CN111588914A - Medicine coating for interventional or implanted medical apparatus and preparation method thereof - Google Patents

Abstract

The invention relates to a medicine coating of an interventional or implanted medical device and a preparation method thereof. The core of the drug coating of the interventional or implantable medical device is a grafted drug copolymer. The preparation method comprises the steps of under the action of a catalyst, covalently connecting an active drug and a hydrophilic substrate to prepare a grafted drug copolymer, dissolving and dispersing the grafted drug copolymer by a solvent, coating the surface of an interventional or implanted medical device with the grafted drug copolymer, and drying the grafted drug copolymer to obtain the grafted drug copolymer. The covalent attachment can enhance the homogeneity of the drug and the matrix coating, improve the hydrophilic and hydrophobic balance of the drug and the adhesion-release balance of the drug coating to the surface of the medical device, and enhance the efficiency of drug absorption by tissues, penetration in interstitial tissues, and uptake by cells. The invention enhances the homogeneity, uniformity and stability of the medical appliance drug coating, reduces drug loading, reduces drug loss, reduces drug entering blood circulation, and increases the absorption of the drug in target tissues and cells, thereby reducing toxicity and improving drug efficacy.

Description

Medicine coating for interventional or implanted medical apparatus and preparation method thereof

Technical Field

The invention belongs to the field of medical instruments, and particularly relates to a drug coating of an interventional or implanted medical instrument and a preparation method thereof.

Background

Coronary atherosclerotic heart disease is a heart disease caused by coronary artery angiogenesis atherosclerotic lesions, resulting in stenosis or obstruction of the lumen of a blood vessel, resulting in myocardial ischemia, hypoxia or necrosis, and is often referred to as "coronary heart disease". The main means for treating coronary heart disease is Percutaneous Coronary Intervention (PCI), i.e. opening and blocking the lumen to realize revascularization.

In the last 70 th century, human beings firstly performed Percutaneous Transluminal Coronary Angioplasty (PTCA), and the stenosis of coronary arteries was dilated by a pure balloon, which began to intervene in the treatment of coronary heart disease. Although PTCA can eliminate vascular stenosis instantly, severe early vascular recoil and intermediate and distant vascular restenosis occur, with restenosis rates as high as 30% -50%. Bare Metal Stents (BMS) are the second milestone of interventional therapy, eliminating immediate vascular stenosis while greatly reducing the incidence of acute reocclusion, but the target vascular restenosis rate is still as high as 30%. Drug Eluting Stents (DES) are the third milestone of interventional therapy to reduce restenosis rates to about 5%, essentially meeting clinical requirements. However, once in-stent restenosis occurs, it is difficult to manage and the restenosis rate after implantation of the new DES is as high as 43%. Also, the introduction of drugs and polymers can induce delayed endothelialization and the risk of late thrombosis. In addition, it still fails to provide satisfactory therapeutic effects on small vessel lesions, bifurcation lesions, long lesions, disseminated lesions, and the like. The metal stent is retained in the coronary artery for a long time after being implanted, and restricts the normal relaxation of the coronary artery. With the advancement of technology, Bioabsorbable Vascular Stents (BVS) were introduced. BVS gradually degrades while providing good vascular support in the early stages, allowing the coronary arteries to return to a normal diastolic state. BVS, however, does not perform as well as the vessel support during implantation as DES, and the continued degradation of the polymer and the stent leads to severe inflammatory reactions and thrombosis.

The drug-coated balloon (DCB) is characterized in that drugs are added on the surface of the balloon, and when the balloon is conveyed to a target lesion, the drug is released to a target blood vessel by temporarily expanding the balloon, so that the stenosis or occlusion of the blood vessel is inhibited. The advent of DCB may provide another fourth generation revolutionary solution beyond BVS. DCB has good clinical treatment effect on stent stenosis, small vessel lesion, bifurcation lesion, long lesion, diffusion lesion and the like, can avoid damaging blood vessels, and does not influence the normal relaxation of coronary arteries.

The drug balloon of beransertplex germany using patent technology (WO 02076509 patent family and WO2004028610 patent family) is currently a widely used DCB in clinical practice. The DCB uses the Youyuwei display (iopromide injection) as a hydrophilic matrix and is mixed with paclitaxel to prepare a medicine coating. The drug coating of DCB has significant drawbacks. Firstly, the incompatibility of the solubility of iopromide and paclitaxel leads to poor integrity, homogeneity and uniformity of the coating, and easy shedding. Secondly, the iopromide injection is mixed with paclitaxel, so that hydrophobic drugs cannot be effectively carried into tissues and cells, and the vascular absorption is only 5% -20%; large amounts of drugs enter the blood circulation and may cause systemic toxicity. Thirdly, the iopromide injection has complex components, and auxiliary materials can cause local vascular irritation or inflammation.

The patent of invention granted under publication No. CN101610798B uses water-soluble additives such as polyethylene glycol fatty acid ester and surfactant to mix hydrophobic drugs such as paclitaxel with hydrogen bond and van der waals force to prepare the balloon drug coating. However, hydrogen bonds and van der waals forces are weak acting forces, and the defects that hydrophobic drugs cannot be effectively carried into tissues and cells exist, and the use of polyethylene glycol fatty acid ester and surfactant can cause local aggregation of lipoprotein and macrophage at the acting part, so that inflammatory factors are released, and local inflammation or thrombus is induced.

