CN112472878A - Plugging device containing composite coating and preparation method thereof - Google Patents
Plugging device containing composite coating and preparation method thereof Download PDFInfo
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- CN112472878A CN112472878A CN202011456036.2A CN202011456036A CN112472878A CN 112472878 A CN112472878 A CN 112472878A CN 202011456036 A CN202011456036 A CN 202011456036A CN 112472878 A CN112472878 A CN 112472878A
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- coating
- occluder
- drug
- expandable material
- expandable
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- 239000003999 initiator Substances 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 229960003504 silicones Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000001029 thermal curing Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
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- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a stopper containing a composite coating and a preparation method thereof, wherein the stopper comprises a stopper and a composite coating, wherein a disc-shaped net and a tubular net are integrally formed; the composite coating comprises a double coating of a drug coating for inhibiting scars and/or antagonizing hemagglutination and an expandable coating, or a single coating formed by mixing a drug raw material for inhibiting scars and/or antagonizing hemagglutination and an expandable material; the setting mode of the drug coating is as follows: the composite coating is formed on the surface of the occluder; and/or the composite coating is formed on the surface of the flow resisting membrane in the occluder. The occluder comprises a double coating or a single coating of a drug coating for inhibiting scars and/or antagonizing hemagglutination and an expandable coating, can reduce the incidence rate of postoperative keloids and high atrioventricular conduction block, can also achieve the aim of reducing surface thrombosis of the occluder after implantation by singly or jointly antagonizing the hemagglutination drug coating, and greatly reduces the incidence rate of postoperative residual shunt.
Description
Technical Field
The invention particularly relates to a plugging device containing a composite coating and a preparation method thereof.
Background
At present, after the nickel-titanium alloy occluder with harder texture is implanted into the body in an interventional operation, the myocardial tissue is embedded between the two disc surfaces, and due to extrusion, tissue edema oppresses conduction tissues, and high atrioventricular conduction block is easy to occur. Meanwhile, the nickel-titanium alloy wire of the occluder rubs surrounding tissues along with the heart pulsation, the integrity of cardiac muscle is damaged, the cardiac muscle is stimulated for a long time to cause excessive scar hyperplasia, and the conduction tissue is pulled and pressed, so that the degeneration and necrosis of a heart conduction system are caused, and high atrioventricular block is easy to occur at the middle and late stages. In order to prevent and treat the incidence rate of high atrioventricular block after interventional occlusion, dexamethasone is used for the postoperative veins as the most common method at home and abroad at present, has the pharmacological characteristics of anti-inflammation, edema alleviation, tissue hyperplasia reduction and the like, and can theoretically reduce myocardial edema and scar hyperplasia caused by the occluder. Meanwhile, the implantation of the occluder into a heart defect part requires endothelialization for 6 months, so that the oral anticoagulant can prevent the surface thrombosis of the occluder during the period, and the occluder cannot inhibit the surface thrombosis.
In addition, in the using process of the cardiac occluder, the waist diameter of the occluder is generally larger than the defect by about 2-6mm, which is to ensure that the waist diameter has enough strength to support the defect part, thereby ensuring that the occluder does not have the possible risks of the occluder falling off and the like, and ensuring that the defect is completely occluded to reduce residual shunt. Especially in interventional procedures for treating patent foramen ovale, statistical data show that the probability of occurrence of postoperative residual shunting is about 20%. This is probably because the oval hole defect is irregular in shape compared to other congenital heart disease defects, and the straight channel is rarely formed, and is generally irregular in shape such as circular arc or wave. And the waist of the patent foramen ovale occluder is generally not supported on the defect part by the waist of the occluder, and is only occluded by the two disc surfaces. Therefore, if the occluder is designed, the size of the waist can be gradually increased after implantation, so that the occluder can be better supported and attached to the defect, and the occurrence rate of residual shunt can be greatly reduced.
Chinese patent document CN107890357A discloses a paravalvular leakage plugging device, wherein an outer covering membrane is sewn on the waist connector, the outer covering membrane is polytetrafluoroethylene, and because polytetrafluoroethylene has a large expansion coefficient, irregular gaps are filled according to the intrinsic structural form of the paravalvular leakage, so that postoperative residual shunt can be effectively prevented. The patent only connects polytetrafluoroethylene to the waist of the occluder by sewing, only can reduce partial residual shunt at the middle defect part, and cannot effectively reduce residual shunt around the defect part. The patent only connects polytetrafluoroethylene to the waist of the occluder by sewing, only can reduce partial residual shunt at the middle defect part, and cannot effectively reduce residual shunt around the defect part. And the occluder in the patent can not effectively reduce postoperative scar hyperplasia and high atrioventricular block.
In summary, there is no method or device in the prior art that can simultaneously reduce the postoperative scar hyperplasia, high atrioventricular block, surface thrombosis and residual shunt of the occluder implanted in the body.
Disclosure of Invention
The invention provides an occluder with a composite coating and a preparation method thereof, aiming at overcoming the defects that after an occluder in the prior art, keloid and high atrioventricular conduction block are easily caused, a patient needs to take an anticoagulant orally for a long time to prevent thrombosis on the surface of the occluder and the occurrence rate of residual shunt is high after the occluder is used in an interventional operation. The invention solves the technical problems through the following technical scheme. The surface of the occluder and/or the surface of the flow blocking membrane are coated with a double coating comprising a drug coating for inhibiting scars and/or antagonizing hemagglutination and an expandable coating, or comprise a single coating formed by mixing a drug raw material for inhibiting scars and/or antagonizing hemagglutination and an expandable material, so that the occurrence rate of postoperative keloids and high atrioventricular conduction block can be reduced, the occluder can also achieve the purpose of reducing surface thrombosis of the occluder after implantation by using the drug coating for inhibiting the hemagglutination alone or in combination, and the occurrence rate of residual shunt after the operation is greatly reduced.
The invention provides an occluder containing a composite coating, which comprises an occluder and a composite coating, wherein the occluder is formed by integrally forming a disc-shaped net and a tubular net; the composite coating comprises a double coating of a drug coating for inhibiting scars and/or antagonizing hemagglutination and an expandable coating, or comprises a single coating formed by mixing a drug raw material for inhibiting scars and/or antagonizing hemagglutination and an expandable material;
the setting mode of the composite coating is as follows:
mode A: the composite coating is formed on the surface of the occluder;
and/or, mode B: the composite coating is formed on the surface of a flow-blocking film in the stopper.
In the present invention, the disc-shaped net and the tubular net are preferably woven from monofilaments. When the disc-shaped net and the tubular net are woven by monofilaments, the surface of the occluder is the monofilament surface of the occluder.
Wherein, the monofilament surface preferably refers to all surfaces of the monofilament or the outer surface of the occluder formed after the monofilament is woven. In the present invention, the external surface generally refers to a surface which can be directly touched by human hands when the occluder is in vitro or a surface which is directly impacted by blood when the occluder is placed in vivo.
In the present invention, the surface of the flow blocking film is preferably both side surfaces of the flow blocking film or one side surface of the flow blocking film.
