WO2016117744A1 - Bioabsorbable radiopaque marker composition and surgical article comprising same - Google Patents

Bioabsorbable radiopaque marker composition and surgical article comprising same Download PDF

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Publication number
WO2016117744A1
WO2016117744A1 PCT/KR2015/000966 KR2015000966W WO2016117744A1 WO 2016117744 A1 WO2016117744 A1 WO 2016117744A1 KR 2015000966 W KR2015000966 W KR 2015000966W WO 2016117744 A1 WO2016117744 A1 WO 2016117744A1
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WIPO (PCT)
Prior art keywords
radiopaque marker
marker composition
poly
lactide
xenon
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PCT/KR2015/000966
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French (fr)
Korean (ko)
Inventor
금창헌
유현승
서준혁
송석범
박준규
김성현
김한기
조재화
기병윤
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주식회사 바이오알파
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Publication of WO2016117744A1 publication Critical patent/WO2016117744A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • 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
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/14—Post-treatment to improve physical properties
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/18—Materials at least partially X-ray or laser opaque
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3966—Radiopaque markers visible in an X-ray image
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0096—Markers and sensors for detecting a position or changes of a position of an implant, e.g. RF sensors, ultrasound markers
    • A61F2250/0098—Markers and sensors for detecting a position or changes of a position of an implant, e.g. RF sensors, ultrasound markers radio-opaque, e.g. radio-opaque markers
    • 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

Definitions

  • the present invention relates to a bioabsorbable radiopaque marker composition and a surgical article comprising the same. More specifically, the present invention relates to a bioabsorbable radiopaque marker composition and a surgical article including the same, which can be used to accurately locate a stent through radiation such as X-rays or gamma rays after performing a stent.
  • Stents are luminal dilatation apparatuses used to expand narrowed passages due to stenosis, and are widely used for the treatment of cancer diseases or vascular diseases.
  • metal stents used in vivo are magnesium, potassium, calcium, titanium, chromium, iron, cobalt and nickel and their alloys are used as biocompatible metal materials, which are short-lived as 3-4 cycle atoms of the periodic table. Radiation such as X-rays having a wavelength (10 to 0.01 nanometers) or gamma rays (0.01 to 0.00001 nanometers) can be easily transmitted.
  • biodegradable polymers used in drug-release stents and biodegradable polymer stents are also transmitted through radiation, so it is impossible to specify their location when implanted into the human body.
  • a method of attaching a metal radiopaque material of five or more cycles of the periodic table such as gold, platinum, talthanum, tungsten, and talnium to a specific portion of the stent is used to check its location.
  • a metal radiopaque material of five or more cycles of the periodic table such as gold, platinum, talthanum, tungsten, and talnium
  • additional space is required in the stent, and a process of bonding a metal radiopaque marker to the stent is required.
  • metal radiopaque markers when the metal radiopaque markers are implanted into the human body, only a portion in which the metal radiopaque markers are installed can be confirmed.
  • metal radiopaque markers such as gold, platinum, taltanium, tungsten, and talnium having non-degradable properties in vivo are in vivo. It may remain permanent and cause a problem of foreign body reaction in vivo, and if the metal radiopaque marker mounted on the stent is removed, it may cause other problems because it is circulated in vivo without being discharged out of the living body.
  • the present invention seeks to provide a bioabsorbable radiopaque marker composition and a surgical article comprising the same.
  • One aspect of the invention may be a bioabsorbable radiopaque marker composition comprising iodine, xenon or a combination thereof.
  • the iodine source providing iodine is selected from the group consisting of iodine, hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide and povidone iodine
  • the xenon source comprising at least one and providing xenon may include at least one selected from the group consisting of xenon difluoride, xenon tetrafluoride and xenon hexafluoride.
  • This aspect may further comprise a biodegradable polymer.
  • the biodegradable polymer may be dissolved in a hydrophilic solvent.
  • the solvent is water; Alcohols including methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehydes including ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde and acetaldehyde; Alkanes including dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents including benzene, toluene and xylene; Ethers including ethers, di-propyl ethers, petroleum ethers and methyl-t-butyl ethers; Ketones including propanone, butanone, pentanone, hex
  • the biodegradable polymer is poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co- Glycolide, poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide -co-caprolactone, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxone, poly Amide esters, polypeptides, polyorthoesters, polymaleic acid, polyphosphazenes, polyanhydrides, polycephaanhydrides, polyhydroxyalkanoates, polyhydroxybutyrates, polycyanoacrylates, polydopamine
  • the content of the biodegradable polymer may be 0.01 to 90% by weight relative to the total weight of the composition.
  • the total content of iodine and xenon may be 0.01 to 95% by weight relative to the total weight of the composition.
  • Another aspect of the present invention may be a surgical article comprising the composition, specifically, a stent or polymer screw coated with the composition, a biodegradable polymer stent, a scaffold or a surgical suture containing the composition.
  • the surgical article may also be a support for tissue regeneration, bio nanofibers, hydrogels, bio sponges, pins, screws, screws, rods, fillers, implants or living implants.
  • bioabsorptive radiopaque marker composition that can not act as a radiopaque marker in the human body due to the transmission of radiation such as X-rays.
  • Bioabsorbable radiopaque marker composition according to an aspect of the present invention may include iodine, xenon or a combination thereof.
  • Iodine may be provided from an iodine source. Specifically, it may be provided from solid iodine or a compound containing iodine.
  • Iodide containing iodine may include hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide, povidone iodine or combinations thereof.
  • the iodine compound may be dissolved and completely present in an ionic state, or, if not partially dissolved, may be present in a compound state.
  • Xenon may be provided from a xenon source. Specifically, it may be supplied from a compound containing xenon gas or xenon.
  • the xenon compound containing xenon may include xenon difluoride, xenon tetrafluoride, xenon hexafluoride or combinations thereof.
  • the xenon compound may be dissolved and completely present in an ionic state, or, if not partially dissolved, may be present in a compound state.
  • X-rays When X-rays are irradiated to the bioabsorbable radiopaque marker composition of the present aspect, X-rays do not penetrate. This is because iodine and xenon have large atomic groups. Thus, for example, when the stent coated with the composition of the present aspect is operated, the position of the stent can be accurately determined through X-ray imaging, and thus there is an advantage that the follow-up can be observed.
  • X-rays are generally used for medical purposes, and the wavelength range of X-rays is 0.01 to 10 nanometers, or the wavelength range of gamma rays is 0.00001 to 0.01 nanometers.
  • Iodine, xenon and compounds thereof are water; Alcohol solvents such as methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehyde solvents such as ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde, acetaldehyde; Alkanes solvents such as dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents such as benzene, toluene and xylene; Ether solvents such as ether, di-propyl ether, petroleum ether and methyl t-butyl ether; Ketone solvents such as
  • iodine, xenon and compounds thereof have the property of being easily absorbed or released in vivo. Therefore, unlike metal radiopaque markers such as gold, platinum, taltanium, tungsten, and talnium, they do not remain in the living body and are discharged to the outside of the body, so that problems such as foreign body reactions do not occur.
  • the composition of this aspect may be a bioabsorbable radiopaque marker composition for a stent that can be applied to the stent.
  • the iodine and iodine compounds, xenon and xenon compounds are radiopaque materials that can be used in a living body.
  • Astantin (At) and radon (Rn) are 6 cycles of non-metallic materials that are radiopaque and thus capable of functioning as an opaque marker in vivo, but are harmful to the living body, so they are useful for stent and biotransplantation. impossible to use.
  • Bioabsorbable radiopaque marker composition of the present aspect may further comprise a biodegradable polymer.
  • the biodegradable polymer is not particularly limited as long as it can be degraded in the human body.
  • synthetic biodegradable polymer or natural biodegradable polymer may be used.
  • Biodegradable polymers include poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co-glycolide, Poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide-co-capro Lactones, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxoneone, polyamide esters, polypeptides , Polyorthoester type, polymaleic acid, polyphosphazene, polyanhydride, polycephaanhydride, polyhydroxide alkanoate, polyhydroxybutyrate,
  • the molecular weight of the biodegradable polymer is preferably 1,000 to 3,000,000. If the molecular weight is less than 1,000, it is impossible to form a polymer coating layer and a matrix, and if the molecular weight is greater than 3,000,000, the molecular weight may be too large to prevent biodegradation of the polymer.
  • the content of the biodegradable polymer may be 0.01 to 90% by weight relative to the total weight of the composition. If the content of the biodegradable polymer is less than 0.01% by weight may be impossible to form the polymer coating layer and the matrix, when the content of more than 90% by weight may be too high viscosity may be impossible to manufacture the polymer coating and matrix.
  • Biodegradable polymers may be dissolved in a solvent.
  • the solvent is not particularly limited as long as it can dissolve the biodegradable polymer.
  • the solvent is water; Alcohol solvents such as methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehyde solvents such as ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde, acetaldehyde; Alkanes solvents such as dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents such as benzene, toluene and xylene; Ether solvents such as ether,
  • Biodegradable polymers include cardiovascular materials such as stents, surgical sutures, support for tissue regeneration, bio nanofibers, hydrogels, bio sponges; Dental materials such as pins, screws, screws, rods, and implants; Or nerve / orthopedic / plastic surgery implants such as pins, screws, screws, scaffolds for tissue regeneration, rods, fillers, and the like;
  • iodine or xenon is a structure in which a biodegradable polymer is present as a matrix.
  • iodine and the like present in the portion are also detached and discharged to the outside.
  • the iodine and the like are completely discharged to the outside and the radiopacity may disappear.
  • Either an iodine source or a xenon source may be used, or an iodine source and a xenon source may be used together.
  • the total content of iodine and xenon combined may be 0.01 to 95% by weight based on the total weight of the composition. If less than 0.01% by weight may not appear radiopaque properties, if more than 95% by weight iodine is not completely dissolved and precipitation may occur.
  • the bioabsorbable radiopaque marker composition of this aspect can be manufactured by the following method.
  • a biodegradable polymer is weighed and added to a solvent. At this time, the biodegradable polymer is completely dissolved by stirring.
  • Solvents include water; Alcohol solvents such as methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehyde solvents such as ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde, acetaldehyde; Alkanes solvents such as dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents such as benzene, toluene and xylene; Ether solvents such as ether, di-propyl ether, petroleum ether and methyl t-butyl ether; Ketone solvents such as propanone, butanone, pen
  • Biodegradable polymers include poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co-glycolide, Poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide-co-capro Lactones, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxoneone, polyamide esters, polypeptides , Polyorthoester type, polymaleic acid, polyphosphazene, polyanhydride, polycephaanhydride, polyhydroxide alkanoate, polyhydroxybutyrate,
  • the biodegradable polymer may be used in an amount of 0.01 to 90% by weight based on the total weight of the final composition. If the content of the biodegradable polymer is less than 0.01% by weight may be impossible to form the polymer coating layer and the matrix, when the content of more than 90% by weight may be too high viscosity may be impossible to manufacture the polymer coating and matrix.
