WO2023083086A1 - Cathéter à ballonnet revêtu de médicament et à élution de médicament, et son procédé de préparation - Google Patents

Cathéter à ballonnet revêtu de médicament et à élution de médicament, et son procédé de préparation Download PDF

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Publication number
WO2023083086A1
WO2023083086A1 PCT/CN2022/129463 CN2022129463W WO2023083086A1 WO 2023083086 A1 WO2023083086 A1 WO 2023083086A1 CN 2022129463 W CN2022129463 W CN 2022129463W WO 2023083086 A1 WO2023083086 A1 WO 2023083086A1
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drug
glycero
microspheres
balloon
adhesive
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PCT/CN2022/129463
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English (en)
Chinese (zh)
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马勤川
潘远航
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上海博脉安医疗科技有限公司
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Publication of WO2023083086A1 publication Critical patent/WO2023083086A1/fr

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    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/148—Materials at least partially resorbable by the body
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • 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
    • A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
    • 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
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • 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
    • 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
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes

Definitions

  • the invention relates to the field of drug equipment preparation, in particular to a drug coating, a drug-eluting balloon catheter and a preparation method thereof.
  • the main means of treating vascular stenosis is implantation of drug-eluting stents.
  • patients need to take antithrombotic drugs orally for a long time and affect subsequent surgical treatment, and there is a problem of late stent thrombosis. Therefore, as a new interventional medical concept, "intervention without implantation" is being accepted by more and more clinicians and patients, and drug-eluting balloon (DCB) is a new type of interventional treatment concept. product.
  • DCB drug-eluting balloon
  • drug-eluting balloons are coated with anti-proliferative drugs on the surface of the balloon.
  • the drug carried on the surface of the balloon is quickly transferred to the blood vessel wall and retained for a period of time, thereby inhibiting the proliferation of the vascular intimal.
  • Human clinical studies have confirmed that the restenosis of blood vessels at the lesion usually occurs 1 to 3 months after balloon angioplasty, and the restenosis reaches the peak at about 3 months, which requires the drugs on the balloon to penetrate into the blood vessels In the wall, and the effective drug concentration is maintained long enough to minimize restenosis.
  • the drug balloons on the market mainly use paclitaxel as an anti-proliferative drug, among which paclitaxel-releasing balloon catheter Sequence Please from Braun, Germany is the representative. Because rapamycin is poorly fat-soluble, it cannot penetrate into the blood vessel wall quickly, and its retention time in the tissue is short, so the therapeutic effect is not good, so it is difficult to apply to drug balloons. At present, there is no rapamycin drug in China. Balloon listing. In foreign countries, the Magic Touch balloon catheter of the medical equipment company Concept Medical uses rapamycin nanocrystals as an anti-proliferative drug for the drug balloon, but the retention time of the tissue concentration is short, less than 1 month. M.A.
  • rapamycin microspheres as an anti-proliferation drug for drug balloons, and its technical route adopts recyclable liposome technology, which has been widely used in anti-tumor drugs, but the production process Spraying with heptane has disadvantages such as poor coating uniformity and low drug stability. Therefore, the drug balloon currently on the market is mainly paclitaxel.
  • paclitaxel itself can inhibit the proliferation of smooth muscle cells by acting on cells to cause apoptosis or death, that is, paclitaxel has certain cytotoxicity. Rapamycin and its derivatives achieve the purpose of anti-proliferation through a cytostatic mechanism, that is, acting on cells to stop their growth.
  • rapamycin In view of the fact that the safety of rapamycin is generally better than that of paclitaxel, the safety of rapamycin has been confirmed clinically, and it has been widely used in drug stents. Therefore, a drug coated with rapamycin was developed.
  • the drug balloon dilatation catheter will have a wide range of application scenarios.
  • the object of the present invention is to provide a drug coating, a drug-eluting balloon catheter and a preparation method thereof, which solve the problems of poor drug tissue absorption and short retention time in tissues.
  • a drug coating including drug microspheres, an adhesive and a dispersant, and the drug microspheres are made by encapsulating drugs with biological materials.
  • the biomaterial is racemic polylactic acid or poly(lactic-co-glycolic acid).
  • the drug is a fat-soluble drug.
  • the drug is one or more of macrolide immunosuppressants, rapamycin, eulimus, everolimus, rapamycin, zotarolimus mix.
  • the adhesive is phospholipid and/or cholesterol.
  • the adhesive is 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-SN-glycero-3-phosphocholine (DPPC), 1,2-Dierucoyl-SN-glycero-3-phosphorylcholine (DEPC), 1,2-dimyristoyl-SN-glycero-3-phosphorylcholine (DMPC), 1 , A mixture of one or more of 2-distearoyl-SN-glycero-3-phosphocholine (DSPC) and cholesterol.