In the present invention, the occluder may be an atrial septal defect occluder, a patent ductus arteriosus occluder, a ventricular septal defect occluder, a patent foramen ovale occluder, a left atrial appendage occluder, a blood vessel occluder or an orifice embolization device. In the invention, the material of the occluder is a bioabsorbable material or other non-bioabsorbable materials, preferably a bioabsorbable material; preferably, the bioabsorbable material comprises polylactide, polyglycolide, polycaprolactone, polydioxanone, polyhydroxybutyrate, polyhydroxyalkanoate, polyanhydride, polyphosphate, polyurethane or polycarbonate, and derivatives, blends of two or more thereof, or copolymers of the corresponding monomers.
In the present invention, when the composite coating layer is a double coating layer, the drug coating layer preferably includes an active layer composed of a pharmaceutically active ingredient and a drug carrier.
The mass of the active pharmaceutical ingredient in the drug coating is preferably 1-30% w/w of the total mass of the drug coating, and more preferably 5-25% w/w of the total mass of the drug coating.
In the present invention, when the composite coating is a double coating, the drug coating preferably further comprises a slow release layer coated on the outer surface of the active layer.
In the invention, when the composite coating is a double coating, the mass concentration of the expandable material in the expandable material solution is 3-20% w/v.
In the present invention, when the composite coating is a double coating, the thickness of the expandable coating or the drug coating is preferably 5 to 1000 μm.
In the present invention, when the composite coating is a double coating, the volume multiple of the expandable material in the expandable coating expanding after contacting with water is preferably 3 to 200, and more preferably 5 to 170.
In the present invention, when the composite coating layer is a single coating layer, the pharmaceutical raw material preferably includes a pharmaceutical active ingredient and a pharmaceutical carrier.
Wherein, the mass of the active pharmaceutical ingredient in the raw pharmaceutical material is preferably 1-30% w/w of the total mass of the single coating, and more preferably 5-25% w/w of the total mass of the single coating.
In the invention, when the composite coating is a single coating, the mass concentration of the expandable material in the expandable material solution is preferably 3-20% w/v.
In the invention, when the composite coating is a single coating, the thickness of the single coating is preferably 5-1000 μm.
In the present invention, when the composite coating is a single coating, the volume multiple of the expandable material in the single coating expanding after contacting with water is preferably 3 to 200, and more preferably 5 to 170.
In the present invention, the pharmaceutically active ingredient preferably comprises 5-fluorouracil, mitomycin C, dexamethasone, rapamycin, prednisone, corticosteroids, silicones, retinoids, tranilast, verapamil, allopurinol, antihistamines, paclitaxel, triclosan, interleukin antibodies, immunosuppressive agents, heparin, clopidogrel, aspirin, dipyridamole, warfarin, dicoumarin, rivaroxaban, dabigatran, apixaban, edoxaban, or transforming growth factor antibodies, and derivatives or mixtures thereof.
In the present invention, the drug carrier or the sustained release layer is preferably a bioabsorbable material; the bioabsorbable material preferably comprises polycaprolactone, polylactide, polyglycolide, polydioxanone, polytrimethylene carbonate, polyhydroxybutyrate, polyhydroxyalkanoate, polyanhydride, polyphosphate, polyamino acid, cellulose, collagen or chitosan, and derivatives, blends of two or more thereof or copolymers of the corresponding monomers.
In the present invention, the swellable material preferably comprises polyvinyl alcohol, polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, acrylamide, polyacrylic acid, hydrolyzed polyacrylonitrile, polyethyleneimine, ethoxylated polyethyleneimine, polyallylamine, polysuccinimide ester, polysuccinimide glutarate, polyethylene glycol amine, polyhydroxyethylmethacrylate, polylysine, polyethyleneimine, trilysine, four-arm polyethylene glycol amine, four-arm polyethylene glycol succinimide ester, four-arm polyethylene glycol succinimide glutarate, four-arm polyethylene glycol succinimide succinate, four-arm polyethylene glycol succinimide carbonate, hyaluronic acid, chitosan, collagen, gelatin, fibrin, dextran or agarose, and derivatives, blends of two or more thereof, or copolymers of the corresponding monomers.
In the invention, the distribution of the composite coating is reasonably arranged. When the composite coating is a double coating, the double coating is preferably arranged in any one of the following four ways:
the first method is as follows: the surface of the stopper is sequentially provided with a double coating of a drug coating and an expandable coating;
the second method comprises the following steps: the surface of the flow-resistant film of the occluder is sequentially provided with a double coating of a drug coating and an expandable coating;
the third method comprises the following steps: the surface of the stopper is sequentially provided with a double coating of an expandable coating and a drug coating;
the method is as follows: the surface of the flow-resistant film of the occluder is sequentially provided with a double coating of an expandable coating and a drug coating;
when the composite coating is a single coating, the single coating is preferably disposed in any one of the following two ways:
the fifth mode is as follows: the surface of the stopper is provided with a single coating formed by mixing a raw material containing a medicament for inhibiting scars and/or antagonizing hemagglutination and an expandable material;
the method six: the surface of the flow-resisting film in the blocking device is provided with a single coating layer formed by mixing the medicine raw material for inhibiting scars and/or antagonizing hemagglutination and the expandable material.
The invention also provides a preparation method of the plugging device, when the composite coating is a double coating, the coating process in the preparation method is coated according to any one scheme of the following four modes:
the first scheme is as follows: sequentially coating a medicine mixed solution formed by medicine raw materials and an expandable material solution formed by an expandable material on the surface of the stopper;
scheme II: sequentially coating a medicine mixed solution formed by medicine raw materials and an expandable material solution formed by an expandable material on the surface of the flow-resisting membrane of the occluder;
the third scheme is as follows: sequentially coating an expandable material solution formed by an expandable material and a medicine mixed solution formed by medicine raw materials on the surface of the stopper;
and the scheme is as follows: sequentially coating an expandable material solution formed by an expandable material and a medicine mixed solution formed by medicine raw materials on the surface of the flow-resisting membrane of the occluder;
when the composite coating is a single coating, the coating process in the preparation method is applied in any one of the following two ways:
and a fifth scheme: mixing a medicine mixed solution formed by medicine raw materials with an expandable material solution formed by an expandable material, and coating the mixture on the surface of the occluder;
scheme six: and mixing a medicine mixed solution formed by the medicine raw materials with an expandable material solution formed by an expandable material, and coating the mixture on the surface of the flow-resisting membrane of the occluder.
In the present invention, when coating according to the first or second embodiment, the coating process preferably comprises the steps of: (1) coating a medicine mixed solution formed by medicine raw materials on the surface of the plugging device in the mode A and/or the surface of the flow resisting membrane in the mode B, and drying; (2) performing plasma treatment on the surface of the occluder in the mode A and/or the surface of the flow-resisting membrane in the mode B attached with the drug coating; (3) and (3) coating the surface of the occluder in the mode A and/or the surface of the flow blocking membrane in the mode B with an expandable material solution, then performing crosslinking curing, and drying.
In the present invention, when coating in the third or fourth embodiment, the coating process preferably comprises the steps of: (1) performing plasma treatment on the surface of the occluder in the mode A and/or the surface of the flow-resisting membrane in the mode B; (2) coating an expandable material solution formed by an expandable material on the surface of the occluder in the mode A and/or the surface of the flow blocking membrane in the mode B, and then drying after crosslinking and curing; (3) and (3) coating the surface of the plugging device in the mode A and/or the surface of the flow resisting membrane in the mode B which are attached with the expandable coating with a medicine mixed solution formed by the medicine raw materials, and drying.