  • biodegradable polymer those having a molecular weight of 1,000 to 3,000,000 can be used.
  • iodine, a compound containing iodine, a compound containing xenon, a xenon, or a combination thereof can be added to the solution, followed by stirring to dissolve it.
  • iodine compounds containing iodine hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide, povidone iodine or a combination thereof can be used.
  • a xenon-containing xenon compound As a xenon-containing xenon compound, a xenon difluoride, xenon tetrafluoride, xenon hexafluoride, or a combination thereof can be used.
  • Either an iodine source or a xenon source can be used, and an iodine source and a xenon source can also be used together.
  • the total content of iodine and xenon may be used in an amount of 0.01 to 95% by weight based on the total weight of the composition. If less than 0.01% by weight may not appear radiopaque properties, if more than 95% by weight iodine is not completely dissolved and precipitation may occur.
  • Another aspect of the invention may be a surgical article comprising the bioabsorbable radiopaque marker composition.
  • Surgical articles to which the bioabsorbable radiopaque marker composition may be applied may be various, and any article that is present in the human body after surgery may be applicable.
  • the surgical article includes a cardiovascular material such as a stent, a surgical suture, a support for tissue regeneration, bio nanofibers, a hydrogel, and a bio sponge; Dental materials such as pins, screws, screws, rods, and implants; Or nerve / orthopedic / plastic surgery implants such as pins, screws, screws, scaffolds for tissue regeneration, rods, fillers, and the like.
  • a cardiovascular material such as a stent, a surgical suture, a support for tissue regeneration, bio nanofibers, a hydrogel, and a bio sponge
  • Dental materials such as pins, screws, screws, rods, and implants
  • nerve / orthopedic / plastic surgery implants such as pins, screws, screws, scaffolds for tissue regeneration, rods, fillers, and the like.
  • Such surgical articles include stents.
  • the stent may be coated with a bioabsorbable radiopaque marker composition or the polymer material for the stent matrix may contain a bioabsorbable radiopaque marker composition.
  • a biodegradable polymer stent may be used as well as a metal stent.
  • an ultrasonic spray injection method, an electrospinning method, an immersion method, or the like may be used as a method of coating the bioabsorbable radiopaque marker composition on the stent.
  • the stent can be more uniformly coated with the radiopaque marker composition for bioabsorption, as compared with the electrospinning or dipping method. If the stent containing the bioabsorbable radiopaque marker composition is present in the human body, the location of the stent in the human body may be accurately determined by irradiation.
  • a surgical suture is a surgical suture containing a bioabsorbable radiopaque marker composition.
  • Surgical sutures containing a bioabsorbable radiopaque marker composition can be prepared using conventional radiation methods. That is, the bioabsorbable radiopaque marker composition and the polymer material for surgical suture matrix may be melted and then extruded. In this way, a suture containing a bioabsorbable radiopaque marker composition can be produced in the surgical suture itself.
  • scaffolding is a scaffold containing the radiopaque marker composition for bioabsorption.
  • the scaffold containing the bioabsorbable radiopaque marker composition can be prepared according to a conventional scaffold manufacturing method. Specifically, after mixing the bio-absorption radiopaque marker composition, the ice particles for forming the scaffold pores, the usual scaffolding particles, such as sodium carbonate or sodium hydrogen carbonate, a solvent and a polymer material, and then the mixture into the mold It can manufacture by inserting and compressing.
  • a surgical adhesive is a surgical adhesive containing a bioabsorbable radiopaque marker composition.
  • Surgical adhesives containing bioabsorbable radiopaque marker compositions can be prepared according to conventional adhesive manufacturing processes. Specifically, the surgical adhesive containing the marker composition may be prepared by dissolving the radiopaque marker composition for bioabsorption and the polymer material in a conventional solvent.
  • a polymer screw is Another example.
  • a method of coating the marker composition on the polymer skew ultrasonic spraying, electrospinning or dipping may be used.
  • the polymer screw containing the marker composition may be prepared by mixing the radiopaque marker composition for bioabsorption with a polymer material and then subjecting the polymer material to a conventional mold injection process.
  • the prepared marker composition was coated by ultrasonic spray spray on the stent.
  • an ultrasonic spray device (Sonotech, MedicoatPSI) was used, the voltage of the ultrasonic vibrator was adjusted to 0.9 mV, the spray flow rate to 0.03 ml / min, and the coating was performed for 40 seconds.
  • the rotational speed of the stent was 50 RPM, and the moving speed was 0.03 cm / sec.
  • the stent coated with the marker composition was vacuum dried in a vacuum dryer at 40 ° C. for 24 hours.
  • the thickness of the marker composition coating layer was 2 um.
  • the drug release coating solution was coated on the stent coated with the marker composition using an ultrasonic spray device. Coating was carried out for 1 minute 30 seconds under the same conditions as when coating the marker composition.
  • the drug release coating layer had a thickness of 6 um.
  • a drug release coating solution was prepared by dissolving 10 g of paclitaxel and 10 g of poly-carprolactone in 80 g of tetrahydrofuran (THF) as a solvent.
  • the spinning speed was adjusted to 0.5 ml / min, the spinning distance was 10 cm, and the voltage was set to 1000 mV, and a drug release coating layer was formed on the metal stent with the drug release coating solution by using an electrospinning method for 10 minutes. Coating was carried out for 2 minutes.
  • the drug release coating layer was 7 um thick.
  • the voltage of the ultrasonic vibrator was adjusted to 0.5 mV, the spray flow rate to 0.05 ml / min, and the coating was performed for 30 seconds.
  • the rotational speed of the stent was adjusted to 60 RPM and the moving speed was 0.05 cm / sec to coat the marker composition for 1 minute.
  • the thickness of the marker coating layer was 3 um.
  • 0.7 g of the marker composition was dissolved in 0.3 g of 1-10 um ice particles and 9 g of polylactide-co-glycolide in 10 g of chloroform, using a circular frame of 2 cm in diameter and 2 mm in height. To prepare a scaffold.
  • the orthopedic polymer screw was impregnated in the marker composition for 3 minutes and then dried in air to prepare a polymer screw coated with the marker composition.
  • 50 g of the prepared marker composition was adjusted to a screw speed of 70 rpm, a chamber temperature of 200 degrees, and a voltage of 1100 mV to prepare a surgical suture through electrospinning.
  • the marker composition was extruded through an extruder having an extrusion rotation speed of 200 rpm and a chamber temperature of 220 degrees to form a pattern using a femtosecond laser having a voltage controlled at 1350 mV to prepare a biodegradable polymer stent.
  • the marker composition was extruded through an extruder having an extrusion rotation speed of 250 rpm and a chamber temperature of 210 ° C.
  • a biodegradable polymer stent was prepared by pattern formation using a femtosecond laser whose voltage was controlled at 1300 mV.
  • the drug release coating solution was coated by ultrasonic spray spraying on the metal stent. Specifically, the voltage of the ultrasonic vibrator was adjusted to 0.9 mV, the spray flow rate to 0.03 ml / min, and the coating was performed for 40 seconds. The rotational speed of the stent was 50 RPM, and the moving speed was 0.03 cm / sec.
  • composition prepared according to Examples and Comparative Examples was dropped on a plastic substrate, and then X-ray imaging was performed by using an X-ray measuring apparatus (LISTEM, PROGEN-R diagnostic X-ray imaging apparatus) to measure X-ray opacity. Opacity was calculated as follows.
  • Level 1 More than 80% opacity
  • the opacity of the Example was slightly reduced, but still maintained the opacity of the first or second grade.
  • the comparative example shows a low impermeability, such as measured in the fourth grade from the initial measurement results.

Abstract

The present invention relates to a bioabsorbable radiopaque marker composition and a surgical article comprising the same. The bioabsorbable radiopaque marker composition according to the present invention comprises iodine, xenon, or a combination thereof. If the surgical article according to the present invention is used, it is possible to accurately trace and observe the position of a stent, etc. within the human body.

Description

생체 흡수용 방사선 불투과성 마커 조성물 및 이를 포함하는 수술용 물품Bio-absorptive radiopaque marker composition and surgical article comprising same
본 발명은 생체 흡수용 방사선 불투과성 마커 조성물 및 이를 포함하는 수술용 물품에 관한 것이다. 보다 상세하게는, 스텐트 등을 시술한 후 엑스선 또는 감마선 등의 방사선을 통하여 스텐트 등의 위치를 정확하게 파악하는데 사용할 수 있는 생체 흡수용 방사선 불투과성 마커 조성물 및 이를 포함하는 수술용 물품에 관한 것이다.The present invention relates to a bioabsorbable radiopaque marker composition and a surgical article comprising the same. More specifically, the present invention relates to a bioabsorbable radiopaque marker composition and a surgical article including the same, which can be used to accurately locate a stent through radiation such as X-rays or gamma rays after performing a stent.
스텐트(Stent)는 협착으로 인해 좁아진 통로를 확장하는데 사용되는 내강 확장기구로서, 암 질환 또는 혈관 질환의 치료를 위한 용도로 많이 사용되고 있다.Stents are luminal dilatation apparatuses used to expand narrowed passages due to stenosis, and are widely used for the treatment of cancer diseases or vascular diseases.
하지만 생체 내에서 사용되는 금속 스텐트는 마그네슘, 칼륨, 칼슘, 타이타늄, 크롬, 철, 코발트 및 니켈 및 이들의 합금들은 생체 적합성 금속 물질로 사용되고 있으며, 이러한 금속 물질들은 주기율표의 3-4주기 원자들로서 짧은 파장을 지닌 엑스선 (10~0.01 나노미터) 또는 감마선 (0.01 ~ 0.00001 나노미터) 등의 방사선들이 쉽게 투과될 수 있다. 더욱이 최근 약물방출 스텐트 및 생분해성 고분자 스텐트에 사용되는 생분해성 고분자 역시 방사선이 투과되기 때문에 이를 인체에 이식할 경우 그 위치를 특정하기가 불가능하다.However, metal stents used in vivo are magnesium, potassium, calcium, titanium, chromium, iron, cobalt and nickel and their alloys are used as biocompatible metal materials, which are short-lived as 3-4 cycle atoms of the periodic table. Radiation such as X-rays having a wavelength (10 to 0.01 nanometers) or gamma rays (0.01 to 0.00001 nanometers) can be easily transmitted. In addition, biodegradable polymers used in drug-release stents and biodegradable polymer stents are also transmitted through radiation, so it is impossible to specify their location when implanted into the human body.
