WO2011099813A2 - Procédé de production de stent imprégné de médicaments et stent ainsi produit - Google Patents

Procédé de production de stent imprégné de médicaments et stent ainsi produit Download PDF

Info

Publication number
WO2011099813A2
WO2011099813A2 PCT/KR2011/000943 KR2011000943W WO2011099813A2 WO 2011099813 A2 WO2011099813 A2 WO 2011099813A2 KR 2011000943 W KR2011000943 W KR 2011000943W WO 2011099813 A2 WO2011099813 A2 WO 2011099813A2
Authority
WO
WIPO (PCT)
Prior art keywords
stent
coating
drug
coated
biodegradable polymer
Prior art date
Application number
PCT/KR2011/000943
Other languages
English (en)
Korean (ko)
Other versions
WO2011099813A3 (fr
Inventor
이승진
장양수
권일근
장미란
심인경
정미라
Original Assignee
이화여자대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 이화여자대학교 산학협력단 filed Critical 이화여자대학교 산학협력단
Publication of WO2011099813A2 publication Critical patent/WO2011099813A2/fr
Publication of WO2011099813A3 publication Critical patent/WO2011099813A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—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
    • 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances

Definitions

  • the present invention relates to a method for producing a drug coated stent and a stent.
  • a drug coated stent is a drug coated stent.
  • Transplantation of stents can be used in combination with balloon angioplasty to be very effective in the treatment of acute vascular obstruction and reduce the risk of restenosis.
  • intra-stent restenosis occurs due to neointimal proliferation in the damaged endometrium after the procedure.
  • the postoperative restenosis rate is 40-50% after balloon dilatation and 25-30% after stent implantation. Therefore, reducing the restenosis rate is the key to interventional procedures.
  • a method of preventing the smooth muscle cell proliferation in the stent, reducing inflammation, and reducing the unevenness by using a polymer coating method is adopted.
  • This drug therapy provides an effective treatment that inhibits proliferation of neoendothelial cells by inhibiting cell proliferation.
  • lowering the dose of the drug while maintaining a higher tissue concentration can reduce toxicity while providing a reducing effect of restenosis, inflammation and thrombosis.
  • Coating methods of drug-containing polymers on the surface of the stent include mechanical coating, dipping coating, charge (electrostatic) coating, ultrasonic coating, gas spray coating, etc., and may be used in combination of two or more methods.
  • Currently developed products often use dipping or immersion methods. However, these methods are uneven and thick in coating thickness.
  • problems include webbing, stringing, peeling of the stent surface, chemical waste, overspray, difficulty controlling the amount of chemical flow, adhesion problems, and long drying times.
  • existing products may have negative effects with vascular endothelial cells due to long-term retention of drug components. Therefore, the drug loading can be controlled for 0 to 6 weeks and can be delivered continuously in order to properly proceed with all processes related to angioplasty and stent implantation, and the stent is inserted into the application site to ' expand ' the stenosis.
  • stents that have a function and at the same time have a stable surface.
  • the problem to be solved by the present invention is to provide a drug coating stent manufacturing method that can increase the stability to the human body.
  • the problem to be solved by the present invention is to deliver a drug-coated stent that can increase the stability to the human body.
  • step (B) coating the coating solution in which the biodegradable polymer and the drug are dissolved in a solvent by spray spinning the stent of step (a);
  • (C) providing a drug coating stent manufacturing method comprising the step of (annealing) the coating surface by leaving the stent on which the coating layer is formed in the step (b) under an organic solvent vapor.
  • the stent may be ones known in the art, and is generally cylindrical in a top and bottom open cylinder, preferably about 2 rails in diameter.
  • the stent of step (a) may be a reticulated or lattice type tubular stent.
  • the material of the stent may be stainless steel, chromium cobalt alloy, etc., and the cobalt chromium alloy is more biocompatible than the stainless steel and is preferable in terms of strength.
  • the stent may be for the prevention, reduction or treatment of stenosis, restenosis, atherosclerosis, atherosclerosis, occlusion, irrigation and / or aneurysm.
  • the stent may be purchased or manufactured commercially available.