In the present invention, when coating in the fifth or sixth embodiment, the coating process preferably comprises the steps of: (1) mixing a medicine mixed solution formed by medicine raw materials with an expandable material solution formed by an expandable material to obtain a mixed solution with a single coating; (2) performing plasma treatment on the surface of the occluder in the mode A and/or the surface of the flow-resisting membrane in the mode B; (3) and (3) coating the mixed solution of the single coating on the surface of the plugging device in the mode A and/or the surface of the flow resisting membrane in the mode B, and then performing crosslinking curing and drying.
In the first to sixth schemes, when the surfaces of the coated stopper are all the surfaces of the stopper or when the flow-blocking film coating the stopper is two side surfaces, the coating is preferably spraying, brushing, mold filling coating, dipping, rolling, spin coating, electrodeposition or vacuum vapor deposition; or, when the surface of the coated stopper is the outer surface of the stopper or when one side surface of the flow-blocking film in the stopper is coated, the coating is preferably spraying, brushing, rolling, spin coating, electrodeposition or vacuum vapor deposition.
In the first to sixth schemes, the formation of the drug mixture preferably includes an operation of stirring the drug active ingredient, the solvent and the drug carrier in the drug mixture; preferably, the stirring time is 6-16 h.
In the first to sixth schemes, the drying temperature is preferably 35 to 60 ℃.
In the first to sixth schemes, the drying time is preferably 6 hours to 8 days.
In the first to sixth embodiments, the solvent in the mixed solution of the drug is preferably one or more of dichloromethane, dimethylacetamide and dimethylsulfoxide, and more preferably dichloromethane.
In the first to sixth embodiments, the mass concentration of the expandable material in the expandable material solution is preferably 3 to 20% w/v.
In the first to sixth embodiments, the plasma treatment time is preferably 5s to 20 min. The plasma treatment can increase the hydrophilicity of the surface of the stopper.
In the first to sixth schemes, the crosslinking curing manner preferably employs chemical reaction, thermal curing, photo-curing, electromagnetic radiation or ionizing radiation.
In the first to sixth schemes, the spraying is usually carried out by a spraying machine; preferably, the spraying speed of the spraying machine is 0.03-0.1 mL/min.
In the first to sixth embodiments, the operation of crosslinking and curing adopts a photo-curing method: the photocuring operation is preferably performed by irradiating the stopper coated with the expandable material solution with an ultraviolet lamp of 280-400 nm. Wherein, the irradiation time of the ultraviolet lamp is preferably 10 s-20 min, more preferably 30 s-16 min. The expandable material solution preferably further comprises a photoinitiator, and the mass concentration of the photoinitiator is preferably 0.05-2% w/v. Among them, the kind of the photoinitiator is preferably 1- [4- (2-hydroxyethoxy) -phenyl ] -2-hydroxy-2-methyl-1-propan-1-one, 2-hydroxy-2-methylpropanol, phenylbis (2,4,6-trimethylbenzoyl) phosphine oxide, dibenzoyldiethylgermane or tetrabenzogermane. The above-mentioned initiators are classified into 1- [4- (2-hydroxyethoxy) -phenyl ] -2-hydroxy-2-methyl-1-propane-1-one), 2-hydroxy-2-methyl propiophenone, phenylbis (2,4, 6-trimethylphenoxy) phosphine oxide, diphenyldimethyldigermane or tetrabenzoylgerane, respectively, under the English designation of "1-" - [4- (2-hydroxyethoxy) -phenyl ] -2-hydroxy-1-propane-1-one ".
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention. It should be noted that all other equivalent alternatives related to the arrangement of a double coating layer containing a drug coating layer for inhibiting scar and/or antagonizing hemagglutination and an expandable coating layer, or a single coating layer containing a drug mixture formed by drug materials and an expandable material solution formed by expandable materials are provided for some or all parts of the occluder and are within the scope of the present invention.
The positive progress effects of the invention are as follows:
the surface of the occluder and/or the surface of the flow blocking film are coated with a double coating comprising a drug coating for inhibiting scars and/or antagonizing hemagglutination and an expandable coating, or are coated with a single coating comprising a drug mixed solution formed by drug raw materials for inhibiting scars and/or antagonizing hemagglutination and an expandable material solution formed by an expandable material, so that the incidence rate of postoperative keloids and high atrioventricular conduction block can be reduced, and the surface thrombosis of the occluder after implantation can be reduced by the drug coating for antagonizing hemagglutination alone or in combination, and the postoperative life quality of a patient can be improved. Meanwhile, after entering the defect or the patent part, the occluder can expand to tightly combine the occluder with the surrounding tissues for occlusion; the occluder which is 2-6mm larger than the defect part is not needed, the size of the sheath tube is reduced, the supporting effect on the defect or the unclosed part is better, the incidence rate of the occluder falling off is further reduced, and the incidence rate of the residual shunt after the operation is greatly reduced. Thereby increasing the indications and allowing smaller children to undergo interventional procedures.
Drawings
Figure 1 is a front view of the atrial septal defect occluder of examples 1 and 4 implanted at the atrial septal defect site of the heart.
Figure 2 is an enlarged view of the atrial septal defect occluder and monofilament of examples 1 and 4.
Figure 3 is a coating profile of a cross-section of a monofilament having a double coating of a drug coating and an expandable coating, in sequence, on all surfaces of the monofilament of the occluder of examples 1 and 2.
Figure 4 is a coating profile of a cross-section of a monofilament having all surfaces of the monofilament of the occluding device of examples 3 and 4 provided with a double coating of an expandable coating and a drug coating in sequence.
FIG. 5 is a coating distribution diagram of a single-coating monofilament cross section formed by mixing a drug-containing raw material and an expandable material on the outer surface of the occluder in examples 5-7.
Fig. 6 is a view showing that the flow blocking film is arranged in the disc-shaped net and the tubular net of the patent ductus arteriosus occluder in examples 8 and 9.
Figure 7 is a view of the occluding membrane of example 10 positioned in the disc-shaped mesh and the tubular mesh of the atrial septal defect occluder.
Fig. 8 is an enlarged side view of the flow blocking membrane of example 8 in which a double coating of a drug coating layer and an expandable coating layer is sequentially provided on one side surface of the flow blocking membrane.
Fig. 9 is an enlarged side view of the flow blocking membrane of example 9 in which the expandable coating layer and the drug coating layer are sequentially provided on both side surfaces of the flow blocking membrane.
Fig. 10 is an enlarged side view of the flow blocking membrane of example 10 in which a single coating layer formed by mixing the drug-containing raw material and the swellable material was formed on both side surfaces of the flow blocking membrane.