이러한 문제점을 해결하기 위하여 스텐트의 특정 부위에 금, 백금, 탈타늄, 텅스텐, 탈늄 등 주기율표의 5 주기 이상의 금속 방사선 불투과성 물질을 부착하여 그 위치를 확인하는 방법이 사용되고 있다. 이러한 금속 방사선 불투과성 물질들을 스텐트와 결합하기 위해서는 스텐트 내에 추가적으로 공간 확보가 요구되고 또한 스텐트에 금속 방사선 불투과성 마커를 결합하는 공정이 필요하다. In order to solve this problem, a method of attaching a metal radiopaque material of five or more cycles of the periodic table such as gold, platinum, talthanum, tungsten, and talnium to a specific portion of the stent is used to check its location. In order to combine these metal radiopaque materials with the stent, additional space is required in the stent, and a process of bonding a metal radiopaque marker to the stent is required.
더욱이, 이러한 금속 방사선 불투과성 마커들을 인체 내에 이식하는 경우에는 금속 방사선 불투과성 마커가 설치된 부분만 한정적으로 확인이 가능하다. 또한, 생분해성 고분자 물질로 제조한 생분해성 스텐트에 금속 방사선 불투과성 마커가 설치되면 생체 내에서 비분해 특징을 가진 금, 백금, 탈타늄, 텅스텐, 탈늄 등의 금속 방사선 불투과성 마커들은 생체 내에서 영구적으로 남아 있게 되어 생체 내에서 이물반응의 문제를 일으킬 수 있고, 스텐트에 장착된 금속 방사선 불투과성 마커가 탈거되는 경우 생체 외부로 배출되지 않고 생체 내에서 순환되기 때문에 다른 문제를 야기시킬 수 있다.In addition, when the metal radiopaque markers are implanted into the human body, only a portion in which the metal radiopaque markers are installed can be confirmed. In addition, when a metal radiopaque marker is installed on a biodegradable stent made of a biodegradable polymer material, metal radiopaque markers such as gold, platinum, taltanium, tungsten, and talnium having non-degradable properties in vivo are in vivo. It may remain permanent and cause a problem of foreign body reaction in vivo, and if the metal radiopaque marker mounted on the stent is removed, it may cause other problems because it is circulated in vivo without being discharged out of the living body.
본 발명은 생체 흡수용 방사선 불투과성 마커 조성물 및 이를 포함하는 수술용 물품을 제공하고자 한다.The present invention seeks to provide a bioabsorbable radiopaque marker composition and a surgical article comprising the same.
본 발명의 일 측면은, 요오드, 제논 또는 이들의 조합을 포함하는 생체 흡수용 방사선 불투과성 마커 조성물일 수 있다.One aspect of the invention may be a bioabsorbable radiopaque marker composition comprising iodine, xenon or a combination thereof.
본 측면에서, 요오드를 제공하는 요오드 소스는 요오드, 요오드화수소, 요오드화나트륨, 요오드화칼륨, 메틸요오드, 요오드화세슘, 요오드산칼륨, 과요오드산나트륨, 요오드화칼슘, 요오드화구리 및 포비돈요오드로 이루어지는 그룹에서 선택된 1종 이상을 포함하고, 제논을 제공하는 제논 소스는 이플루오린화 제논, 사플루오린화 제논 및 육플루오린화 제논으로 이루어진 그룹에서 선택된 1종 이상을 포함할 수 있다.In this aspect, the iodine source providing iodine is selected from the group consisting of iodine, hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide and povidone iodine The xenon source comprising at least one and providing xenon may include at least one selected from the group consisting of xenon difluoride, xenon tetrafluoride and xenon hexafluoride.
본 측면은, 생분해성 고분자를 더 포함할 수 있다. This aspect may further comprise a biodegradable polymer.
본 측면에서, 생분해성 고분자는 친수성 용매에 용해된 상태일 수 있다.In this aspect, the biodegradable polymer may be dissolved in a hydrophilic solvent.
본 측면에서, 용매는, 물; 메탄올, 에탈올, 프로탄올, 부탄올, 펜탄올, 헵탄올, 헥산올, 옥탄올, 노난올 및 데칸올을 포함하는 알콜류; 암모니아, 디메틸서폭사이드, 디메틸포름아마이드, 아세트로나이트릴, 테트라하이드로퓨란, 포름알데하이드, 글루타알데하이드 및 아세트알데히드를 포함하는 알데하이드류; 다이옥산, 클로로포름, 헵탄, 헥산, 펜탄, 옥탄, 노난 및 데칸을 포함하는 알칸류; 벤젠, 톨루엔 및 자이렌을 포함하는 벤젠고리형 용매류; 에테르, 다이-프로필 에테르, 페트로늄 에테르 및 메틸-t-부틸 에테르를 포함하는 에테르류; 프로판온, 부탄온, 펜탄온, 헥산온 및 헵탄온을 포함하는 케톤류; 메틸렌 클로라이드, 사플루오로이소프로판 및 염화탄소로 이루어진 그룹에서 선택된 1종 이상을 포함할 수 있다. In this aspect, the solvent is water; Alcohols including methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehydes including ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde and acetaldehyde; Alkanes including dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents including benzene, toluene and xylene; Ethers including ethers, di-propyl ethers, petroleum ethers and methyl-t-butyl ethers; Ketones including propanone, butanone, pentanone, hexanone and heptanone; It may include one or more selected from the group consisting of methylene chloride, tetrafluoroisopropane and carbon chloride.
본 측면에서, 생분해성 고분자는, 폴리-L-락타이드, 폴리-D-락타이드, 폴리-D,L-락타이드, 폴리글라이콜라이드, 폴리카프로락톤, 폴리-L-락타이드-co-글라이콜라이드, 폴리-D-락타이드-co-글라이콜라이드, 폴리-D,L-락타이드-co-글라이콜라이드, 폴리-L-락타이드-co-카프로락톤, 폴리-D-락타이드-co-카프로락톤, 폴리-D,L-락타이드-co-카프로락톤, 폴리글라이콜라이드-co-카프로락톤, 폴리다이옥산온, 폴리트리메틸렌카보네이트, 폴리글라이콜라이드-co-다이옥산온, 폴리아미드에스터, 폴리펩티드, 폴리오르쏘에스터계, 폴리말레산, 폴리포스파젠, 폴리안하이드라이드, 폴리세바식안하이드라이드, 폴리수산화알카노에이트, 폴리수산화부틸레이트, 폴리시아노아크릴레이트, 폴리도파민, 셀루로오즈, 셀룰로오스 아세테이트 부틸레이트, 셀룰로오즈 트리아세테이트 및 이들의 공중합체로 구성된 그룹에서 선택된 1종 이상을 포함할 수 있다. In this aspect, the biodegradable polymer is poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co- Glycolide, poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide -co-caprolactone, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxone, poly Amide esters, polypeptides, polyorthoesters, polymaleic acid, polyphosphazenes, polyanhydrides, polycephaanhydrides, polyhydroxyalkanoates, polyhydroxybutyrates, polycyanoacrylates, polydopamines, celluloses Rhodes, Cellulose Acetate Butyrate, Cellulose Triacetate It may include at least one selected from the group consisting of a copolymer thereof.
본 측면에서, 생분해성 고분자의 함량은, 조성물 총 중량 대비 0.01 ~ 90 중량%일 수 있다. In this aspect, the content of the biodegradable polymer may be 0.01 to 90% by weight relative to the total weight of the composition.
본 측면에서, 요오드 및 제논의 총 함량은, 조성물 총 중량 대비 0.01 ~ 95 중량%일 수 있다.In this aspect, the total content of iodine and xenon may be 0.01 to 95% by weight relative to the total weight of the composition.
본 발명의 다른 측면은, 상기 조성물을 포함하는 수술용 물품일 수 있으며, 구체적으로는 상기 조성물로 코팅된 스텐트 또는 고분자 스크류, 상기 조성물을 포함하는 생분해성 고분자 스텐트, 스캐폴더 또는 수술용 봉합사일 수 있다. 또한 상기 수술용 물품은 조직 재생용 지지체, 바이오 나노 섬유, 하이드로젤, 바이오 스폰지, 핀, 스크류, 나사, 막대, 필러, 임플란트 또는 생체 이식물일 수 있다.Another aspect of the present invention may be a surgical article comprising the composition, specifically, a stent or polymer screw coated with the composition, a biodegradable polymer stent, a scaffold or a surgical suture containing the composition. have. The surgical article may also be a support for tissue regeneration, bio nanofibers, hydrogels, bio sponges, pins, screws, screws, rods, fillers, implants or living implants.
본 발명에 의하면 엑스선 등의 방사선이 투과하지 못하여 인체 내에서 방사선 불투과성 마커 역할을 할 수 있는 생체 흡수용 방사선 불투과성 마커 조성물을 제공할 수 있다. According to the present invention, it is possible to provide a bioabsorptive radiopaque marker composition that can not act as a radiopaque marker in the human body due to the transmission of radiation such as X-rays.
본 발명에 의한 수술용 물품을 사용하는 경우 그 물품의 인체 내 위치를 정확하게 추적 관찰할 수 있다.When using a surgical article according to the invention it is possible to accurately follow the position of the article in the human body.
이하, 본 발명의 바람직한 실시 형태들을 설명한다. 본 발명의 실시 형태는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 본 발명의 실시 형태는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. Hereinafter, preferred embodiments of the present invention will be described. Embodiment of the present invention can be modified in various other forms, the scope of the present invention is not limited to the embodiments described below. Embodiments of the present invention are provided to more completely describe the present invention to those skilled in the art.
본 발명의 일 측면에 따른 생체 흡수용 방사선 불투과성 마커 조성물은 요오드, 제논 또는 이들의 조합을 포함할 수 있다. Bioabsorbable radiopaque marker composition according to an aspect of the present invention may include iodine, xenon or a combination thereof.
요오드는 요오드 소스로부터 제공될 수 있다. 구체적으로는 고체 요오드 또는 요오드를 함유하는 화합물로부터 제공될 수 있다. 요오드를 함유하는 요오드 화합물은 요오드화수소, 요오드화나트륨, 요오드화칼륨, 메틸요오드, 요오드화세슘, 요오드산칼륨, 과요오드산나트륨, 요오드화칼슘, 요오드화구리, 포비돈요오드 또는 이들의 조합을 포함할 수 있다. 요오드 화합물은 용해되어 완전히 이온 상태로 존재할 수도 있으며, 일부가 용해되지 않은 경우에는 화합물 상태로 존재할 수도 있다.Iodine may be provided from an iodine source. Specifically, it may be provided from solid iodine or a compound containing iodine. Iodide containing iodine may include hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide, povidone iodine or combinations thereof. The iodine compound may be dissolved and completely present in an ionic state, or, if not partially dissolved, may be present in a compound state.