  • the 'biodegradable polymer' is a polymer that is decomposed and released in vivo, so that the drug is not decomposed after being released for a certain period of time so as not to remain in the living body so that all the drugs are released.
  • the biodegradable polymer of step (b) is not particularly limited as long as it can be decomposed in the human body, preferably poly - ⁇ -caprolactone, polyglycol lead, polylactide, and / or polylactide and poly Copolymers of glycolide and the like.
  • the biodegradable polymer preferably has a weight average molecular weight of 100,000 to 200,000, and can control the drug release rate in the above range.
  • the solvent of step (b) may be an organic solvent capable of dissolving a biodegradable polymer and a drug.
  • the organic solvent is preferably acetone, methylene chloride, chloroform, carbon tetrachloride, and / or ethanol.
  • the biodegradable polymer of step (b) may comprise 0.01 to 20% by weight of the coating solution It may be included, preferably from 0.1 to 5% by weight of the coating solution, more preferably from 0.2 to 0.5% by weight.
  • Spray spinning the coating liquid in the concentration range can form a stable coating layer with a uniform thickness throughout the stent. If the concentration is more than 5% by weight, the polymer may stick together between the stent wires during electrospinning. Especially, the annealing may cause the formation of a polymer film at the bent part of the wire. Less radiation per hour is less than less radiation time may be longer. Preferably, the most even distribution of nanoparticles is shown in SEM measurement at 0.2-0.5 weight 3 ⁇ 4>.
  • step (b) is preferably electric spray spinning, it can be coated by spinning the coating liquid at a voltage of 5 ⁇ 25kV and 0.01-0.08ml / min flow rate.
  • the spinning speed is slow, the coating time may be slow and the spinning is not smooth, it is difficult to obtain even particles when more than 0.08ml / min, there is a fear that droplets are formed.
  • the surface is unevenly radiated, and a polymer lump is formed between the stent wires, and even after annealing, the surface does not spread evenly and a web format ion may be generated.
  • the spray radiation may radiate in a direction consistent with the electric field or in a direction crossing the electric field.
  • the spray spinning may be performed while the rod is inserted into the stent, and the insertion may be performed in a state in which the longitudinal outer surface of the rod is in contact with the inner side of the stent. It is inserted.
  • the inner surface of the stent may be formed to be thinner than the outer surface, or may not be formed. By suppressing the formation of the drug coating layer on the inner surface, it is possible to prevent the drug from excessive action in the body part to which the stent is applied.
  • the drug of step (b) is an anticancer drug, an anti-inflammatory drug, a smooth muscle cell proliferation inhibitor, an antithrombotic agent, a growth factor, and / or a radioactive compound, and the like, which have an anti-restriction effect. Any drug can be used.
  • the drug may be included in an amount of 1 to 30 parts by weight based on 100 parts by weight of the biodegradable polymer in the coating solution.
  • the anticancer drug means a drug that exhibits anticancer activity, and for example, alkaloids such as taxol, taxotere, and topotecin, antibiotics such as adrenaline and breo, and metabolic antagonism such as 5-FU. Substances and / or natural products, such as vinca alkaloids (vinblastine, vincristine and vitrell bin).
  • the anti-inflammatory drug means a drug that exhibits anti-inflammatory action, and is, for example, a steroidal agent such as dexamethasone.
  • the smooth muscle cell antiproliferative drug is a smooth muscle cell in the resting state after the stent insertion by the blood vessel damage to the cell cycle can cause cell division and cell proliferation, which acts on smooth muscle Inhibiting the proliferation of cells to inhibit neointima production, for example, sirolimus, and / or paclitaxel.
  • the antithrombotic agent is a drug that inhibits blood clot production and inhibits blood clot formation that may occur during stent implantation, for example, heparin, aspirin, and / or thienopyridine.
  • the growth factor promotes endothelial cell repopulation on the damaged blood vessel surface after the stent implantation to inhibit thrombus generation by the stent, for example, fibroblast growth factor (FGF), and / or vascular endothelial growth factor. (VEGF) and the like.
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • the radioactive compound is a compound used to prevent restenosis after stent implantation, for example, P-32 oligonucleotide (15mer c-myc ant i sense phosphorothioate), and / or phosphorus 32 And so on.