Reference numbers for fig. 1 illustrate: 1 atrial septal defect occluder;
the reference numerals of fig. 2 illustrate: 10 disc net, 101 outer end face of disc net, 102 inner end face of disc net, 20 tubular net, 30 monofilaments;
the reference numerals of fig. 3 illustrate: 30 monofilaments, 40 drug coatings, 50 swellable coatings;
the reference numerals of fig. 4 illustrate: 30 monofilaments, 40 drug coatings, 50 swellable coatings;
the reference numerals of fig. 5 illustrate: 30 filaments, 60 monocoat, 301 all outer surfaces of the filaments;
the reference numerals of fig. 6 illustrate: 10 disk-shaped net, 20 tubular net, 701 attached with double coated flow-blocking film;
the reference numerals of fig. 7 illustrate: 10 disk mesh, 20 tubular mesh, 702 with a single coated flow-blocking film;
the reference numerals of fig. 8 illustrate: 40 drug coating, 50 expandable coating, 70 flow-resistant membrane; a choke membrane 7011 with a double coating layer is attached to one side surface;
the reference numerals of fig. 9 illustrate: 40 drug coating, 50 expandable coating, 70 flow-resistant membrane; the surfaces of both sides are attached with a dual-coating flow resisting film 7012;
the reference numerals of fig. 10 illustrate: 60 single coat, 70 flow barrier film; both side surfaces are attached with single-coated flow blocking films 702.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1 (atrial septal defect occluder, drug coating and expandable coating double coating applied to all surfaces of occluder monofilament in sequence)
As shown in figures 1 and 2, the coating profile of a cross-section of a monofilament having a double coating of a drug coating 40 and an expandable coating 50 on all surfaces of the monofilament 30 in sequence in atrial septal defect occluder 1 is shown in figure 3. Dissolving polyglycolide and dexamethasone in dichloromethane to obtain a medicine mixed solution, and continuously stirring the medicine mixed solution for 16 h. Then adding the medicine mixed solution into a spraying machine, spraying all the surfaces of the monofilaments 30 of the atrial septal defect occluder 1 at the spraying speed of 0.03mL/min, and drying to obtain the occluder with the medicine coating 40, wherein the drying temperature is 60 ℃ and the drying time is 6 hours. Then, the atrial septal defect occluder with the drug coating 40 for inhibiting scar hyperplasia was subjected to plasmatization for 5 seconds to increase the hydrophilicity of the surface of the atrial septal defect occluder. Wherein, the atrial septal defect occluder is an occluder which is integrally formed by a disc-shaped net and a tubular net which are woven by monofilaments made of polydioxanone. Then preparing 3% w/v polyethylene glycol diacrylate solution, and adding 0.05% w/v photoinitiator 2-hydroxy-2-methyl propyl phenol into the solution. Immersing the atrial septal defect occluder into the solution, dip-coating and slowly rotating, using a 365nm ultraviolet lamp to enable the polyethylene glycol diacrylate to be cross-linked and cured for 30s, taking out and drying after the completion, wherein the drying temperature is 60 ℃ and the drying time is 6 hours. Wherein the thickness of the drug coating 40 is 5 μm, and the mass of the pharmaceutically active ingredient accounts for 30% w/w of the total mass of the drug coating 40. The thickness of the expandable coating 50 is 1000 μm, and the expandable material in the expandable coating 50 expands by a volume factor of 3 upon contact with water.
The drug coating 40 in this embodiment is on all surfaces of the monofilament 30 of the atrial septal defect occluder and the swellable coating 50 is on the outermost layer of all surfaces of the monofilament 30. The drug coating in the embodiment can greatly reduce keloid caused by clamping and rubbing of the atrial septal defect occluder on tissues. Moreover, the size of the waist of the occluder can be selected to be the same as that of the atrial septal defect part, and the occluder with the waist 2-6mm larger than the atrial septal defect part is not needed to be used, so that the size of the sheath tube is reduced, the supporting effect at the atrial septal defect part is better, the falling incidence rate of the atrial septal defect occluder is further reduced, the adaptation diseases are increased, and smaller children can accept the interventional operation.
Example 2 (patent foramen ovale occluder with drug coating and expandable coating applied to all surfaces of occluder monofilament in sequence)
The coating profile of the cross section of the monofilament in which all the surfaces of the monofilament in the patent foramen ovale occluder are provided with a double coating of a drug coating and an expandable coating in sequence is shown in figure 3. Dissolving polylactide and prednisone in dimethylacetamide to obtain a medicine mixed solution, and continuously stirring the medicine mixed solution for 12 h. Then adding the medicine mixed solution into a spraying machine, spraying all the surfaces of the monofilaments 30 of the patent foramen ovale stopper at the spraying speed of 0.06mL/min, and drying to obtain the stopper with the medicine coating 40, wherein the drying temperature is 50 ℃ and the drying time is 12 hours. Then, the patent foramen ovale occluder with the drug coating 40 for inhibiting scar hyperplasia was subjected to plasma treatment for 12min to increase the hydrophilicity of the surface of the patent foramen ovale occluder. The patent foramen ovale occluder is an occluder formed by integrally forming a disc-shaped net and a tubular net which are woven by monofilaments made of polylactide. Then preparing a polyvinyl alcohol solution with the concentration of 5% w/v, and adding 0.3% w/v of photoinitiator 1- [4- (2-hydroxyethoxy) -phenyl ] -2-hydroxy-2-methyl-1-propane-1-ketone into the solution. Immersing the patent foramen ovale stopper into the solution, dip-coating and slowly rotating, using an ultraviolet lamp with the wavelength of 370nm to enable polyvinyl alcohol to be cross-linked and cured for 10s, taking out and drying after completion, wherein the drying temperature is 50 ℃ and the drying time is 12 hours. Wherein the thickness of the drug coating 40 is 10 μm, and the mass of the pharmaceutically active ingredient accounts for 25% w/w of the total mass of the drug coating 40. The thickness of the expandable coating 50 is 800 μm, and the expandable material in the expandable coating 50 expands by a volume factor of 5 upon contact with water.
The drug coating 40 in this embodiment is on all surfaces of the monofilament 30 of the patent foramen ovale occluder, and the expandable coating 50 is the outermost layer on all surfaces of the monofilament 30. The drug coating in the embodiment can greatly reduce keloid caused by clamping and rubbing of the patent foramen ovale occluder on tissues. Moreover, the size of the waist of the occluder can be selected to be the same as the size of the patent part of the foramen ovale, and the occluder with the waist 2-6mm larger than the patent part of the foramen ovale is not needed to be used, so that the size of the sheath tube is reduced, the supporting effect on the patent part of the foramen ovale is better, the incidence rate of falling of the patent part of the foramen ovale can be further reduced, the indication is increased, and the smaller infant can accept the intervention operation.