제논은 제논 소스로부터 제공될 수 있다. 구체적으로는 제논 기체 또는 제논을 함유하는 화합물로부터 공급될 수 있다. 제논을 함유하는 제논 화합물은 이플루오린화 제논, 사플루오린화 제논, 육플루오린화 제논 또는 이들의 조합을 포함할 수 있다. 제논 화합물은 용해되어 완전히 이온 상태로 존재할 수도 있으며, 일부가 용해되지 않은 경우에는 화합물 상태로 존재할 수도 있다.Xenon may be provided from a xenon source. Specifically, it may be supplied from a compound containing xenon gas or xenon. The xenon compound containing xenon may include xenon difluoride, xenon tetrafluoride, xenon hexafluoride or combinations thereof. The xenon compound may be dissolved and completely present in an ionic state, or, if not partially dissolved, may be present in a compound state.
본 측면의 생체 흡수용 방사선 불투과성 마커 조성물에 엑스선을 조사하면 엑스선이 투과하지 못한다. 그 이유는 요오드, 제논이 원자단이 크기 때문이다. 따라서, 가령 본 측면의 조성물을 코팅한 스텐트를 시술한 경우 엑스선 촬영을 통하여 스텐트의 위치 등을 정확하게 파악할 수 있어 추적 관찰이 가능하다는 장점이 있다. 엑스선은 일반적으로 의료용으로 사용되는 것으로서, 엑스선의 파장 범위는 0.01~10 나노미터 또는 감마선의 파장범위는 0.00001~0.01 나노미터이다.When X-rays are irradiated to the bioabsorbable radiopaque marker composition of the present aspect, X-rays do not penetrate. This is because iodine and xenon have large atomic groups. Thus, for example, when the stent coated with the composition of the present aspect is operated, the position of the stent can be accurately determined through X-ray imaging, and thus there is an advantage that the follow-up can be observed. X-rays are generally used for medical purposes, and the wavelength range of X-rays is 0.01 to 10 nanometers, or the wavelength range of gamma rays is 0.00001 to 0.01 nanometers.
요오드, 제논 및 그 화합물들은 물; 메탄올, 에탈올, 프로탄올, 부탄올, 펜탄올, 헵탄올, 헥산올, 옥탄올, 노난올, 데칸올 등의 알코올류 용매; 암모니아, 디메틸서폭사이드, 디메틸포름아마이드, 아세트로나이트릴, 테트라하이드로퓨란, 포름알데하이드, 글루타알데하이드, 아세트알데히드 등의 알데하이드류 용매; 다이옥산, 클로로포름, 헵탄, 헥산, 펜탄, 옥탄, 노난, 데칸 등의 알칸류 용매; 벤젠, 톨루엔, 자이렌 등의 벤젠고리형 용매; 에테르, 다이-프로필 에테르, 페트로늄 에테르, 메틸-t-부틸 에테르 등의 에테르류 용매; 프로판온, 부탄온, 펜탄온, 헥산온, 헵탄온 등의 케톤류 용매; 메틸렌 클로라이드, 사플루오로이소프로판, 염화탄소 등 통상의 유기 용매에 쉽게 용해되기 때문에 상기 물질을 용매로 사용할 수 있다. Iodine, xenon and compounds thereof are water; Alcohol solvents such as methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehyde solvents such as ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde, acetaldehyde; Alkanes solvents such as dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents such as benzene, toluene and xylene; Ether solvents such as ether, di-propyl ether, petroleum ether and methyl t-butyl ether; Ketone solvents such as propanone, butanone, pentanone, hexanone and heptanone; The substance can be used as a solvent because it is easily dissolved in common organic solvents such as methylene chloride, tetrafluoroisopropane and carbon chloride.
또한, 요오드, 제논 및 그 화합물들은 생체 내에서 쉽게 흡수되거나 배출되는 특성을 가진다. 따라서, 금, 백금, 탈타늄, 텅스텐, 탈늄 등의 금속 방사선 불투과성 마커와는 달리 생체 내에 잔존하지 않고 체외로 배출되기 때문에 이물반응 등의 문제가 발생하지 않는다. In addition, iodine, xenon and compounds thereof have the property of being easily absorbed or released in vivo. Therefore, unlike metal radiopaque markers such as gold, platinum, taltanium, tungsten, and talnium, they do not remain in the living body and are discharged to the outside of the body, so that problems such as foreign body reactions do not occur.
또한, 통상의 금속 방사선 불투과성 마커를 스텐트에 장착하는 데에는 이를 위한 설계 및 설치 공정이 필요한데, 본 측면에 따르면 이러한 과정이 필요하지 않기 때문에 공정을 단순화 할 수 있어 생산 비용을 절감할 수 있다. In addition, mounting a conventional metal radiopaque marker on the stent requires a design and installation process for this. According to this aspect, since this process is not required, the process can be simplified and the production cost can be reduced.
본 측면의 조성물은 스텐트에 적용할 수 있는 스텐트용 생체 흡수용 방사선 불투과성 마커 조성물일 수 있다. 상기 요오드 및 요오드 화합물, 제논 및 제논 화합물들은 생체에 사용할 수 있는 방사선 불투과성 물질이다. 아스탄틴(At)과 라돈(Rn)은 6 주기의 비금속 물질로 방사선에 대한 불투과성을 가지기 때문에 생체 내에서 불투과성 마커로서의 기능을 수행할 수 있지만 생체에 유해하기 때문에 스텐트 및 생체 이식용으로 사용이 불가능하다. The composition of this aspect may be a bioabsorbable radiopaque marker composition for a stent that can be applied to the stent. The iodine and iodine compounds, xenon and xenon compounds are radiopaque materials that can be used in a living body. Astantin (At) and radon (Rn) are 6 cycles of non-metallic materials that are radiopaque and thus capable of functioning as an opaque marker in vivo, but are harmful to the living body, so they are useful for stent and biotransplantation. impossible to use.
본 측면의 생체 흡수용 방사선 불투과성 마커 조성물은 생분해성 고분자를 더 포함할 수 있다. 생분해성 고분자는 인체 내에서 분해될 수 있는 것이라면, 특별히 제한되지 않는다. 생분해성 고분자로는 합성 생분해성 고분자 또는 천연 생분해성 고분자를 사용할 수 있다.Bioabsorbable radiopaque marker composition of the present aspect may further comprise a biodegradable polymer. The biodegradable polymer is not particularly limited as long as it can be degraded in the human body. As the biodegradable polymer, synthetic biodegradable polymer or natural biodegradable polymer may be used.
생분해성 고분자는, 폴리-L-락타이드, 폴리-D-락타이드, 폴리-D,L-락타이드, 폴리글라이콜라이드, 폴리카프로락톤, 폴리-L-락타이드-co-글라이콜라이드, 폴리-D-락타이드-co-글라이콜라이드, 폴리-D,L-락타이드-co-글라이콜라이드, 폴리-L-락타이드-co-카프로락톤, 폴리-D-락타이드-co-카프로락톤, 폴리-D,L-락타이드-co-카프로락톤, 폴리글라이콜라이드-co-카프로락톤, 폴리다이옥산온, 폴리트리메틸렌카보네이트, 폴리글라이콜라이드-co-다이옥산온, 폴리아미드에스터, 폴리펩티드, 폴리오르쏘에스터계, 폴리말레산, 폴리포스파젠, 폴리안하이드라이드, 폴리세바식안하이드라이드, 폴리수산화알카노에이트, 폴리수산화부틸레이트, 폴리시아노아크릴레이트, 폴리도파민, 셀루로오즈, 셀룰로오스 아세테이트 부틸레이트, 셀룰로오즈 트리아세테이트 및 이들의 공중합체로 구성된 그룹에서 선택되는 1종 이상의 고분자를 포함할 수 있다. Biodegradable polymers include poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co-glycolide, Poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide-co-capro Lactones, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxoneone, polyamide esters, polypeptides , Polyorthoester type, polymaleic acid, polyphosphazene, polyanhydride, polycephaanhydride, polyhydroxide alkanoate, polyhydroxybutyrate, polycyanoacrylate, polydopamine, cellulose, cellulose Acetate butyrate, cellulose triacetate and their aerials It may include one or more polymers selected from the group consisting of coalescing.
생분해성 고분자의 분자량은 1,000 내지3,000,000 이 바람직하다. 분자량이 1,000 보다 작은 경우 고분자 코팅층 및 매트릭스 형성이 불가능하며, 3,000,000 보다 큰 경우 분자량이 너무 커서 고분자의 생분해가 이루어지지 않을 수 있다.The molecular weight of the biodegradable polymer is preferably 1,000 to 3,000,000. If the molecular weight is less than 1,000, it is impossible to form a polymer coating layer and a matrix, and if the molecular weight is greater than 3,000,000, the molecular weight may be too large to prevent biodegradation of the polymer.
생분해성 고분자의 함량은, 조성물 총 중량 대비 0.01 ~ 90 중량%일 수 있다. 생분해성 고분자의 함량이 0.01 중량%보다 적으면 고분자 코팅층 및 매트릭스 형성이 불가능할 수 있고, 90 중량%보다 많으면 점도가 너무 높아져 고분자 코팅 및 매트릭스 제작이 불가능할 수 있다.The content of the biodegradable polymer may be 0.01 to 90% by weight relative to the total weight of the composition. If the content of the biodegradable polymer is less than 0.01% by weight may be impossible to form the polymer coating layer and the matrix, when the content of more than 90% by weight may be too high viscosity may be impossible to manufacture the polymer coating and matrix.
생분해성 고분자는 용매에 용해되어 있을 수 있다. 용매는 생분해성 고분자를 용해시킬 수 있는 것이라면 특별한 제한은 없다. 구체적으로, 용매는 물; 메탄올, 에탈올, 프로탄올, 부탄올, 펜탄올, 헵탄올, 헥산올, 옥탄올, 노난올, 데칸올 등의 알콜류 용매; 암모니아, 디메틸서폭사이드, 디메틸포름아마이드, 아세트로나이트릴, 테트라하이드로퓨란, 포름알데하이드, 글루타알데하이드, 아세트알데히드 등의 알데하이드류 용매; 다이옥산, 클로로포름, 헵탄, 헥산, 펜탄, 옥탄, 노난, 데칸 등의 알칸류 용매; 벤젠, 톨루엔, 자이렌 등의 벤젠고리형 용매; 에테르, 다이-프로필 에테르, 페트로늄 에테르, 메틸-t-부틸 에테르 등의 에테르류 용매; 프로판온, 부탄온, 펜탄온, 헥산온, 헵탄온 등의 케톤류 용매; 메틸렌 클로라이드, 사플루오로이소프로판, 염화탄소 등 통상의 유기 용매로 이루어진 그룹에서 선택된 1종 이상을 포함할 수 있다. Biodegradable polymers may be dissolved in a solvent. The solvent is not particularly limited as long as it can dissolve the biodegradable polymer. Specifically, the solvent is water; Alcohol solvents such as methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehyde solvents such as ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde, acetaldehyde; Alkanes solvents such as dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents such as benzene, toluene and xylene; Ether solvents such as ether, di-propyl ether, petroleum ether and methyl t-butyl ether; Ketone solvents such as propanone, butanone, pentanone, hexanone and heptanone; It may include one or more selected from the group consisting of conventional organic solvents, such as methylene chloride, tetrafluoroisopropane, carbon chloride.