The invention patent application with application publication number CN102657900A discloses a drug balloon based on hydrogen bond effect and a coating method thereof, and the core technology is that the balloon surface is provided with hydrophilic groups by adopting methods of plasma, ozone, ray, illumination and the like, and then the balloon is combined with a hydrophilic group solution containing drugs through hydrogen bond. The main drawback of this invention is that treatment of the balloon with plasma, ozone, radiation, and light may compromise the burst pressure, compliance, fatigue, and aging properties of the balloon, resulting in rupture or failure of the balloon to retract when inflated.

The invention patent application with application publication number CN104984412A discloses a method for coating and modifying a balloon, then immersing the modified balloon into a paclitaxel coating solution, and performing freeze drying to crystallize paclitaxel on the surface of the balloon to form a drug coating. The method has complex preparation process, and multiple freeze drying is needed in the coating process; the paclitaxel crystal coating obtained by the dip coating process is uneven and is easy to fall off; and in the preparation process, the organic solvent is not easy to volatilize, so that high solvent residue is caused, and toxicity is possibly generated.

The invention patent of the publication No. CN103611212B is to coat the drug crystal on the surface of the modified balloon by brushing or rolling to prepare the drug balloon. The balloon surface prepared by the method has uneven drug coating, large particles and easy shedding, and the drug is not easy to be absorbed by tissues.

The invention patent of the publication No. CN103736154B uses organic acid salt and polyalcohol mixed medicine to prepare the medicine coating balloon, and has the defect that the medicine can not be effectively promoted to be absorbed by tissues and cells.

Therefore, in the prior art, modification or surface treatment is basically carried out on the sacculus, and the coating process is complex and is easy to cause uneven coating. In the prior art, a water-soluble matrix, an excipient, an emulsifier and/or a plasticizer are mixed with a medicament or combined with weak acting force such as hydrogen bonds to prepare a medicament coating, but due to the difference of properties such as polarity, molecular weight, solubility and the like among substances, the coating has poor homogeneity, is easy to fall off to generate larger particles, cannot release the medicament in a short time, and cannot enable the medicament to be efficiently absorbed by tissues and cells.

Disclosure of Invention

In order to achieve the aim, the invention provides a drug coating of an interventional or implanted medical device and a preparation method thereof, the drug coating is homogeneous and uniform, the dosage is controllable, and the drug coating has proper combination-release balance, not only can the stability of the coating in the conveying process be kept, but also the drug can be quickly released and efficiently absorbed after the saccule is temporarily expanded, and the technical scheme is as follows:

a drug coating for an interventional or implantable medical device comprising a grafted drug copolymer and a solvent; the grafted drug copolymer is prepared by grafting an active drug and a hydrophilic matrix through covalent bonds.

The active drug is one or more of cytostatic agent, microtubule inhibitor, immunosuppressant, antiinflammatory agent, anticoagulant, mitosis inhibitor, thrombosis inhibitor, lipid lowering agent, and antioxidant.

The hydrophilic matrix contains one or more of hydroxyl, amino, sulfo, carboxyl, ether, ester, alkyl, amide and the like.

The hydrophilic matrix contains one, more or mutual copolymer of polyethylene glycol and derivatives thereof, glycolide-lactide copolymer, polyglycolic acid, polyhydroxyalkanoate, polyamino acid, polylactic acid derivatives, chitosan and derivatives thereof, chitosan hydrochloride, chitosan quaternary ammonium salt, carboxymethyl chitosan, carboxylated chitosan, chitosan glutamate, chitosan lactate, low molecular weight chitosan, iopromide, hyaluronic acid, sodium hyaluronate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, resveratrol, polysorbate, starch, cellulose and derivatives thereof, vegetable gum and animal gum.

The molecular weight of the hydrophilic matrix is 1000-1000000 daltons.

The covalent bond is one or more of amido bond, ester bond, ether bond, ketone bond, ether ketone bond, hydrazone bond, oxime bond, thioether bond, amine bond, imine bond, carbon-carbon bond, carbon-nitrogen bond, carbon-oxygen bond and carbon-sulfur bond.

The covalent bond is not breakable under normal temperature and neutral conditions, and the covalent bond is one or more of temperature sensitive breakage, acid sensitive breakage, alkali sensitive breakage, light sensitive breakage, magnetic field sensitive breakage and ray sensitive breakage.

The weight ratio of the active drug to the hydrophilic matrix is 0.1-10.

The preparation method of the drug coating of the interventional or implanted medical device comprises the following steps:

dissolving a hydrophilic matrix or an active drug, adding a catalyst, reacting for 10-240 min, adding the active drug, and reacting for 6-48 h; purifying to obtain grafted medicine copolymer;

adding the prepared grafted drug copolymer into a solvent, dissolving and dispersing to prepare a drug coating solution, coating the drug coating solution on the surface of an interventional or implanted medical device, and drying to obtain the grafted drug copolymer.