  • DOPC 1,2-dioleoyl-SN-glycero-3-phosphocholine
  • DPPC 1,2-dipalmitoyl-SN-glycero-3-phosphocholine
  • DEPC 1,2-Dierucoyl-SN-glycero-3-phosphorylcholine
  • DMPC 1,2-dimyristoyl-SN-glycero-3-phosphorylcholine
  • the dispersant is PEGylated liposomes and/or polyethylene oxide.
  • the dispersant is 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000), 1 ,2-Distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-rac-glycerol- A mixture of one or more of 3-methoxy polyethylene glycol 2000 (DMG-PEG2000) and polyethylene oxide.
  • the mass ratio of the adhesive to the dispersant is 1:1 ⁇ 10:1.
  • the mass ratio of the drug microspheres to the adhesive is 1:0.5 ⁇ 1:5.
  • a drug-eluting balloon catheter including a balloon: the above-mentioned drug coating is provided on the balloon.
  • Step 1 making the drug microspheres by encapsulating the drug with the biological material
  • Step 2 mixing the adhesive and the dispersant with water
  • Step 3 mixing the drug microspheres obtained in step 1 with the solution obtained in step 2;
  • Step 4 using the needle coating method to apply the solution obtained in step 3 to the balloon surface of the drug-eluting balloon catheter.
  • the biological material is racemic polylactic acid or polylactic acid-glycolic acid copolymer
  • the drug is a macrolide immunosuppressant, rapamycin, umelimus, everolimus , rapamycin, a mixture of one or more of zotarolimus
  • the adhesive is 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2 -Dipalmitoyl-SN-glycero-3-phosphorylcholine (DPPC), 1,2-Dierucoyl-SN-glycero-3-phosphorylcholine (DEPC), 1,2-dimyristoyl-SN - a mixture of one or more of glycerol-3-phosphorylcholine (DMPC), 1,2-distearoyl-SN-glycero-3-phosphorylcholine (DSPC), cholesterol;
  • the dispersant is 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene
  • anti-proliferation drugs are wrapped with degradable biomaterials, made into microspheres, and then the microspheres are coated on the surface of the balloon with excipients; the excipients contain adhesives and dispersants,
  • the adhesive agent can adhere the microspheres to the vessel wall, and the dispersant is to fully disperse the microspheres, increase the lubricity of the coating, promote drug absorption, and solve the problem of drug tissue absorption. Poor ability, short retention time in the organization, etc.
  • Fig. 1 is a schematic diagram of the structure of a balloon catheter according to an embodiment of the present invention
  • Fig. 2 is a schematic structural view of the winding of the balloon according to the embodiment of the present invention.
  • Fig. 3 is a schematic diagram of the microsphere structure of the encapsulated drug of the embodiment of the present invention.
  • Figure 4 is a scanning electron micrograph of the microspheres prepared in Example 1 of the present invention.
  • Figure 5 is a scanning electron micrograph of the balloon drug coating prepared in Example 2 of the present invention.
  • FIG. 6 is an angiogram of the superficial femoral artery before the balloon implantation according to an embodiment of the present invention
  • Fig. 7 is an angiogram of the superficial femoral artery during balloon implantation according to an embodiment of the present invention.
  • Fig. 8 is an angiogram of the superficial femoral artery after balloon implantation according to an embodiment of the present invention.
  • Example embodiments will now be described more fully with reference to the accompanying drawings.
  • Example embodiments may, however, be embodied in many forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the example embodiments to those skilled in the art.
  • the same reference numerals denote the same or similar structures in the drawings, and thus their repeated descriptions will be omitted.
  • a drug coating, a drug-eluting balloon catheter and a preparation method thereof are provided.
  • FIG. 1 it is a typical drug-eluting balloon catheter, including a drug-coated balloon.
  • the drug coating on the balloon is transferred to the vessel wall.
  • the drug coating on the drug-eluting balloon catheter balloon of the embodiment of the present invention includes drug microspheres, an adhesive and a dispersant.
  • Drug microspheres are made by encapsulating drugs in biological materials.
  • the above-mentioned method for preparing a drug-eluting balloon catheter includes the following steps:
  • Step 1 making microspheres by encapsulating drugs with biomaterials
  • Biomaterials are a type of natural or synthetic special functional materials that are used to contact and interact with living systems, and can diagnose, treat, replace, repair, or induce regeneration of their cells, tissues, and organs, also known as biomedical materials.
  • the anti-proliferation drug is wrapped with a degradable biological material and made into a microsphere form.
  • the degradable biomaterial is preferably racemic polylactic acid (PDLLA), poly(lactic-co-glycolic acid) (75% DL-lactide/25% glycolide copolymer, PLGA). And preferably, the viscosity range of PDLLA is 0.15-0.75 dl/g, and the viscosity range of PLGA is 0.15-0.75 dl/g.
  • the drugs that affect the embedding in the microspheres are fat-soluble drugs, which are macrolide immunosuppressants, rapamycin, eulimus, everolimus, rapamycin, and zotarolimus. One or a mixture of two or more of them.
  • the diameter of the microspheres ranges from 1 to 10 ⁇ m.
  • Step 2 mixing the adhesive and the dispersant with water; preferably, the adhesive and the dispersant are placed in a glass vial, added with water, and stirred magnetically for 3-6 hours to mix.