생분해성 고분자는 스텐트, 수술용 봉합사, 조직 재생용 지지체, 바이오 나노 섬유, 하이드로젤, 바이오 스폰지와 같은 심혈관계 재료; 핀, 스크류, 나사, 막대, 임플란트 등의 치과재료; 또는 핀, 스크류, 나사, 조직 재생용 지지체, 막대, 필러 등의 신경/정형/성형외과용 생체 이식물; 등에 본 측면의 조성물을 코팅하는 경우 코팅층에서 베이스 또는 매트릭스 역할을 한다. 즉 요오드 또는 제논이 생분해성 고분자를 매트릭스로 하여 존재하는 구조이다. 생분해성 고분자가 분해되면서 그 부분에 존재하던 요오드 등도 탈리되어 체외로 배출되며, 생분해성 고분자가 완전히 분해되면 요오드 등도 완전히 체외로 배출되어 방사선 불투과성이 사라질 수 있다. Biodegradable polymers include cardiovascular materials such as stents, surgical sutures, support for tissue regeneration, bio nanofibers, hydrogels, bio sponges; Dental materials such as pins, screws, screws, rods, and implants; Or nerve / orthopedic / plastic surgery implants such as pins, screws, screws, scaffolds for tissue regeneration, rods, fillers, and the like; When coating the composition of the present aspect and the like serves as a base or matrix in the coating layer. That is, iodine or xenon is a structure in which a biodegradable polymer is present as a matrix. As the biodegradable polymer is decomposed, iodine and the like present in the portion are also detached and discharged to the outside. When the biodegradable polymer is completely decomposed, the iodine and the like are completely discharged to the outside and the radiopacity may disappear.
요오드 소스나 제논 소스 중 어느 하나를 사용할 수도 있고, 또는 요오드 소스 및 제논 소스를 함께 사용할 수 있다. 요오드 및 제논을 합한 총 함량은, 조성물 총 중량 대비 0.01 ~ 95 중량%일 수 있다. 0.01 중량%보다 적을 경우 방사선 불투과성 특성이 나타나지 않을 수 있고, 95 중량%보다 많을 경우에는 요오드가 전부 용해되지 않고 침전이 발생할 수 있다.Either an iodine source or a xenon source may be used, or an iodine source and a xenon source may be used together. The total content of iodine and xenon combined may be 0.01 to 95% by weight based on the total weight of the composition. If less than 0.01% by weight may not appear radiopaque properties, if more than 95% by weight iodine is not completely dissolved and precipitation may occur.
본 측면의 생체 흡수용 방사선 불투과성 마커 조성물은 다음과 같은 방법에 따라 제조할 수 있다. The bioabsorbable radiopaque marker composition of this aspect can be manufactured by the following method.
먼저, 용매에 생분해성 고분자를 칭량하여 투입한다. 이때 계속적으로 교반을 수행하여 생분해성 고분자를 완전히 용해시킨다. First, a biodegradable polymer is weighed and added to a solvent. At this time, the biodegradable polymer is completely dissolved by stirring.
용매로는 물; 메탄올, 에탈올, 프로탄올, 부탄올, 펜탄올, 헵탄올, 헥산올, 옥탄올, 노난올, 데칸올 등의 알콜류 용매; 암모니아, 디메틸서폭사이드, 디메틸포름아마이드, 아세트로나이트릴, 테트라하이드로퓨란, 포름알데하이드, 글루타알데하이드, 아세트알데히드 등의 알데하이드류 용매; 다이옥산, 클로로포름, 헵탄, 헥산, 펜탄, 옥탄, 노난, 데칸 등의 알칸류 용매; 벤젠, 톨루엔, 자이렌 등의 벤젠고리형 용매; 에테르, 다이-프로필 에테르, 페트로늄 에테르, 메틸-t-부틸 에테르 등의 에테르류 용매; 프로판온, 부탄온, 펜탄온, 헥산온, 헵탄온 등의 케톤류 용매; 메틸렌 클로라이드, 사플루오로이소프로판, 염화탄소 등 통상의 유기 용매로 이루어진 그룹에서 선택된 1종 이상을 사용할 수 있다. Solvents include water; Alcohol solvents such as methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehyde solvents such as ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde, acetaldehyde; Alkanes solvents such as dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents such as benzene, toluene and xylene; Ether solvents such as ether, di-propyl ether, petroleum ether and methyl t-butyl ether; Ketone solvents such as propanone, butanone, pentanone, hexanone and heptanone; One or more selected from the group consisting of conventional organic solvents such as methylene chloride, tetrafluoroisopropane and carbon chloride can be used.
생분해성 고분자로는 폴리-L-락타이드, 폴리-D-락타이드, 폴리-D,L-락타이드, 폴리글라이콜라이드, 폴리카프로락톤, 폴리-L-락타이드-co-글라이콜라이드, 폴리-D-락타이드-co-글라이콜라이드, 폴리-D,L-락타이드-co-글라이콜라이드, 폴리-L-락타이드-co-카프로락톤, 폴리-D-락타이드-co-카프로락톤, 폴리-D,L-락타이드-co-카프로락톤, 폴리글라이콜라이드-co-카프로락톤, 폴리다이옥산온, 폴리트리메틸렌카보네이트, 폴리글라이콜라이드-co-다이옥산온, 폴리아미드에스터, 폴리펩티드, 폴리오르쏘에스터계, 폴리말레산, 폴리포스파젠, 폴리안하이드라이드, 폴리세바식안하이드라이드, 폴리수산화알카노에이트, 폴리수산화부틸레이트, 폴리시아노아크릴레이트, 폴리도파민, 셀루로오즈, 셀룰로오스 아세테이트 부틸레이트, 셀룰로오즈 트리아세테이트 및 이들의 공중합체로 이루어진 그룹에서 선택되는 1종 이상의 고분자를 사용할 수 있다.Biodegradable polymers include poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co-glycolide, Poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide-co-capro Lactones, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxoneone, polyamide esters, polypeptides , Polyorthoester type, polymaleic acid, polyphosphazene, polyanhydride, polycephaanhydride, polyhydroxide alkanoate, polyhydroxybutyrate, polycyanoacrylate, polydopamine, cellulose, cellulose Acetate butyrate, cellulose triacetate and their balls It can be used at least one polymer selected from the group consisting of a polymer.
생분해성 고분자는 최종 조성물 총 중량 대비 0.01 내지 90 중량% 사용할 수 있다. 생분해성 고분자의 함량이 0.01 중량%보다 적으면 고분자 코팅층 및 매트릭스 형성이 불가능할 수 있고, 90 중량%보다 많으면 점도가 너무 높아져 고분자 코팅 및 매트릭스 제작이 불가능할 수 있다.The biodegradable polymer may be used in an amount of 0.01 to 90% by weight based on the total weight of the final composition. If the content of the biodegradable polymer is less than 0.01% by weight may be impossible to form the polymer coating layer and the matrix, when the content of more than 90% by weight may be too high viscosity may be impossible to manufacture the polymer coating and matrix.
생분해성 고분자로는 분자량이 1,000 내지 3,000,000 인 것을 사용할 수 있다.As the biodegradable polymer, those having a molecular weight of 1,000 to 3,000,000 can be used.
다음으로, 상기 용액에 요오드, 요오드를 함유하는 화합물, 제논, 제논을 함유하는 화합물 또는 이들을 조합하여 투입하고 교반을 실시하여 용해시킬 수 있다. Next, iodine, a compound containing iodine, a compound containing xenon, a xenon, or a combination thereof can be added to the solution, followed by stirring to dissolve it.
요오드를 함유하는 요오드 화합물로는 요오드화수소, 요오드화나트륨, 요오드화칼륨, 메틸요오드, 요오드화세슘, 요오드산칼륨, 과요오드산나트륨, 요오드화칼슘, 요오드화구리, 포비돈요오드 또는 이들의 조합하여 사용할 수 있다.As iodine compounds containing iodine, hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide, povidone iodine or a combination thereof can be used.
제논을 함유하는 제논 화합물로는 이플루오린화 제논, 사플루오린화 제논, 육플루오린화 제논 또는 이들을 조합하여 사용할 수 있다.As a xenon-containing xenon compound, a xenon difluoride, xenon tetrafluoride, xenon hexafluoride, or a combination thereof can be used.
요오드 소스나 제논 소스 중 어느 하나를 사용할 수 있으며, 또한 요오드 소스 및 제논 소스를 함께 사용할 수 있다. 요오드 및 제논을 합한 총 함량은 조성물 총 중량 대비 0.01 내지 95 중량% 사용할 수 있다. 0.01 중량%보다 적을 경우 방사선 불투과성 특성이 나타나지 않을 수 있고, 95 중량%보다 많을 경우에는 요오드가 전부 용해되지 않고 침전이 발생할 수 있다.Either an iodine source or a xenon source can be used, and an iodine source and a xenon source can also be used together. The total content of iodine and xenon may be used in an amount of 0.01 to 95% by weight based on the total weight of the composition. If less than 0.01% by weight may not appear radiopaque properties, if more than 95% by weight iodine is not completely dissolved and precipitation may occur.
본 발명의 다른 측면은 상기 생체 흡수용 방사선 불투과성 마커 조성물을 포함하는 수술용 물품일 수 있다. 상기 생체 흡수용 방사선 불투과성 마커 조성물을 적용할 수 있는 수술용 물품에는 다양한 것이 있을 수 있으며, 수술 후 인체 내에 존재하게 되는 물품이라면 모두 적용 가능하다. Another aspect of the invention may be a surgical article comprising the bioabsorbable radiopaque marker composition. Surgical articles to which the bioabsorbable radiopaque marker composition may be applied may be various, and any article that is present in the human body after surgery may be applicable.
구체적으로 상기 수술용 물품에는 스텐트, 수술용 봉합사, 조직 재생용 지지체, 바이오 나노 섬유, 하이드로젤, 바이오 스폰지와 같은 심혈관계 재료; 핀, 스크류, 나사, 막대, 임플란트 등의 치과재료; 또는 핀, 스크류, 나사, 조직 재생용 지지체, 막대, 필러 등의 신경/정형/성형외과용 생체 이식물 등이 포함될 수 있다.Specifically, the surgical article includes a cardiovascular material such as a stent, a surgical suture, a support for tissue regeneration, bio nanofibers, a hydrogel, and a bio sponge; Dental materials such as pins, screws, screws, rods, and implants; Or nerve / orthopedic / plastic surgery implants such as pins, screws, screws, scaffolds for tissue regeneration, rods, fillers, and the like.