The catalyst is dicyclohexylcarbodiimide, 4-dimethylaminopyridine, N-hydroxysuccinimide, N-hydroxythiosuccinimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, a Katt condensation reagent, acetic anhydride, ammonium persulfate or potassium persulfate.

The solvent is one or more of water, ethanol, methanol, acetonitrile, acetone, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, butanol, chloroform, dichloromethane, methyl formate, ethyl acetate, ethyl formate, methyl acetate, propyl formate, methyl propionate, ethyl propionate, phenyl acetate, octyl acrylate, methyl benzoate, N-hexane, acetic acid, isopropanol, diethyl ether, isopropyl ether, propanol and ethanol.

The grafted drug copolymer is dissolved or dispersed in a solvent to form a product which is a solution, suspension, emulsion, suspension or colloid.

The drug coating liquid is processed by one or more methods of emulsification, ultrasound, homogenate and evaporation to form drug coating particles or drug coating nanoparticles; the size of the drug coating particle or the drug coating nanoparticle is 1 nm-100 μm.

The drug coating particles or drug coating nanoparticles are coated on the surface of the medical device.

The coating process is one or more of dip coating, smearing, spraying and volumetric quantitative coating equipment.

The drying mode of the coating is one or more of natural drying, purified air drying, nitrogen drying, freeze drying, drying and vacuum drying. The drying time is 5 min-72 h.

The thickness of the coating is 0 to 50 μm.

The drug loading rate on the surface of the medical instrument is 0.1-10 mu g/mm 2.

The medical device is a balloon dilation catheter, an infusion catheter, a fenestrated balloon, a dual lumen balloon, a porous balloon, an weeping balloon, a cutting balloon, a laser catheter, a thrombectomy catheter, an atherectomy device, a stent graft, a patch, or a guidewire.

The balloon dilatation catheter is a pre-dilatation balloon, a delivery balloon, a post-dilatation balloon, a compliance balloon, a non-compliance balloon, a semi-compliance balloon, a blood vessel balloon, a urethra balloon, an esophagus balloon or a biliary tract balloon.

The stent is a vascular stent, a urethral stent, an esophageal stent or a biliary stent.

The bracket is made of one or more of stainless steel, cobalt-based alloy, iron-based alloy, magnesium-based alloy, platinum-based alloy, titanium-based alloy, nickel-based alloy, zinc-based alloy and high polymer.

The functional tissue of the medical device is one or more of coronary artery vascular system, peripheral vascular system, cerebrovascular system, esophagus, air passage, sinus, trachea, colon, bile duct, urinary tract, prostate and brain channel.

The medical device is a drug coating balloon or a drug eluting stent.

Compared with the prior art, the invention has the beneficial effects that: covalently bonding the hydrophilic matrix and the active agent to form a single component, a graft drug copolymer; the covalent connection mode can enhance the homogeneity of the drug and the matrix coating, improve the hydrophilic and hydrophobic balance of the drug and the adhesion-release balance of the drug coating and the surface of the medical appliance, enhance the efficiency of the drug absorbed by tissues, penetrated in interstitial tissues and taken by cells, and solve the problems of uneven coating, easy shedding, complex and uncontrollable process and the like existing in the mixed drug of various water-soluble matrixes, excipients, emulsifiers and/or plasticizers. In addition, the homogeneity, the uniformity and the stability of the drug coating provided by the invention are enhanced, the drug loading capacity is reduced, the drug loss is reduced, the drug enters blood circulation, and the absorption of the drug at a target site and cells is increased, so that the toxicity is reduced, and the efficacy is improved.

Drawings

FIG. 1 is a schematic diagram of the structure of a grafted drug copolymer coated balloon according to the present invention;

in the figure: 1. and 2, a balloon, and a grafted drug copolymer coating.

Detailed Description

The invention discloses a drug coating of an interventional or implanted medical device, a preparation method and application thereof, and a person skilled in the art can appropriately improve process parameters by referring to the content. It is specifically noted that similar alternatives and modifications will be apparent to those skilled in the art, all of which are intended to be encompassed by the present invention. While the methods and references of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.

In the prior art, after an active medicament and a hydrophilic matrix are mixed in a solvent, coating is carried out, which is equivalent to a mixed coating of two components; the invention firstly makes a covalent chemical reaction between the active drug and the hydrophilic substrate to form a graft copolymer, and then carries out coating, which is equivalent to a single-component coating of the graft copolymer.

In the embodiment of the invention, the drug coating can be coated on the surface of an interventional or implanted medical device, the hydrophilic matrix can enhance the absorption of active drugs by tissues and cells through covalent connection, the interventional or implanted medical device coated with the drug coating, such as DCB and DES, can stably deliver the drugs to target lesions, the coating is not damaged in the delivery process, the drug can be quickly released to the lesion site through the temporary expansion of the balloon, and the released drugs can be efficiently absorbed and utilized by the tissues and the cells.