Example 3 (patent ductus arteriosus occluder with expandable coating and drug coating applied to all surfaces of the occluder monofilament in sequence)
The patent ductus arteriosus occluder is subjected to plasma treatment for 9min to increase the hydrophilicity of the surface of the patent ductus arteriosus occluder. The patent ductus arteriosus occluder is an occluder formed by integrally weaving a disc-shaped net and a tubular net which are woven by monofilaments 30 made of polycaprolactone. Then preparing polyethylene glycol dimethacrylate solution with the concentration of 12% w/v, and adding 1% w/v photoinitiator phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide into the solution. Immersing the patent ductus arteriosus occluder into the solution, dip-coating and slowly rotating, using a 280nm ultraviolet lamp to enable polyethylene glycol dimethacrylate to be cross-linked and cured for 16min, taking out and drying after completion, wherein the drying temperature is 40 ℃ and the drying time is 12 hours. Then, the drug carriers polycaprolactone and mitomycin C are dissolved in dimethyl sulfoxide, and the mixed solution is continuously stirred for 10 hours. Then adding the medicine mixed solution into a spraying machine, and spraying all the surfaces of the monofilaments 30 of the patent ductus arteriosus occluder at a spraying speed of 0.05 mL/min. After the spraying is finished, the plugging device is placed into a vacuum oven, the temperature is set to be 40 ℃, the time is 1 day, and the plugging device is obtained after drying. A cross-sectional view of a monofilament 30 with an expandable coating 50 and a drug coating 40 attached in sequence is shown in fig. 4. The thickness of the drug coating 40 is 500 μm, the mass of the pharmaceutically active ingredient being 5% w/w of the total mass of the drug coating 40. The thickness of the expandable coating 50 is 500 μm and the expandable material in the expandable coating 50 expands upon contact with water by a volume factor of 170.
Example 4 (atrial septal defect occluder, inflatable coating and drug coating in sequence coated on all surfaces of occluder monofilament)
The atrial septal defect occluder 1 is subjected to plasma treatment for 20min to increase the hydrophilicity of the surface of the atrial septal defect occluder 1. As shown in fig. 1 and 2, the atrial septal defect occluder 1 is an occluder in which a disk-shaped net 10 and a tubular net 20, which are woven from monofilaments 30 of polylactide material, are integrally formed. Then preparing a polyacrylic acid solution with the concentration of 20% w/v, and adding 2% w/v of photoinitiator tetraphenylgermane into the solution. Immersing the atrial septal defect occluder 1 into the solution, dip-coating and slowly rotating, using a 400nm ultraviolet lamp to enable polyacrylic acid to be cross-linked and solidified for 20min, taking out and drying after completion, wherein the drying temperature is 45 ℃ and the drying time is 2 days. Next, the drug carriers, polyglycolide and rapamycin, were dissolved in methylene chloride, and the mixture was continuously stirred for 6 hours. Then adding the medicine mixed solution into a spraying machine, and spraying all the surfaces of the monofilaments 30 of the atrial septal defect occluder 1 at a spraying speed of 0.1 mL/min. After the spraying is finished, the plugging device is placed into a vacuum oven, the temperature is set to be 35 ℃, the time is 8 days, and the plugging device is obtained after drying. A cross-sectional view of a monofilament 30 with an expandable coating 50 and a drug coating 40 attached in sequence is shown in fig. 4. Wherein the thickness of the drug coating 40 is 1000 μm, and the mass of the pharmaceutically active ingredient accounts for 1% w/w of the total mass of the drug coating 40. The thickness of the expandable coating 50 is 5 μm, and the expandable material in the expandable coating 50 expands by a volume factor of 200 upon contact with water.
The expandable coating 50 in this embodiment is on all surfaces of the monofilament 30 of the atrial septal defect occluder and the drug coating 40 is the outermost layer on all surfaces of the monofilament 30. The drug coating in the embodiment can greatly reduce keloid caused by clamping and rubbing of the atrial septal defect occluder on tissues. Moreover, the size of the waist of the occluder can be selected to be the same as the size of the defect, and the occluder with the waist larger than the defect part by 2-6mm is not needed, so that the size of the sheath used is reduced, the support effect at the defect part is better, and the incidence rate of the occluder falling off is further reduced.
Example 5 (left atrial appendage occluder with a single coating of drug containing material mixed with expandable material applied to the outer surface of the disk and tubular meshes of the occluder)
Dissolving drug carriers polyhydroxybutyrate and corticosteroid in dimethylacetamide, and continuously stirring the mixed solution for 10 hours to obtain a drug mixed solution; simultaneously preparing an acrylamide solution with the concentration of 8% w/v, and adding 1% w/v of photoinitiator dibenzoyl diethylgermane into the solution to obtain an expandable material solution; the drug mixture is then mixed with the expandable material solution to form a single coating 60 mixture. And then carrying out plasma treatment on the left atrial appendage occluder for 15min so as to increase the hydrophilicity of the surface of the left atrial appendage occluder. The left auricle occluder is an occluder formed by integrally weaving a disc-shaped net and a tubular net which are woven by monofilaments 30 made of polyhydroxybutyrate. The outer surfaces of the disc-shaped mesh and the tubular mesh of the left atrial appendage occluder are brushed with the mixed solution of the single coating 60. The outer surface of the left auricle occluder refers to a surface which can be directly touched by a human hand when the occluder is in vitro or a surface directly impacted by blood when the occluder is placed in vivo. A cross-sectional view of the monofilament 30 with a single coating 60 of scar inhibiting medication and swellable material is shown in figure 5. the single coating 60 is applied to all outer surfaces 301 of the monofilament, i.e., the surfaces that the individual's hands can directly touch when the occluder is in vitro or directly impacted by blood when placed in vivo. After the brush coating is finished, a 280nm ultraviolet lamp is used for crosslinking and curing the acrylamide for 16min, and the acrylamide is dried after the crosslinking and curing is finished, wherein the drying temperature is 45 ℃ and the drying time is 2 days. Wherein the thickness of the single coating 60 is 500 μm, the mass of the pharmaceutically active ingredient accounts for 15% w/w of the total mass of the single coating 60, and the volume multiple of the expandable material in the single coating 60 after being exposed to water is 90.
Example 6 (ventricular septal defect occluder, setting a single coating of drug-containing material mixed with expandable material applied to the outer surface of disk-shaped and tubular meshes of the occluder)
Dissolving drug carriers of polydioxanone and paclitaxel in dimethyl sulfoxide, and continuously stirring the mixed solution for 16h to obtain a drug mixed solution; meanwhile, preparing a polyethylene glycol solution with the concentration of 3% w/v, and adding 0.1% w/v of photoinitiator 2-hydroxy-2-methylpropylphenol into the solution to obtain an expandable material solution; the drug mixture is then mixed with the expandable material solution to form a single coating 60 mixture. Then, the ventricular septal defect occluder is subjected to plasma treatment for 3min to increase the hydrophilicity of the surface of the ventricular septal defect occluder. The ventricular septal defect occluder is formed by integrally weaving a disc-shaped net 10 and a tubular net 20 which are made of monofilaments 30 made of polydioxanone. And then adding the mixed solution of the single coating into a spraying machine, and spraying the outer surfaces of the disc-shaped net and the tubular net of the ventricular septal defect occluder at a spraying speed of 0.1 mL/min. The outer surface of the ventricular septal defect occluder refers to a surface which can be directly touched by hands when the occluder is in vitro or a surface directly impacted by blood when the occluder is placed in vivo. After the spraying is finished, a 365nm ultraviolet lamp is used for crosslinking and curing the polyethylene glycol for 10s, and the polyethylene glycol is dried after the curing is finished, wherein the drying temperature is 50 ℃ and the drying time is 12 hours. A cross-sectional view of a monofilament 30 having attached thereto a single coating 60 comprising a scar inhibiting drug and a swellable material is shown in FIG. 5, wherein the thickness of the single coating 60 is 1000 μm, the mass of the pharmaceutically active ingredient is 30% w/w of the total mass of the single coating 60, and the swellable material in the single coating 60 swells with water by a factor of 3.
