WO2014163097A1 - Balloon catheter for drug administration and process for producing same - Google Patents

Balloon catheter for drug administration and process for producing same Download PDF

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Publication number
WO2014163097A1
WO2014163097A1 PCT/JP2014/059680 JP2014059680W WO2014163097A1 WO 2014163097 A1 WO2014163097 A1 WO 2014163097A1 JP 2014059680 W JP2014059680 W JP 2014059680W WO 2014163097 A1 WO2014163097 A1 WO 2014163097A1
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WO
WIPO (PCT)
Prior art keywords
drug
balloon
balloon catheter
drug administration
layer
Prior art date
Application number
PCT/JP2014/059680
Other languages
French (fr)
Japanese (ja)
Inventor
恵子 山下
英資 古市
Original Assignee
テルモ株式会社
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Filing date
Publication date
Application filed by テルモ株式会社 filed Critical テルモ株式会社
Priority to JP2015510109A priority Critical patent/JP6307492B2/en
Publication of WO2014163097A1 publication Critical patent/WO2014163097A1/en

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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
    • A61L29/14—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
    • 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
    • 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
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • A61L2300/608—Coatings having two or more layers
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers
    • 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
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
    • 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
    • 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
    • A61M2025/1075—Balloon catheters with special features or adapted for special applications having a balloon composed of several layers, e.g. by coating or embedding
    • 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
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril

Definitions

  • the present invention relates to a drug administration balloon catheter and a method for producing the same.
  • paclitaxel which is useful as an antineoplastic agent
  • a water-swellable polymer for example, dimethylacrylamide-glycidyl methacrylate copolymer
  • the drug paclitaxel
  • the affected area for example, the inner wall of the blood vessel
  • the present inventor has found that this phenomenon is caused by the fact that the hydrophobic interaction between the hydrophobic region of the water-swellable polymer (for example, the glycidyl methacrylate region of the copolymer) and the drug is too strong, and these hydrophobic regions are Because of its strong affinity with the balloon surface, the drug is located on the balloon surface side together with the hydrophobic region of the polymer, and the hydrophilic region (for example, dimethylacrylamide region) of the copolymer is placed on top of the drug. Therefore, it was inferred that even when the balloon was in contact with the affected area, the drug was difficult to be released (transferred) from the balloon to the affected area.
  • the hydrophobic region of the water-swellable polymer for example, the glycidyl methacrylate region of the copolymer
  • the drug is located on the balloon surface side together with the hydrophobic region of the polymer, and the hydrophilic region (for example, dimethylacrylamide region) of the copolymer
  • An object of the present invention is to provide a drug administration balloon catheter that can stably hold a drug when delivering the drug to an affected area and can quickly release the drug to the affected area.
  • the present inventor Having a balloon, On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer, A balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer stably holds the drug when delivering the drug to the affected area. It has been found that the drug administration balloon catheter can be quickly released into the affected area simultaneously with the balloon expansion.
  • the inventor of the present application A pre-coating step of forming a copolymer layer by applying a pre-coating composition comprising a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A on the outer surface of the balloon in the balloon catheter;
  • a drug coating composition containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer to form a drug layer
  • the drug administration balloon catheter manufacturing method stably holds the drug when delivering the drug to the affected area, and quickly releases the drug to the affected area simultaneously with the balloon expansion in the affected area.
  • the present inventors have found that a drug administration balloon catheter that can be obtained is obtained.
  • the present invention provides the following drug administration balloon catheter, a manufacturing method thereof, and a treatment method using the same.
  • 1. Having a balloon, On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer, A drug administration balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer.
  • a drug coating composition containing polyethylene glycol and / or polypropylene glycol, paclitaxel and organic solvent B on the copolymer layer to form a drug layer.
  • the method for producing a drug administration balloon catheter according to 7 above wherein the concentration of paclitaxel is 0.3 to 9% by mass in the composition for drug coating. 9. 9. The method for producing a drug administration balloon catheter according to 7 or 8 above, wherein the concentration of the polyethylene glycol and / or polypropylene glycol is 0.1 to 10% by mass in the drug coating composition. 10. 10. The method for producing a drug administration balloon catheter according to any one of 7 to 9 above, wherein the concentration of the dimethylacrylamide-glycidyl methacrylate copolymer is 0.1 to 1% by mass in the precoat composition. 11. 11. The method for producing a drug administration balloon catheter according to any one of 7 to 10, further comprising at least one drying step after the pre-coating step.
  • the drug administration balloon catheter of the present invention can stably hold a drug on the balloon when delivering the drug to the affected area, and can quickly release the drug to the affected area when administering the drug.
  • a drug can be stably held on the balloon when the drug is delivered to the affected area, and can be quickly released to the affected area when the drug is administered.
  • An administration balloon catheter can be manufactured.
  • the drug can be stably held on the balloon when the drug is delivered to the affected area, and the drug can be quickly released simultaneously with the balloon expansion in the affected area when the drug is administered.
  • FIG. 1 is a cross-sectional view schematically showing a part of a drug administration balloon included in the drug administration balloon catheter of the present invention.
  • FIG. 2 is a partial cross-sectional view schematically showing an experimental apparatus used for performing in vitro drug coat layer resistance evaluation in the present invention.
  • FIG. 3 is a partial cross-sectional view schematically showing a state in which the drug administration balloon catheter of the present invention is inserted into an agarose gel tube.
  • FIG. 4 is a graph showing the results of the PTX remaining rate and the PTX transfer rate in the examples of the present invention.
  • 1 is a front view schematically showing one embodiment of a drug administration balloon catheter of the present invention.
  • FIG. 6 is an enlarged cross-sectional view schematically showing a balloon and its vicinity in the drug administration balloon catheter shown in FIG. 5.
  • the drug administration balloon catheter of the present invention comprises: Having a balloon, On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer, A drug administration balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer.
  • the drug administration balloon catheter of the present invention has a specific copolymer layer and a drug layer formed by paclitaxel and polyethylene glycol and / or polypropylene glycol on the outer surface of the balloon, thereby delivering the drug to the affected area.
  • the drug paclitaxel
  • retainability stably held on the balloon
  • Can be released hereinafter sometimes referred to as releasing property).
  • the drug (paclitaxel) is strongly hydrophobic, and the dimethylacrylamide-glycidyl methacrylate copolymer also has a hydrophobic portion (mainly a main chain, a repeating unit of glycidyl methacrylate). Therefore, an affinity due to hydrophobicity occurs between the drug (paclitaxel) and the hydrophobic portion of the dimethylacrylamide-glycidyl methacrylate copolymer (lubricant). Thus, it is considered that paclitaxel is difficult to be released at the affected area and difficult to move to the lumen (tissue).
  • polyethylene glycol and / or polypropylene glycol contained in the drug layer relaxes the affinity between paclitaxel and the base material and / or lubricant, making it easier to release paclitaxel at the affected area and to move to the lumen.
  • the inventor of this application estimates that this is possible.
  • polyethylene glycol and / or polypropylene glycol increases the solubility of water-insoluble drugs and has a relatively high affinity with water-insoluble drugs, polyethylene glycol and / or polypropylene glycol is contained in the drug layer.
  • the drug administration balloon catheter of the present invention is capable of delivering a sufficient amount of drug to the affected area in vivo, with the drug layer hardly eluting from the balloon into water or falling off from the drug layer due to friction or the like. is assumed.
  • the drug administration balloon catheter of the present invention is excellent in the retention of the drug layer at the time of delivery and the drug tissue transferability (release property) at the time of drug administration, and can achieve both of them.
  • the drug administration balloon catheter of the present invention has at least a balloon, a copolymer layer, a drug layer, and a catheter.
  • a laminate of the balloon, the copolymer layer, and the drug layer may be hereinafter referred to as a drug administration balloon.
  • the drug administration balloon catheter of the present invention may be mentioned as one of preferred embodiments having a balloon at the tip of the drug administration balloon catheter.
  • FIG. 5 is a front view schematically showing one embodiment of the drug administration balloon catheter of the present invention.
  • reference numeral 51 denotes a drug administration balloon catheter of the present invention.
  • the drug administration balloon catheter 51 includes a shaft main body 52 and a balloon (expansion body) disposed at the tip (distal end) of the shaft main body 52. 53).
  • a drug administration balloon catheter 51 shown in FIG. 5 is an over-the-wire type in which a guide wire lumen 210 is opened by a hub 54 fixed to a proximal end portion of a shaft main body 52.
  • the drug delivery balloon catheter may be of other types.
  • the shaft main body 52 is a concentric double tube of a guide wire guiding tubular member (hereinafter referred to as an inner tube shaft) 621 and a balloon expanding tubular member (hereinafter referred to as an outer tube shaft) 622.
  • the distal end 221 of the outer tube shaft 622 is located slightly on the rear end side from the distal end of the inner tube shaft 621.
  • a balloon expansion lumen 220 is formed between the inner periphery of the outer tube shaft 622 and the outer periphery 621b of the inner tube shaft 621.
  • the balloon 53 is foldable and expandable by a change in internal pressure.
  • the body 630 expands into a cylindrical shape (preferably a cylindrical shape) having substantially the same diameter by a fluid injected into the balloon 53, and a base end side of the body 630.
  • a proximal end reduced diameter portion 632 provided via a gradually decreasing diameter portion 631 that smoothly reduces the diameter
  • a distal end reduced diameter portion 634 provided via a gradually decreasing diameter portion 633 that smoothly reduces the diameter on the distal end side of the body portion 630.
  • the body portion 630 at the time of expansion may not be a perfect cylinder, but may be a polygonal column shape.
  • the balloon 53 When the balloon 53 is not expanded (not shown), the balloon 53 can be folded on the outer periphery of the inner tube shaft 621.
  • the balloon 53 at the time of expansion forms an expansion space 300 between the outer periphery 621b of the inner tube shaft 621.
  • the base end portion side of the expansion space 300 communicates with the balloon expansion lumen 220 of the outer tube shaft 622 on the entire circumference thereof. Since the expansion lumen 220 has a relatively large volume, the balloon 53 (expansion space 300 ) The expansion fluid is surely injected into the inside.
  • the distal diameter reducing portion 634 is fixed to the outer periphery 621b of the inner tube shaft 621, and the proximal diameter reduced diameter portion 632 is fixed to the distal end 221 of the outer tube shaft 622 in a liquid-tight manner by an adhesive or heat fusion.
  • L1 represents the length of the balloon 53
  • L2 represents the length of the trunk 630
  • ⁇ represents the outer diameter when the balloon 53 is expanded.
  • A shows a part of the cross section of the balloon 53. 5 and 6, the copolymer layer and the drug layer are omitted.
  • FIG. 1 is a cross-sectional view schematically showing a part of a drug administration balloon included in the drug administration balloon catheter of the present invention.
  • symbol 10 is a cross section of a part of drug administration balloon which the drug administration balloon catheter of this invention has.
  • the drug administration balloon 10 has a balloon 12, a copolymer layer 14 on the outer upper surface of the balloon 12, and a drug layer 16 on the copolymer layer 14. It can be said that the drug administration balloon 10 forms a laminate including the balloon 12, the copolymer layer 14, and the drug layer 16.
  • the drug administration balloon 10 can be, for example, an enlarged part of the cross section of the balloon 53 shown by part A in FIG.
  • the thickness of each layer and its ratio are not limited to FIG.
  • the drug administration balloon is excellent in lubricity by having a copolymer layer.
  • the copolymer layer constituting the drug administration balloon can cover at least a part of or the entire outer surface of the balloon.
  • the film thickness of the copolymer layer may not be uniform. Since the drug administration balloon has a drug layer on the surface of the copolymer layer, it has excellent retention during the drug delivery process and release at the affected area.
  • the drug layer constituting the drug administration balloon can cover at least a part or the whole of the outer surface of the balloon via the copolymer layer.
  • the film thickness of the drug layer may not be uniform.
  • the balloon constituting the drug administration balloon catheter of the present invention is not particularly limited as long as it is a balloon generally used for a balloon catheter.
  • the balloon material include polyamides.
  • Specific polyamides include, for example, polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), polyhexamethylene sebacamide (nylon 610), Polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), homo- or copolymers such as polydodecanolactam (nylon 12); caprolactam / lauryl lactam copolymer (nylon 6/12), caprolactam / Aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ⁇ -aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylenediammonium
  • the balloon used as a raw material when producing the drug administration balloon catheter of the present invention (hereinafter sometimes referred to as a raw material balloon) is not particularly limited.
  • the raw material balloon has a functional group capable of reacting with a group (for example, an epoxy group) included in the dimethylacrylamide-glycidyl methacrylate copolymer.
  • the functional group include a proton donating group, and specific examples include an amino group, an imino group, a hydroxyl group, a carboxyl group, and a mercapto group.
  • the raw material balloon When the raw material balloon has such a functional group, it reacts with a copolymer layer (dimethylacrylamide-glycidyl methacrylate copolymer) formed on the outer surface thereof, and the polymer layer is difficult to peel off from the balloon. This is because the balloon can be excellent in wettability.
  • the balloon materials can be used alone or in combination of two or more.
  • the production of the balloon and the balloon catheter is not particularly limited. For example, a conventionally well-known thing is mentioned.
  • the copolymer layer is formed of a dimethylacrylamide-glycidyl methacrylate copolymer.
  • the dimethylacrylamide-glycidyl methacrylate copolymer is a copolymer of dimethylacrylamide (N, N-dimethylacrylamide) and glycidyl methacrylate.
  • the dimethylacrylamide-glycidyl methacrylate copolymer is, for example, a compound represented by the following formula.
  • the polymerization form of the dimethylacrylamide-glycidyl methacrylate copolymer is not particularly limited.
  • any of a random copolymer, a block copolymer, and a graft copolymer may be used.
  • a block copolymer is preferable from the viewpoint of excellent drug retention during delivery and release at an affected area, and excellent balloon catheter lubricity.
  • the kinematic viscosity at 30 ° C. of the dimethylacrylamide-glycidyl methacrylate copolymer is 2.0 to 5.0 cSt from the viewpoint of excellent drug retention, release at the affected area, and excellent balloon catheter lubricity. Is preferred.
  • the ratio of the number of repeating units of dimethylacrylamide (n in the above formula) to the number of repeating units of glycidyl methacrylate (m in the above formula) constituting the dimethylacrylamide-glycidyl methacrylate copolymer is maintained during the drug delivery process.
  • m + n can be set to a value satisfying the weight average molecular weight.
  • the dimethylacrylamide-glycidyl methacrylate copolymer is not particularly limited for its production. For example, a conventionally well-known thing is mentioned.
  • the dimethylacrylamide-glycidyl methacrylate copolymers can be used alone or in combination of two or more.
  • the drug layer is formed of polyethylene glycol and / or polypropylene glycol and paclitaxel.
  • Polyethylene glycol (polyoxyethylene diol) used in the drug layer is a compound having a main chain having an oxyethylene group as a repeating unit and two hydroxy groups. The two hydroxy groups are preferably bonded to both ends of the main chain.
  • Polypropylene glycol (polyoxypropylene diol) used for the drug layer is a compound having a main chain having an oxypropylene group as a repeating unit and two hydroxy groups. The two hydroxy groups are preferably bonded to both ends of the main chain.
  • polyethylene glycol and polypropylene glycol one preferred embodiment is to use polyethylene glycol.
  • the weight average molecular weight of polyethylene glycol or polypropylene glycol is preferably 200 to 2000, and preferably 300 to 1000, from the viewpoint of excellent retention during drug delivery, release at the affected area, and excellent tissue penetration. More preferably.
  • Polyethylene glycol and polypropylene glycol are not particularly limited for their production. Polyethylene glycol and polypropylene glycol can be used alone or in combination of two or more.
  • Paclitaxel used in the drug layer is a compound represented by the following formula.
  • the method for producing paclitaxel is not particularly limited. For example, a conventionally well-known thing is mentioned.
  • Paclitaxel can be used, for example, as a therapeutic agent for vascular diseases such as anticancer agents and intravascular stenosis.
  • the amount of polyethylene glycol and / or polypropylene glycol is excellent in retention during drug delivery, release in the affected area, and excellent tissue permeability.
  • the amount is preferably 30 to 300 parts by mass, more preferably 40 to 250 parts by mass with respect to 100 parts by mass of paclitaxel.
  • the amount of the dimethylacrylamide-glycidyl methacrylate copolymer is excellent in the retention in the drug delivery process, the release in the affected area, and the lubricity of the balloon catheter.
  • the amount is preferably 1 to 10 parts by mass, more preferably 4 to 10 parts by mass with respect to 100 parts by mass.
  • the amount of paclitaxel per unit surface area of the balloon constituting the drug administration balloon is excellent from the viewpoint of retention and release, excellent drug effect, and excellent side effect reduction. It is preferably 1 to 10 ⁇ g / mm 2 , and more preferably 1 to 4 ⁇ g / mm 2 .
  • the drug administration balloon catheter of the present invention can be applied to, for example, treatment of vascular stenosis and in-stent restenosis lesions.