In embodiments of the invention, the active agent is an antibiotic, paclitaxel and derivatives thereof, taxane, taxol, docetaxel, epothilone, nocodazole, cabazitaxel, combretastatin, docetaxel trihydrate, vinorelbine tartrate, combretastatin disodium phosphate, albendazole, triclabendazole, vinflunine tartrate, rapamycin and derivatives thereof, everolimus, zotarolimus, tacrolimus, baisirolimus, temsirolimus, chrysophanol, ditholimus, 5-fluorouracil, dexamethasone, probucol, colchicine, heparin, warfarin, vitamin K antagonists, aspirin, prostaglandins, nitrolipins, lysimphetamine, vinblastine, vincristine, vinblastine, griseofulvin, penicillin, cephamycin, actinomycin D, daunorubicin, doxorubicin and derivatives thereof, Camptothecin and its derivatives, anti-tumor antibody drugs, cyclophosphamide, cisplatin, acemetacin, resveratrol, argatroban, statins, aminoptericin, antimycosin, arsenic trioxide, aspirin, berberine, ginkgol, folium Ginkgo extract, hormone, plant alkaloid, Tripterygium wilfordii compounds, ranulin, tirofiban, abciximab, and eptifibatide.

In an embodiment of the invention, the active drug is one or more of heparin, paclitaxel, rapamycin.

In an embodiment of the present invention, the hydrophilic matrix is one, more or a copolymer of polyethylene glycol and its derivatives, glycolide-lactide copolymer, polyglycolic acid, polyhydroxyalkanoate, polyamino acid, polylactic acid derivatives, chitosan and its derivatives, chitosan hydrochloride, chitosan quaternary ammonium salt, carboxymethyl chitosan, carboxylated chitosan, chitosan glutamate, chitosan lactate, low molecular weight chitosan, iopromide, hyaluronic acid, sodium hyaluronate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, resveratrol, polysorbate, starch, cellulose and its derivatives, vegetable gum, animal gum.

In other embodiments of the invention, the hydrophilic matrix is a polyamino acid and a chitosan derivative.

In an embodiment of the invention, the hydrophilic matrix has a molecular weight of 1000 daltons, 500000 daltons or 1000000 daltons. In other embodiments of the invention, the hydrophilic matrix has a molecular weight of 4000 daltons, 12000 daltons or 20000 daltons.

In the embodiment of the invention, the covalent bond is one or more of an amide bond, an ester bond, an ether bond, a ketone bond, an ether ketone bond, a hydrazone bond, an oxime bond, a thioether bond, an amine bond, an imine bond, a carbon-carbon bond, a carbon-nitrogen bond, a carbon-oxygen bond and a carbon-sulfur bond; in other embodiments of the invention, the covalent bond is an amide, ester, or hydrazone bond.

In embodiments of the invention, the mass ratio of active drug to hydrophilic matrix is 0.1, 5 or 10; in other embodiments of the invention, the mass ratio of active drug to hydrophilic matrix is 0.5, 1 or 2.

In an embodiment of the present invention, a method for preparing a drug coating for an interventional or implantable medical device comprises the steps of:

dissolving hydrophilic matrix, adding catalyst, reacting for 10min, 120min or 240min, adding active drug, and reacting for 6h, 27h or 48 h. Purifying to obtain the grafted medicine copolymer.

In other embodiments of the present invention, a method for preparing a drug coating for an interventional or implantable medical device comprises the steps of:

dissolving the active drug, adding a catalyst, reacting for 10min, 120min or 240min, adding a hydrophilic matrix, reacting for 6h, 27h or 48h, and purifying to obtain the graft drug copolymer.

In the examples of the present invention, the catalyst is dicyclohexylcarbodiimide, 4-dimethylaminopyridine,N-hydroxysuccinimide,NHydroxy thiosuccinimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2- (7-azobenzotriazol) -N,N,N',N'-tetramethyluronium hexafluorophosphate,OOne or more of benzotriazole-tetramethylurea hexafluorophosphate, a kat condensation reagent, acetic anhydride, ammonium persulfate and potassium persulfate.

In the examples of the present invention, the solvent is water, ethanol, methanol, acetonitrile, acetone, dimethyl sulfoxide, methanol, acetone, methanol, ethanol, acetone, methanol,N,N-one or more of dimethylformamide, tetrahydrofuran, butanol, chloroform, dichloromethane, methyl formate, ethyl acetate, ethyl formate, methyl acetate, propyl formate, methyl propionate, ethyl propionate, phenyl acetate, octyl acrylate, methyl benzoate, n-hexane, acetic acid, isopropanol, diethyl ether, isopropyl ether, propanol, ethanol; in bookIn other embodiments of the invention, the solvent is chloroform, ethanol or tetrahydrofuran.

In embodiments of the invention, the grafted drug copolymer is dissolved or dispersed in a solvent to form a solution, suspension, emulsion, cloud, or colloid; in other embodiments of the invention, the grafted drug copolymer is dissolved or dispersed in a solvent to form a suspension.

In an embodiment of the present invention, the drug coating solution is applied directly to the surface of the medical device.

