituent content of ionometer: sodium ion 610mM, magnesium ion 4.5mM, calcium ion 12.5mM, chloride ion 610.0mM, phosphoric acid hydrogen radical ion 5.0mM, bicarbonate ion 18.0mM.Bionical calcifying solution A employing magnetic stirring apparatus stirs, takes out after bionical deposition processes 24-36 hour, and the distilled water ultrasonic cleaning, drying at room temperature, the tubular bone internal fixator surface obtains the calcium phosphate amorphous layer of thickness 7.5-9.0 μ m, densification.
4) the bionical deposition processes of osteoid apatite crystalline phase layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is that bionical calcifying solution B presses the active constituent content of ionometer among 50 ℃ of molten B of bionical calcification: sodium ion 120.0mM, potassium ion 5.0mM, magnesium ion 3.5mM, calcium ion 2.5mM, chloride ion 120.0mM, phosphoric acid hydrogen radical ion 1.0mM, bicarbonate ion 11.0mM, sulfate ion 0.5mM.Took out in bionical deposition processes 72-144 hour, the distilled water ultrasonic cleaning, drying at room temperature, further deposit thickness is 60-80 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous layer.
5) 10 gram degradable poly L-lactides and the anti-restenosis medicaments rapamycin of 5 grams are dissolved in the chloroform of 20ml, again the surface there is the Ultimum Ti intravascular stent of porous ceramic film bottom to be immersed in this solution, soak time is 1.5 minutes, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 20-30 μ m;
6) take out support at last, under the room temperature vacuum dry 24-72 hour, standby.
Obviously, the above embodiment of the present invention only is in order to clearly demonstrate example of the present invention, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field; also can make other changes in different forms on the basis of the above description; here need not also can't give all embodiments exhaustive, and these belong to conspicuous variation or the change that spirit of the present invention amplified out and still are in protection scope of the present invention.
Claims (5)
1. anti-restenosis medicament slow release type intravascular stent, it is characterized in that this support by pipe network shape intravascular stent, attached to the porous ceramic film bottom on the pipe network shape intravascular stent, form attached to the medicine carrying degradable surface layer on the porous ceramic film bottom, pipe network shape intravascular stent is made by Ultimum Ti or rustless steel; The porous ceramic film bottom is the calcium phosphate bioceramic porous film layer in the intravascular stent surface preparation; Medicine carrying degradable surface layer is composited by biodegradable polymer and described anti-restenosis medicine; The porous ceramic film bottom of being addressed has double-decker, is made up of calcium phosphate amorphous layer that contacts with intravascular stent and the porous osteolith stone crystalline phase layer that covers on the calcium phosphate amorphous layer, and wherein, calcium phosphate amorphous layer thickness is 1-10 μ m; The osteoid apatite layer thickness is 10-100 μ m;
The step of preparation is:
1) at first processes intravascular stent;
2) intravascular stent is carried out surface activation process, go on foot bionical deposition processes by two then, obtain the porous ceramic film bottom of forming successively by fine and close calcium phosphate amorphous layer and porous osteolith stone crystalline phase layer on the intravascular stent surface;
3) surface there is the intravascular stent of porous ceramic film bottom be immersed in the mixed solution with described anti-restenosis medicine, biodegradable polymer and solvent composition, soak time is 0.5-2 minute, can repeatedly soak, take out support between per twice immersion, and in air, vaporing away solvent, the THICKNESS CONTROL of medicine carrying degradable surface layer is between 1-100 μ m;
4) take out support at last, under the room temperature vacuum dry 24-72 hour, obtain anti-restenosis medicament slow release type intravascular stent.
2. anti-restenosis medicament slow release type intravascular stent as claimed in claim 1, it is characterized in that, the biodegradable polymer of being addressed is biodegradable heparinization macromolecule, or be a kind of in the homopolymer of Acetic acid, hydroxy-, bimol. cyclic ester, L-lactide, three kinds of materials of 6-caprolactone or the copolymer and with the copolymer of multifunctional amino acid.
3. anti-restenosis medicament slow release type intravascular stent as claimed in claim 1 is characterized in that, the certain drug of being addressed comprises one or more the mixture in heparin sodium, rapamycin, losartan, dactinomycin, the ciclosporin A.
4. anti-restenosis medicament slow release type intravascular stent as claimed in claim 1 is characterized in that it is the ebullient H of 10%-60% that surface activation process adopts concentration
2O
2Aqueous solution, the processing time is 10-90 minute, take out flushing after, be immersed in temperature again and be 30-80 ℃, concentration and be in the NaOH aqueous solution of 1-10M 6-48 hour.