  • paclitaxel as a drug (anticancer drug)
  • restenosis and thrombosis can be prevented.
  • the method for producing a drug administration balloon catheter of the present invention comprises: A pre-coating step of forming a copolymer layer by applying a pre-coating composition comprising a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A on the outer surface of the balloon in the balloon catheter; By providing a drug coating composition containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer to form a drug layer, It is a manufacturing method of a medicine administration balloon catheter which manufactures a medicine administration balloon catheter of an invention.
  • the method for producing a drug administration balloon catheter of the present invention includes a precoat process and a drug coat process.
  • the precoat step is a step of forming a copolymer layer by applying a precoat composition containing a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A onto the outer surface of the balloon in the balloon catheter.
  • the balloon catheter used in the precoat process is not particularly limited.
  • a balloon having the same material as the above-described raw material balloon can be used.
  • the balloon may be pretreated in advance with, for example, an organic solvent, primer irradiation, or UV irradiation.
  • the precoat composition used in the precoat step contains a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A.
  • the dimethylacrylamide-glycidyl methacrylate copolymer contained in the precoat composition is the same as described above.
  • the dimethylacrylamide-glycidyl methacrylate copolymers can be used alone or in combination of two or more.
  • the organic solvent A contained in the precoat composition is not particularly limited as long as it is an organic solvent capable of dissolving and / or dispersing the dimethylacrylamide-glycidyl methacrylate copolymer. For example, tetrahydrofuran and chloroform are mentioned.
  • the organic solvents A can be used alone or in combination of two or more.
  • the precoat composition can be produced by mixing the organic solvent A and a dimethylacrylamide-glycidyl methacrylate copolymer.
  • concentration of the dimethylacrylamide-glycidyl methacrylate copolymer is preferably 0.1 to 1% by mass in the precoat composition from the viewpoint of excellent retention and release properties and excellent lubricity. More preferably, it is -0.7 mass%.
  • the method for applying the precoat composition on the outer surface of the balloon is not particularly limited. Examples of the method include expanding the balloon and immersing the balloon in the precoat composition, or applying or spraying the precoat composition onto the balloon. For the application, for example, a brush, a pipette, or an automatic application device can be used. A copolymer layer can be formed on the outer surface of the balloon by the precoat process.
  • a composition for drug coating containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer formed on the outer surface of the balloon in the pre-coating step as described above. It is the process of providing and forming a chemical
  • the composition for drug coating used in the drug coating step contains polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B.
  • the polyethylene glycol and / or polypropylene glycol contained in the drug coating composition is not particularly limited. For example, the thing similar to the above is mentioned. Paclitaxel contained in the composition for drug coating is the same as described above.
  • the organic solvent B contained in the composition for drug coating is not particularly limited as long as it is an organic solvent capable of dissolving and / or dispersing paclitaxel.
  • an organic solvent capable of dissolving and / or dispersing paclitaxel For example, absolute ethanol, acetone, and tetrahydrofuran are mentioned.
  • the organic solvents B can be used alone or in combination of two or more.
  • a drug coat composition for example, it can be produced by mixing polyethylene glycol and / or polypropylene glycol, paclitaxel and organic solvent B.
  • a drug coating composition by dissolving polyethylene glycol and / or polypropylene glycol in advance in absolute ethanol and dissolving paclitaxel in a mixed solvent of absolute ethanol and acetone in advance.
  • the concentration of paclitaxel is 0.3 to 9% by mass in the drug coating composition from the viewpoints of excellent retention during delivery and release at the affected area, excellent drug effect, and excellent side effect reduction. It is preferably 1.5 to 4.0% by mass.
  • the concentration of polyethylene glycol and / or polypropylene glycol is excellent in the retention during the drug delivery process, the release in the affected area, the effect of the drug, and the excellent tissue penetration.
  • the content is preferably from 0.1 to 10% by mass, and more preferably from 1.0 to 8.0% by mass.
  • the method for applying the composition for drug coating on the copolymer layer is not particularly limited.
  • a method of immersing the balloon in the drug coating composition, or applying or spraying the drug coating composition on the balloon can be mentioned.
  • a brush, a pipette, or an automatic application device can be used.
  • a drug layer is formed on the copolymer layer by a drug coating process.
  • the method for producing a drug administration balloon catheter of the present invention can further include at least one drying step as necessary.
  • a drying step By providing a drying step, the organic solvent A and / or the organic solvent B can be removed.
  • the timing for providing the drying step is not particularly limited as long as it is after the precoat step. For example, it can be between the precoat step and the drug coat step and / or after the drug coat step.
  • the drying process is preferably provided between the precoat process and the drug coat process or after the drug coat process, and more preferably provided between the precoat process and the drug coat process and after the drug coat process. Drying in the drying step can be performed at 20 to 30 ° C. for about 0.25 to 2 hours.
  • the drying can be performed at 20 to 60 ° C. for about 3 to 48 hours.
  • the drug administration balloon catheter of the present invention is manufactured through a wrapping step of folding the obtained balloon (drug administration balloon) as necessary. Can do.
  • the treatment method of the present invention comprises: A delivery step of delivering the drug delivery balloon catheter of the invention into the lumen; An expansion step in which a balloon of the drug administration balloon catheter is expanded in a radial direction of the balloon, and the balloon is in contact with the inside of the lumen; And a transition step in which paclitaxel forming the drug layer moves to the lumen from the drug layer of the balloon.
  • the treatment method of the present invention is excellent in retention in the drug delivery process and release in the affected area by using the drug administration balloon catheter of the present invention, and effectively exerts the drug efficacy while reducing side effects. Can do.
  • the drug administration balloon catheter of the present invention is delivered into the lumen.
  • the drug administration balloon catheter used in the treatment method of the present invention is not particularly limited as long as it is the drug administration balloon catheter of the present invention.
  • Examples of the lumen to which the drug administration balloon catheter is applied include blood vessels and in-stent stents.
  • the method of delivering the drug administration balloon catheter into the lumen is the same as that of a conventionally known balloon catheter. For example, when a drug administration balloon catheter is delivered to a stenosis of a coronary artery or a peripheral blood vessel, a guiding catheter that is cylindrical from the patient's wrist or crotch artery is inserted to the entrance of the heart coronary artery and guided. By inserting the guide wire into the catheter and inserting the drug administration balloon catheter along the guide wire, the drug administration balloon can be delivered to the stenosis.
  • the balloon (drug administration balloon) of the drug administration balloon catheter is expanded in the radial direction of the balloon (drug administration balloon), and the balloon (drug administration balloon) comes into contact with the inside of the lumen.
  • the method of expanding the balloon in the radial direction of the balloon inside the lumen is the same as that of a conventionally known balloon.
  • paclitaxel forming the drug layer is transferred from the drug layer of the balloon to the lumen (lumen wall).
  • a method of transferring (also referred to as action or release) a drug to a lumen is performed by expanding a balloon (drug administration balloon) that is expanded inside the lumen, and the balloon (drug administration balloon) is in contact with the inside of the lumen. In this state, it can be carried out by holding for several tens of seconds to several minutes. As a result, the lumen is expanded, and the drug in the drug layer acts on and penetrates the lumen tissue.
  • the treatment method of the present invention can be applied to, for example, treatment of vascular stenosis and in-stent restenosis lesions.
  • paclitaxel as a drug (anticancer drug), for example, restenosis and thrombosis can be prevented.
  • DMAA / GMA copolymer dimethylacrylamide-glycidyl methacrylate copolymer
  • 29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50 ° C., and hydrochloric acid was removed under reduced pressure at 50 ° C. for 3 hours to 22.5 g of the resulting oligoester and 4.5 g of methyl ethyl ketone.
  • the reaction product was reprecipitated with diethyl ether to obtain polyglycidyl methacrylate (PGMA) having a peroxide group in the molecule. Subsequently, 8 g of this PGMA and 60 g of dimethylacrylamide (DMAA) were dissolved in 500 g of chlorobenzene and heated to 80 ° C. to conduct a polymerization reaction for about 3 hours. This solution was dropped into a large amount of hexane to precipitate a polymer, and the precipitate was filtered.
  • PGMA polyglycidyl methacrylate
  • DMAA dimethylacrylamide
  • the precipitate separated by filtration was repeatedly purified using tetrahydrofuran (THF) as a good solvent and diethyl ether as a poor solvent, and then the pressure was reduced to obtain a block copolymer.
  • the obtained block copolymer is hereinafter referred to as DMAA / GMA copolymer. This is sometimes referred to as MII polymer.
  • the number (molar ratio) of repeating units by GMA is one molecule of GMA per 12 molecules of DMAA.
  • the kinematic viscosity at 30 ° C. of the DMAA / GMA copolymer is 2.5 to 4.5 cSt.
  • DMAA / GMA copolymer (MII polymer) produced as described above is dissolved in tetrahydrofuran in the amount shown in Table 1 below to produce a precoat composition (DMAA / GMA solution) having the concentration shown in Table 1 below.
  • DMAA / GMA solution DMAA / GMA solution having the concentration shown in Table 1 below.
  • ⁇ Manufacture of composition for drug coat Polyethylene glycol (HO (CH 2 CH 2 O) n H, trade name PEG400, manufactured by Kanto Chemical Co., Ltd., average molecular weight 380 to 420) is mixed with absolute ethanol to prepare a 50 mass% PEG400 solution.
  • paclitaxel is dissolved in a mixed solution of absolute ethanol and acetone (anhydrous ethanol 2 mL, acetone 2 mL) to prepare a 40 mg / mL PTX solution.
  • the PEG400 solution and the PTX solution prepared as described above were mixed in a necessary amount so that the concentration of PEG400 and paclitaxel was the concentration of PEG400 and paclitaxel in the composition for drug coating shown in Table 1 below.
  • a composition is prepared.
  • a balloon catheter (produced by Terumo Corporation, material of the balloon portion (extended portion) is nylon 12), and the surface area of the balloon is 188.4Mm 2, the length L2 of the body portion of the balloon be 20mm
  • the diameter of the balloon portion in the folded state is about 1 mm, and the outer diameter ⁇ of the balloon when expanded is 3 mm.
  • the precoat composition produced as described above was applied onto the outer surface of the balloon by an automatic coating apparatus (the amount of the precoat composition applied onto the balloon is 10 ⁇ L), and 25 ° C.
  • a copolymer layer is formed by drying under the above conditions.
  • FIG. 4 is a graph showing the results of the PTX residual rate in the delivery operation and the PTX transfer rate (release property) to the mimic blood vessel (agarose gel tube) in the example of the present invention.
  • the vertical axis represents the PTX residual rate in the delivery operation of each example, the PTX transfer rate (release) to the mimic blood vessel (agarose gel tube) (both units are%), and I to IX on the horizontal axis Preparation Examples 1 to 8 and Comparative Example 1 are shown in this order.
  • Table 1 shows the correspondence between I to IX and Preparation Examples 1 to 8 and Comparative Example 1.
  • the hatched bar graph indicates the PTX remaining rate in the delivery operation
  • the black bar graph indicates the PTX transfer rate (release) to the mimic blood vessel (agarose gel tube).
  • FIG. 2 is a partial cross-sectional view schematically showing an experimental apparatus used for performing in vitro drug layer resistance evaluation in the present invention.
  • symbol 29 shows the experimental apparatus used in order to perform an in vitro chemical
  • the experimental device 29 has a mimic blood vessel 25 and a guiding catheter 20.
  • the mimic blood vessel 25 is hollow inside and has a pre-branch portion 26, a branch portion 27, and a branch portion 28.
  • the mimic blood vessel 25 branches from the pre-branch portion 26 to the branch portion 27 and the branch portion 28, and the angle between the branch portions 27 and 28 is about 90 °.
  • the guiding catheter 20 has a distal end portion 22, a catheter shaft 24, and a guide wire (not shown) in the guiding catheter 20, and the inside of the guiding catheter 20 is 37 ° C. phosphate buffered saline (PBS). Is filled with.
  • PBS phosphate buffered saline
  • a length from Terumo's guiding catheter (trade name Heartrail II; a position where a balloon catheter is inserted (not shown)) to the distal end portion 22 is about 115 cm, and the outside of the balloon catheter lumen. The diameter was 0.8325 mm (2.5 F).
  • the drug layer resistance test in the delivery operation was performed as follows. First, the guiding catheter 20 is inserted from the branch portion 28 and the insertion is stopped when the distal end portion 22 reaches the branch portion 27. At this time, the catheter shaft 24 of the guiding catheter 20 forms an angle of 90 ° according to the shape of the branch portions 27 and 28. Next, the drug administration balloon catheter (not shown) manufactured as described above is inserted into the guiding catheter 20 along the guide wire, and the delivery operation is advanced toward the distal end portion 22. The delivery operation was performed until the tip of the tip reached the tip 22. The delivery operation from insertion of the drug administration balloon catheter to arrival at the tip was performed in 1 minute. After reaching the tip, the balloon portion of the drug administration balloon catheter was taken out from the tip 22 and the balloon portion (expansion portion) was collected.
  • the collected balloon portion was measured as follows to evaluate the drug layer resistance test. First, the collected balloon part was immersed in 10 mL of methanol, and then shaken for 10 minutes using a shaker to collect (extract) paclitaxel remaining in the balloon. The amount of PTX in the resulting methanol solution was measured by high-performance liquid chromatography using an ultraviolet-visible absorptiometer at an absorbance of 227 nm. Also, for the drug administration balloon catheter before the drug layer resistance test (drug administration balloon catheter manufactured as described above), paclitaxel was extracted with methanol in the same manner as described above, and the same measurement was performed to determine the amount of paclitaxel. It was.
  • the amount of PTX remaining in the balloon is calculated by applying the measured amount of PTX in the balloon after the drug layer resistance test and the measured amount of PTX in the balloon of the drug-administered balloon catheter manufactured as described above to the following formula. did.
  • the amount of PTX (the amount of PTX applied to the balloon) of the balloon of the drug administration balloon catheter in the manufactured state is defined as (100%) (the same applies hereinafter).
  • PTX remaining rate (%) (Measured amount of PTX in the balloon after drug layer resistance test (after delivery operation)) ⁇ (Measured amount of PTX in the balloon of the drug administration balloon catheter manufactured as described above)
  • the results are shown in Table 1.
  • the balloon PTX remaining rate after the delivery operation is preferably 60% or more with respect to the amount of PTX applied to the balloon from the viewpoint of excellent drug delivery.
  • PTX transferability release by agarose gel tube
  • agarose gel tube was prepared by the following procedure. Weigh out 5.32 g of agarose (Invitrogen), add 400 mL of phosphate buffered saline (PBS), mix, place in a high-pressure steam sterilizer, dissolve the agarose at 100 ° C.
  • PBS phosphate buffered saline
  • FIG. 3 is a partial cross-sectional view schematically showing a state in which the drug administration balloon catheter of the present invention is inserted into an agarose gel tube.
  • symbol 30 shows a chemical
  • symbol 36 shows the agarose gel tube manufactured as mentioned above.
  • the drug administration balloon catheter 30 has a balloon 32 at its distal end, and the balloon 32 is connected to a catheter shaft 34.
  • the agarose gel tube 36 has a phosphate buffered saline (PBS) 38 at 37 ° C. therein.
  • PBS phosphate buffered saline
  • FIG. 3A the balloon 32 is in a state before expansion
  • FIG. 3B the balloon 32 is in an expanded state.
  • the drug transfer test first, the drug administration balloon catheter 30 is pre-incubated in 10 mL PBS at 37 ° C. Next, as shown in FIG. 3A, the drug administration balloon catheter 30 is inserted into the agarose gel tube 36. Then, as shown in FIG. 3B, the balloon 32 was expanded and held for 1 minute while the balloon 32 was in contact with the inner wall of the agarose gel tube 36.
  • the balloon 32 was closed and the drug administration balloon catheter 30 was recovered from the agarose gel tube 36. Thereafter, in order to quantify the drug adsorbed only on the inner wall of the agarose gel tube, the PBS inside the agarose gel tube is removed, and the drug migration test is completed.
  • the agarose gel tube after the drug transferability test is immersed in 5 mL of methanol, and the PTX transferred to the agarose gel tube after being crushed is collected. Transferability was evaluated by measurement by high performance liquid chromatography using a photometer.
  • the amount of PTX of the drug administration balloon catheter (drug administration balloon catheter in the state manufactured as described above) obtained before the drug transfer test is 100%.
  • PTX transcription rate (%) (Measured amount of PTX in the agarose gel tube after the drug transfer test) ⁇ (Measured amount of PTX in the balloon of the drug-administered balloon catheter manufactured as described above)
  • the results are shown in Table 1.
  • the PTX migration to the gel is preferably 5% or more with respect to the amount of PTX applied to the balloon from the viewpoint of excellent tissue migration of the drug.
  • Comparative Example 1 in which the drug layer does not contain polyethylene glycol or polypropylene glycol is assumed to have a low paclitaxel transfer rate and a low tissue transferability of the drug.