In the embodiment of the invention, the drug coating liquid is subjected to one or more methods of emulsification, ultrasound, homogenization and evaporation to form drug coating particles or drug coating nanoparticles; the size of the drug coating particle or drug coating nanoparticle is 1 nm, 50 μm or 100 μm; in embodiments of the invention, the drug-coated microparticles or drug-coated nanoparticles are 1 μm, 5 μm, or 10 μm in size.

In embodiments of the invention, the coating process is one or more of dip coating, painting, spraying, by means of volumetric dosing equipment; in other embodiments of the invention, the coating is by spraying.

In the embodiment of the invention, the drying mode is one or more of natural drying, purified air drying, nitrogen drying, freeze drying, drying and vacuum drying; in other embodiments of the present invention, the drying manner is vacuum drying and natural drying.

In the embodiment of the invention, the drying time is 5min, 36h or 72 h; in other embodiments of the invention, the drying time is 10min, 12h or 24 h.

In embodiments of the invention, the coating thickness is 0 μm, 25 μm or 50 μm; in other embodiments of the invention the coating thickness is 6 μm, 18 μm or 30 μm.

In an embodiment of the invention, the drug loading on the surface of the medical device is 0.1 mug/mm²，5μg/mm²Or 10. mu.g/mm²(ii) a In other embodiments of the invention, the drug loading on the surface of the medical device is 0.5 μ g/mm^2。1.75μg/mm²Or 3. mu.g/mm²。

The invention also provides application of the drug coating in interventional or implanted medical devices, wherein the medical devices are balloon dilatation catheters, infusion catheters, puncture balloons, double-cavity balloons, porous balloons, weeping balloons, cutting balloons, laser catheters, thrombus aspiration catheters, atherectomy devices, stents, stent grafts, covered stents, patches or guide wires.

In the technical scheme, the drug coating is applied to the surface of the medical appliance, so that the drug coating can be kept stable and is not damaged in the conveying process in the medical appliance body; when the medical device is delivered to the target lesion and the balloon is expanded, the drug coating contacts the tissue wall, rapidly cracks, adheres to the tissue wall. The active drug needs to be taken into the cell to exert the drug effect, and the drug entering the cell can be excreted or degraded by the cell to generate a drug resistance mechanism similar to the drug resistance. The graft drug copolymer has optimized physicochemical properties on the premise of not influencing the drug effect, and comprises the following components: carry electric charges, and facilitate the permeation from the tissue wall to the tissue interstitium; small molecules are changed into macromolecules, so that the retention in interstitial tissues is facilitated, and the macromolecules can be efficiently absorbed by cells through endocytosis; the structure is modified, so that the cell efflux and the recognition of a degradation matrix can be avoided, and the resistance of the cell to the medicament is avoided, thereby enhancing the bioavailability of the medicament.

In embodiments of the invention, the medical device is a balloon dilation catheter, an infusion catheter, a fenestrated balloon, a dual lumen balloon, a porous balloon, a weeping balloon, a cutting balloon, a laser catheter, a thrombus aspiration catheter, an atherectomy device, a stent graft, a covered stent, a patch, a guidewire; in other embodiments of the invention, the medical devices are balloon dilation catheters and stents.

In an embodiment of the invention, the balloon in the balloon dilatation catheter is a pre-dilatation balloon, a delivery balloon, a post-dilatation balloon, a compliance balloon, a non-compliance balloon, a semi-compliance balloon, a blood vessel balloon, a urethra balloon, an esophagus balloon or a biliary tract balloon.

In an embodiment of the invention, the tissue of action of the medical device is one or more of coronary vascular system, peripheral vascular system, cerebrovascular system, oesophagus, airway, sinus, trachea, colon, bile duct, urinary tract, prostate, brain channel.

In an embodiment of the invention, the medical device is a drug-coated balloon.

In an embodiment of the invention, the medical device is a drug eluting stent.

The invention solves the problems that the surface coating of the medical appliance is inhomogeneous, uneven and unstable, can not release the medicine quickly and can not enable the medicine to be absorbed by tissues and cells efficiently. In the PCI operation process, the drug coating is not damaged in the conveying process, so that the drug is quickly released from the surface of the medical instrument and enters tissues, and is efficiently taken by cells to play the drug effect.

For a further understanding of the present invention, preferred embodiments of the present invention will be described below with reference to examples. The description is intended to be illustrative of the features and advantages of the invention, and should not be taken to limit the scope of the invention.

Example 1

Weighing 1g of polyglutamic acid (with the molecular weight of 1000000 daltons), 0.1g of dicyclohexylcarbodiimide and 0.1g of 4-dimethylaminopyridine, putting the mixture into a flask, adding dichloromethane, stirring and reacting for 30min, adding 0.1g of paclitaxel, reacting for 12h at room temperature, dialyzing (with the molecular weight cutoff of 14000 daltons) until no paclitaxel can be detected in a dialysis medium, and freeze-drying to obtain the paclitaxel-polyglutamic acid graft copolymer.

Example 2

Weighing 1g of polyglutamic acid (molecular weight 20000 daltons), 0.25g of dicyclohexylcarbodiimide and 0.25g of 4-dimethylaminopyridine, putting the mixture into a flask, adding dichloromethane, stirring to react for 30min, adding 0.1g of paclitaxel, reacting for 12h at room temperature, dialyzing (molecular weight cut-off 14000 daltons) until no paclitaxel can be detected in a dialysis medium, and freeze-drying to obtain the paclitaxel-polyglutamic acid graft copolymer.