Example 7 (patent foramen ovale stopper with a single coating of a mixture of drug-containing material and expandable material applied to the outer surface of the disk-shaped and tubular meshes of the stopper)
Dissolving drug carrier polyglycolide and triclosan in dichloromethane, and continuously stirring the mixed solution for 6h to obtain a drug mixed solution; meanwhile, preparing a polyethyleneimine solution with the concentration of 20% w/v, and adding 2% w/v of photoinitiator phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide into the solution to obtain an expandable material solution; the drug mixture is then mixed with the expandable material solution to form a single coating 60 mixture. Then, the patent foramen ovale occluder is subjected to plasma treatment for 20min so as to increase the hydrophilicity of the surface of the patent foramen ovale occluder. The patent foramen ovale occluder is an occluder formed by integrally forming a disc-shaped net and a tubular net which are woven by monofilaments 30 made of poly (glycolide-lactide). And adding the mixed solution of the single coating into a spraying machine, and spraying the outer surfaces of the disc-shaped net and the tubular net of the patent foramen ovale stopper at a spraying rate of 0.03 mL/min. The outer surface of the patent foramen ovale stopper refers to the surface which can be directly touched by hands when the stopper is in vitro or the surface which is directly impacted by blood when the stopper is placed in vivo, wherein the surface is formed after monofilament weaving is completed. And after the spraying is finished, a 400nm ultraviolet lamp is used for crosslinking and curing the polyethyleneimine for 20min, and the polyethyleneimine is dried after the curing is finished, wherein the drying temperature is 60 ℃ and the drying time is 6 hours. A cross-sectional view of a monofilament 30 having attached thereto a single coating 60 comprising a scar inhibiting drug and a swellable material is shown in FIG. 5, wherein the thickness of the single coating 60 is 5 μm, the mass of the pharmaceutically active ingredient is 1% w/w of the total mass of the single coating 60, and the swellable material in the single coating 60 swells with water by a factor of 200.
The occluders of embodiments 2-7 can also achieve better effects of inhibiting scar hyperplasia and reducing the incidence of residual shunt.
Example 8 (atrial septal defect occluder with a single coating of drug containing material mixed with expandable material applied to all surfaces of the disk and tubular meshes of the occluder)
Dissolving drug carriers of polydioxanone and warfarin in dimethyl sulfoxide, and continuously stirring the mixed solution for 8 hours to obtain a drug mixed solution; meanwhile, preparing a polyethylene glycol solution with the concentration of 10% w/v, and adding 0.05% w/v of photoinitiator dibenzoyl diethylgermane into the solution to obtain an expandable material solution; the drug mixture is then mixed with the expandable material solution to form a single coating 60 mixture. The surface of the atrial septal defect occluder 1 is then subjected to a plasma treatment for 5 seconds to increase the hydrophilicity of the surface of the atrial septal defect occluder 1. The atrial septal defect occluder is formed by integrally forming a disc-shaped net 10 and a tubular net 20 which are made of polydioxanone. Dip-coating all the surfaces of the disc-shaped net and the tubular net of the atrial septal defect occluder, and after the dip-coating is finished, using an ultraviolet lamp with the wavelength of 370nm to enable polyethylene glycol to be crosslinked and cured for 30s, and drying after the completion, wherein the drying temperature is 40 ℃ and the drying time is 5 days. An atrial septal defect occluder attached with a single coating 60 containing warfarin, a drug that antagonizes blood clotting, and an expandable material is shown in fig. 1, in which the thickness of the single coating 60 is 20 μm, the mass of the pharmaceutically active ingredient accounts for 5% w/w of the total mass of the single coating 60, and the volume multiple of the expandable material in the single coating 60 that expands upon contact with water is 170.
The single coating in the embodiment can greatly reduce the surface thrombosis of the implanted plugging device after the implantation of the plug, and improve the postoperative life quality of patients. Moreover, the size of the waist of the occluder can be selected to be the same as that of the atrial septal defect part, and the occluder with the waist 2-6mm larger than the atrial septal defect part is not needed to be used, so that the size of the sheath tube is reduced, the supporting effect at the atrial septal defect part is better, the falling incidence rate of the atrial septal defect occluder is further reduced, the adaptation diseases are increased, and smaller children can accept the interventional operation.
Example 9 (patent ductus arteriosus occluder with drug coating and expandable coating applied to the surface of the flow-obstructing membrane of the occluder in sequence)
Dissolving polyhydroxyalkanoate and 5-fluorouracil in dimethylacetamide to obtain a medicine mixed solution, and continuously stirring the medicine mixed solution for 14 hours. And then adding the medicine mixed solution into a spraying machine, rotationally coating one side surface of the flow blocking film 70 of the patent ductus arteriosus occluder, and drying to obtain the flow blocking film with the medicine coating 40, wherein the drying temperature is 50 ℃ and the drying time is 2 days. Then, the flow-obstructing membrane attached with the drug coating 40 for inhibiting scar hyperplasia was subjected to plasma treatment for 5min to increase the hydrophilicity of the flow-obstructing membrane surface. Wherein, the patent ductus arteriosus occluder is an occluder which is integrally formed by a disc-shaped net and a tubular net which are made of polyhydroxyalkanoate materials. Then, a polyallylamine solution with a concentration of 10% w/v was prepared, and 0.5% w/v of a photoinitiator tetraphenylgermane was added to the solution. The surface of the fluid-resistant membrane on the side having the drug coating is then brushed with a solution containing the swellable material. And (3) crosslinking and curing the polyallylamine by using an ultraviolet lamp with the wavelength of 375nm for 12min, taking out after the curing, and drying at the drying temperature of 50 ℃ for 2 days to obtain a choked flow film 7011 with a double coating attached to one side surface, as shown in fig. 8. The flow blocking film 7011 with the double coating on one side surface is placed into the disc-shaped net and the tubular net in the patent ductus arteriosus occluder to match the sizes of the disc-shaped net and the tubular net, as shown in fig. 6, and the flow blocking film 701 with the double coating in fig. 6 refers to the flow blocking film 7011 with the double coating on one side surface in the embodiment. Wherein the thickness of the drug coating 40 is 10 μm, and the mass of the pharmaceutically active ingredient accounts for 20% w/w of the total mass of the drug coating 40. The thickness of the expandable coating 50 is 100 μm and the expandable material in the expandable coating 50 expands upon contact with water by a volume factor of 8.