  • Examples 1 to 8 have a drug transfer rate of 5% or more, and are expected to be excellent in tissue transferability.
  • the drug remaining rate on the balloon after the delivery operation is high.
  • the drug administration balloon catheter of the present invention prevents a drug from dropping off from the balloon during delivery, and prevents the drug from eluting before the balloon is delivered to the affected part. The drug can be delivered, and it is considered that the drug is efficiently released at the affected area after delivery.
  • the drug administration balloon catheter of the present invention is excellent in tissue transfer of drugs and excellent in delivery.
  • Drug administration balloon (part) DESCRIPTION OF SYMBOLS 12 Balloon 14 Copolymer layer 16 Drug layer 20 Guiding catheter 22 Tip part 24 Catheter shaft 25 Mimic blood vessel 26 Pre-branch part 27, 28 Branch part 29 Experimental apparatus 30 Drug administration balloon catheter 32 Balloon 34 Catheter shaft 36 Agarose gel tube 38 Phosphate buffered saline (PBS) 51 Drug Administration Balloon Catheter 52 Shaft Main Body 53 Balloon 54 Hub 621 Inner Tube Shaft 621b Outer Diameter 210 Guide Wire Lumen 622 Outer Tube Shaft 220 Balloon Expansion Lumen 221 Tip 630 Body 631 Gradually Reduced Diameter 632 Base Radius 633 Part 634 Tip diameter reducing part 300 Expansion space

Abstract

The purpose of the present invention is to provide: a balloon catheter for drug administration, said balloon catheter being capable of not only keeping a drug stably during the stage of carrying the drug to an affected part but also releasing the drug quickly with the expansion of the balloon when has arrived at the affected part; and a process for producing the same. The present invention is a balloon catheter for drug administration, said balloon catheter comprising: a balloon; a copolymer layer which is made from a dimethylacrylamide/glycidyl methacrylate copolymer and which is present on the outer surface of the balloon; and a drug layer which comprises polyethylene glycol and/or polypropylene glycol and paclitaxel and which is present on the copolymer layer. The present invention is also a process for producing the same.

Description

薬剤投与バルーンカテーテル及びその製造方法Drug administration balloon catheter and method for manufacturing the same
　本発明は薬剤投与バルーンカテーテル及びその製造方法に関する。 The present invention relates to a drug administration balloon catheter and a method for producing the same.
　各種病気の治療において、病変部位に高濃度の薬剤を投与して治療することが望ましい場合が多い。しかしながら、一般的な経口投与や静注投与によって薬剤を投与する方法では、病変部位に対して有効な薬剤量を確保するために人体に薬剤を多量に投与することとなり、そのため、人体が危険になるほど他の部位に損傷を与えたり、悪感や苦痛を与えたりするなどの副作用を伴う場合がある。
　このため、病巣部や拡張した血管内壁に対して直接薬剤を投与できる方法として、薬剤投与用カテーテルへの期待が高まっている。
　一方、バルーンカテーテルにおいて、潤滑性を発現させるために、バルーンの外表面にゲル等を付与する場合がある。本願出願人はこれまでに、分子内に反応性官能基が存在する水膨潤性重合体を使用して、湿潤時に潤滑性を発現することができる医療器具を提案している（特許文献１）。 In the treatment of various diseases, it is often desirable to treat a lesion by administering a high concentration of the drug. However, in general methods of administering a drug by oral administration or intravenous administration, a large amount of the drug is administered to the human body in order to secure an effective amount of the drug to the lesion site. It may be accompanied by side effects such as damaging other parts, feeling bad or painful.
For this reason, expectation for a catheter for drug administration is increasing as a method for directly administering a drug to a lesion site or an expanded inner wall of a blood vessel.
On the other hand, in a balloon catheter, gel or the like may be applied to the outer surface of the balloon in order to develop lubricity. The applicant of the present application has proposed a medical device that can exhibit lubricity when wet using a water-swellable polymer having a reactive functional group in the molecule (Patent Document 1). .
特開平０６－２８５１５２号公報Japanese Patent Laid-Open No. 06-285152
　しかし、本願発明者は、抗悪性腫瘍剤として有用なパクリタキセル（ＰＴＸ）を、分子内に反応性官能基が存在する水膨潤性重合体（例えば、ジメチルアクリルアミド－グリシジルメタクリレート共重合体）をバルーンの外表面に有するバルーンカテーテルに単に付与して、当該バルーンカテーテルを患部（例えば、血管内壁）に薬剤（パクリタキセル）を投与するために使用した場合、バルーンを拡張してバルーンが患部に接触しても、バルーンの外表面上にある薬剤がバルーンに保持されたまま維持され、バルーンから患部へ薬剤を放出されにくいことを見出した。
　本願発明者は、この現象の原因は、水膨潤性重合体の疎水性領域（例えば共重合体のグリシジルメタクリレート領域）と薬剤との疎水性相互作用が強すぎ、かつ、これらの疎水性領域がバルーン表面と強い親和性をもつため、薬剤が重合体の疎水領域と共にバルーン表面側に位置し、該薬剤の上部に共重合体の親水性領域（例えばジメチルアクリルアミド領域）が覆いかぶさるように位置するため、バルーンが患部と接触しても薬剤がバルーンから患部へ放出（移行）しにくいことにあると推察した。
　このため、本願発明者は、バルーンにコーティングした薬剤を患部までにデリバリーする際には薬剤（パクリタキセル）をバルーン上に安定に保持し、患部でのバルーン拡張と同時に素早くバルーン表面から薬剤を患部へ放出することができる薬剤投与バルーンカテーテルを実現するためには、水膨潤性重合体へのパクリタキセルの上記保持及び水膨潤性重合体からのパクリタキセルの上記放出に適した薬剤コート層が必要であると考えた。
　本発明は、患部まで薬剤をデリバリーする際には薬剤を安定に保持し、患部に素早く薬剤を患部へ放出することができる薬剤投与バルーンカテーテルを提供することを目的とする。 However, the inventor of the present invention uses paclitaxel (PTX), which is useful as an antineoplastic agent, and a water-swellable polymer (for example, dimethylacrylamide-glycidyl methacrylate copolymer) having a reactive functional group in the molecule as a balloon. If the balloon catheter is simply applied to the balloon catheter on the outer surface and used to administer the drug (paclitaxel) to the affected area (for example, the inner wall of the blood vessel), The present inventors have found that the drug on the outer surface of the balloon is maintained while being held by the balloon, and the drug is hardly released from the balloon to the affected part.
The present inventor has found that this phenomenon is caused by the fact that the hydrophobic interaction between the hydrophobic region of the water-swellable polymer (for example, the glycidyl methacrylate region of the copolymer) and the drug is too strong, and these hydrophobic regions are Because of its strong affinity with the balloon surface, the drug is located on the balloon surface side together with the hydrophobic region of the polymer, and the hydrophilic region (for example, dimethylacrylamide region) of the copolymer is placed on top of the drug. Therefore, it was inferred that even when the balloon was in contact with the affected area, the drug was difficult to be released (transferred) from the balloon to the affected area.
For this reason, when delivering the drug coated on the balloon to the affected area, the inventor of the present application stably holds the drug (paclitaxel) on the balloon, and at the same time the balloon is expanded at the affected area, the drug is quickly transferred from the balloon surface to the affected area. In order to realize a drug administration balloon catheter that can be released, a drug coat layer suitable for the above-described retention of paclitaxel in a water-swellable polymer and the above-mentioned release of paclitaxel from the water-swellable polymer is necessary. Thought.
An object of the present invention is to provide a drug administration balloon catheter that can stably hold a drug when delivering the drug to an affected area and can quickly release the drug to the affected area.
　本発明者は、上記課題を解決すべく鋭意研究した結果、
　バルーンを有し、
　前記バルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体によって形成される共重合体層を有し、
　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルとによって形成される薬剤層を有するバルーンカテーテルが、患部まで薬剤をデリバリーする際には薬剤を安定に保持し、患部でのバルーン拡張と同時に素早く薬剤を患部へ放出することができる薬剤投与バルーンカテーテルとなることを見出した。パクリタキセルとポリエチレングリコール及び／又はポリプロピレングリコールを混ぜてコーティングすることで、共重合体の疎水性領域（グリシジルメタクリレート）とパクリタキセルの疎水性相互作用を緩和することができ、かつ、ポリエチレングリコール及び／又はポリプロピレングリコールと共存することで、パクリタキセルが患部で素早く放出することが明らかとなった。
　また、本願発明者は、
　バルーンカテーテルにおけるバルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体と有機溶剤Ａとを含むプレコート用組成物を付与して、共重合体層を形成するプレコート工程と、
　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを含む薬剤コート用組成物を付与して、薬剤層を形成する薬剤コート工程とを有することによって、本発明の薬剤投与バルーンカテーテルを製造する、薬剤投与バルーンカテーテルの製造方法によれば、患部まで薬剤をデリバリーする際には薬剤を安定に保持し、患部でのバルーン拡張と同時に素早く薬剤を患部に放出することができる薬剤投与バルーンカテーテルが得られることを見出し、本発明を完成させた。 As a result of earnest research to solve the above problems, the present inventor,
Having a balloon,
On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer,
A balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer stably holds the drug when delivering the drug to the affected area. It has been found that the drug administration balloon catheter can be quickly released into the affected area simultaneously with the balloon expansion. By coating a mixture of paclitaxel and polyethylene glycol and / or polypropylene glycol, the hydrophobic interaction between the hydrophobic region of the copolymer (glycidyl methacrylate) and paclitaxel can be mitigated, and polyethylene glycol and / or polypropylene Co-existence with glycol revealed that paclitaxel was released quickly in the affected area.
In addition, the inventor of the present application
A pre-coating step of forming a copolymer layer by applying a pre-coating composition comprising a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A on the outer surface of the balloon in the balloon catheter;
By providing a drug coating composition containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer to form a drug layer, According to the method of manufacturing a drug administration balloon catheter of the invention, the drug administration balloon catheter manufacturing method stably holds the drug when delivering the drug to the affected area, and quickly releases the drug to the affected area simultaneously with the balloon expansion in the affected area. The present inventors have found that a drug administration balloon catheter that can be obtained is obtained.
　すなわち、本発明は、次の薬剤投与バルーンカテーテル、及びその製造方法、並びにこれを用いる治療方法を提供する。
　１．　バルーンを有し、
　前記バルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体によって形成される共重合体層を有し、
　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルとによって形成される薬剤層を有する、薬剤投与バルーンカテーテル。
　２．　前記ポリエチレングリコール及び／又はポリプロピレングリコールの量が、前記パクリタキセル１００質量部に対して、３０～３００質量部である上記１に記載の薬剤投与バルーンカテーテル。
　３．　前記ジメチルアクリルアミド－グリシジルメタクリレート共重合体の量が、前記パクリタキセル１００質量部に対して、１～１０質量部である上記１又は２に記載の薬剤投与バルーンカテーテル。
　４．　前記バルーンの単位表面積あたりの前記パクリタキセルの量が、０．１～１０μｇ／ｍｍ2である上記１～３のいずれかに記載の薬剤投与バルーンカテーテル。
　５．　前記バルーンが、前記ジメチルアクリルアミド－グリシジルメタクリレート共重合体と反応可能な官能基を有する、上記１～４のいずれかに記載の薬剤投与バルーンカテーテル。
　６．　上記１～５のいずれかに記載の薬剤投与バルーンカテーテルは、当該薬剤投与バルーンカテーテルの先端に前記バルーンを有する上記１～５のいずれかに記載の薬剤投与バルーンカテーテル。
　７．　バルーンカテーテルにおけるバルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体と有機溶剤Ａとを含むプレコート用組成物を付与して、共重合体層を形成するプレコート工程と、
　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを含む薬剤コート用組成物を付与して、薬剤層を形成する薬剤コート工程とを有することによって、上記１～６のいずれかに記載の薬剤投与バルーンカテーテルを製造する、薬剤投与バルーンカテーテルの製造方法。
　８．　前記パクリタキセルの濃度が、前記薬剤コート用組成物中の０．３～９質量％である上記７に記載の薬剤投与バルーンカテーテルの製造方法。
　９．　前記ポリエチレングリコール及び／又はポリプロピレングリコールの濃度が、前記薬剤コート用組成物中の０．１～１０質量％である上記７又は８に記載の薬剤投与バルーンカテーテルの製造方法。
　１０．　前記ジメチルアクリルアミド－グリシジルメタクリレート共重合体の濃度が、前記プレコート用組成物中の０．１～１質量％である上記７～９のいずれかに記載の薬剤投与バルーンカテーテルの製造方法。
　１１．　前記プレコート工程の後、さらに、少なくとも１つの乾燥工程を有する上記７～１０のいずれかに記載の薬剤投与バルーンカテーテルの製造方法。
　１２．　上記１～６のいずれかに記載の薬剤投与バルーンカテーテルを管腔の内部に送達する送達ステップと、
　前記薬剤投与バルーンカテーテルが有するバルーンが前記バルーンの径方向に拡張して、前記バルーンが前記管腔の内部と接する拡張ステップと、
　前記バルーンが有する薬剤層から、前記薬剤層を形成するパクリタキセルが前記管腔に移行する移行ステップとを有する治療方法。 That is, the present invention provides the following drug administration balloon catheter, a manufacturing method thereof, and a treatment method using the same.
1. Having a balloon,
On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer,
A drug administration balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer.
2. 2. The drug administration balloon catheter according to 1 above, wherein the amount of the polyethylene glycol and / or polypropylene glycol is 30 to 300 parts by mass with respect to 100 parts by mass of the paclitaxel.
3. 3. The drug administration balloon catheter according to 1 or 2 above, wherein the amount of the dimethylacrylamide-glycidyl methacrylate copolymer is 1 to 10 parts by mass with respect to 100 parts by mass of the paclitaxel.
4). 4. The drug administration balloon catheter according to any one of 1 to 3 above, wherein the amount of the paclitaxel per unit surface area of the balloon is 0.1 to 10 μg / mm 2 .
5. 5. The drug administration balloon catheter according to any one of the above 1 to 4, wherein the balloon has a functional group capable of reacting with the dimethylacrylamide-glycidyl methacrylate copolymer.
6). 6. The drug administration balloon catheter according to any one of 1 to 5 above, wherein the drug administration balloon catheter according to any one of 1 to 5 has the balloon at the tip of the drug administration balloon catheter.
7). A pre-coating step of applying a pre-coating composition comprising a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A on the outer surface of the balloon in the balloon catheter to form a copolymer layer;
By providing a drug coating composition containing polyethylene glycol and / or polypropylene glycol, paclitaxel and organic solvent B on the copolymer layer to form a drug layer, A method for producing a drug administration balloon catheter, wherein the drug administration balloon catheter according to any one of 1 to 6 is produced.
8). 8. The method for producing a drug administration balloon catheter according to 7 above, wherein the concentration of paclitaxel is 0.3 to 9% by mass in the composition for drug coating.
9. 9. The method for producing a drug administration balloon catheter according to 7 or 8 above, wherein the concentration of the polyethylene glycol and / or polypropylene glycol is 0.1 to 10% by mass in the drug coating composition.
10. 10. The method for producing a drug administration balloon catheter according to any one of 7 to 9 above, wherein the concentration of the dimethylacrylamide-glycidyl methacrylate copolymer is 0.1 to 1% by mass in the precoat composition.
11. 11. The method for producing a drug administration balloon catheter according to any one of 7 to 10, further comprising at least one drying step after the pre-coating step.
12 A delivery step of delivering the drug administration balloon catheter according to any of 1 to 6 above into the lumen;
An expansion step in which a balloon of the drug administration balloon catheter is expanded in a radial direction of the balloon, and the balloon is in contact with the inside of the lumen;
And a transition step in which paclitaxel forming the drug layer moves to the lumen from the drug layer of the balloon.
　本発明の薬剤投与バルーンカテーテルは、患部まで薬剤をデリバリーする際には薬剤をバルーン上に安定に保持し、薬剤投与の際には患部に素早く薬剤を放出することができる。
　本発明の薬剤投与バルーンカテーテルの製造方法によれば、患部まで薬剤をデリバリーする際には薬剤をバルーン上に安定に保持し、薬剤投与の際には患部に素早く薬剤を放出することができる薬剤投与バルーンカテーテルを製造することができる。
　本発明の治療方法によれば、患部まで薬剤をデリバリーする際には薬剤をバルーン上に安定に保持し、薬剤投与の際には患部でのバルーン拡張と同時に素早く薬剤を放出することができる。 The drug administration balloon catheter of the present invention can stably hold a drug on the balloon when delivering the drug to the affected area, and can quickly release the drug to the affected area when administering the drug.
According to the method for producing a drug administration balloon catheter of the present invention, a drug can be stably held on the balloon when the drug is delivered to the affected area, and can be quickly released to the affected area when the drug is administered. An administration balloon catheter can be manufactured.