Example 3

Weighing 0.5g of carboxyl-terminated polyethylene glycol (molecular weight is 1000 daltons), 0.1g of dicyclohexylcarbodiimide and 0.1g of 4-dimethylaminopyridine, putting the mixture into a flask, adding dichloromethane, stirring and reacting for 30min, adding 1g of paclitaxel, reacting for 12h at room temperature, dialyzing (molecular weight cut-off is 2000 daltons) until no paclitaxel can be detected in a dialysis medium, and freeze-drying to obtain the paclitaxel-polyethylene glycol graft copolymer.

Example 4

Weighing 0.5g of carboxyl-terminal polyethylene glycol (molecular weight 20000 daltons), 0.1g of dicyclohexylcarbodiimide and 0.1g of 4-dimethylaminopyridine, placing the mixture into a flask, adding dichloromethane, stirring and reacting for 30min, adding 0.5g of paclitaxel, reacting for 12h at room temperature, dialyzing (molecular weight cut-off 14000 daltons) until no paclitaxel can be detected in a dialysis medium, and freeze-drying to obtain the paclitaxel-polyethylene glycol graft copolymer.

Example 5

Weighing 1g of carboxylated chitosan (with the molecular weight of 10000 daltons), 0.2g of dicyclohexylcarbodiimide and 0.2g of 4-dimethylaminopyridine, putting the materials into a flask, adding an ethanol/water mixture (with the volume ratio of 50/50), stirring for reacting for 60min, adding 1g of paclitaxel, reacting for 24h at room temperature, dialyzing (with the molecular weight cutoff of 6000 daltons) until no paclitaxel can be detected in a dialysis medium, and freeze-drying to obtain the paclitaxel-carboxylated chitosan graft copolymer.

Example 6

Weighing 1g hyaluronic acid (molecular weight 100000 daltons), 0.1g 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.1gNPutting the hydroxysuccinimide into a flask, adding water, stirring for reacting for 20min, adding 0.5g of doxorubicin hydrochloride, reacting for 24h at room temperature, dialyzing (the cut-off molecular weight is 50000 daltons) until no doxorubicin is detected in a dialysis medium, and freeze-drying to obtain the doxorubicin-hyaluronic acid graft copolymer.

Example 7

0.5g of polyglycolic acid (molecular weight 8000 Dalton), 0.2g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.2g ofNAnd (3) putting the hydroxysuccinimide into a flask, adding dimethyl sulfoxide, stirring to react for 60min, adding 1g of adriamycin hydrochloride, reacting for 24h at room temperature, dialyzing (the molecular weight cutoff is 3500 daltons) until no adriamycin can be detected in a dialysis medium, and freeze-drying to obtain the adriamycin-polyglycolic acid graft copolymer.

Example 8

Weighing 1g of aldehyde group-terminated polyethylene glycol (molecular weight 2000 daltons) and dissolving in dimethyl sulfoxide; and (2) additionally weighing 0.5g of adriamycin hydrochloride to be dissolved in boric acid buffer solution (pH 8.0), slowly dripping the adriamycin solution into the polyethylene glycol solution at the tail end of the aldehyde group while stirring, stirring for reaction for 24 hours, adding 0.1g of sodium borohydride, continuously stirring for 24 hours, dialyzing (with the molecular weight cutoff of 1000 daltons) until no adriamycin can be detected in a dialysis medium, and freeze-drying to obtain the acid-sensitive imine bond-connected adriamycin-polyethylene glycol graft copolymer. The graft drug copolymer was not significantly degraded under neutral and alkaline conditions for 7 days, and partially degraded under acidic conditions for 1 day, as measured by thin layer chromatography.

Example 9

The graft drug copolymer prepared in example 1 was dispersed in an ethanol/water mixture (volume ratio 50/50), sprayed on the balloon surface of the balloon dilatation catheter, and vacuum dried for 24 h. The spraying parameters are as follows: the spraying parameters are 0.05ml/min of injection pump flow, 0.8W of ultrasonic power, 7psi of nitrogen pressure, 350rpm of rotation speed and 0.1mm/s of forward speed. The thickness of the coating was measured by a microscope measuring system to be 10 μm.

Example 10

The graft drug copolymer prepared in example 2 was dispersed in ethanol, sprayed on the balloon surface of the balloon dilatation catheter, and oven-dried at 40 ℃ for 4 h. The spraying parameters are as follows: the spraying parameters are 0.05ml/min of injection pump flow, 0.8W of ultrasonic power, 7psi of nitrogen pressure, 50rpm of rotating speed and 0.1mm/s of advancing speed. The coating thickness was measured by a microscope measurement system to be 8 μm.