이러한 수술용 물품의 대표적인 예로 스텐트를 들 수 있다. 스텐트에 생체 흡수용 방사선 불투과성 마커 조성물을 코팅하거나 또는 스텐트 매트릭스용 고분자 물질 자체에 생체 흡수용 방사선 불투과성 마커 조성물을 함유시켜 사용할 수 있다. 스텐트로는 금속 스텐트는 물론이고 생분해성 고분자 스텐트도 사용할 수 있다. 스텐트에 생체 흡수용 방사선 불투과성 마커 조성물을 코팅하는 방법으로는 초음파 스프레이 분사법, 전기방사법, 침지법 등을 이용할 수 있다. 초음파 스프레이 분사법의 경우 전기방사법 또는 침지법에 비하여 스텐트에 생체 흡수용 방사선 불투과성 마커 조성물을 보다 균일하게 코팅할 수 있다는 장점이 있다. 생체 흡수용 방사선 불투과성 마커 조성물이 포함된 스텐트가 인체 내에 존재하는 경우 방사선을 조사하여 스텐트의 인체 내 위치를 정확하게 파악할 수 있다. Representative examples of such surgical articles include stents. The stent may be coated with a bioabsorbable radiopaque marker composition or the polymer material for the stent matrix may contain a bioabsorbable radiopaque marker composition. As the stent, a biodegradable polymer stent may be used as well as a metal stent. As a method of coating the bioabsorbable radiopaque marker composition on the stent, an ultrasonic spray injection method, an electrospinning method, an immersion method, or the like may be used. In the case of the ultrasonic spray injection method, there is an advantage in that the stent can be more uniformly coated with the radiopaque marker composition for bioabsorption, as compared with the electrospinning or dipping method. If the stent containing the bioabsorbable radiopaque marker composition is present in the human body, the location of the stent in the human body may be accurately determined by irradiation.
다른 예로, 수술용 봉합사를 들 수 있다. 즉 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 수술용 봉합사이다. 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 수술용 봉합사는 통상적인 방사법을 이용하여 제조할 수 있다. 즉 생체 흡수용 방사선 불투과성 마커 조성물과 수술용 봉합사 매트릭스용 고분자 물질을 용융시킨 후, 이를 압출하여 제조할 수 있다. 이렇게 하여 수술용 봉합사 자체에 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 봉합사를 제조할 수 있다.Another example is a surgical suture. In other words, it is a surgical suture containing a bioabsorbable radiopaque marker composition. Surgical sutures containing a bioabsorbable radiopaque marker composition can be prepared using conventional radiation methods. That is, the bioabsorbable radiopaque marker composition and the polymer material for surgical suture matrix may be melted and then extruded. In this way, a suture containing a bioabsorbable radiopaque marker composition can be produced in the surgical suture itself.
또 다른 예로, 스캐폴더를 들 수 있다. 즉 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 스캐폴더이다. 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 스캐폴더는 통상의 스캐폴더 제조방법에 따라 제조할 수 있다. 구체적으로, 생체 흡수용 방사선 불투과성 마커 조성물, 스캐폴더 기공 형성을 위한 얼음 입자, 탄산나트륨 또는 탄산수소나트륨 등의 통상의 스캐폴더용 입자 생성 물질, 용매 및 고분자 물질을 혼합한 후, 혼합물을 금형에 넣고 압축함으로써 제조할 수 있다. Another example is scaffolding. That is, it is a scaffold containing the radiopaque marker composition for bioabsorption. The scaffold containing the bioabsorbable radiopaque marker composition can be prepared according to a conventional scaffold manufacturing method. Specifically, after mixing the bio-absorption radiopaque marker composition, the ice particles for forming the scaffold pores, the usual scaffolding particles, such as sodium carbonate or sodium hydrogen carbonate, a solvent and a polymer material, and then the mixture into the mold It can manufacture by inserting and compressing.
또 다른 예로, 수술용 접착제를 들 수 있다. 즉, 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 수술용 접착제이다. 생체 흡수용 방사선 불투과성 마커 조성물이 함유된 수술용 접착제는 통상의 접착제 제조공정에 따라 제조할 수 있다. 구체적으로 생체 흡수용 방사선 불투과성 마커 조성물과 고분자 물질을 통상의 용매에 용해시킴으로써 마커 조성물이 함유된 수술용 접착제를 제조할 수 있다.Another example is a surgical adhesive. That is, it is a surgical adhesive containing a bioabsorbable radiopaque marker composition. Surgical adhesives containing bioabsorbable radiopaque marker compositions can be prepared according to conventional adhesive manufacturing processes. Specifically, the surgical adhesive containing the marker composition may be prepared by dissolving the radiopaque marker composition for bioabsorption and the polymer material in a conventional solvent.
또 다른 예로, 고분자 스크류를 들 수 있다. 생체 흡수용 방사선 불투과성 마커 조성물이 코팅된 고분자 스크류 또는 생체 흡수용 방사선 불투과성 마커 조성물을 함유하는 고분자 스크류이다. 고분자 스큐류에 마커 조성물을 코팅하는 방법으로는 초음파 스프레이 분사법, 전기 방사법 또는 침지법을 사용할 수 있다. 마커 조성물이 함유된 고분자 스크류는 생체 흡수용 방사선 불투과성 마커 조성물과 고분자 물질을 혼합한 후 이를 통상의 금형 사출 공정을 거침으로써 제조할 수 있다.Another example is a polymer screw. A polymer screw coated with a bioabsorbable radiopaque marker composition or a polymer screw containing a bioabsorbable radiopaque marker composition. As a method of coating the marker composition on the polymer skew, ultrasonic spraying, electrospinning or dipping may be used. The polymer screw containing the marker composition may be prepared by mixing the radiopaque marker composition for bioabsorption with a polymer material and then subjecting the polymer material to a conventional mold injection process.
이하에서는 실시예 및 비교예를 통하여 본 발명에 대하여 보다 상세하게 설명한다. 하지만 본 발명이 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples. However, the present invention is not limited to the examples.
<실시예 1><Example 1>
용매인 테트라하이드로퓨란 95 g 에 생분해성 고분자인 폴리 L-락타이드 4 g 과 고체 요오드(iodine) 1 g 을 투입한 후 1 시간 동안 교반을 실시하여 용해시켜 마커 조성물을 제조하였다.4 g of polyl-lactide and 1 g of solid iodine were added to 95 g of tetrahydrofuran as a solvent, followed by stirring for 1 hour to dissolve to prepare a marker composition.
별도로, 테트라하이드로퓨란 95 g 에 폴리 L-락트산 5 g 을 투입하여 용해시킨 후, 여기에 시롤리무스 5 g 을 투입하여 용해시켜 약물방출 코팅액을 제조하였다. Separately, 5 g of poly L-lactic acid was added and dissolved in 95 g of tetrahydrofuran, and then 5 g of sirolimus was added and dissolved therein, thereby preparing a drug release coating solution.
다음으로, 금속 스텐트의 표면에 붙은 물질을 제거하기 위하여 초음파 세척기를 이용하여 에탄올과 증류수의 혼합용매로 1시간 세척하고 50℃의 열풍건조기에서 24 시간 동안 건조시켰다. Next, in order to remove the substance adhered to the surface of the metal stent, using an ultrasonic cleaner for 1 hour with a mixed solvent of ethanol and distilled water and dried for 24 hours in a hot air dryer at 50 ℃.
다음으로, 제조한 마커 조성물을 스텐트에 초음파 스프레이 분사하여 코팅하였다. 구체적으로는, 초음파 스프레이 장치(소노텍, MedicoatPSI)를 사용하였으며, 초음파 진동자의 전압을 0.9 mV, 스프레이 유속을 0.03 ml/min 로 조정하고, 40 초 동안 코팅을 진행하였다. 스텐트의 회전속도는 50 RPM, 이동속도는 0.03 cm/sec 로 하였다.Next, the prepared marker composition was coated by ultrasonic spray spray on the stent. Specifically, an ultrasonic spray device (Sonotech, MedicoatPSI) was used, the voltage of the ultrasonic vibrator was adjusted to 0.9 mV, the spray flow rate to 0.03 ml / min, and the coating was performed for 40 seconds. The rotational speed of the stent was 50 RPM, and the moving speed was 0.03 cm / sec.
다음으로, 마커 조성물이 코팅된 스텐트를 40 ℃의 진공 건조기에서 24 시간 동안 진공 건조시켰다. 마커 조성물 코팅층의 두께는 2 um 이었다.Next, the stent coated with the marker composition was vacuum dried in a vacuum dryer at 40 ° C. for 24 hours. The thickness of the marker composition coating layer was 2 um.
다음으로, 초음파 스프레이 장치를 이용하여 마커 조성물이 코팅된 스텐트 상에 약물방출 코팅액을 코팅하였다. 코팅은 마커 조성물을 코팅하는 경우와 동일한 조건에서 1 분 30 초 동안 실시하였다. 약물방출 코팅층의 두께는 6 um 이었다.Next, the drug release coating solution was coated on the stent coated with the marker composition using an ultrasonic spray device. Coating was carried out for 1 minute 30 seconds under the same conditions as when coating the marker composition. The drug release coating layer had a thickness of 6 um.
이렇게 하여 이중 코팅층 구조를 가지는 금속 스텐트를 제작하였다. In this way, a metal stent having a double coating layer structure was manufactured.
<실시예 2> <Example 2>
용매인 다이메틸설폭사이드에 90 g 에 폴리카프로락톤 5 g 과 제논 5 g 을 투입한 후 1 시간 동안 교반을 실시하면서 용해시켜 마커 조성물을 제조하였다. 5 g of polycaprolactone and 5 g of xenon were added to 90 g of dimethyl sulfoxide as a solvent, and then dissolved by stirring for 1 hour to prepare a marker composition.
별도로, 용매인 테트라하이드로퓨란(Tetrahydrofuran, THF) 80 g 에 파크리탁셀(Paclitaxel) 10 g 과 폴리카프로락톤(poly-carprolactone) 10 g 을 용해시켜 약물방출 코팅액을 제조하였다. Separately, a drug release coating solution was prepared by dissolving 10 g of paclitaxel and 10 g of poly-carprolactone in 80 g of tetrahydrofuran (THF) as a solvent.