  • the adhesive is a phospholipid, and preferably a glycerophospholipid and/or cholesterol.
  • 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC)
  • 1,2-dipalmitoyl-SN-glycerol- 3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC)
  • 1,2-dierucoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn- Glycero-3-Phosphatidylcholine, DEPC
  • 1,2-dimyristoyl-SN-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC)
  • the phospholipid adhesives of the embodiments of the present invention have amphiphilic properties, absorb water and swell when in contact with water, have good adhesion, and can adhere drugs to the blood vessel wall, and are not easily washed away by blood flow; at the same time, because the cell membrane
  • the main component of phospholipids is phospholipids. Choosing phospholipids as an adhesive has the advantage of good biocompatibility. Phospholipids can allow drugs to pass through the internal hydrophobic core area of the plasma membrane of endothelial cells and promote drug absorption by the blood vessel wall.
  • Preferred dispersing agents are PEGylated liposomes, ie PEG-liposome derivatives (phospholipids coupled to PEG) and/or polyethylene oxide.
  • the preferred dispersant is 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxyl (polyethylene glycol)-2000 (DSPE-mPEG2000), 1,2-distearyl Acyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-rac-glycerol-3-methoxypoly Ethylene glycol 2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, DMG-PEG2000), one of polyethylene oxide or a mixture of two or more of them.
  • the PEGylated liposome of the embodiment of the present invention has better water solubility and can prevent drug aggregation. After the balloon is expanded in the blood vessel, the coating can be evenly dispersed and it is not easy to cause thrombus. At the same time, PEGylated liposomes can reduce the recognition and uptake of the monocyte-macrophage system, and can passively accumulate liposomes in tissues by enhancing the osmotic retention effect. At the same time, polyethylene oxide has good water solubility, swells after absorbing water, and has lubricity, which can prevent drug aggregation and reduce drug loss during delivery.
  • the mass ratio of the adhesive agent and the dispersant is 1:1 ⁇ 10:1.
  • steps 1 and 2 are not limited.
  • Step 3 mixing the microspheres obtained in step 1 with the solution obtained in step 2, and ultrasonically dispersing;
  • the mass ratio of the microspheres to the adhesive in step 2 is 1:0.5-1:5.
  • Step 4 using the needle coating method to apply the solution obtained in step 3 to the balloon surface of the drug-eluting balloon catheter.
  • Needle coating method that is to use a balloon folding machine to fold the balloon so that the balloon is kept in three or five folded flaps, that is, the cross section of the outer periphery of the balloon has three or five "V" shaped spaces.
  • FIG. 2 it is a schematic structural view of the coiled balloon.
  • the balloon is dried, coiled, and heat-cured to obtain the drug-eluting balloon catheter provided with the drug coating of the embodiment of the present invention.
  • the drug coating, the drug-eluting balloon catheter provided with the drug coating and the preparation method thereof in the embodiments of the present invention solve the problems of poor drug tissue absorption and short retention time in the tissue.
  • PLGA (75% DL-lactide/25% glycolide, viscosity 0.2dl/g);
  • Polyvinyl alcohol (PVA) solution Weigh 20g of polyvinyl alcohol (molecular weight 1.3-23,000 Da, degree of alcoholysis 98%) into a 1L beaker, add 400mL of water, stir in a water bath at 95°C for 30min to dissolve, cool to room temperature, Transfer to a 1L volumetric flask, add water to volume, and store in a 4°C refrigerator.
  • PVA Polyvinyl alcohol
  • microspheres put the microspheres into a vacuum drying oven and dry them at room temperature for 48 hours to prepare the microspheres with a drug loading of 30.2% rapamycin by weight as shown in FIG. 4 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-Dioleoyl-SN-Glycero-3-phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); 1,2-Dipalmitoyl- SN-Glycero-3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC); Cholesterol (Cholesterol);
  • Dispersant polyethylene oxide
  • the coating was dried for 16 hours to obtain a drug-coated balloon catheter, as shown in FIG. 5 , the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm 2 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC); 1,2-dipalmitoyl-SN - glycerol-3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC); cholesterol (Cholesterol);
  • Dispersant polyethylene oxide
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours at room temperature, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm 2 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC); 1,2-dipalmitoyl-SN - glycerol-3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC); cholesterol (Cholesterol);
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours at room temperature, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm 2 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-Dioleoyl-SN-Glycero-3-Phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); Cholesterol;
  • Dispersant 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, DMG-PEG2000) ;
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours at room temperature, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm 2 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-Dioleoyl-SN-Glycero-3-Phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); Cholesterol;
  • Dispersant polyethylene oxide