According to the treatment method of the present invention, the drug can be stably held on the balloon when the drug is delivered to the affected area, and the drug can be quickly released simultaneously with the balloon expansion in the affected area when the drug is administered.
図１は、本発明の薬剤投与バルーンカテーテルが有する薬剤投与バルーンの一部を模式的に表す断面図である。FIG. 1 is a cross-sectional view schematically showing a part of a drug administration balloon included in the drug administration balloon catheter of the present invention. 図２は、本発明においてｉｎ　ｖｉｔｒｏの薬剤コート層耐性評価を行うために使用した実験装置を模式的に表す一部断面図である。FIG. 2 is a partial cross-sectional view schematically showing an experimental apparatus used for performing in vitro drug coat layer resistance evaluation in the present invention. 図３は、アガロースゲルチューブ内に本発明の薬剤投与バルーンカテーテルが挿入されている状態を模式的に示す一部断面図である。FIG. 3 is a partial cross-sectional view schematically showing a state in which the drug administration balloon catheter of the present invention is inserted into an agarose gel tube. 図４は、本発明の実施例における、ＰＴＸ残存率、ＰＴＸ転写率の結果を示すグラフである。FIG. 4 is a graph showing the results of the PTX remaining rate and the PTX transfer rate in the examples of the present invention. 本発明の薬剤投与バルーンカテーテルの一実施形態を模式的に示す正面図である。1 is a front view schematically showing one embodiment of a drug administration balloon catheter of the present invention. 図５に示す薬剤投与バルーンカテーテルにおけるバルーン及びその近傍を模式的に示す拡大断面図である。FIG. 6 is an enlarged cross-sectional view schematically showing a balloon and its vicinity in the drug administration balloon catheter shown in FIG. 5.
　本発明について以下詳細に説明する。
　まず本発明の薬剤投与バルーンカテーテルについて以下に説明する。
　本発明の薬剤投与バルーンカテーテルは、
　バルーンを有し、
　前記バルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体によって形成される共重合体層を有し、
　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルとによって形成される薬剤層を有する、薬剤投与バルーンカテーテルである。 The present invention will be described in detail below.
First, the drug administration balloon catheter of the present invention will be described below.
The drug administration balloon catheter of the present invention comprises:
Having a balloon,
On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer,
A drug administration balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer.
　本発明の薬剤投与バルーンカテーテルは、バルーンの外表面上に特定の共重合体層と、パクリタキセルとポリエチレングリコール及び／又はポリプロピレングリコールとによって形成される薬剤層とを有することによって、薬剤を患部までデリバリーする際には薬剤（パクリタキセル）を安定にバルーン上に保持し（以下これを保持性ということがある。）、薬剤投与の際には患部に素早く（具体的にはバルーン拡張と同時に）薬剤を放出する（以下これを放出性ということがある。）ことができる。 The drug administration balloon catheter of the present invention has a specific copolymer layer and a drug layer formed by paclitaxel and polyethylene glycol and / or polypropylene glycol on the outer surface of the balloon, thereby delivering the drug to the affected area. When the drug is administered, the drug (paclitaxel) is stably held on the balloon (hereinafter sometimes referred to as “retainability”). Can be released (hereinafter sometimes referred to as releasing property).
　本発明において、薬剤（パクリタキセル）は疎水性が強く、ジメチルアクリルアミド－グリシジルメタクリレート共重合体も疎水性の部分（主に主鎖、グリシジルメタクリレートによる繰り返し単位）を有する。よって薬剤（パクリタキセル）と、ジメチルアクリルアミド－グリシジルメタクリレート共重合体（潤滑剤）の疎水性部分との間には疎水性による親和性が生じる。これによってパクリタキセルは患部で放出されにくく管腔（組織）へ移行することが困難となっていると考えられる。またバルーン（基材）が疎水性を有する場合、上記に加え、バルーンとの疎水性によって生じる親和性によって、薬剤は管腔（組織）へより移行しにくくなる。
　薬剤層に含まれるポリエチレングリコール及び／又はポリプロピレングリコールは、パクリタキセルと基材及び／又は潤滑剤との間の親和性を緩和し、パクリタキセルを患部で放出しやすくし管腔へ移行しやすくすることができると本願発明者は推測する。
　しかし、その一方、ポリエチレングコール及び／又はポリプロピレングリコールは水不溶性薬剤の溶解度を高め、水不溶性薬剤との親和性が比較的高いため、薬剤層にポリエチレングリコール及び／又はポリプロピレングリコールが含まれていることによって、デリバリーの際に薬剤がポリエチレングリコール及び／又はポリプロピレングリコールとともに溶出することが懸念される。しかし、本発明の薬剤投与バルーンカテーテルは、薬剤層がバルーンから水へ溶出したり、摩擦等によって薬剤層から脱落等をすることがほとんどなく、生体内で十分な薬剤量を患部に送達できると想定される。
　このように、本発明の薬剤投与バルーンカテーテルは、デリバリー時における薬剤層の保持性と薬剤投与の際の薬剤組織移行性（放出性）に優れ、これらを両立させることができる。 In the present invention, the drug (paclitaxel) is strongly hydrophobic, and the dimethylacrylamide-glycidyl methacrylate copolymer also has a hydrophobic portion (mainly a main chain, a repeating unit of glycidyl methacrylate). Therefore, an affinity due to hydrophobicity occurs between the drug (paclitaxel) and the hydrophobic portion of the dimethylacrylamide-glycidyl methacrylate copolymer (lubricant). Thus, it is considered that paclitaxel is difficult to be released at the affected area and difficult to move to the lumen (tissue). When the balloon (base material) has hydrophobicity, in addition to the above, due to the affinity generated by the hydrophobicity with the balloon, the drug is less likely to migrate to the lumen (tissue).
Polyethylene glycol and / or polypropylene glycol contained in the drug layer relaxes the affinity between paclitaxel and the base material and / or lubricant, making it easier to release paclitaxel at the affected area and to move to the lumen. The inventor of this application estimates that this is possible.
However, since polyethylene glycol and / or polypropylene glycol increases the solubility of water-insoluble drugs and has a relatively high affinity with water-insoluble drugs, polyethylene glycol and / or polypropylene glycol is contained in the drug layer. Therefore, there is a concern that the drug elutes together with polyethylene glycol and / or polypropylene glycol during delivery. However, the drug administration balloon catheter of the present invention is capable of delivering a sufficient amount of drug to the affected area in vivo, with the drug layer hardly eluting from the balloon into water or falling off from the drug layer due to friction or the like. is assumed.
Thus, the drug administration balloon catheter of the present invention is excellent in the retention of the drug layer at the time of delivery and the drug tissue transferability (release property) at the time of drug administration, and can achieve both of them.
　本発明の薬剤投与バルーンカテーテルは、バルーンと共重合体層と薬剤層とカテーテルとを少なくとも有する。バルーンと共重合体層と薬剤層との積層体を以下薬剤投与バルーンということがある。本発明の薬剤投与バルーンカテーテルは、当該薬剤投与バルーンカテーテルの先端にバルーンを有するのが好ましい態様の１つとして挙げられる。 The drug administration balloon catheter of the present invention has at least a balloon, a copolymer layer, a drug layer, and a catheter. A laminate of the balloon, the copolymer layer, and the drug layer may be hereinafter referred to as a drug administration balloon. The drug administration balloon catheter of the present invention may be mentioned as one of preferred embodiments having a balloon at the tip of the drug administration balloon catheter.
　本発明の薬剤投与バルーンカテーテルについて添付の図面を用いて以下に説明する。本発明の薬剤投与バルーンカテーテルは添付の図面に制限されない。また各構成部材の大きさ、他の部材との大きさの比率等は添付の図面に制限されない。
　図５は、本発明の薬剤投与バルーンカテーテルの一実施形態を模式的に示す正面図である。
　図５において、符号５１は本発明の薬剤投与バルーンカテーテルであり、薬剤投与バルーンカテーテル５１は、シャフト本体部５２と、シャフト本体部５２の先端部（遠位端）に配置されたバルーン（拡張体）５３とを備える。図５に示す薬剤投与バルーンカテーテル５１は、ガイドワイヤルーメン２１０がシャフト本体部５２の基端部に固着されたハブ５４で開口するオーバーザワイヤタイプのものである。薬剤投与バルーンカテーテルは他のタイプのものであってもよい。 The drug administration balloon catheter of the present invention will be described below with reference to the accompanying drawings. The drug administration balloon catheter of the present invention is not limited to the attached drawings. Further, the size of each constituent member, the ratio of the size to other members, and the like are not limited to the attached drawings.
FIG. 5 is a front view schematically showing one embodiment of the drug administration balloon catheter of the present invention.
In FIG. 5, reference numeral 51 denotes a drug administration balloon catheter of the present invention. The drug administration balloon catheter 51 includes a shaft main body 52 and a balloon (expansion body) disposed at the tip (distal end) of the shaft main body 52. 53). A drug administration balloon catheter 51 shown in FIG. 5 is an over-the-wire type in which a guide wire lumen 210 is opened by a hub 54 fixed to a proximal end portion of a shaft main body 52. The drug delivery balloon catheter may be of other types.
　図６は、図５に示す薬剤投与バルーンカテーテルにおけるバルーン及びその近傍を模式的に示す拡大断面図である。
　図６に示すように、シャフト本体部５２は、ガイドワイヤー案内用管状部材（以下、内管シャフト）６２１と、バルーン拡張用管状部材（以下、外管シャフト）６２２との同心二重管であり、外管シャフト６２２の先端２２１は、内管シャフト６２１の先端より若干後端側に位置する。そして、外管シャフト６２２の内周と内管シャフト６２１の外周６２１ｂとの間にバルーン拡張用ルーメン２２０が形成される。 6 is an enlarged cross-sectional view schematically showing the balloon and the vicinity thereof in the drug administration balloon catheter shown in FIG.
As shown in FIG. 6, the shaft main body 52 is a concentric double tube of a guide wire guiding tubular member (hereinafter referred to as an inner tube shaft) 621 and a balloon expanding tubular member (hereinafter referred to as an outer tube shaft) 622. The distal end 221 of the outer tube shaft 622 is located slightly on the rear end side from the distal end of the inner tube shaft 621. A balloon expansion lumen 220 is formed between the inner periphery of the outer tube shaft 622 and the outer periphery 621b of the inner tube shaft 621.
　バルーン５３は、内圧の変化により折り畳みおよび拡張可能であり、内部に注入される流体によりほぼ同一径の筒状（好ましくは円筒状）に拡張する胴部６３０と、胴部６３０の基端側に滑らかに縮径する漸減径部６３１を経て設けられた基端縮径部６３２と、胴部６３０の先端側に滑らかに縮径する漸減径部６３３を経て設けられた先端縮径部６３４とを有する。拡張時の胴部６３０は、完全な円筒でなくてもよく、多角柱状のものであってもよい。バルーン５３は、拡張させない状態（図示せず）では、内管シャフト６２１の外周に折りたたまれた状態となることができる。
　拡張時のバルーン５３は、内管シャフト６２１の外周６２１ｂとの間に、拡張空間３００を形成する。拡張空間３００の基端部側は、その全周において、外管シャフト６２２のバルーン拡張用ルーメン２２０と連通しており、拡張用ルーメン２２０は比較的大きい容積を有するので、バルーン５３（拡張空間３００）内への拡張用流体の注入が確実である。 The balloon 53 is foldable and expandable by a change in internal pressure. The body 630 expands into a cylindrical shape (preferably a cylindrical shape) having substantially the same diameter by a fluid injected into the balloon 53, and a base end side of the body 630. A proximal end reduced diameter portion 632 provided via a gradually decreasing diameter portion 631 that smoothly reduces the diameter, and a distal end reduced diameter portion 634 provided via a gradually decreasing diameter portion 633 that smoothly reduces the diameter on the distal end side of the body portion 630. Have. The body portion 630 at the time of expansion may not be a perfect cylinder, but may be a polygonal column shape. When the balloon 53 is not expanded (not shown), the balloon 53 can be folded on the outer periphery of the inner tube shaft 621.
The balloon 53 at the time of expansion forms an expansion space 300 between the outer periphery 621b of the inner tube shaft 621. The base end portion side of the expansion space 300 communicates with the balloon expansion lumen 220 of the outer tube shaft 622 on the entire circumference thereof. Since the expansion lumen 220 has a relatively large volume, the balloon 53 (expansion space 300 ) The expansion fluid is surely injected into the inside.
　先端縮径部６３４は内管シャフト６２１の外周６２１ｂに、また基端縮径部６３２が外管シャフト６２２の先端２２１に接着剤または熱融着などにより液密に固着されている。
　図６において、Ｌ１はバルーン５３の長さを表し、Ｌ２は胴部６３０の長さを表し、φはバルーン５３が拡張した際の外径を表す。Ａはバルーン５３の断面の一部を示す。
　図５、図６において、共重合体層、薬剤層は省略されている。 The distal diameter reducing portion 634 is fixed to the outer periphery 621b of the inner tube shaft 621, and the proximal diameter reduced diameter portion 632 is fixed to the distal end 221 of the outer tube shaft 622 in a liquid-tight manner by an adhesive or heat fusion.
In FIG. 6, L1 represents the length of the balloon 53, L2 represents the length of the trunk 630, and φ represents the outer diameter when the balloon 53 is expanded. A shows a part of the cross section of the balloon 53.
5 and 6, the copolymer layer and the drug layer are omitted.
　図１は、本発明の薬剤投与バルーンカテーテルが有する薬剤投与バルーンの一部を模式的に表す断面図である。
　図１において、符号１０は、本発明の薬剤投与バルーンカテーテルが有する薬剤投与バルーンの一部の断面である。薬剤投与バルーン１０は、バルーン１２、バルーン１２の外上面上に共重合体層１４及び共重合体層１４の上に薬剤層１６を有する。薬剤投与バルーン１０は、バルーン１２、共重合体層１４及び薬剤層１６を有する積層体を形成するということができる。また、薬剤投与バルーン１０は、例えば、図６中のＡ部で示される、バルーン５３の断面の一部を拡大したものとすることができる。各層の厚さ、その比率は図１に限定されない。 FIG. 1 is a cross-sectional view schematically showing a part of a drug administration balloon included in the drug administration balloon catheter of the present invention.
In FIG. 1, the code | symbol 10 is a cross section of a part of drug administration balloon which the drug administration balloon catheter of this invention has. The drug administration balloon 10 has a balloon 12, a copolymer layer 14 on the outer upper surface of the balloon 12, and a drug layer 16 on the copolymer layer 14. It can be said that the drug administration balloon 10 forms a laminate including the balloon 12, the copolymer layer 14, and the drug layer 16. In addition, the drug administration balloon 10 can be, for example, an enlarged part of the cross section of the balloon 53 shown by part A in FIG. The thickness of each layer and its ratio are not limited to FIG.
　薬剤投与バルーンは共重合体層を有することによって潤滑性に優れる。薬剤投与バルーンを構成する共重合体層は、バルーンの外表面の少なくとも一部又はその全部を被覆することができる。共重合体層の膜厚は均一でなくてもよい。
　薬剤投与バルーンは共重合体層の表面に薬剤層を有することによって薬剤のデリバリー過程での保持性及び患部での放出性に優れる。薬剤投与バルーンを構成する薬剤層は、共重合体層を介して、バルーンの外表面の少なくとも一部又はその全部を被覆することができる。薬剤層の膜厚は均一でなくてもよい。 The drug administration balloon is excellent in lubricity by having a copolymer layer. The copolymer layer constituting the drug administration balloon can cover at least a part of or the entire outer surface of the balloon. The film thickness of the copolymer layer may not be uniform.
Since the drug administration balloon has a drug layer on the surface of the copolymer layer, it has excellent retention during the drug delivery process and release at the affected area. The drug layer constituting the drug administration balloon can cover at least a part or the whole of the outer surface of the balloon via the copolymer layer. The film thickness of the drug layer may not be uniform.
　バルーンについて以下に説明する。
　本発明の薬剤投与バルーンカテーテルを構成するバルーンは、一般的にバルーンカテーテルに使用されるバルーンであれば特に制限されない。バルーンの材料としては、例えば、ポリアミド類が挙げられる。具体的なポリアミド類としては、例えば、ポリテトラメチレンアジパミド（ナイロン４６）、ポリカプロラクタム（ナイロン６）、ポリヘキサメチレンアジパミド（ナイロン６６）、ポリヘキサメチレンセバカミド（ナイロン６１０）、ポリヘキサメチレンドデカミド（ナイロン６１２）、ポリウンデカノラクタム（ナイロン１１）、ポリドデカノラクタム（ナイロン１２）などの単独又は共重合体；カプロラクタム／ラウリルラクタム共重合体（ナイロン６／１２）、カプロラクタム／アミノウンデカン酸共重合体（ナイロン６／１１）、カプロラクタム／ω－アミノノナン酸共重合体（ナイロン６／９）、カプロラクタム／ヘキサメチレンジアンモニウムアジペート共重合体（ナイロン６／６６）などの共重合体、アジピン酸とメタキシレンジアミンとの共重合体；ヘキサメチレンジアミンとｍ，ｐ－フタル酸との共重合体などの芳香族ポリアミド；ナイロン６、ナイロン６６、ナイロン１１、ナイロン１２などをハードセグメントとし、ポリアルキレングリコール、ポリエーテルまたは脂肪族ポリエステルなどをソフトセグメントとするブロック共重合体であるポリアミドエラストマーが挙げられる。 The balloon will be described below.