다음으로, 금속 스텐트의 표면에 붙은 물질을 제거하기 위하여 초음파 세척기를 이용하여 에탄올과 증류수의 혼합용매로 1시간 세척하고 50℃의 열풍건조기에서 24 시간 동안 건조시켰다. Next, in order to remove the substance adhered to the surface of the metal stent, using an ultrasonic cleaner for 1 hour with a mixed solvent of ethanol and distilled water and dried for 24 hours in a hot air dryer at 50 ℃.
다음으로, 방사 속도를 0.5 ml/min, 방사 거리를 10 cm, 전압을 1000 mV로 조절 하여, 10 분간 전기방사법을 이용하여 약물방출 코팅액으로 금속 스텐트 상에 약물방출 코팅층을 형성하였다. 코팅은 2 분 동안 실시하였다. 약물방출 코팅층의 두께는 7 um 이었다.Next, the spinning speed was adjusted to 0.5 ml / min, the spinning distance was 10 cm, and the voltage was set to 1000 mV, and a drug release coating layer was formed on the metal stent with the drug release coating solution by using an electrospinning method for 10 minutes. Coating was carried out for 2 minutes. The drug release coating layer was 7 um thick.
다음으로, 초음파 스프레이 방법을 이용하여 상기 약물방출 코팅액이 코팅된 스텐트 상에 초음파 진동자의 전압을 0.5 mV, 스프레이 유속을 0.05 ml/min 로 조정하고, 30 초 동안 코팅을 진행하였다. 스텐트의 회전속도는 60 RPM, 이동속도는 0.05 cm/sec로 조절하여 마커 조성물을 1 분간 코팅하였다. 마커 코팅층의 두께는 3 um 이었다. Next, on the stent coated with the drug release coating solution by using the ultrasonic spray method, the voltage of the ultrasonic vibrator was adjusted to 0.5 mV, the spray flow rate to 0.05 ml / min, and the coating was performed for 30 seconds. The rotational speed of the stent was adjusted to 60 RPM and the moving speed was 0.05 cm / sec to coat the marker composition for 1 minute. The thickness of the marker coating layer was 3 um.
이렇게 하여 이중 코팅층 구조를 가지는 금속 스텐트를 제작하였다. In this way, a metal stent having a double coating layer structure was manufactured.
<실시예 3><Example 3>
용매인 클로로포름(chloroform) 60 g 에 폴리락타이드-co-글라이콜라이드(poly (lactide-co-glycolide)) 36 g 과 요오드 4 g 을 투입한 후 1 시간 동안 교반하면서 용해시켜 마커 조성물을 제조하였다. 36 g of polylactide-co-glycolide (poly (lactide-co-glycolide)) and 4 g of iodine were added to 60 g of chloroform, a solvent, and dissolved by stirring for 1 hour to prepare a marker composition. .
다음으로, 마커 조성물 0.7 g 에, 크기가 1~10 um 아이스 파티클 0.3 g, 및 폴리락타이드-co-글라이콜라이드 9 g을 클로로포름 10 g 에 용해시켜 지름 2 cm, 높이 2 mm 원형틀을 이용하여 스캐폴더를 제조하였다.Next, 0.7 g of the marker composition was dissolved in 0.3 g of 1-10 um ice particles and 9 g of polylactide-co-glycolide in 10 g of chloroform, using a circular frame of 2 cm in diameter and 2 mm in height. To prepare a scaffold.
<실시예 4><Example 4>
용매인 클로로포름 60 g 에 폴리락타이드 34 g 과 제논 6 g 을 투입한 후 1 시간 동안 교반하면서 용해시켜 마커 조성물을 제조하였다. 34 g of polylactide and 6 g of xenon were added to 60 g of chloroform as a solvent, and then dissolved by stirring for 1 hour to prepare a marker composition.
다음으로, 마커 조성물에 정형외과용 고분자 스크류를 3 분 동안 함침시킨 후 공기 중에서 건조시켜 마커 조성물이 코팅된 고분자 스크류를 제조하였다.Next, the orthopedic polymer screw was impregnated in the marker composition for 3 minutes and then dried in air to prepare a polymer screw coated with the marker composition.
<실시예 5>Example 5
용매인 아세트로나이트릴에 70 g 폴리다이옥산온 18 g 과 요오드 12 g 을 투입한 후 1 시간 동안 교반을 실시하면서 용해시켜 마커조성물을 제조하였다. 18 g of 70 g polydioxanone and 12 g of iodine were added to acetonitrile as a solvent, and then dissolved by stirring for 1 hour to prepare a marker composition.
다음으로, 상기의 제조된 마커 조성물 50 g를 스크류 속도 70 rpm, 챔버온도 200 도, 전압 1100 mV로 조절하여 전기방사를 통하여 수술용 봉합사를 제조하였다.Next, 50 g of the prepared marker composition was adjusted to a screw speed of 70 rpm, a chamber temperature of 200 degrees, and a voltage of 1100 mV to prepare a surgical suture through electrospinning.
<실시예 6><Example 6>
용매인 클로로포름 60 g 에 폴리락타이드 32 g 과 요도드 8 g 을 투입한 후 1 시간 동안 교반을 실시하면서 용해시켜 마커 조성물을 제조하였다. 32 g of polylactide and 8 g of iodod were added to 60 g of chloroform, which was a solvent, and dissolved by stirring for 1 hour to prepare a marker composition.
다음으로, 상기의 마커 조성물을 압출 회전속도 200 rpm 챔버 온도 220 도인 압출기를 통하여 압출 후에 전압이 1350 mV로 제어된 팸토초레이저를 이용하여 패턴 형성을 실시 하여 생분해성 고분자 스텐트를 제조하였다.Next, the marker composition was extruded through an extruder having an extrusion rotation speed of 200 rpm and a chamber temperature of 220 degrees to form a pattern using a femtosecond laser having a voltage controlled at 1350 mV to prepare a biodegradable polymer stent.
<실시예 7><Example 7>
용매인 다이메틸설폭사이드에 80 g 에 폴리시아노아크릴레이트 18 g 과 요오드 2 g 을 투입한 후 1 시간 동안 교반을 실시하면서 용해시켜 마커 조성물을 포함한 수술용 접착제를 제조하였다. 18 g of polycyanoacrylate and 2 g of iodine were added to 80 g of a solvent, dimethyl sulfoxide, and dissolved by stirring for 1 hour to prepare a surgical adhesive including a marker composition.
<비교예 1>Comparative Example 1
테트라하이드로퓨란 80 g 에 폴리 L-락타이드 20 g 을 투입한 후 교반을 실시하면서 용해시킨 후, 상기 용액을 이용하여 상기의 마커 조성물을 압출 회전속도 250 rpm 챔버 온도 210℃ 인 압출기를 통하여 압출 후에 전압이 1300 mV로 제어된 팸토초레이저를 이용하여 패턴 형성을 실시 하여 생분해성 고분자 스텐트를 제조하였다After adding 20 g of poly L-lactide to 80 g of tetrahydrofuran and dissolving it under stirring, using the solution, the marker composition was extruded through an extruder having an extrusion rotation speed of 250 rpm and a chamber temperature of 210 ° C. A biodegradable polymer stent was prepared by pattern formation using a femtosecond laser whose voltage was controlled at 1300 mV.
다음으로, 생분해성 고분자 스텐트의 말단에 2mm의 원형 홈을 뚫고 백금 1 g 을 압력을 가하여 장착하였다.Next, a 2 mm circular groove was drilled at the end of the biodegradable polymer stent and 1 g of platinum was applied under pressure.
<비교예 2>Comparative Example 2
용매인 다이메틸설폭사이드 80 g 에 폴리락타이드 19 g 과 시롤리무스 1 g 을 투입하고 교반을 실시하면서 용해시켜 약물방출 코팅액을 제조하였다.19 g of polylactide and 1 g of sirolimus were added to 80 g of dimethyl sulfoxide, which was a solvent, and dissolved with stirring to prepare a drug release coating solution.
다음으로, 약물방출 코팅액을 금속 스텐트에 초음파 스프레이 분사하여 코팅하였다. 구체적으로는, 초음파 진동자의 전압을 0.9 mV, 스프레이 유속을 0.03 ml/min 로 조정하고, 40 초 동안 코팅을 진행하였다. 스텐트의 회전속도는 50 RPM, 이동속도는 0.03 cm/sec 로 하였다.Next, the drug release coating solution was coated by ultrasonic spray spraying on the metal stent. Specifically, the voltage of the ultrasonic vibrator was adjusted to 0.9 mV, the spray flow rate to 0.03 ml / min, and the coating was performed for 40 seconds. The rotational speed of the stent was 50 RPM, and the moving speed was 0.03 cm / sec.
다음으로, 상기 금속 스텐트 말단에 3 mm의 원형 홈을 뚫은 후에 금 2 g 을 압력을 가하여 장착시켰다.Next, a 3 mm circular groove was drilled at the end of the metal stent, and then 2 g of gold was mounted under pressure.
<평가><Evaluation>
실시예 및 비교예에 따라 제조된 각 조성물을 플라스틱 기판 상에 떨어뜨린 후 엑스선 측정장치(LISTEM, PROGEN-R 진단용 X선 촬영장치) 이용하여 엑스선 촬영을 하여 엑스선 불투과도를 측정하였다. 불투과도는 다음과 같이 계산하였다.Each composition prepared according to Examples and Comparative Examples was dropped on a plastic substrate, and then X-ray imaging was performed by using an X-ray measuring apparatus (LISTEM, PROGEN-R diagnostic X-ray imaging apparatus) to measure X-ray opacity. Opacity was calculated as follows.
(불투과도)(%) = (사진 상 측정된 불투과 면적)/(실제 면적) ×100(Opacity) (%) = (Opaque area measured on photo) / (actual area) × 100
불투과도 계산 결과를 표 1에 나타내었다. 제조한 후 바로 측정하고("초기"로 표기함), 12개월 경과 후 또 측정하였다. 다음과 같은 기준에 따라 등급을 정하였다.The results of the opacity calculation are shown in Table 1. Immediately after preparation (measured as "initial"), was measured again after 12 months. The rating was made according to the following criteria.
1 등급 : 불투과도 80% 이상, Level 1: More than 80% opacity,
2 등급 : 불투과도 80% 이하, 2 grade: less than 80% impermeability,
3 등급 : 불투과도 50% 이하, 3 grade: opacity less than 50%,
4 등급 : 불투과도 20% 이하, 4 grade: less than 20% of opacity,
5 등급: 구별 불가.5 Ratings: Indistinguishable.