Example 10 (patent ductus arteriosus occluder, expandable coating and drug coating in sequence coated on the surface of the flow-obstructing membrane of the occluder)
And carrying out plasma treatment on the flow resisting membrane of the plugging device for 10min to increase the hydrophilicity of the surface of the flow resisting membrane. Then preparing a four-arm polyethylene glycol amine with the concentration of 16% w/v and a four-arm polyethylene glycol succinimide ester solution with the concentration of 16% w/v. Placing the flow-resisting film into a mould for preparing a coating, injecting the solution into the mould, preparing the coating on the surface of the flow-resisting film by a mould filling and coating method, so that the four-arm polyethylene glycol amine and the four-arm polyethylene glycol succinimide ester are crosslinked and cured, and then taking out and drying the film at the drying temperature of 45 ℃ for 2 days. Then, the drug carriers polyamino acid and verapamil are dissolved in dimethyl sulfoxide, and the mixture is continuously stirred for 8 hours. The blocker film with the expandable coating is then roll coated with a drug solution. After the roll coating is finished, the choking film is put into a vacuum oven, the temperature is set to be 37 ℃, the time is 3 days, and the choking film 7012 with double coatings attached to the surfaces of both sides is obtained after drying. An enlarged side view of the flow blocking film 7012 with the double coating layers attached to both side surfaces is shown in fig. 9. The patent ductus arteriosus occluder is an occluder which is integrally formed by a disc-shaped net and a tubular net which are made of polycaprolactone materials. The flow blocking film 7012 with the double coating layers attached to both side surfaces is placed in the disk-shaped net and the tubular net in the patent ductus arteriosus occluder to match the size of the disk-shaped net and the tubular net, as shown in fig. 6, and the flow blocking film 701 with the double coating layers attached to the two side surfaces in fig. 6 refers to the flow blocking film 7012 with the double coating layers attached to both side surfaces in the present embodiment. The thickness of the drug coating 40 is 300 μm with the mass of the pharmaceutically active ingredient accounting for 10% w/w of the total mass of the drug coating 40. The thickness of the expandable coating 50 is 6 μm, and the expandable material in the expandable coating 50 expands with water by a volume factor of 100.
Example 11 (atrial septal defect occluder with a single coating of drug-containing material mixed with swellable material applied to the surface of the occluding membrane)
Dissolving drug carriers of poly (trimethylene carbonate) and allopurinol in dimethylacetamide, and continuously stirring the mixed solution for 14h to obtain drug mixed solution; simultaneously preparing a four-arm polyethylene glycol amine with the concentration of 14% w/v and a four-arm polyethylene glycol succinimide glutarate solution with the concentration of 14% w/v to obtain an expandable material solution; the drug mixture is then mixed with the expandable material solution to form a single coating 60 mixture. Then the flow-resisting membrane in the atrial septal defect occluder is subjected to plasma treatment for 6min to increase the hydrophilicity. The atrial septal defect occluder is an occluder which is integrally formed by a disc-shaped net and a tubular net which are made of poly (glycolide-lactide). And (3) carrying out roller coating on the choking membrane 70 by using the solution, after the roller coating is finished, crosslinking and curing the four-arm polyethylene glycol amine and the four-arm polyethylene glycol succinimide glutarate, and drying at 35 ℃ for 8 days to obtain the choking membrane 702 with single coatings attached to the surfaces of two sides. The flow-blocking membranes 702 with single coatings on both sides are placed into the disc-like and tubular meshes in the atrial septal defect occluder to match the size of the disc-like and tubular meshes, as shown in figures 7 and 10. Wherein the thickness of the single coating layer 60 is 100 μm, the mass of the pharmaceutical active ingredient accounts for 25% w/w of the total mass of the single coating layer 60, and the volume multiple of the expandable material in the single coating layer 60 expanded after contacting water is 5.
The occluders of examples 9-11 also achieve better effects of inhibiting scar hyperplasia and reducing the incidence of residual shunt.
Claims (10)
1. An occluder containing a composite coating is characterized by comprising an occluder and a composite coating, wherein the occluder is formed by integrally forming a disc-shaped net and a tubular net; the composite coating comprises a double coating of a drug coating for inhibiting scars and/or antagonizing hemagglutination and an expandable coating, or comprises a single coating formed by mixing a drug raw material for inhibiting scars and/or antagonizing hemagglutination and an expandable material;
the setting mode of the composite coating is as follows:
mode A: the composite coating is formed on the surface of the occluder;
and/or, mode B: the composite coating is formed on the surface of a flow-blocking film in the stopper.
2. The occlusion device of claim 1, wherein the disc-shaped mesh and the tubular mesh are woven from monofilaments; when the disc-shaped net and the tubular net are woven by monofilaments, the surface of the occluder is the monofilament surface of the occluder; wherein, the monofilament surface refers to all surfaces of the monofilament or the outer surface of the stopper formed after the monofilament is woven;
and/or the surface of the flow resistance film is the surface of two sides of the flow resistance film or the surface of one side of the flow resistance film;
and/or the occluder is an atrial septal defect occluder, an arterial duct patent occluder, an ventricular septal defect occluder, a patent foramen ovale occluder, a left atrial appendage occluder, a blood vessel occluder or a cavity embolism device.
3. The occlusion device of claim 1, wherein the occlusion device is made of a bioabsorbable material or other non-bioabsorbable material, preferably a bioabsorbable material; preferably, the bioabsorbable material comprises polylactide, polyglycolide, polycaprolactone, polydioxanone, polyhydroxybutyrate, polyhydroxyalkanoate, polyanhydride, polyphosphate, polyurethane or polycarbonate, and derivatives, blends of two or more thereof or copolymers of the corresponding monomers;
and/or, when the composite coating is a double coating, the drug coating comprises an active layer consisting of a drug active ingredient and a drug carrier;
wherein the mass of the active pharmaceutical ingredient in the drug coating layer preferably accounts for 1-30% w/w of the total mass of the drug coating layer; more preferably 5-25% w/w of the total mass of the drug coating;
and/or the drug coating also comprises a slow release layer coated on the outer surface of the active layer;
and/or the mass concentration of the expandable material in the expandable material solution is 3-20% w/v;
and/or the thickness of the expandable coating or the drug coating is 5-1000 μm;
and/or the volume multiple of the expandable material in the expandable coating after being expanded when meeting water is 3-200, preferably 5-170.
4. The occlusion device of claim 1, wherein when the composite coating is a single coating, the drug material comprises a pharmaceutically active ingredient and a drug carrier;
wherein, the mass of the active ingredients in the raw materials preferably accounts for 1-30% w/w of the total mass of the single coating, and more preferably accounts for 5-25% w/w of the total mass of the single coating;
and/or the mass concentration of the expandable material in the expandable material solution is 3-20% w/v;
and/or the thickness of the single coating is 5-1000 μm;
and/or the volume multiple of the expandable material in the single coating expanding after meeting water is 3-200, preferably 5-170.