The balloon constituting the drug administration balloon catheter of the present invention is not particularly limited as long as it is a balloon generally used for a balloon catheter. Examples of the balloon material include polyamides. Specific polyamides include, for example, polytetramethylene adipamide (nylon 46), polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66), polyhexamethylene sebacamide (nylon 610), Polyhexamethylene dodecamide (nylon 612), polyundecanolactam (nylon 11), homo- or copolymers such as polydodecanolactam (nylon 12); caprolactam / lauryl lactam copolymer (nylon 6/12), caprolactam / Aminoundecanoic acid copolymer (nylon 6/11), caprolactam / ω-aminononanoic acid copolymer (nylon 6/9), caprolactam / hexamethylenediammonium adipate copolymer (nylon 6/66), etc. Coalescence, adipic acid and metaxy Copolymer with hexamethylenediamine; aromatic polyamide such as copolymer of hexamethylenediamine and m, p-phthalic acid; nylon 6, nylon 66, nylon 11, nylon 12, etc. as hard segments, polyalkylene glycol, poly Examples thereof include polyamide elastomers that are block copolymers having ether or aliphatic polyester as a soft segment.
　本発明の薬剤投与バルーンカテーテルを製造する際に原料として使用されるバルーン（以下これを原料バルーンということがある。）は特に制限されない。例えば、上記と同様の材料のものが挙げられる。また、原料バルーンは、ジメチルアクリルアミド－グリシジルメタクリレート共重合体が有する基（例えばエポキシ基）と反応可能な官能基を有するのが好ましい態様の１つとして挙げられる。当該官能基としては、例えば、プロトン供与性基が挙げられ、具体的には例えば、アミノ基、イミノ基、水酸基、カルボキシル基、メルカプト基が挙げられる。原料バルーンがこのような官能基を有する場合、その外表面上に形成される共重合体層（ジメチルアクリルアミド－グリシジルメタクリレート共重合体）と反応して、重合体層がバルーンから剥離等しにくくなり、湿潤性に優れるバルーンとすることができるからである。
　バルーンの材料はそれぞれ単独でまたは２種以上を組み合わせて使用することができる。バルーン、バルーンカテーテルはその製造について特に制限されない。例えば、従来公知のものが挙げられる。 The balloon used as a raw material when producing the drug administration balloon catheter of the present invention (hereinafter sometimes referred to as a raw material balloon) is not particularly limited. For example, the thing of the material similar to the above is mentioned. In addition, the raw material balloon has a functional group capable of reacting with a group (for example, an epoxy group) included in the dimethylacrylamide-glycidyl methacrylate copolymer. Examples of the functional group include a proton donating group, and specific examples include an amino group, an imino group, a hydroxyl group, a carboxyl group, and a mercapto group. When the raw material balloon has such a functional group, it reacts with a copolymer layer (dimethylacrylamide-glycidyl methacrylate copolymer) formed on the outer surface thereof, and the polymer layer is difficult to peel off from the balloon. This is because the balloon can be excellent in wettability.
The balloon materials can be used alone or in combination of two or more. The production of the balloon and the balloon catheter is not particularly limited. For example, a conventionally well-known thing is mentioned.
　共重合体層について以下に説明する。
　本発明において、共重合体層はジメチルアクリルアミド－グリシジルメタクリレート共重合体によって形成される。
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体は、ジメチルアクリルアミド（Ｎ，Ｎ－ジメチルアクリルアミド）とグリシジルメタクリレートとの共重合体である。
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体は例えば下記式で表される化合物である。
Figure JPOXMLDOC01-appb-C000001
 The copolymer layer will be described below.
In the present invention, the copolymer layer is formed of a dimethylacrylamide-glycidyl methacrylate copolymer.
The dimethylacrylamide-glycidyl methacrylate copolymer is a copolymer of dimethylacrylamide (N, N-dimethylacrylamide) and glycidyl methacrylate.
The dimethylacrylamide-glycidyl methacrylate copolymer is, for example, a compound represented by the following formula.
Figure JPOXMLDOC01-appb-C000001
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体の重合形態は特に制限されない。例えば、ランダム共重合体、ブロック共重合体、グラフト共重合体のいずれであってもよい。なかでも、デリバリー過程での薬剤の保持性、患部での放出性により優れ、バルーンカテーテルの潤滑性に優れるという観点から、ブロック共重合体であるのが好ましい。
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体の３０℃における動粘度は、薬剤の保持性、患部での放出性により優れ、バルーンカテーテルの潤滑性に優れるという観点から、２．０～５．０ｃＳｔであるのが好ましい。
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体を構成する、ジメチルアクリルアミドの繰り返し単位数（上記式中のｎ）とグリシジルメタクリレートの繰り返し単位数（上記式中のｍ）の比は、薬剤のデリバリー過程での保持性、患部での放出性により優れ、バルーンカテーテルの潤滑性に優れるという観点から、ｍ：ｎ＝１～６：１～１００であるのが好ましい。ｍ＋ｎは上記重量平均分子量を満たす値とすることができる。
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体はその製造について特に制限されない。例えば、従来公知のものが挙げられる。ジメチルアクリルアミド－グリシジルメタクリレート共重合体はそれぞれ単独でまたは２種以上を組み合わせて使用することができる。 The polymerization form of the dimethylacrylamide-glycidyl methacrylate copolymer is not particularly limited. For example, any of a random copolymer, a block copolymer, and a graft copolymer may be used. Among these, a block copolymer is preferable from the viewpoint of excellent drug retention during delivery and release at an affected area, and excellent balloon catheter lubricity.
The kinematic viscosity at 30 ° C. of the dimethylacrylamide-glycidyl methacrylate copolymer is 2.0 to 5.0 cSt from the viewpoint of excellent drug retention, release at the affected area, and excellent balloon catheter lubricity. Is preferred.
The ratio of the number of repeating units of dimethylacrylamide (n in the above formula) to the number of repeating units of glycidyl methacrylate (m in the above formula) constituting the dimethylacrylamide-glycidyl methacrylate copolymer is maintained during the drug delivery process. M: n = 1 to 6: 1 to 100 is preferable from the standpoint of superiority and release at the affected area and excellent lubricity of the balloon catheter. m + n can be set to a value satisfying the weight average molecular weight.
The dimethylacrylamide-glycidyl methacrylate copolymer is not particularly limited for its production. For example, a conventionally well-known thing is mentioned. The dimethylacrylamide-glycidyl methacrylate copolymers can be used alone or in combination of two or more.
　薬剤層について以下に説明する。
　本発明において、薬剤層はポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルとによって形成される。
　薬剤層に使用されるポリエチレングリコール（ポリオキシエチレンジオール）は、オキシエチレン基を繰り返し単位とする主鎖と２つのヒドロキシ基とを有する化合物である。２つのヒドロキシ基は主鎖の両末端にそれぞれ結合するのが好ましい。
　薬剤層に使用されるポリプロピレングリコール（ポリオキシプロピレンジオール）は、オキシプロピレン基を繰り返し単位とする主鎖と２つのヒドロキシ基とを有する化合物である。２つのヒドロキシ基は主鎖の両末端にそれぞれ結合するのが好ましい。
　ポリエチレングリコール及びポリプロピレングリコールのうち、ポリエチレングリコールを使用するのが好ましい態様の１つとして挙げられる。
　ポリエチレングリコール又はポリプロピレングリコールの重量平均分子量は、薬剤のデリバリー過程での保持性、患部での放出性により優れ、組織浸透性に優れるという観点から、２００～２０００であるのが好ましく、３００～１０００であるのがより好ましい。
　ポリエチレングリコール、ポリプロピレングリコールはその製造について特に制限されない。ポリエチレングリコール、ポリプロピレングリコールはそれぞれ単独でまたは２種以上を組み合わせて使用することができる。 The drug layer will be described below.
In the present invention, the drug layer is formed of polyethylene glycol and / or polypropylene glycol and paclitaxel.
Polyethylene glycol (polyoxyethylene diol) used in the drug layer is a compound having a main chain having an oxyethylene group as a repeating unit and two hydroxy groups. The two hydroxy groups are preferably bonded to both ends of the main chain.
Polypropylene glycol (polyoxypropylene diol) used for the drug layer is a compound having a main chain having an oxypropylene group as a repeating unit and two hydroxy groups. The two hydroxy groups are preferably bonded to both ends of the main chain.
Among polyethylene glycol and polypropylene glycol, one preferred embodiment is to use polyethylene glycol.
The weight average molecular weight of polyethylene glycol or polypropylene glycol is preferably 200 to 2000, and preferably 300 to 1000, from the viewpoint of excellent retention during drug delivery, release at the affected area, and excellent tissue penetration. More preferably.
Polyethylene glycol and polypropylene glycol are not particularly limited for their production. Polyethylene glycol and polypropylene glycol can be used alone or in combination of two or more.
　薬剤層に使用されるパクリタキセルは下記式で表される化合物である。パクリタキセルの製造方法は特に制限されない。例えば、従来公知のものが挙げられる。
　パクリタキセルは例えば、抗がん剤、血管内狭窄などの血管疾患治療剤として使用することができる。
Figure JPOXMLDOC01-appb-C000002
 Paclitaxel used in the drug layer is a compound represented by the following formula. The method for producing paclitaxel is not particularly limited. For example, a conventionally well-known thing is mentioned.
Paclitaxel can be used, for example, as a therapeutic agent for vascular diseases such as anticancer agents and intravascular stenosis.
Figure JPOXMLDOC01-appb-C000002
　薬剤層において、ポリエチレングリコール及び／又はポリプロピレングリコールの量（及びの場合は両者の合計量）は、薬剤のデリバリー過程での保持性、患部での放出性により優れ、組織浸透性に優れるという観点から、パクリタキセル１００質量部に対して、３０～３００質量部であるのが好ましく、４０～２５０質量部であるのがより好ましい。 In the drug layer, the amount of polyethylene glycol and / or polypropylene glycol (and in this case, the total amount of both) is excellent in retention during drug delivery, release in the affected area, and excellent tissue permeability. The amount is preferably 30 to 300 parts by mass, more preferably 40 to 250 parts by mass with respect to 100 parts by mass of paclitaxel.
　本発明の薬剤投与バルーンカテーテルにおいて、ジメチルアクリルアミド－グリシジルメタクリレート共重合体の量は、薬剤のデリバリー過程での保持性、患部での放出性により優れ、バルーンカテーテルの潤滑性に優れるという観点から、パクリタキセル１００質量部に対して、１～１０質量部であるであるのが好ましく、４～１０質量部であるのがより好ましい。 In the drug-administered balloon catheter of the present invention, the amount of the dimethylacrylamide-glycidyl methacrylate copolymer is excellent in the retention in the drug delivery process, the release in the affected area, and the lubricity of the balloon catheter. The amount is preferably 1 to 10 parts by mass, more preferably 4 to 10 parts by mass with respect to 100 parts by mass.
　本発明の薬剤投与バルーンカテーテルにおいて、薬剤投与バルーンを構成するバルーンの単位表面積あたりのパクリタキセルの量は、保持性、放出性により優れ、薬剤の効果に優れ、副作用軽減に優れるという観点から、０．１～１０μｇ／ｍｍ2であるであるであるのが好ましく、１～４μｇ／ｍｍ2であるのがより好ましい。 In the drug administration balloon catheter of the present invention, the amount of paclitaxel per unit surface area of the balloon constituting the drug administration balloon is excellent from the viewpoint of retention and release, excellent drug effect, and excellent side effect reduction. It is preferably 1 to 10 μg / mm 2 , and more preferably 1 to 4 μg / mm 2 .
　本発明の薬剤投与バルーンカテーテルは、例えば、血管狭窄症、ステント内再狭窄病変の治療に適用することができる。薬剤（抗がん剤）としてパクリタキセルを利用することで、例えば、再狭窄、血栓症を防止することができる。 The drug administration balloon catheter of the present invention can be applied to, for example, treatment of vascular stenosis and in-stent restenosis lesions. By using paclitaxel as a drug (anticancer drug), for example, restenosis and thrombosis can be prevented.
　次に、本発明の薬剤投与バルーンカテーテルの製造方法について以下に説明する。
　本発明の薬剤投与バルーンカテーテルの製造方法は、
　バルーンカテーテルにおけるバルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体と有機溶剤Ａとを含むプレコート用組成物を付与して、共重合体層を形成するプレコート工程と、
　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを含む薬剤コート用組成物を付与して、薬剤層を形成する薬剤コート工程とを有することによって、本発明の薬剤投与バルーンカテーテルを製造する、薬剤投与バルーンカテーテルの製造方法である。 Next, a method for producing the drug administration balloon catheter of the present invention will be described below.
The method for producing a drug administration balloon catheter of the present invention comprises:
A pre-coating step of forming a copolymer layer by applying a pre-coating composition comprising a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A on the outer surface of the balloon in the balloon catheter;
By providing a drug coating composition containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer to form a drug layer, It is a manufacturing method of a medicine administration balloon catheter which manufactures a medicine administration balloon catheter of an invention.
　本発明の薬剤投与バルーンカテーテルの製造方法は、プレコート工程と薬剤コート工程とを有する。
　まず、プレコート工程について以下に説明する。
　本発明において、プレコート工程は、バルーンカテーテルにおけるバルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体と有機溶剤Ａとを含むプレコート用組成物を付与して、共重合体層を形成する工程である。
　プレコート工程において使用される、バルーンカテーテルは特に制限されない。例えば、バルーンとして上記の原料バルーンと同様なものを有するものが挙げられる。バルーンは、予め、例えば、有機溶剤やプライマー照射、ＵＶ照射等の前処理が施されていてもよい。 The method for producing a drug administration balloon catheter of the present invention includes a precoat process and a drug coat process.
First, the precoat process will be described below.
In the present invention, the precoat step is a step of forming a copolymer layer by applying a precoat composition containing a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A onto the outer surface of the balloon in the balloon catheter. It is.
The balloon catheter used in the precoat process is not particularly limited. For example, a balloon having the same material as the above-described raw material balloon can be used. The balloon may be pretreated in advance with, for example, an organic solvent, primer irradiation, or UV irradiation.
　プレコート工程において使用されるプレコート用組成物はジメチルアクリルアミド－グリシジルメタクリレート共重合体と有機溶剤Ａとを含む。
　プレコート用組成物に含まれるジメチルアクリルアミド－グリシジルメタクリレート共重合体は上記と同様である。ジメチルアクリルアミド－グリシジルメタクリレート共重合体はそれぞれ単独でまたは２種以上を組み合わせて使用することができる。
　プレコート用組成物に含まれる有機溶剤Ａは、ジメチルアクリルアミド－グリシジルメタクリレート共重合体を溶解及び／又は分散させることが可能な有機溶剤であれば特に制限されない。例えば、テトラヒドロフラン、クロロホルムが挙げられる。
　有機溶剤Ａはそれぞれ単独でまたは２種以上を組み合わせて使用することができる。 The precoat composition used in the precoat step contains a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A.
The dimethylacrylamide-glycidyl methacrylate copolymer contained in the precoat composition is the same as described above. The dimethylacrylamide-glycidyl methacrylate copolymers can be used alone or in combination of two or more.
The organic solvent A contained in the precoat composition is not particularly limited as long as it is an organic solvent capable of dissolving and / or dispersing the dimethylacrylamide-glycidyl methacrylate copolymer. For example, tetrahydrofuran and chloroform are mentioned.
The organic solvents A can be used alone or in combination of two or more.
　プレコート用組成物は有機溶剤Ａとジメチルアクリルアミド－グリシジルメタクリレート共重合体とを混合することによって製造することができる。
　ジメチルアクリルアミド－グリシジルメタクリレート共重合体の濃度は、保持性、放出性により優れ、潤滑性に優れるという観点から、プレコート用組成物中の０．１～１質量％であるのが好ましく、０．３～０．７質量％であるのがより好ましい。 The precoat composition can be produced by mixing the organic solvent A and a dimethylacrylamide-glycidyl methacrylate copolymer.
The concentration of the dimethylacrylamide-glycidyl methacrylate copolymer is preferably 0.1 to 1% by mass in the precoat composition from the viewpoint of excellent retention and release properties and excellent lubricity. More preferably, it is -0.7 mass%.