5. anti-restenosis medicament slow release type intravascular stent as claimed in claim 1 is characterized in that bionical deposition processes of two steps comprises the steps:
1) the bionical calcifying solution A of preparation: bionical calcifying solution A presses the active constituent content of ionometer:
Sodium ion 500-850mM, magnesium ion 4.5-6.0mM, calcium ion 10.0-13.5mM, chloride ion 500-800mM, phosphoric acid hydrogen radical ion 4.0-6.0mM, bicarbonate ion 15.0-30.0mM;
2) the bionical calcifying solution B of preparation: bionical calcifying solution B presses the active constituent content of ionometer:
Sodium ion 100.0-180.0mM, potassium ion 4.0-5.5mM, magnesium ion 3.0-4.5mM, calcium ion 2.0-3.5mM, chloride ion 80.0-150.0mM, phosphoric acid hydrogen radical ion 0.5-1.5mM, bicarbonate ion 6.5-12.0mM, sulfate ion 0.5-1.0mM;
3) the bionical deposition processes of calcium phosphate amorphous layer: the intravascular stent immersion temperature that surface activation process is crossed is among the 10-30 ℃ of bionical calcifying solution A, under stirring condition, take out after bionical deposition processes 12-36 hour, clean, drying, the intravascular stent surface obtains the calcium phosphate amorphous layer of thickness 1-10 μ m;
4) the bionical deposition processes of porous osteolith stone crystalline phase layer: the intravascular stent immersion temperature that the surface is had the calcium phosphate amorphous layer is among the 30-50 ℃ of bionical calcifying solution B, took out in bionical deposition processes 12-144 hour, clean, drying, further deposit thickness is 10-100 μ m, porous osteoid apatite crystalline phase layer on the intravascular stent surface phosphoric acid calcium amorphous layer.
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| CNB2004100139222A CN100371032C (en) | 2004-01-16 | 2004-01-16 | Re-stricture preventing medicinal sustained releasing bracket and its preparation |
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| CN100435756C (en) * | 2005-01-31 | 2008-11-26 | 上海市第一人民医院 | Arsenic trioxide control release elution stent |
| EP1865882A4 (en) * | 2005-04-05 | 2013-05-08 | Elixir Medical Corp | Degradable implantable medical devices |
| CN100381183C (en) * | 2005-10-13 | 2008-04-16 | 上海交通大学 | Method for preparing digestive tract stent carried with medicines of micro-/nanometer balls |
| CN101406713B (en) * | 2007-10-12 | 2012-09-19 | 微创医疗器械(上海)有限公司 | Artificial blood vessel bracket and preparation method thereof |
| CN101185779B (en) * | 2007-12-19 | 2010-06-02 | 上海赢生医疗科技有限公司 | Method for preparing medicine sustained-releasing bracket |
| CN102470196A (en) * | 2009-08-27 | 2012-05-23 | 泰尔茂株式会社 | Medical device for drug delivery |
| CN101785880B (en) * | 2009-12-31 | 2013-05-29 | 东南大学 | Blood vessel bracket utilizing titanium oxide nanotube to load medicine |
| CN109394399A (en) * | 2018-10-22 | 2019-03-01 | 乐畅医疗器械(上海)有限公司 | A kind of medicine slow release stent |
| CN113041410A (en) * | 2019-12-27 | 2021-06-29 | 上海微创医疗器械（集团）有限公司 | Medicine-carrying implantation medical apparatus and preparation method thereof |
| CN111529150B (en) * | 2020-04-28 | 2023-02-24 | 东南大学苏州医疗器械研究院 | Sinus duct stent and preparation method thereof |
| CN116687634B (en) * | 2023-07-24 | 2023-11-03 | 上海宏普医疗器械有限公司 | Puncture tectorial membrane support that ultrasonic wave was carried down |
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| US5531735A (en) * | 1994-09-27 | 1996-07-02 | Hercules Incorporated | Medical devices containing triggerable disintegration agents |
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| CN1413594A (en) * | 2002-08-07 | 2003-04-30 | 杨巍 | Medicine for prevention and curing reangiostenosis |
| CN1429547A (en) * | 2002-01-04 | 2003-07-16 | 中国科学院化学研究所 | Coronary artery skeleton medicinal coating for preventing restenosis of blood vessel |
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| US5531735A (en) * | 1994-09-27 | 1996-07-02 | Hercules Incorporated | Medical devices containing triggerable disintegration agents |
| CN1355005A (en) * | 2001-12-13 | 2002-06-26 | 华东理工大学 | Medicine eluted cardiovascular frame and its preparing process |
| CN1429547A (en) * | 2002-01-04 | 2003-07-16 | 中国科学院化学研究所 | Coronary artery skeleton medicinal coating for preventing restenosis of blood vessel |
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| CN1413594A (en) * | 2002-08-07 | 2003-04-30 | 杨巍 | Medicine for prevention and curing reangiostenosis |
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