5. The occluding device of claim 3 or 4, wherein the pharmaceutically active ingredient comprises 5-fluorouracil, mitomycin C, dexamethasone, rapamycin, prednisone, corticosteroids, silicone, retinoids, tranilast, verapamil, allopurinol, antihistamines, paclitaxel, triclosan, interleukin antibodies, immunosuppressants, heparin, clopidogrel, aspirin, dipyridamole, warfarin, dicoumarin, rivaroxaban, dabigatran, apixaban, edoxaban, or transforming growth factor antibodies, and derivatives or mixtures thereof;
and/or, the drug carrier or the slow release layer is a bioabsorbable material; preferably, the bioabsorbable material comprises polycaprolactone, polylactide, polyglycolide, polydioxanone, polytrimethylene carbonate, polyhydroxybutyrate, polyhydroxyalkanoate, polyanhydride, polyphosphate, polyamino acid, cellulose, collagen or chitosan, and derivatives, blends of two or more of them or copolymers of the corresponding monomers;
and/or the swellable material comprises polyvinyl alcohol, polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, acrylamide, polyacrylic acid, hydrolyzed polyacrylonitrile, polyethyleneimine, ethoxylated polyethyleneimine, polyallylamine, polysuccinimidyl ester, polysuccinimidyl glutarate, polyethylene glycol amine, polyhydroxyethylmethacrylate, polylysine, polyethyleneimine, trilysine, four-arm polyethylene glycol amine, four-arm polyethylene glycol succinimide ester, four-arm polyethylene glycol succinimide glutarate, four-arm polyethylene glycol succinimide succinate, four-arm polyethylene glycol succinimide carbonate, hyaluronic acid, chitosan, collagen, gelatin, fibrin, dextran or agarose, and derivatives, blends of two or more thereof, or copolymers of the corresponding monomers.
6. The occlusion device of claim 1, wherein the double coating is disposed in any one of four ways:
the first method is as follows: the surface of the stopper is sequentially provided with a double coating of a drug coating and an expandable coating;
the second method comprises the following steps: the surface of the flow-resistant film in the plugging device is sequentially provided with a double coating of a drug coating and an expandable coating;
the third method comprises the following steps: the surface of the stopper is sequentially provided with a double coating of an expandable coating and a drug coating;
the method is as follows: the surface of the flow-resistant film in the plugging device is sequentially provided with a double coating of an expandable coating and a drug coating;
or the single coating layer is arranged in any one of the following two ways:
the fifth mode is as follows: the surface of the plugging device is provided with a single coating formed by mixing a raw material containing a medicament for inhibiting scars and/or antagonizing hemagglutination and a material containing an expandable material;
the method six: the surface of the flow-resisting film in the blocking device is provided with a single coating layer formed by mixing the medicine raw material containing scar-inhibiting and/or anti-hemagglutination and the expandable material.
7. The method for preparing the occlusion device according to any one of claims 1-6, wherein when the composite coating is a double coating, the coating process in the preparation method is applied according to any one of the following four ways:
the first scheme is as follows: sequentially coating a medicine mixed solution formed by medicine raw materials and an expandable material solution formed by an expandable material on the surface of the stopper;
scheme II: sequentially coating a medicine mixed solution formed by medicine raw materials and an expandable material solution formed by an expandable material on the surface of the flow-resisting membrane of the occluder;
the third scheme is as follows: sequentially coating an expandable material solution formed by an expandable material and a medicine mixed solution formed by medicine raw materials on the surface of the stopper;
and the scheme is as follows: sequentially coating an expandable material solution formed by an expandable material and a medicine mixed solution formed by medicine raw materials on the surface of the flow-resisting membrane of the occluder;
when the composite coating is a single coating, the coating process in the preparation method is applied in any one of the following two ways:
and a fifth scheme: mixing a medicine mixed solution formed by medicine raw materials with an expandable material solution formed by an expandable material, and coating the mixture on the surface of the occluder;
scheme six: and mixing a medicine mixed solution formed by the medicine raw materials with an expandable material solution formed by an expandable material, and coating the mixture on the surface of the flow-resisting membrane of the occluder.
8. The method of claim 7, wherein when coating in scheme one or scheme two, the coating process comprises the steps of: (1) coating a medicine mixed solution formed by medicine raw materials on the surface of the plugging device in the mode A and/or the surface of the flow resisting membrane in the mode B, and drying; (2) performing plasma treatment on the surface of the occluder in the mode A and/or the surface of the flow-resisting membrane in the mode B attached with the drug coating; (3) coating an expandable material solution formed by an expandable material on the surface of the occluder in the mode A and/or the surface of the flow blocking membrane in the mode B, then performing crosslinking curing, and drying;
when coated in scheme three or scheme four, the process of coating comprises the steps of: (1) performing plasma treatment on the surface of the occluder in the mode A and/or the surface of the flow-resisting membrane in the mode B; (2) coating an expandable material solution formed by an expandable material on the surface of the occluder in the mode A and/or the surface of the flow blocking membrane in the mode B, and then drying after crosslinking and curing; (3) coating the surface of the plugging device in the mode A and/or the surface of the flow-resisting membrane in the mode B with the expandable coating by using a medicine mixed solution formed by medicine raw materials, and drying;
when coating in scheme five or scheme six, the process of coating comprises the following steps; (1) mixing a medicine mixed solution formed by medicine raw materials with an expandable material solution formed by an expandable material to obtain a mixed solution with a single coating; (2) performing plasma treatment on the surface of the occluder in the mode A and/or the surface of the flow-resisting membrane in the mode B; (3) and (3) coating the mixed solution of the single coating on the surface of the plugging device in the mode A and/or the surface of the flow resisting membrane in the mode B, and then performing crosslinking curing and drying.
9. The method according to claim 8, wherein in the first to sixth embodiments, when the surface of the coated stopper is all the surfaces of the stopper or when the flow-blocking film coating the stopper is both-side surfaces, the coating is spray coating, brush coating, die filling coating, dip coating, roll coating, spin coating, electrodeposition or vacuum vapor deposition; or when the surface of the coated stopper is the outer surface of the stopper or when one side surface of a flow-resistant film in the stopper is coated, the coating is spraying, brushing, rolling, rotary coating, electrodeposition or vacuum vapor deposition;
and/or, in schemes one-six, the formation of the drug mixed solution comprises the operation of stirring the drug active ingredient, the solvent and the drug carrier in the drug mixed solution; preferably, the stirring time is 6-16 h;
and/or in the first to sixth schemes, the drying temperature is 35-60 ℃;
and/or, in the first to sixth schemes, the drying time is 6 hours to 8 days;
and/or, in the first to sixth schemes, the solvent in the drug mixture solution comprises one or more of dichloromethane, dimethylacetamide and dimethyl sulfoxide, preferably dichloromethane;
and/or in the first to sixth schemes, the mass concentration of the expandable material in the expandable material solution is 3-20% w/v;
and/or, in the first to sixth schemes, the plasma treatment time is 5 s-20 min;
and/or, in the first to sixth schemes, the crosslinking curing mode adopts chemical reaction, warm curing, photocuring, electromagnetic radiation or ionizing radiation.
10. The method according to claim 9, wherein in the first to sixth embodiments, the spraying is performed by a spray coater; preferably, the spraying speed of the spraying machine is 0.03-0.1 mL/min;
and/or, in the first to sixth schemes, the operation of crosslinking and curing adopts a photo-curing method: the photocuring is preferably performed by irradiating the stopper coated with the expandable material solution by using an ultraviolet lamp of 280-400 nm; the irradiation time of the ultraviolet lamp is preferably 10 s-20 min, more preferably 30 s-16 min;
and/or the expandable material solution further comprises a photoinitiator, and the mass concentration of the photoinitiator is preferably 0.05-2% w/v;
wherein the photoinitiator is 1- [4- (2-hydroxyethoxy) -phenyl ] -2-hydroxy-2-methyl-1-propane-1-one, 2-hydroxy-2-methylpropanol, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide, dibenzoyldiethylgermane or tetraphenylgermane.
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