　バルーンの外表面上にプレコート用組成物を付与する方法は特に制限されない。例えば、バルーンを拡張して、バルーンをプレコート用組成物に浸漬する、プレコート用組成物をバルーンに塗布する又は噴霧する方法が挙げられる。付与に際しては例えば、刷毛、ピペット、自動塗布装置を使用することができる。
　プレコート工程によって、バルーンの外表面上に共重合体層を形成することができる。 The method for applying the precoat composition on the outer surface of the balloon is not particularly limited. Examples of the method include expanding the balloon and immersing the balloon in the precoat composition, or applying or spraying the precoat composition onto the balloon. For the application, for example, a brush, a pipette, or an automatic application device can be used.
A copolymer layer can be formed on the outer surface of the balloon by the precoat process.
　次に、薬剤コート工程について以下に説明する。
　薬剤コート工程は、上記のとおりプレコート工程でバルーンの外表面上に形成された共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを含む薬剤コート用組成物を付与して、薬剤層を形成する工程である。
　薬剤コート工程において使用される薬剤コート用組成物は、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを含む。
　薬剤コート用組成物に含まれるポリエチレングリコール及び／又はポリプロピレングリコールは特に制限されない。例えば、上記と同様のものが挙げられる。薬剤コート用組成物に含まれるパクリタキセルは上記と同様である。
　薬剤コート用組成物に含まれる有機溶剤Ｂは、パクリタキセルを溶解及び／又は分散させることができる有機溶剤であれば特に制限されない。例えば、無水エタノール、アセトン、テトラヒドロフランが挙げられる。有機溶剤Ｂはそれぞれ単独でまたは２種以上を組み合わせて使用することができる。 Next, the drug coating process will be described below.
In the drug coating step, a composition for drug coating containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer formed on the outer surface of the balloon in the pre-coating step as described above. It is the process of providing and forming a chemical | medical agent layer.
The composition for drug coating used in the drug coating step contains polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B.
The polyethylene glycol and / or polypropylene glycol contained in the drug coating composition is not particularly limited. For example, the thing similar to the above is mentioned. Paclitaxel contained in the composition for drug coating is the same as described above.
The organic solvent B contained in the composition for drug coating is not particularly limited as long as it is an organic solvent capable of dissolving and / or dispersing paclitaxel. For example, absolute ethanol, acetone, and tetrahydrofuran are mentioned. The organic solvents B can be used alone or in combination of two or more.
　薬剤コート用組成物の製造方法としては、例えば、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを混合することによって製造することができる。また、ポリエチレングリコール及び／又はポリプロピレングリコールを予め無水エタノールに溶解させ、パクリタキセルを予め無水エタノール及びアセトンの混合溶媒に溶解させ、これらを合わせて薬剤コート用組成物を作ることができる。 As a method for producing a drug coat composition, for example, it can be produced by mixing polyethylene glycol and / or polypropylene glycol, paclitaxel and organic solvent B. In addition, it is possible to prepare a drug coating composition by dissolving polyethylene glycol and / or polypropylene glycol in advance in absolute ethanol and dissolving paclitaxel in a mixed solvent of absolute ethanol and acetone in advance.
　パクリタキセルの濃度は、デリバリー過程での保持性、患部での放出性により優れ、薬剤の効果に優れ、副作用軽減に優れるという観点から、薬剤コート用組成物中の０．３～９質量％であるのが好ましく、１．５～４．０質量％であるのがより好ましい。
　ポリエチレングリコール及び／又はポリプロピレングリコールの濃度は、薬剤のデリバリー過程での保持性、患部での放出性により優れ、薬剤の効果に優れ、組織浸透性に優れるという観点から、薬剤コート用組成物中の０．１～１０質量％であるのが好ましく、１．０～８．０質量％であるのがより好ましい。 The concentration of paclitaxel is 0.3 to 9% by mass in the drug coating composition from the viewpoints of excellent retention during delivery and release at the affected area, excellent drug effect, and excellent side effect reduction. It is preferably 1.5 to 4.0% by mass.
The concentration of polyethylene glycol and / or polypropylene glycol is excellent in the retention during the drug delivery process, the release in the affected area, the effect of the drug, and the excellent tissue penetration. The content is preferably from 0.1 to 10% by mass, and more preferably from 1.0 to 8.0% by mass.
　前記共重合体層の上に薬剤コート用組成物を付与する方法は特に制限されない。例えば、共重合体層を有するバルーンを拡張した状態で、バルーンを薬剤コート用組成物に浸漬する、薬剤コート用組成物をバルーンに塗布する又は噴霧する方法が挙げられる。付与に際しては例えば、刷毛、ピペット、自動塗布装置を使用することができる。
　薬剤コート工程によって、共重合体層の上に薬剤層を形成する。 The method for applying the composition for drug coating on the copolymer layer is not particularly limited. For example, in a state where a balloon having a copolymer layer is expanded, a method of immersing the balloon in the drug coating composition, or applying or spraying the drug coating composition on the balloon can be mentioned. For the application, for example, a brush, a pipette, or an automatic application device can be used.
A drug layer is formed on the copolymer layer by a drug coating process.
　本発明の薬剤投与バルーンカテーテルの製造方法は、必要に応じて、さらに、少なくとも１つの乾燥工程を有することができる。乾燥工程を設けることによって有機溶剤Ａ及び／又は有機溶剤Ｂを除去することができる。乾燥工程を設けるタイミングはプレコート工程後であれば特に制限されない。例えば、プレコート工程と薬剤コート工程との間、及び／又は、薬剤コート工程の後とすることができる。
　乾燥工程は、プレコート工程と薬剤コート工程との間、又は、薬剤コート工程後に設けるのが好ましく、プレコート工程と薬剤コート工程との間、及び、薬剤コート工程後に設けるのがより好ましい。
　乾燥工程における乾燥は２０～３０℃の条件下で０．２５～２時間程度行うことができる。
　薬剤コート工程後に乾燥工程を設ける場合、その乾燥は２０～６０℃の条件下で３～４８時間程度行うことができる。 The method for producing a drug administration balloon catheter of the present invention can further include at least one drying step as necessary. By providing a drying step, the organic solvent A and / or the organic solvent B can be removed. The timing for providing the drying step is not particularly limited as long as it is after the precoat step. For example, it can be between the precoat step and the drug coat step and / or after the drug coat step.
The drying process is preferably provided between the precoat process and the drug coat process or after the drug coat process, and more preferably provided between the precoat process and the drug coat process and after the drug coat process.
Drying in the drying step can be performed at 20 to 30 ° C. for about 0.25 to 2 hours.
When a drying step is provided after the drug coating step, the drying can be performed at 20 to 60 ° C. for about 3 to 48 hours.
　薬剤コート工程後、又は、薬剤コート工程後の乾燥工程後に、必要に応じて、さらに、得られたバルーン（薬剤投与バルーン）をたたむラッピング工程を経て、本発明の薬剤投与バルーンカテーテルを製造することができる。 After the drug coating step or the drying step after the drug coating step, the drug administration balloon catheter of the present invention is manufactured through a wrapping step of folding the obtained balloon (drug administration balloon) as necessary. Can do.
　本発明の治療方法について以下に説明する。
　本発明の治療方法は、
　本発明の薬剤投与バルーンカテーテルを管腔の内部に送達する送達ステップと、
　前記薬剤投与バルーンカテーテルが有するバルーンが前記バルーンの径方向に拡張して、前記バルーンが前記管腔の内部と接する拡張ステップと、
　前記バルーンが有する薬剤層から、前記薬剤層を形成するパクリタキセルが前記管腔に移行する移行ステップとを有する治療方法である。 The treatment method of the present invention will be described below.
The treatment method of the present invention comprises:
A delivery step of delivering the drug delivery balloon catheter of the invention into the lumen;
An expansion step in which a balloon of the drug administration balloon catheter is expanded in a radial direction of the balloon, and the balloon is in contact with the inside of the lumen;
And a transition step in which paclitaxel forming the drug layer moves to the lumen from the drug layer of the balloon.
　本発明の治療方法は、本発明の薬剤投与バルーンカテーテルを使用することによって、薬剤のデリバリー過程における保持性、患部における放出性に優れ、副作用を軽減しながら薬剤の薬効を効果的に発揮させることができる。 The treatment method of the present invention is excellent in retention in the drug delivery process and release in the affected area by using the drug administration balloon catheter of the present invention, and effectively exerts the drug efficacy while reducing side effects. Can do.
　本発明の治療方法においては、まず、送達ステップにおいて、本発明の薬剤投与バルーンカテーテルを管腔の内部に送達する。
　本発明の治療方法において使用される薬剤投与バルーンカテーテルは本発明の薬剤投与バルーンカテーテルであれば特に制限されない。
　薬剤投与バルーンカテーテルが適用される管腔としては、例えば、血管、留置後のステント内が挙げられる。
　薬剤投与バルーンカテーテルを管腔内に送達する方法は、従来公知のバルーンカテーテルと同様である。例えば、薬剤投与バルーンカテーテルを冠動脈または末梢血管の狭窄部に送達する場合には、患者の手首または太股の動脈から筒状になっているガイディングカテーテルを心臓冠動脈の入口部まで挿入し、ガイディングカテーテルの中にガイドワイヤーを挿入し、薬剤投与バルーンカテーテルをガイドワイヤーに沿って挿入することで、薬剤投与バルーンを狭窄部に送達することができる。 In the treatment method of the present invention, first, in the delivery step, the drug administration balloon catheter of the present invention is delivered into the lumen.
The drug administration balloon catheter used in the treatment method of the present invention is not particularly limited as long as it is the drug administration balloon catheter of the present invention.
Examples of the lumen to which the drug administration balloon catheter is applied include blood vessels and in-stent stents.
The method of delivering the drug administration balloon catheter into the lumen is the same as that of a conventionally known balloon catheter. For example, when a drug administration balloon catheter is delivered to a stenosis of a coronary artery or a peripheral blood vessel, a guiding catheter that is cylindrical from the patient's wrist or crotch artery is inserted to the entrance of the heart coronary artery and guided. By inserting the guide wire into the catheter and inserting the drug administration balloon catheter along the guide wire, the drug administration balloon can be delivered to the stenosis.
　次に、拡張ステップにおいて、薬剤投与バルーンカテーテルが有するバルーン（薬剤投与バルーン）がバルーン（薬剤投与バルーン）の径方向に拡張して、バルーン（薬剤投与バルーン）が管腔の内部と接する。
　バルーンが管腔の内部でバルーンの径方向に拡張する方法は、従来公知のバルーンと同様である。 Next, in the expansion step, the balloon (drug administration balloon) of the drug administration balloon catheter is expanded in the radial direction of the balloon (drug administration balloon), and the balloon (drug administration balloon) comes into contact with the inside of the lumen.
The method of expanding the balloon in the radial direction of the balloon inside the lumen is the same as that of a conventionally known balloon.
　次に、移行ステップにおいて、バルーンが有する薬剤層から、薬剤層を形成するパクリタキセルが管腔（管腔壁）に移行する。
　管腔に薬剤を移行（作用又は放出ともいう。）させる方法は、管腔の内部で拡張させたバルーン（薬剤投与バルーン）を拡張し、バルーン（薬剤投与バルーン）が管腔の内部と接したままの状態で、数十秒間～数分間保持することによって行うことができる。これにより、管腔が拡張され、薬剤層の薬剤が管腔組織に作用し、浸透する。
　本発明の治療方法は、例えば、血管狭窄症、ステント内再狭窄病変の治療に適用することができる。薬剤（抗がん剤）としてパクリタキセルを利用することで、例えば、再狭窄、血栓症を防止することができる。 Next, in the transition step, paclitaxel forming the drug layer is transferred from the drug layer of the balloon to the lumen (lumen wall).
A method of transferring (also referred to as action or release) a drug to a lumen is performed by expanding a balloon (drug administration balloon) that is expanded inside the lumen, and the balloon (drug administration balloon) is in contact with the inside of the lumen. In this state, it can be carried out by holding for several tens of seconds to several minutes. As a result, the lumen is expanded, and the drug in the drug layer acts on and penetrates the lumen tissue.
The treatment method of the present invention can be applied to, for example, treatment of vascular stenosis and in-stent restenosis lesions. By using paclitaxel as a drug (anticancer drug), for example, restenosis and thrombosis can be prevented.
　以下に、実施例を示して本発明を具体的に説明する。ただし、本発明はこれらに限定されない。
＜ジメチルアクリルアミド－グリシジルメタクリレート共重合体（ＤＭＡＡ／ＧＭＡ共重合体）の製造＞
　アジピン酸２塩化物７２．３ｇ中に５０℃でトリエチレングリコ－ル２９．７ｇを滴下した後、５０℃で３時間塩酸を減圧除去して得られたオリゴエステル２２．５ｇにメチルエチルケトン４．５ｇを加え、水酸化ナトリウム５ｇ，３１％過酸化水素６．９３ｇ，界面活性剤ジオクチルホスフェ－ト０．４４ｇ、水１２０ｇよりなる溶液中に滴下し、－５℃で２０分間反応させた。得られた生成物は、水洗、メタノ－ル洗浄を繰り返した後、乾燥させて分子内に複数のパ－オキサイド基を有するポリ過酸化物を（ＰＰＯ）を得た。
　続いて、このＰＰＯを重合開始剤として０．５ｇ、グリシジルメタクリレ－ト（ＧＭＡ）９．５ｇを、ベンゼン３０ｇを溶媒として、６５℃２４時間、減圧下で撹拌しながら重合した。反応物は、ジエチルエ－テルで再沈して、分子内にパ－オキサイド基を有するポリグリシジルメタクリレート（ＰＧＭＡ）を得た。続いて、このＰＧＭＡ　８ｇ、ジメチルアクリルアミド（ＤＭＡＡ）　６０ｇをクロロベンゼン　５００ｇに溶かして、８０℃に加熱して約３ｈｒ重合反応を行った。この溶液を、大量のヘキサンに滴下して、重合体を沈澱させ、その沈澱物を濾過した。濾別された沈澱物をテトラヒドロフラン（ＴＨＦ）を良溶媒、ジエチルエーテルを貧溶媒として精製を繰り返した後、減圧してブロック共重合体を得た。
　得られたブロック共重合体を以下ＤＭＡＡ／ＧＭＡ共重合体と表す。これをＭＩＩポリマーということがある。
　ＤＭＡＡ／ＧＭＡ共重合体が有する、ＤＭＡＡによる繰り返し単位の数：ＧＭＡによる繰り返し単位の数（モル比）は、ＤＭＡＡ１２分子に対してＧＭＡが１分子である。
　ＤＭＡＡ／ＧＭＡ共重合体の３０℃における動粘度は２．５～４．５ｃＳｔである。 Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these.
<Production of dimethylacrylamide-glycidyl methacrylate copolymer (DMAA / GMA copolymer)>
29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50 ° C., and hydrochloric acid was removed under reduced pressure at 50 ° C. for 3 hours to 22.5 g of the resulting oligoester and 4.5 g of methyl ethyl ketone. Was added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of surfactant dioctyl phosphate, and 120 g of water, and reacted at −5 ° C. for 20 minutes. The obtained product was repeatedly washed with water and methanol, and then dried to obtain a polyperoxide (PPO) having a plurality of peroxide groups in the molecule.
Subsequently, 0.5 g of this PPO as a polymerization initiator, 9.5 g of glycidyl methacrylate (GMA), and 30 g of benzene as a solvent were polymerized with stirring at 65 ° C. for 24 hours under reduced pressure. The reaction product was reprecipitated with diethyl ether to obtain polyglycidyl methacrylate (PGMA) having a peroxide group in the molecule. Subsequently, 8 g of this PGMA and 60 g of dimethylacrylamide (DMAA) were dissolved in 500 g of chlorobenzene and heated to 80 ° C. to conduct a polymerization reaction for about 3 hours. This solution was dropped into a large amount of hexane to precipitate a polymer, and the precipitate was filtered. The precipitate separated by filtration was repeatedly purified using tetrahydrofuran (THF) as a good solvent and diethyl ether as a poor solvent, and then the pressure was reduced to obtain a block copolymer.
The obtained block copolymer is hereinafter referred to as DMAA / GMA copolymer. This is sometimes referred to as MII polymer.
The number of repeating units by DMAA that the DMAA / GMA copolymer has: The number (molar ratio) of repeating units by GMA is one molecule of GMA per 12 molecules of DMAA.
The kinematic viscosity at 30 ° C. of the DMAA / GMA copolymer is 2.5 to 4.5 cSt.
＜プレコート用組成物の製造＞
　上述のとおり製造したＤＭＡＡ／ＧＭＡ共重合体（ＭＩＩポリマー）を下記表１に示す量でテトラヒドロフランに溶解して、下記表１に示す濃度のプレコート用組成物（ＤＭＡＡ／ＧＭＡ溶液）を製造する。
＜薬剤コート用組成物の製造＞
　ポリエチレングリコール（ＨＯ（ＣＨ2ＣＨ2Ｏ）nＨ、商品名ＰＥＧ４００、関東化学製、平均分子量３８０～４２０）を無水エタノールと混合し、５０質量％のＰＥＧ４００溶液を調製する。
　一方、パクリタキセル（ＰＴＸ）を無水エタノール及びアセトン混合液（無水エタノール　２ｍＬ、アセトン　２ｍＬ）に溶解し、４０ｍｇ／ｍＬＰＴＸ溶液を調製する。
　ＰＥＧ４００、パクリタキセルの濃度が下記表１に示す薬剤コート用組成物中のＰＥＧ４００、パクリタキセルの濃度となるように、上記のように調製した、ＰＥＧ４００溶液とＰＴＸ溶液を、必要量で混合し、薬剤コート用組成物を調製する。 <Preparation of precoat composition>
The DMAA / GMA copolymer (MII polymer) produced as described above is dissolved in tetrahydrofuran in the amount shown in Table 1 below to produce a precoat composition (DMAA / GMA solution) having the concentration shown in Table 1 below.