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours at room temperature, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm 2 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC); 1,2-dimyristoyl- SN-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC); cholesterol (Cholesterol);
  • Dispersant polyethylene oxide
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours at room temperature, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm 2 .
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-Dioleoyl-SN-Glycero-3-phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); -SN-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC); cholesterol (Cholesterol);
  • Dispersant polyethylene oxide
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm2.
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-dipalmitoyl-SN-glycero-3-phosphorylcholine (DPPC), 1,2-dierucoyl-SN-glycero-3-phosphorylcholine (DEPC); cholesterol (Cholesterol);
  • Dispersant 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000);
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm2.
  • Microsphere the rapamycin microsphere that embodiment 1 makes;
  • Binder 1,2-dipalmitoyl-SN-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC); cholesterol ( Cholesterol);
  • Dispersant 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-1000 (DSPE-mPEG1000);
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm2.
  • Rapamycin API crystal form, particle size 30-120 ⁇ m
  • Step 4 Combine the solutions of Step 2 and Step 3, vortex to mix, and ultrasonically disperse until the rapamycin crystals are completely dispersed.
  • the drug-coated balloon catheter was obtained after the coating was dried for 16 hours, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 ⁇ g/mm2.
  • the drug-coated balloon catheters prepared in Examples 2 to 6 and Comparative Example 1 above were folded and wound, covered with a protective sleeve, and sterilized by ethylene oxide for animal experiments. Choose the bare balloon as a control to evaluate the safety of the drug coating. Evaluate the drug transfer/delivery characteristics at 1h, 1d, 7d, and 28d time points and the target tissue uptake of the drug in vivo.
  • mice white pig for experiment; gender: male or female; body weight 35-40kg.
  • the total number of experimental animals 12 cases.
  • Figs. 6-8 they are angiograms of the superficial femoral artery before, during, and after implantation of the balloon, respectively.
  • vessels were immediately stored on dry ice and sent to a third-party testing facility for analysis.
  • Mobile phase mobile phase A: 5mM ammonium acetate (containing 0.05% formic acid); mobile phase B: acetonitrile (containing 0.05% formic acid);
  • the time point 1 hour after implantation is mainly to investigate the performance of the coating on the blood vessel wall (anti-blood flow erosion ability).
  • the drug concentration in the tissue of Comparative Example 1 is 38.1 ⁇ g/g, and the technical solution Example 2
  • the tissue drug concentration was 502.9 ⁇ g/g;
  • the drug absorption effect was mainly investigated at the time point of implantation 1 day.
  • the tissue drug concentration in Comparative Example 1 was 5.4 ⁇ g/g, and the tissue drug concentration in Example 2 of the technical solution was 244.0 ⁇ g/g;
  • the tissue drug concentration in Comparative Example 1 was 0.061 ⁇ g/g, and the tissue drug concentration in Example 2 of the technical solution was 56.1 ⁇ g/g;
  • the drug concentration in the tissue of Example 4 was low because no dispersant was added, the microspheres aggregated, and the coating was uneven; the drug concentration in the tissue of Example 5 was low because DMG-PEG2000 was too water-soluble, and the adhesion of the coating was not outstanding ; Embodiment 6 tissue drug concentration is low because only used adhesive DEPC and cholesterol, coating adhesion is not outstanding.
  • the release time of rapamycin can be prolonged, so that the retention time of rapamycin in tissues can be prolonged.
  • the drug coating of the technical solution of the embodiment of the present invention has good blood vessel adhesion and strong anti-blood flow erosion ability.
  • rapamycin is slowly released, and the retention time in tissues Longer, at 28 days, the tissue drug concentration is still as high as 35.1 ⁇ g/g.
  • a drug-coated, drug-eluting balloon catheter and a preparation method thereof adopt "oleoyl lecithin + palmitoyl lecithin + cholesterol + polyethylene oxide + rapamycin Microspheres", the coating has a better ability to adhere to the blood vessel wall; use different types of phospholipids and hydrophilic compounds, optimize their optimal ratio, and obtain a drug coating that resists blood flow erosion and has good adhesion performance ; The coating can firmly adhere the microspheres to the blood vessel wall without being washed away by the blood flow, and can promote the entry of the microspheres into the vessel wall; rapamycin and PLGA form microspheres in the form of doping, Ray Pamycin is evenly distributed inside the PLGA microspheres.
  • the hydrophilic compound is polyethylene oxide, which can increase the coating Lubricity, and polyethylene oxide swells with water, has strong adhesion properties, solves the problem that rapamycin in the prior art cannot quickly penetrate into the blood vessel wall, and wraps rapamycin Embedded in degradable materials and made into microspheres, the release time of rapamycin can be extended and the retention time of rapamycin in tissues can be extended.
  • the technical solution of the embodiment of the present invention can make rapamycin remain in the tissue for a long time, which has wide application value.