표 1
불투과성 등급(불투과도%)
초기 12개월 후
실시예 1 1 등급 (97%) 1 등급 (96%)
실시예 2 1 등급 (93%) 1 등급 (90%)
실시예 3 1 등급 (85%) 2 등급 (75%)
실시예 4 2 등급 (77%) 2 등급 (75%)
실시예 5 1 등급 (85%) 2 등급 (78%)
실시예 6 1 등급 (92%) 1 등급 (88%)
실시예 7 2 등급 (70%) 2 등급 (68%)
실시예 8 1 등급 (84%) 2 등급 (78%)
실시예 9 1 등급 (87%) 2 등급 (75%)
실시예 10 2 등급 (72%) 2 등급 (45%)
실시예 11 1 등급 (94%) 1 등급 (91%)
비교예 1 4 등급 (15%) 5 등급 (구별불가)
비교예 2 4 등급 (12%) 4 등급 (10%)
Table 1
Impermeability rating (% impermeability)
Early 12 months later
Example 1 1 rating (97%) 1 rating (96%)
Example 2 1 rating (93%) 1 rating (90%)
Example 3 1 rating (85%) 2 Stars (75%)
Example 4 2 Stars (77%) 2 Stars (75%)
Example 5 1 rating (85%) 2 Stars (78%)
Example 6 1 Rating (92%) 1 rating (88%)
Example 7 2 stars (70%) 2 Stars (68%)
Example 8 1 rating (84%) 2 Stars (78%)
Example 9 1 rating (87%) 2 Stars (75%)
Example 10 2 Stars (72%) 2 stars (45%)
Example 11 1 Rating (94%) 1 rating (91%)
Comparative Example 1 4 Ratings (15%) 5 star (not distinguishable)
Comparative Example 2 4 Ratings (12%) 4 Ratings (10%)
표 1을 참조하면, 초기 측정 결과와 12개월 후 측정 결과를 대비해 보면, 실시예의 경우에는 불투과도가 다소 감소하기는 하였으나 여전히 1 등급 또는 2 등급의 불투과도를 여전히 유지하고 있었다. 하지만 비교예의 경우에는 초기 측정 결과부터 4 등급으로 측정되는 등 낮은 불투과도를 보이고 있다. Referring to Table 1, in contrast to the initial measurement results and the measurement results after 12 months, the opacity of the Example was slightly reduced, but still maintained the opacity of the first or second grade. However, the comparative example shows a low impermeability, such as measured in the fourth grade from the initial measurement results.
본 발명에 의한 수술용 물품을 사용하는 경우 그 물품의 인체 내 위치를 정확하게 추적 관찰할 수 있다.When using a surgical article according to the invention it is possible to accurately follow the position of the article in the human body.

Claims (15)

  1. 요오드, 제논 또는 이들의 조합을 포함하는 생체 흡수용 방사선 불투과성 마커 조성물.Bioabsorbable radiopaque marker composition comprising iodine, xenon or a combination thereof.
  2. 제 1항에 있어서, The method of claim 1,
    상기 요오드를 제공하는 요오드 소스는 요오드, 요오드화수소, 요오드화나트륨, 요오드화칼륨, 메틸요오드, 요오드화세슘, 요오드산칼륨, 과요오드산나트륨, 요오드화칼슘, 요오드화구리 및 포비돈요오드로 이루어지는 그룹에서 선택된 1종 이상을 포함하고, 상기 제논을 공급하는 제논 소스는 이플루오린화 제논, 사플루오린화 제논 및 육플루오린화 제논으로 이루어진 그룹에서 선택된 1종 이상을 포함하는 생체 흡수용 방사선 불투과성 마커 조성물.The iodine source providing the iodine is at least one selected from the group consisting of iodine, hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodide, sodium iodide, calcium iodide, copper iodide and povidone iodine And a xenon source for supplying xenon, wherein the xenon source comprises at least one selected from the group consisting of xenon difluoride, xenon tetrafluoride and xenon hexafluoride.
  3. 제1항에 있어서, The method of claim 1,
    생분해성 고분자를 더 포함하는 생체 흡수용 방사선 불투과성 마커 조성물.Bioabsorbable radiopaque marker composition further comprising a biodegradable polymer.
  4. 제3항에 있어서, The method of claim 3,
    상기 생분해성 고분자는 친수성 용매에 용해된 상태인 생체 흡수용 방사선 불투과성 마커 조성물.The biodegradable polymer is a bioabsorbable radiopaque marker composition in a state dissolved in a hydrophilic solvent.
  5. 제4항에 있어서, The method of claim 4, wherein
    상기 용매는, 물; 메탄올, 에탈올, 프로탄올, 부탄올, 펜탄올, 헵탄올, 헥산올, 옥탄올, 노난올 및 데칸올을 포함하는 알콜류; 암모니아, 디메틸서폭사이드, 디메틸포름아마이드, 아세트로나이트릴, 테트라하이드로퓨란, 포름알데하이드, 글루타알데하이드 및 아세트알데히드를 포함하는 알데하이드류; 다이옥산, 클로로포름, 헵탄, 헥산, 펜탄, 옥탄, 노난 및 데칸을 포함하는 알칸류; 벤젠, 톨루엔 및 자이렌을 포함하는 벤젠고리형 용매류; 에테르, 다이-프로필 에테르, 페트로늄 에테르 및 메틸-t-부틸 에테르를 포함하는 에테르류; 프로판온, 부탄온, 펜탄온, 헥산온 및 헵탄온을 포함하는 케톤류; 메틸렌 클로라이드, 사플루오로이소프로판 및 염화탄소로 이루어진 그룹에서 선택된 1종 이상을 포함하는 생체 흡수용 방사선 불투과성 마커 조성물.The solvent is water; Alcohols including methanol, ethanol, protanol, butanol, pentanol, heptanol, hexanol, octanol, nonanol and decanol; Aldehydes including ammonia, dimethylsuppoxide, dimethylformamide, acetonitrile, tetrahydrofuran, formaldehyde, glutaaldehyde and acetaldehyde; Alkanes including dioxane, chloroform, heptane, hexane, pentane, octane, nonane and decane; Benzene ring solvents including benzene, toluene and xylene; Ethers including ethers, di-propyl ethers, petroleum ethers and methyl-t-butyl ethers; Ketones including propanone, butanone, pentanone, hexanone and heptanone; A bioabsorbable radiopaque marker composition comprising at least one member selected from the group consisting of methylene chloride, tetrafluoroisopropane and carbon chloride.
  6. 제3항에 있어서, The method of claim 3,
    상기 생분해성 고분자는, 폴리-L-락타이드, 폴리-D-락타이드, 폴리-D,L-락타이드, 폴리글라이콜라이드, 폴리카프로락톤, 폴리-L-락타이드-co-글라이콜라이드, 폴리-D-락타이드-co-글라이콜라이드, 폴리-D,L-락타이드-co-글라이콜라이드, 폴리-L-락타이드-co-카프로락톤, 폴리-D-락타이드-co-카프로락톤, 폴리-D,L-락타이드-co-카프로락톤, 폴리글라이콜라이드-co-카프로락톤, 폴리다이옥산온, 폴리트리메틸렌카보네이트, 폴리글라이콜라이드-co-다이옥산온, 폴리아미드에스터, 폴리펩티드, 폴리오르쏘에스터계, 폴리말레산, 폴리포스파젠, 폴리안하이드라이드, 폴리세바식안하이드라이드, 폴리수산화알카노에이트, 폴리수산화부틸레이트, 폴리시아노아크릴레이트, 폴리도파민, 셀루로오즈, 셀룰로오스 아세테이트 부틸레이트, 셀룰로오즈 트리아세테이트 및 이들의 공중합체로 이루어진 그룹에서 선택되는 1종 이상을 포함하는 생체 흡수용 방사선 불투과성 마커 조성물.The biodegradable polymer is poly-L-lactide, poly-D-lactide, poly-D, L-lactide, polyglycolide, polycaprolactone, poly-L-lactide-co-glycolide , Poly-D-lactide-co-glycolide, poly-D, L-lactide-co-glycolide, poly-L-lactide-co-caprolactone, poly-D-lactide-co- Caprolactone, poly-D, L-lactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxone, polyamide ester, Polypeptides, polyorthoesters, polymaleic acid, polyphosphazenes, polyanhydrides, polycephaanhydrides, polyalkanohydroxides, polyhydroxybutyrates, polycyanoacrylates, polydopamines, celluloses, Cellulose acetate butyrate, cellulose triacetate and their Bioabsorbable radiopaque marker composition comprising at least one member selected from the group consisting of copolymers.
  7. 제3항에 있어서, The method of claim 3,
    상기 생분해성 고분자의 함량은, 상기 조성물 총 중량 대비 0.01 ~ 90 중량%인 생체 흡수용 방사선 불투과성 마커 조성물.Content of the biodegradable polymer, bioabsorbable radiopaque marker composition is 0.01 to 90% by weight based on the total weight of the composition.
  8. 제1항에 있어서, The method of claim 1,
    상기 요오드 및 제논의 총 함량은, 상기 조성물 총 중량 대비 0.01 ~ 95 중량%인 생체 흡수용 방사선 불투과성 마커 조성물.The total content of the iodine and xenon, bioabsorbable radiopaque marker composition is 0.01 to 95% by weight relative to the total weight of the composition.
  9. 제1항의 생체 흡수용 방사선 불투과성 마커 조성물로 코팅된 스텐트.A stent coated with the bioabsorbable radiopaque marker composition of claim 1.
  10. 제1항의 생체 흡수용 방사선 불투과성 마커 조성물로 코팅된 고분자 스크류.A polymer screw coated with the bioabsorbable radiopaque marker composition of claim 1.
  11. 제1항의 생체 흡수용 방사선 불투과성 마커 조성물을 포함하는 생분해성 고분자 스텐트.A biodegradable polymer stent comprising the bioabsorbable radiopaque marker composition of claim 1.
  12. 제1항의 생체 흡수용 방사선 불투과성 마커 조성물을 포함하는 스캐폴더.A scaffold comprising the bioabsorbable radiopaque marker composition of claim 1.
  13. 제1항의 생체 흡수용 방사선 불투과성 마커 조성물을 포함하는 수술용 봉합사.Surgical suture comprising the bioabsorbable radiopaque marker composition of claim 1.
  14. 제1항의 생체 흡수용 방사선 불투과성 마커 조성물을 포함하는 수술용 물품.A surgical article comprising the bioabsorbable radiopaque marker composition of claim 1.
  15. 제14항에 있어서, 상기 수술용 물품은 조직 재생용 지지체, 바이오 나노 섬유, 하이드로젤, 바이오 스폰지, 핀, 스크류, 나사, 막대, 필러, 임플란트 및 생체 이식물로 이루어진 그룹에서 선택된 1종 이상을 포함하는 수술용 물품.15. The surgical article of claim 14 wherein the surgical article comprises at least one member selected from the group consisting of support for tissue regeneration, bio nanofibers, hydrogels, bio sponges, pins, screws, screws, rods, fillers, implants, and living implants. Surgical articles comprising.
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