<Manufacture of composition for drug coat>
Polyethylene glycol (HO (CH 2 CH 2 O) n H, trade name PEG400, manufactured by Kanto Chemical Co., Ltd., average molecular weight 380 to 420) is mixed with absolute ethanol to prepare a 50 mass% PEG400 solution.
On the other hand, paclitaxel (PTX) is dissolved in a mixed solution of absolute ethanol and acetone (anhydrous ethanol 2 mL, acetone 2 mL) to prepare a 40 mg / mL PTX solution.
The PEG400 solution and the PTX solution prepared as described above were mixed in a necessary amount so that the concentration of PEG400 and paclitaxel was the concentration of PEG400 and paclitaxel in the composition for drug coating shown in Table 1 below. A composition is prepared.
＜コーティング＞
・プレコート工程
　まず、バルーンカテーテル（テルモ社製、バルーン部分（拡張部)の素材はナイロン１２）であり、バルーンの表面積が１８８．４ｍｍ2であり、バルーンの胴部の長さＬ２が２０ｍｍであり、たたまれた状態のバルーン部分の直径は約１ｍｍであり、拡張したときのバルーンの外径φが３ｍｍである。）を拡張し、バルーンの外表面上に、上述のとおり製造したプレコート用組成物を自動塗布装置によって塗布し（バルーン上に付与されたプレコート用組成物の量は１０μＬである。）、２５℃の条件下で乾燥させ共重合体層を形成する。
・薬剤コート工程
　引き続き、上述のとおり製造した薬剤コート用組成物を共重合体層の上にピペットによってコートし（共重合体層上に付与された薬剤コート用組成物の量は２４．４μＬである。）、２５～３０℃の条件下で数時間乾燥させ薬剤層を形成して、バルーンをラッピング機で折りたたみ、薬剤投与バルーンカテーテルを製造する。
　製造例１～８を実施例１～８とする。 <Coating>
· Precoated Step First, a balloon catheter (produced by Terumo Corporation, material of the balloon portion (extended portion) is nylon 12), and the surface area of the balloon is 188.4Mm 2, the length L2 of the body portion of the balloon be 20mm The diameter of the balloon portion in the folded state is about 1 mm, and the outer diameter φ of the balloon when expanded is 3 mm. The precoat composition produced as described above was applied onto the outer surface of the balloon by an automatic coating apparatus (the amount of the precoat composition applied onto the balloon is 10 μL), and 25 ° C. A copolymer layer is formed by drying under the above conditions.
-Drug coating step Subsequently, the composition for drug coating produced as described above was coated on the copolymer layer with a pipette (the amount of the composition for drug coating applied on the copolymer layer was 24.4 μL). And a drug layer is formed by drying for several hours under conditions of 25-30 ° C., and the balloon is folded with a lapping machine to produce a drug administration balloon catheter.
Production Examples 1 to 8 are referred to as Examples 1 to 8.
［評価］
　上記のとおり得られた薬剤投与バルーンカテーテルを用いて、以下の試験を行い、デリバリー操作における薬剤コート層の耐性（ＰＴＸ残存率）、模倣血管（アガロースゲルチューブ）を用いたＰＴＸの放出性（ＰＴＸ転写率）を評価した。結果を表１、図４に示す。
　図４は、本発明の実施例における、デリバリー操作におけるＰＴＸ残存率、模倣血管（アガロースゲルチューブ）へのＰＴＸ転写率（放出性）の結果を示すグラフである。図４において、縦軸は各例のデリバリー操作におけるＰＴＸ残存率、模倣血管（アガロースゲルチューブ）へのＰＴＸ転写率（放出性）（いずれも単位は％）を表し、横軸のＩ～ＩＸは、調製例１～８、比較例１を順に表す。Ｉ～ＩＸと調製例１～８、比較例１との対応を表１に示す。図４中、斜線の棒グラフはデリバリー操作におけるＰＴＸ残存率を示し、黒色の棒グラフは模倣血管（アガロースゲルチューブ）へのＰＴＸ転写率（放出性）を示す。 [Evaluation]
Using the drug administration balloon catheter obtained as described above, the following tests were conducted. The drug coat layer resistance (PTX residual rate) in the delivery operation, the release property of PTX using the mimic blood vessel (agarose gel tube) (PTX) The transfer rate was evaluated. The results are shown in Table 1 and FIG.
FIG. 4 is a graph showing the results of the PTX residual rate in the delivery operation and the PTX transfer rate (release property) to the mimic blood vessel (agarose gel tube) in the example of the present invention. In FIG. 4, the vertical axis represents the PTX residual rate in the delivery operation of each example, the PTX transfer rate (release) to the mimic blood vessel (agarose gel tube) (both units are%), and I to IX on the horizontal axis Preparation Examples 1 to 8 and Comparative Example 1 are shown in this order. Table 1 shows the correspondence between I to IX and Preparation Examples 1 to 8 and Comparative Example 1. In FIG. 4, the hatched bar graph indicates the PTX remaining rate in the delivery operation, and the black bar graph indicates the PTX transfer rate (release) to the mimic blood vessel (agarose gel tube).
＜Ｉｎ　ｖｉｔｒｏ評価＞
・デリバリー操作における薬剤層耐性評価
　上記のとおり製造された薬剤投与バルーンカテーテルについて、バルーンの外表面にコートされた薬剤層が病変患部に送達する過程でどれだけ溶出及び／又は脱落するかを評価するために、模倣血管を用いて以下の薬剤層耐性試験を行った。
　まず、上述のとおり製造された薬剤投与バルーンカテーテルと、ガイディングカテーテル（ガイディングカテーテルの内部は予め３７℃のリン酸緩衝生理食塩水（ＰＢＳ）で満たされている。）と、９０度の角度がついている中空の模倣血管とを準備する。 <In vitro evaluation>
・ Evaluation of drug layer resistance in delivery operation For drug-administered balloon catheters manufactured as described above, evaluate how much the drug layer coated on the outer surface of the balloon elutes and / or drops during delivery to the affected area. Therefore, the following drug layer resistance test was performed using a mimic blood vessel.
First, a drug administration balloon catheter manufactured as described above, a guiding catheter (the inside of the guiding catheter is prefilled with 37 ° C. phosphate buffered saline (PBS)), and an angle of 90 degrees. Prepare a hollow imitation vessel with
　添付の図面を用いてデリバリー操作における薬剤層耐性試験を以下に説明する。図２は、本発明においてｉｎ　ｖｉｔｒｏの薬剤層耐性評価を行うために使用した実験装置を模式的に表す一部断面図である。
　図２において、符号２９は、本発明においてｉｎ　ｖｉｔｒｏの薬剤層耐性評価を行うために使用した実験装置を示す。実験装置２９は、模倣血管２５と、ガイディングカテーテル２０とを有する。模倣血管２５は内部が中空であり、分岐前部分２６、分岐部２７、分岐部２８を有する。模倣血管２５は分岐前部分２６から分岐部２７及び分岐部２８へ分岐しており、分岐部２７、２８の間の角度は約９０°である。ガイディングカテーテル２０は先端部２２、カテーテルシャフト２４及びガイディングカテーテル２０内にガイドワイヤー（図示せず。）を有し、ガイディングカテーテル２０の内部は３７℃のリン酸緩衝生理食塩水（ＰＢＳ）で満たされている。ガイディングカテーテル２０として、テルモ社製ガイディングカテーテル（商品名Ｈｅａｒｔｒａｉｌ　ＩＩ；バルーンカテーテルを挿入する位置（図示せず。）から先端部２２までの長さは約１１５ｃｍであり、バルーンカテーテル用ルーメンの外径は０．８３２５ｍｍ（２．５Ｆ）である。）を使用した。 The drug layer resistance test in the delivery operation will be described below with reference to the accompanying drawings. FIG. 2 is a partial cross-sectional view schematically showing an experimental apparatus used for performing in vitro drug layer resistance evaluation in the present invention.
In FIG. 2, the code | symbol 29 shows the experimental apparatus used in order to perform an in vitro chemical | medical agent tolerance evaluation in this invention. The experimental device 29 has a mimic blood vessel 25 and a guiding catheter 20. The mimic blood vessel 25 is hollow inside and has a pre-branch portion 26, a branch portion 27, and a branch portion 28. The mimic blood vessel 25 branches from the pre-branch portion 26 to the branch portion 27 and the branch portion 28, and the angle between the branch portions 27 and 28 is about 90 °. The guiding catheter 20 has a distal end portion 22, a catheter shaft 24, and a guide wire (not shown) in the guiding catheter 20, and the inside of the guiding catheter 20 is 37 ° C. phosphate buffered saline (PBS). Is filled with. As the guiding catheter 20, a length from Terumo's guiding catheter (trade name Heartrail II; a position where a balloon catheter is inserted (not shown)) to the distal end portion 22 is about 115 cm, and the outside of the balloon catheter lumen. The diameter was 0.8325 mm (2.5 F).
　デリバリー操作における薬剤層耐性試験は以下のようにして行った。
　まず、ガイディングカテーテル２０が分岐部２８から挿入され、先端部２２が分岐部２７へ至ったところで挿入を停止する。このときガイディングカテーテル２０が有するカテーテルシャフト２４は分岐部２７、２８の形状にしたがって、９０°の角度をなす。
　次に、上述のとおり製造された薬剤投与バルーンカテーテル（図示せず。）を、ガイディングカテーテル２０内にガイドワイヤーに沿って挿入し、先端部２２へ向かってデリバリー操作を進め、薬剤投与バルーンカテーテルの先端が先端部２２に到達するまでのデリバリー操作を行った。薬剤投与バルーンカテーテルの挿入から先端到達までのデリバリー操作を１分間で行い、先端到達後、薬剤投与バルーンカテーテルのバルーン部分を先端部２２から出してバルーン部分(拡張部)を回収した。 The drug layer resistance test in the delivery operation was performed as follows.
First, the guiding catheter 20 is inserted from the branch portion 28 and the insertion is stopped when the distal end portion 22 reaches the branch portion 27. At this time, the catheter shaft 24 of the guiding catheter 20 forms an angle of 90 ° according to the shape of the branch portions 27 and 28.
Next, the drug administration balloon catheter (not shown) manufactured as described above is inserted into the guiding catheter 20 along the guide wire, and the delivery operation is advanced toward the distal end portion 22. The delivery operation was performed until the tip of the tip reached the tip 22. The delivery operation from insertion of the drug administration balloon catheter to arrival at the tip was performed in 1 minute. After reaching the tip, the balloon portion of the drug administration balloon catheter was taken out from the tip 22 and the balloon portion (expansion portion) was collected.
　回収したバルーン部分を以下のように測定して薬剤層耐性試験の評価を行った。
　まず、回収したバルーン部分をメタノール１０ｍＬに浸して、その後、１０分間、振とう機を用いて振とうし、バルーンに残存したパクリタキセルを回収（抽出）した。
　得られたメタノール溶液中のＰＴＸ量を、２２７ｎｍでの吸光度で、紫外可視吸光光度計を用いて高速液体クロマトグラフィーで測定した。
　また、薬剤層耐性試験前の薬剤投与バルーンカテーテル（上記のとおり製造された状態の薬剤投与バルーンカテーテル）についても上記と同様にメタノールでパクリタキセルを抽出し、同様の測定を行い、パクリタキセルの量を求めた。
　薬剤層耐性試験後のバルーンにおけるＰＴＸの測定量と、上記のとおり製造された状態の薬剤投与バルーンカテーテルのバルーンにおけるＰＴＸの測定量を下記式に当てはめて、バルーンにおけるＰＴＸ残存率（％）を算出した。製造された状態の薬剤投与バルーンカテーテルのバルーンが有するＰＴＸの量（バルーンに塗布されたＰＴＸ量）を（１００％）とする（以下同様）。
ＰＴＸ残存率（％）
＝（薬剤層耐性試験後（デリバリー操作後）のバルーンにおけるＰＴＸの測定量）÷（上記のとおり製造された状態の薬剤投与バルーンカテーテルのバルーンにおけるＰＴＸの測定量）
　結果を表１に示す。
　デリバリー操作後のバルーンＰＴＸ残存率は薬剤のデリバリー性に優れるという観点から、バルーンに塗布したＰＴＸ量に対して６０%以上あるのが好ましい。 The collected balloon portion was measured as follows to evaluate the drug layer resistance test.
First, the collected balloon part was immersed in 10 mL of methanol, and then shaken for 10 minutes using a shaker to collect (extract) paclitaxel remaining in the balloon.
The amount of PTX in the resulting methanol solution was measured by high-performance liquid chromatography using an ultraviolet-visible absorptiometer at an absorbance of 227 nm.
Also, for the drug administration balloon catheter before the drug layer resistance test (drug administration balloon catheter manufactured as described above), paclitaxel was extracted with methanol in the same manner as described above, and the same measurement was performed to determine the amount of paclitaxel. It was.
The amount of PTX remaining in the balloon is calculated by applying the measured amount of PTX in the balloon after the drug layer resistance test and the measured amount of PTX in the balloon of the drug-administered balloon catheter manufactured as described above to the following formula. did. The amount of PTX (the amount of PTX applied to the balloon) of the balloon of the drug administration balloon catheter in the manufactured state is defined as (100%) (the same applies hereinafter).
PTX remaining rate (%)
= (Measured amount of PTX in the balloon after drug layer resistance test (after delivery operation)) ÷ (Measured amount of PTX in the balloon of the drug administration balloon catheter manufactured as described above)
The results are shown in Table 1.
The balloon PTX remaining rate after the delivery operation is preferably 60% or more with respect to the amount of PTX applied to the balloon from the viewpoint of excellent drug delivery.
　本評価系において、デリバリー操作後のバルーンＰＴＸ残存薬剤量が５８％を上回る場合、薬剤のＰＢＳへの溶出が少なく、デリバリー操作における薬剤保持能が良好であり、多くの薬剤を病変患部に送達することができる。一方、５８％以下の場合、デリバリー操作で剥がれる及び／又はＰＢＳへ溶出する薬剤量が多いため、安全面でも好ましくなく、また病変患部へ送達できる薬剤量が少ないので組織移行性も期待できない。したがって、本評価系では、デリバリー操作後にバルーンに残存するパクリタキセル量が５８％を上回ると送達過程において良好な薬剤保持能があると判断でき、６０％以上であるのが好ましく、６０％を上回るのがより好ましい。 In this evaluation system, when the amount of drug remaining in balloon PTX after delivery operation exceeds 58%, drug elution into PBS is small, drug retention in delivery operation is good, and many drugs are delivered to the affected area. be able to. On the other hand, when it is 58% or less, since the amount of the drug that is peeled off and / or eluted into the PBS is large, it is not preferable in terms of safety. Therefore, in this evaluation system, if the amount of paclitaxel remaining in the balloon after the delivery operation exceeds 58%, it can be determined that there is a good drug retention ability in the delivery process, and it is preferably 60% or more, more than 60%. Is more preferable.
・アガロースゲルチューブによるＰＴＸ移行性（放出性）評価
　上記のとおり製造された薬剤投与バルーンカテーテルについて、バルーンの外表面にコートされた薬剤層中のパクリタキセルが病変患部（組織）にどれだけ移行するかを評価するために、模倣血管としてアガロースゲルチューブを用いてＰＴＸ（組織）移行性（放出性）評価を行った。
［アガロースゲルチューブの作成］
　アガロースゲルチューブは以下の手順で作製した。アガロース（Ｉｎｖｉｔｒｏｇｅｎ）５．３２ｇを量り取り、リン酸緩衝生理食塩水（ＰＢＳ）４００ｍＬを加え混合後、高圧蒸気滅菌器に入れ、１００℃、１５分でアガロースを溶解し、１．３３％アガロース溶液を調製する。溶解後、５０～７０℃の温浴中で保持する。一方、無水エタノール５ｍＬを入れた５０ｍＬのガラス管を５０℃の温浴につけ、１．３３％アガロース溶液１５ｍＬを加え混和する。その後、混合液約１．７ｍＬをチューブ作製用シリンジに分注する。引き続き、軸棒（外径３ｍｍ）をシリンジに差しいれ固定する。固まったら軸棒を抜き取ることで内径３ｍｍ、長さ５０ｍｍのアガロースゲルチューブを作製する。アガロースゲルチューブはＰＢＳを入れた容器に移し冷蔵保存する。 ・ Evaluation of PTX transferability (release) by agarose gel tube For the drug-administered balloon catheter manufactured as described above, how much paclitaxel in the drug layer coated on the outer surface of the balloon is transferred to the affected lesion (tissue) Therefore, PTX (tissue) transferability (release property) was evaluated using an agarose gel tube as a mimic blood vessel.