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Abstract

La présente invention concerne un cathéter à ballonnet revêtu de médicament et à élution de médicament, et son procédé de préparation. Le procédé comprend : l'encapsulation d'un médicament avec un matériau biologique pour préparer des microsphères, le mélange des microsphères avec un agent d'adhérence et un dispersant, et le revêtement de la surface de ballonnet d'un cathéter à ballonnet à élution de médicament avec la solution obtenue en utilisant un procédé de revêtement d'aiguille. La présente invention résout les problèmes de capacité médiocre du tissu à absorber un médicament et de temps de rétention court dans le tissu.
PCT/CN2022/129463 2021-11-09 2022-11-03 Cathéter à ballonnet revêtu de médicament et à élution de médicament, et son procédé de préparation WO2023083086A1 (fr)

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CN116271254B (zh) * 2022-07-08 2024-04-02 上海申淇医疗科技有限公司 球囊导管涂层及其制备方法、球囊导管
CN116570775A (zh) * 2023-05-16 2023-08-11 万瑞飞鸿(北京)医疗器材有限公司 一种药物涂层、血管支架及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN205041957U (zh) * 2015-08-28 2016-02-24 上海申淇医疗科技有限公司 一种药物球囊和药物球囊导管
CN107073178A (zh) * 2014-07-18 2017-08-18 M.A.医学联合公司 提供药物微贮库的接触转移的管腔内可扩张导管的涂层
CN108744233A (zh) * 2018-06-28 2018-11-06 山东吉威医疗制品有限公司 一种药物球囊扩张导管及其工艺
CN112867514A (zh) * 2018-10-15 2021-05-28 M.A.医学联合公司 提供药物微贮库的接触转移的管腔内可扩张导管的涂层
US20210259976A1 (en) * 2020-02-21 2021-08-26 GIE Medical, Inc. Polymer-encapsulated drug particles

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107073178A (zh) * 2014-07-18 2017-08-18 M.A.医学联合公司 提供药物微贮库的接触转移的管腔内可扩张导管的涂层
CN205041957U (zh) * 2015-08-28 2016-02-24 上海申淇医疗科技有限公司 一种药物球囊和药物球囊导管
CN108744233A (zh) * 2018-06-28 2018-11-06 山东吉威医疗制品有限公司 一种药物球囊扩张导管及其工艺
CN112867514A (zh) * 2018-10-15 2021-05-28 M.A.医学联合公司 提供药物微贮库的接触转移的管腔内可扩张导管的涂层
US20210259976A1 (en) * 2020-02-21 2021-08-26 GIE Medical, Inc. Polymer-encapsulated drug particles

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