Example 11

The graft drug copolymer prepared in example 3 was dispersed in chloroform, sprayed on the balloon surface of the balloon dilatation catheter, and naturally dried for 24 hours. The spraying parameters are as follows: the spraying parameters are 0.05ml/min of injection pump flow, 0.8W of ultrasonic power, 7psi of nitrogen pressure, 350rpm of rotation speed and 0.1mm/s of forward speed. The coating thickness was measured by a microscope measurement system to be 12 μm.

Example 12

The graft drug copolymer prepared in example 4 was dispersed in ethanol, and the balloon of the balloon dilatation catheter was immersed in it for 10min, dried naturally for 10min, repeated 10 times, and finally dried under vacuum for 4 h. The coating thickness was measured by a microscope measurement system to be 30 μm.

Example 13

The graft drug copolymer prepared in example 5 was dispersed in water, and pulsed ultrasonic probe was used for 30min (output 100W, working 2s, intermittent 2 s) in ice bath to obtain graft drug copolymer nanoparticles with a particle size of 622 nm. And (3) spraying the grafted drug copolymer nanoparticles on the surface of the balloon dilatation catheter, and drying for 2h in vacuum. The thickness of the coating was measured by a microscope measuring system to be 10 μm.

Example 14

The graft drug copolymer prepared in example 6 was dispersed in water, and pulsed ultrasonic probe was used for 30min (output 100W, working 2s, intermittent 2 s) in ice bath to obtain graft drug copolymer nanoparticles with a particle size of 330 nm. And (3) spraying the grafted drug copolymer nanoparticles on the surface of the balloon dilatation catheter, and naturally drying for 4 h. The coating thickness was measured by a microscope measurement system to be 12 μm.

Example 15

The graft drug copolymer prepared in example 7 was dispersed in water, and pulsed ultrasonic probe was used for 30min (output 100W, working 2s, intermittent 2 s) in ice bath to obtain graft drug copolymer nanoparticles with a particle size of 125 nm. And (3) immersing the balloon of the balloon dilatation catheter into the grafted drug copolymer nanoparticles for 10min, naturally drying for 10min, repeating for 6 times, and finally vacuum drying for 2 h. The thickness of the coating was measured by a microscope measuring system to be 16 μm.

Example 16

The graft drug copolymer prepared in example 8 was dispersed in water, and pulsed ultrasonic probe was used for 30min (output 100W, working 2s, intermittent 2 s) in ice bath to obtain graft drug copolymer nanoparticles with a particle size of 218 nm. And (3) spraying the grafted drug copolymer nanoparticles on the outer surface of the stainless steel bracket, and naturally drying for 1 h. And spraying hydroxyl-terminated polyethylene glycol (with a molecular weight of 6000 daltons) on the surface of the grafted drug copolymer coating, and naturally drying for 1 hour. The thickness of the inner coating and the thickness of the outer coating are both 6 μm measured by a microscope measuring system.

Comparative example 1

Mixing 50mg paclitaxel, 2ml iopromide injection and 1ml ethanol to obtain medicinal coatingThe layer liquid is sprayed on the surface of the saccule dilating catheter until the density of the medicine in the coating reaches 3 mu g/mm²And naturally drying for 2 h. The coating thickness was measured by a microscope measurement system to be 12 μm.

Drug loading measurement

The grafted drug copolymer coated balloon prepared in examples 9-15, the grafted drug copolymer coated stent prepared in example 16, and the iopromide drug-loaded coated balloon prepared in comparative example 1 were immersed in acetonitrile and subjected to ultrasound for 10 min. Filtering the acetonitrile eluate with 0.45 μm filter membrane, and injecting the filtrate into High Performance Liquid Chromatograph (HPLC) for drug detection. The amount of drug in each of the examples and comparative examples used to prepare the drug coated medical devices is shown in table 1 by HPLC:

TABLE 1 drug loading test results

Numbering	Designed dose (mug/mm)2）	The dosage is measured (mu g/mm)2）	Deviation (%)
				Example 9	2.00	2.11	5.5
Example 10	2.00	2.10	5.0
				Example 11	3.00	2.98	0.7
Example 12	6.00	5.84	2.7
				Example 13	2.00	1.91	4.5
Example 14	3.00	3.20	6.7
				Example 15	4.00	3.88	3.0
Example 16	1.00	1.05	5.0
				Comparative example 1	3.00	3.12	4.0

Therefore, the grafted drug copolymer is coated on the surface of an interventional or implanted medical device, so that the drug loading of the coating can meet the design requirement, and the drug loading is controllable.

Drug coating firmness test

The stent portion of the graft drug copolymer-coated stent prepared in example 16 was immersed in 50ml of water for injection, the balloon was inflated to the rated burst pressure to expand the stent, and the balloon was withdrawn to the withdrawal vessel. The elution solution was counted by a particle counter, and the number of particles of 50ml of water for injection was detected as the number of particles of the blank liquid. The results were found to meet the acceptance criteria: in the eluent, the number of particles with the diameter of more than or equal to 10 mu m is not more than 6000; not more than 600 particles with a diameter of 25 μm; the particles having a particle size of 100 μm or more are zero. The grafted drug copolymer is shown to be coated on the surface of the interventional or implanted medical device to form a firm and stable drug coating.