[Create agarose gel tube]
The agarose gel tube was prepared by the following procedure. Weigh out 5.32 g of agarose (Invitrogen), add 400 mL of phosphate buffered saline (PBS), mix, place in a high-pressure steam sterilizer, dissolve the agarose at 100 ° C. for 15 minutes, and add 1.33% agarose solution To prepare. After dissolution, hold in a warm bath at 50-70 ° C. Meanwhile, a 50 mL glass tube containing 5 mL of absolute ethanol is placed in a 50 ° C. warm bath, and 15 mL of 1.33% agarose solution is added and mixed. Thereafter, about 1.7 mL of the mixed solution is dispensed into a tube preparation syringe. Subsequently, the shaft rod (outer diameter 3 mm) is inserted into the syringe and fixed. Once solidified, the shaft rod is removed to produce an agarose gel tube having an inner diameter of 3 mm and a length of 50 mm. Transfer the agarose gel tube to a container containing PBS and store it in a refrigerator.
［ＰＴＸ移行性（放出性）評価方法］
　上述のとおり製造された薬剤投与バルーンカテーテルと上述のとおり製造したアガロースゲルチューブ（アガロースゲルチューブの内部は３７℃のＰＢＳで満たされている。）を準備する。
　添付の図面を用いて薬剤移行性試験を以下に説明する。図３は、アガロースゲルチューブ内に本発明の薬剤投与バルーンカテーテルが挿入されている状態を模式的に示す一部断面図である。
　図３において、符号３０は薬剤投与バルーンカテーテルを示し、符号３６は上述のとおり製造したアガロースゲルチューブを示す。薬剤投与バルーンカテーテル３０はその先端にバルーン３２を有し、バルーン３２はカテーテルシャフト３４に接続する。アガロースゲルチューブ３６はその内部に３７℃のリン酸緩衝生理食塩水（ＰＢＳ）３８を有する。図３Ａにおいてバルーン３２は拡張前の状態であり、図３Ｂにおいてバルーン３２は拡張した状態である。
　薬剤移行性試験は、まず、薬剤投与バルーンカテーテル３０を３７℃の１０ｍＬＰＢＳ中であらかじめインキュベートする。
　次に、図３Ａに示すように、薬剤投与バルーンカテーテル３０をアガロースゲルチューブ３６に挿入する。そして、図３Ｂに示すように、バルーン３２を拡張し、バルーン３２がアガロースゲルチューブ３６の内壁に接した状態で１分間保持した。このとき、拡張されたバルーン３２の表面のほとんどがアガロースゲルチューブ３６の内壁に接した。１分経過後バルーン３２を閉じてアガロースゲルチューブ３６から薬剤投与バルーンカテーテル３０を回収した。その後、アガロースゲルチューブの内壁のみに吸着した薬剤を定量するためにアガロースゲルチューブ内部のＰＢＳを除去し、薬剤移行性試験を終了する。 [PTX transferability (release) evaluation method]
A drug administration balloon catheter manufactured as described above and an agarose gel tube manufactured as described above (the interior of the agarose gel tube is filled with PBS at 37 ° C.) are prepared.
The drug migration test will be described below with reference to the accompanying drawings. FIG. 3 is a partial cross-sectional view schematically showing a state in which the drug administration balloon catheter of the present invention is inserted into an agarose gel tube.
In FIG. 3, the code | symbol 30 shows a chemical | medical agent administration balloon catheter, and the code | symbol 36 shows the agarose gel tube manufactured as mentioned above. The drug administration balloon catheter 30 has a balloon 32 at its distal end, and the balloon 32 is connected to a catheter shaft 34. The agarose gel tube 36 has a phosphate buffered saline (PBS) 38 at 37 ° C. therein. In FIG. 3A, the balloon 32 is in a state before expansion, and in FIG. 3B, the balloon 32 is in an expanded state.
In the drug transfer test, first, the drug administration balloon catheter 30 is pre-incubated in 10 mL PBS at 37 ° C.
Next, as shown in FIG. 3A, the drug administration balloon catheter 30 is inserted into the agarose gel tube 36. Then, as shown in FIG. 3B, the balloon 32 was expanded and held for 1 minute while the balloon 32 was in contact with the inner wall of the agarose gel tube 36. At this time, most of the surface of the expanded balloon 32 was in contact with the inner wall of the agarose gel tube 36. After 1 minute, the balloon 32 was closed and the drug administration balloon catheter 30 was recovered from the agarose gel tube 36. Thereafter, in order to quantify the drug adsorbed only on the inner wall of the agarose gel tube, the PBS inside the agarose gel tube is removed, and the drug migration test is completed.
　薬剤移行性試験後のアガロースゲルチューブを５ｍＬのメタノールに浸し、砕いてアガロースゲルチューブに転写したＰＴＸを回収することで、当該ゲルへ移行したＰＴＸの量を、上記と同様にして、紫外可視吸光光度計を用いて高速液体クロマトグラフィーによって測定して転写性を評価した。上記のとおり求められた、薬剤移行性試験前の薬剤投与バルーンカテーテル（上記のとおり製造された状態の薬剤投与バルーンカテーテル）のＰＴＸの量を１００％とする。
ＰＴＸ転写率（％）
＝（薬剤移行性試験後のアガロースゲルチューブにおけるＰＴＸの測定量）÷（上記のとおり製造された状態の薬剤投与バルーンカテーテルのバルーンにおけるＰＴＸの測定量）
　結果を表１に示す。
　当該ゲルへのＰＴＸ移行性は、薬剤の組織移行性に優れるという観点から、バルーンに塗布したＰＴＸ量に対して５％以上であることが好ましい。 The agarose gel tube after the drug transferability test is immersed in 5 mL of methanol, and the PTX transferred to the agarose gel tube after being crushed is collected. Transferability was evaluated by measurement by high performance liquid chromatography using a photometer. The amount of PTX of the drug administration balloon catheter (drug administration balloon catheter in the state manufactured as described above) obtained before the drug transfer test is 100%.
PTX transcription rate (%)
= (Measured amount of PTX in the agarose gel tube after the drug transfer test) ÷ (Measured amount of PTX in the balloon of the drug-administered balloon catheter manufactured as described above)
The results are shown in Table 1.
The PTX migration to the gel is preferably 5% or more with respect to the amount of PTX applied to the balloon from the viewpoint of excellent tissue migration of the drug.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表１に示す、記号Ａ～Ｈ、Ｓの詳細は以下のとおりである。
・Ｓ１～Ｓ８：調製例１～８を指す。調製例１～８は図４のＩ～ＶＩＩＩに対応する。
・Ｓ９：比較例１を指す。比較例１は図４のＩＸに対応する。
・Ａ１：プレコート用組成物
・Ａ２：バルーン１個当たりのプレコート用組成物中のMIIPolymerの量(mg)
・Ａ３：プレコート用組成物中のMIIPolymerの濃度(質量%)
・Ｂ１：薬剤コート用組成物
・Ｂ２：バルーン１個当たりの薬剤コート用組成物中のPEG400の量(mg)
・Ｂ３：薬剤コート用組成物中のPEG400溶液の濃度（質量%）
・Ｂ４：バルーン１個当たりの薬剤コート用組成物中のPTXの量(mg)
・Ｂ５：薬剤コート用組成物中のPTXの濃度(質量％)
・Ｃ：プレコート用組成物、薬剤コート用組成物に使用した各成分の質量比（mg/mg/mg）
・Ｄ：プレコート工程後のバルーン単位面積当たりの共重合体の量（μg/mm2)
・Ｅ：薬剤コート工程後のバルーン単位面積当たりのPTXの量（μg/mm2)
・Ｆ：薬剤コート工程後のバルーン単位面積当たりのPEG400の量（μg/mm2)
・Ｇ１：デリバリー後のバルーンPTX残存率(%)
・Ｇ２：Ｇ１の結果を図４の斜線の棒グラフに示す。
・Ｈ１：ゲルへのPTX転写率(%)
・Ｈ２：Ｈ１の結果を図４の黒色の棒グラフに示す。 Details of symbols A to H and S shown in Table 1 are as follows.
S1-S8: refers to Preparation Examples 1-8. Preparation Examples 1 to 8 correspond to I to VIII in FIG.
S9: refers to Comparative Example 1. Comparative Example 1 corresponds to IX in FIG.
A1: Precoat composition A2: Amount of MIIPolymer (mg) in the precoat composition per balloon
A3: MIIPolymer concentration (mass%) in the precoat composition
B1: Composition for drug coating B2: Amount of PEG400 (mg) in the composition for drug coating per balloon
B3: Concentration (mass%) of the PEG400 solution in the composition for drug coating
B4: Amount of PTX in the drug coating composition per balloon (mg)
B5: PTX concentration (mass%) in the composition for drug coating
C: Mass ratio of each component used in the precoat composition and drug coat composition (mg / mg / mg)
D: Amount of copolymer per unit area of balloon after pre-coating process (μg / mm 2 )
E: Amount of PTX per unit area of balloon after drug coating process (μg / mm 2 )
F: Amount of PEG400 per unit area of balloon after drug coating process (μg / mm 2 )
・ G1: Balloon PTX remaining rate after delivery (%)
G2: The result of G1 is shown in the shaded bar graph in FIG.
・ H1: PTX transfer rate to gel (%)
-H2: The result of H1 is shown in the black bar graph of FIG.
　表１、図４に示す結果から明らかなように、薬剤層がポリエチレングリコール又はポリプロピレングリコールを含有しない比較例１は、パクリタキセル転写率が低く、薬剤の組織移行性が低いことが想定される。
　これに対して、実施例１～８は薬剤の転写率が５％以上あり、組織移行性に優れることが想定される。
　また、実施例１～８は、デリバリー操作後のバルーン上の薬剤残存率が高い。このことから、本発明の薬剤投与バルーンカテーテルは、デリバリー中において、薬剤がバルーンから脱落することや、バルーンが患部に送達する前に薬剤が溶出してしまうことを防止して、患部に多量の薬剤をデリバリーでき、送達後は患部で効率良く薬剤を放出すると考えられる。
　このように、本発明の薬剤投与バルーンカテーテルは、薬剤の組織移行性に優れ、デリバリー性に優れる。 As is clear from the results shown in Table 1 and FIG. 4, Comparative Example 1 in which the drug layer does not contain polyethylene glycol or polypropylene glycol is assumed to have a low paclitaxel transfer rate and a low tissue transferability of the drug.
In contrast, Examples 1 to 8 have a drug transfer rate of 5% or more, and are expected to be excellent in tissue transferability.
In Examples 1 to 8, the drug remaining rate on the balloon after the delivery operation is high. From this, the drug administration balloon catheter of the present invention prevents a drug from dropping off from the balloon during delivery, and prevents the drug from eluting before the balloon is delivered to the affected part. The drug can be delivered, and it is considered that the drug is efficiently released at the affected area after delivery.
As described above, the drug administration balloon catheter of the present invention is excellent in tissue transfer of drugs and excellent in delivery.
　１０　　　薬剤投与バルーン（一部）
　１２　　　バルーン
　１４　　　共重合体層
　１６　　　薬剤層
　２０　　　ガイディングカテーテル
　２２　　　先端部
　２４　　　カテーテルシャフト
　２５　　　模倣血管
　２６　　　分岐前部分
　２７、２８　　　分岐部
　２９　　　実験装置
　３０　　　薬剤投与バルーンカテーテル
　３２　　　バルーン
　３４　　　カテーテルシャフト
　３６　　　アガロースゲルチューブ
　３８　　　リン酸緩衝生理食塩水（ＰＢＳ）
　５１　　　薬剤投与バルーンカテーテル
　５２　　　シャフト本体部
　５３　　　バルーン
　５４　　　ハブ
　６２１　　内管シャフト
　６２１ｂ　外周
　２１０　　ガイドワイヤルーメン
　６２２　　外管シャフト
　２２０　　バルーン拡張用ルーメン
　２２１　　先端
　６３０　　胴部
　６３１　　漸減径部
　６３２　　基端縮径部
　６３３　　漸減径部
　６３４　　先端縮径部
　３００　　拡張空間 10 Drug administration balloon (part)
DESCRIPTION OF SYMBOLS 12 Balloon 14 Copolymer layer 16 Drug layer 20 Guiding catheter 22 Tip part 24 Catheter shaft 25 Mimic blood vessel 26 Pre-branch part 27, 28 Branch part 29 Experimental apparatus 30 Drug administration balloon catheter 32 Balloon 34 Catheter shaft 36 Agarose gel tube 38 Phosphate buffered saline (PBS)
51 Drug Administration Balloon Catheter 52 Shaft Main Body 53 Balloon 54 Hub 621 Inner Tube Shaft 621b Outer Diameter 210 Guide Wire Lumen 622 Outer Tube Shaft 220 Balloon Expansion Lumen 221 Tip 630 Body 631 Gradually Reduced Diameter 632 Base Radius 633 Part 634 Tip diameter reducing part 300 Expansion space

Claims (6)

  1. 　バルーンを有し、
    　前記バルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体によって形成される共重合体層を有し、
    　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルとによって形成される薬剤層を有する、薬剤投与バルーンカテーテル。     Having a balloon,
    On the outer surface of the balloon, has a copolymer layer formed by dimethylacrylamide-glycidyl methacrylate copolymer,
    A drug administration balloon catheter having a drug layer formed of polyethylene glycol and / or polypropylene glycol and paclitaxel on the copolymer layer.
  2. 　前記ポリエチレングリコール及び／又は前記ポリプロピレングリコールの量が、前記パクリタキセル１００質量部に対して、３０～３００質量部である請求項１に記載の薬剤投与バルーンカテーテル。 The drug administration balloon catheter according to claim 1, wherein the amount of the polyethylene glycol and / or the polypropylene glycol is 30 to 300 parts by mass with respect to 100 parts by mass of the paclitaxel.
  3. 　前記ジメチルアクリルアミド－グリシジルメタクリレート共重合体の量が、前記パクリタキセル１００質量部に対して、１～１０質量部である請求項１又は２に記載の薬剤投与バルーンカテーテル。 The drug administration balloon catheter according to claim 1 or 2, wherein the amount of the dimethylacrylamide-glycidyl methacrylate copolymer is 1 to 10 parts by mass with respect to 100 parts by mass of the paclitaxel.
  4. 　バルーンカテーテルにおけるバルーンの外表面上に、ジメチルアクリルアミド－グリシジルメタクリレート共重合体と有機溶剤Ａとを含むプレコート用組成物を付与して、共重合体層を形成するプレコート工程と、
    　前記共重合体層の上に、ポリエチレングリコール及び／又はポリプロピレングリコールとパクリタキセルと有機溶剤Ｂとを含む薬剤コート用組成物を付与して、薬剤層を形成する薬剤コート工程とを有することによって、請求項１～３のいずれかに記載の薬剤投与バルーンカテーテルを製造する、薬剤投与バルーンカテーテルの製造方法。     A pre-coating step of forming a copolymer layer by applying a pre-coating composition comprising a dimethylacrylamide-glycidyl methacrylate copolymer and an organic solvent A on the outer surface of the balloon in the balloon catheter;
    A drug coating step of forming a drug layer by applying a composition for drug coating containing polyethylene glycol and / or polypropylene glycol, paclitaxel, and organic solvent B on the copolymer layer is claimed. Item 4. A method for producing a drug administration balloon catheter, wherein the drug administration balloon catheter according to any one of Items 1 to 3 is produced.
  5. 　前記プレコート工程の後、さらに、少なくとも１つの乾燥工程を有する請求項４に記載の薬剤投与バルーンカテーテルの製造方法。 The method for producing a drug administration balloon catheter according to claim 4, further comprising at least one drying step after the pre-coating step.
  6. 　請求項１～３のいずれかに記載の薬剤投与バルーンカテーテルを管腔の内部に送達する送達ステップと、
    　前記薬剤投与バルーンカテーテルが有するバルーンが前記バルーンの径方向に拡張して、前記バルーンが前記管腔の内部と接する拡張ステップと、
    　前記バルーンが有する薬剤層から、前記薬剤層を形成するパクリタキセルが前記管腔に移行する移行ステップとを有する治療方法。     A delivery step of delivering the drug administration balloon catheter according to any of claims 1 to 3 to the inside of a lumen;
    An expansion step in which a balloon of the drug administration balloon catheter is expanded in a radial direction of the balloon, and the balloon is in contact with the inside of the lumen;
    And a transition step in which paclitaxel forming the drug layer moves to the lumen from the drug layer of the balloon.
PCT/JP2014/059680 2013-04-01 2014-04-01 Balloon catheter for drug administration and process for producing same WO2014163097A1 (en)

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