Simulated post-implant drug content testing

The blood vessel simulation device is manufactured according to standard YY/T0807 Standard test method for stability of saccule-expanded vascular stent preinstalled on a delivery system. The grafted drug copolymer coated balloons prepared in examples 9 to 15, the grafted drug copolymer coated stent prepared in example 16, and the iopromide drug-loaded coated balloon prepared in comparative example 1 were passed through a blood vessel simulator for 3 times, and then the remaining drug amount was measured by HPLC. The HPLC detection results are shown in Table 2:

TABLE 2 dose loss after 3 passes of the vascular simulation device

Numbering	Designed dose (mug/mm)2）	The residual drug amount (μ g/mm)2）	Deviation (%)
				Example 9	2.00	1.92	4.0
Example 10	2.00	1.91	4.5
				Example 11	3.00	2.95	1.7
Example 12	6.00	5.71	4.8
				Example 13	2.00	1.91	4.5
Example 14	3.00	2.92	2.7
				Example 15	4.00	3.81	4.7
Example 16	1.00	0.97	3.0
				Comparative example 1	3.00	2.12	29.3

It can be seen that the deviation of the drug loading of the medical device prepared in examples 9-16 in the vascular simulation device after 3 passes is equivalent to that in table 1, indicating that the surface coating is stable and no drug is lost; the deviation of the drug amount of the medical apparatus prepared in the comparative example 1 before and after passing through the blood vessel simulation device for 3 times is obviously larger than that of the drug loading amount in the table 1, which indicates that the surface coating is damaged and the drug loss is serious.

Drug release test

And (3) taking the grafted drug copolymer coating balloon prepared in the examples 9-15 and the iopromide drug-loaded coating balloon prepared in the comparative example 1, immersing the grafted drug copolymer coating balloon in a phosphate buffer solution, and standing for 1 min. Filling the balloon to the nominal pressure, keeping the pressure for 30s, and immediately taking out the balloon after pressure relief. And eluting the residual medicine amount on the balloon by using acetonitrile, and calculating the medicine release rate. The results are shown in Table 3:

TABLE 3 drug Release results

Numbering	Designed dose (mug/mm)2）	The residual drug amount (μ g/mm)2）	Drug Release Rate (%)
				Example 9	2.00	0.35	82.5
Example 10	2.00	0.38	81.0
				Example 11	3.00	0.48	84.0
Example 12	6.00	0.76	87.3
				Example 13	2.00	0.31	84.5
Example 14	3.00	0.42	86.0
				Example 15	4.00	0.57	85.8
Comparative example 1	3.00	0.45	85.0

Therefore, the grafted drug copolymer coating balloons prepared in examples 9-15 and the iopromide drug-loaded coating balloon prepared in comparative example 1 can effectively release drugs within balloon expansion time of 30s, and the drug release rates are both greater than 80%.

The above description of the embodiments is only intended to facilitate the understanding of the core ideas of the present invention. It should be noted that it is possible for a person skilled in the art to make modifications and variations to the present invention without departing from the principle of the invention, and these modifications and variations also fall within the scope of the invention as claimed.

Claims (7)

1. A drug coating for an interventional or implantable medical device comprising a grafted drug copolymer and a solvent; the grafted drug copolymer is prepared by grafting an active drug and a hydrophilic matrix through covalent bonds.

2. The drug coating of an interventional or implantable medical device according to claim 1, wherein the active drug is one or more of a cytostatic agent, a microtubule inhibitor, an immunosuppressive agent, an anti-inflammatory agent, an anticoagulant, a mitotic inhibitor, a thrombosis inhibitor, a lipid-lowering agent, an antioxidant.

3. The drug coating of an interventional or implantable medical device according to claim 1, wherein the hydrophilic matrix comprises one or more of hydroxyl, amino, sulfo, carboxyl, ether, ester, alkyl, and amide groups.

4. The pharmaceutical coating according to claim 1, wherein the covalent bond is one or more of an amide bond, an ester bond, an ether bond, a ketone bond, an ether ketone bond, a hydrazone bond, an oxime bond, a thioether bond, an amine bond, an imine bond, a carbon-carbon bond, a carbon-nitrogen bond, a carbon-oxygen bond, a carbon-sulfur bond.

5. The drug coating of an interventional or implantable medical device according to claim 4, wherein the covalent bond is non-cleavable under normal temperature and neutral conditions, the covalent bond being one or more of temperature sensitive cleavage, acid sensitive cleavage, base sensitive cleavage, light sensitive cleavage, magnetic field sensitive cleavage, radiation sensitive cleavage.

6. The preparation method of the drug coating of the interventional or implanted medical device is characterized by comprising the following steps:

dissolving a hydrophilic matrix or an active drug, adding a catalyst, reacting for 10-240 min, adding the active drug, and reacting for 6-48 h; purifying to obtain grafted medicine copolymer;

adding the prepared grafted drug copolymer into a solvent, dissolving and dispersing to prepare a drug coating solution, coating the drug coating solution on the surface of an interventional or implanted medical device, and drying to obtain the grafted drug copolymer.

7. The method of claim 6, wherein the drug-coated particles or nanoparticles are coated on the surface of the medical device.

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