  • the coating may have a coating layer thickness of 0.01 to 100. There is a concern that the coating effect is insufficient at less than 0.01, and there is a fear that the coating layer is nonuniform at more than 100.
  • the organic solvent is left in the sealed space, and the organic solvent is saturated with the organic solvent vapor, and the stent coated in the step (b) is left in the sealed space.
  • the leaving time can be adjusted appropriately depending on the type of the polymer, the thickness of the coating layer, the type of the solvent from several seconds to several days.
  • the organic solvent may dissolve biodegradable polymers such as methylene chloride (MC), acetone, dimethyl sulfoxide (DMS0), and / or 1,2-dichloroethane. You can use a solvent that has some volatility and Saturate the chamber several hours in advance in the burr.
  • planarization of the surface of the step (C) has a flat coating surface, it is possible to inhibit thrombus formation, adhesion and proliferation of blood vessels, which may be caused by an uneven surface.
  • the stent is fixed to a freely rotatable mold, and can be coated by a method of spraying the coating liquid while slowly moving the piece emitting the coating liquid up and down.
  • the present invention provides a stent produced by the manufacturing method of the present invention.
  • the manufacturing method of the present invention can avoid prolonged retention of the drug at the site of use, and can produce a drug coated stent having a flat and uniform coating layer formed on its surface.
  • the stent is inserted into the organ of the human body and has a natural function of expanding the stenosis, and at the same time, a drug for inhibiting proliferation is added to prevent restenosis, and the surface of the stent maximizes stability with the human body. It has the advantage that it can be partially coated differently.
  • Figure 1 is a photograph of the stent surface after the surface coating step in one embodiment of the present invention.
  • FIG. 2 is a surface photograph of a stent after undergoing surface planarization in an embodiment of the present invention.
  • FIG 3 is a photograph of the surface of the stent after the stent manufactured in one embodiment of the present invention is expanded with a balloon.
  • Figure 4 is a differential scanning microscope picture of the thickness of the coating layer formed on the inside and outside of the stent prepared in one embodiment of the present invention.
  • FIG. 5 is a view showing a coating apparatus used in an embodiment of the present invention (10: stent; 20: rod; 30: syringe; 40: syringe pump).
  • a stent (DIO, NOVUS) was prepared.
  • the stent surface was washed with methanol and dried.
  • Polylactide and polyglycolide copolymers ⁇ PLGA; poly (lactic-co-glycolic acid); PLGA 53:47; ? ⁇ and paclitaxel (Samyang Corp.) were dissolved in a main solution of acetone and a side solution of ethanol 9: 1 mixture to prepare a transparent coating solution.
  • the coating solution was coated on the dried stent by an electrospray method.
  • the apparatus used for the electrospray spinning was an electric sprayer (equipped with a syringe to a KD scientific pump, a form as shown in FIG. 5), and coated under the following conditions.
  • the voltage during electrospinning was 10 kV
  • the flow rate of the coating liquid was 0.02 ml / min
  • 1 ml of the total coating liquid was spun.
  • the coating solution was spun while spinning the stent while spinning.
  • Methylene chloride solution was placed in a closed chamber and left for 24 hours at (21-23 ° C) to saturate the inside of the chamber with methylene chloride vapor.
  • the stent coated in (2) was placed in the chamber and left for 2 hours to flatten the coating surface. As a result, a drug coated stent having a smooth surface was prepared.
  • the stent was coated in the following manner to mainly coat the stent outer surface with a drug.
  • the apparatus shown in FIG. 5 was used, and the same stent as the stent prepared in Example 1- (1) was used.
  • electrospinning was performed using the syringe 30 and the syringe pump 40. After connecting the + electrode to the syringe 30, the-electrode to the rod 20 and applying a high voltage to the drug and the polymer was coated on the stent in the unit of nanoparticles.
  • the rod was rotated at a constant speed, and as shown in FIG. 5, except that the rod 20 was coated in the state inserted into the stent 10, the same as in Example 1- (2).
  • Coating was carried out under the coating conditions. After the coating was completed, the rod inserted into the stent was removed from the stent. At this time, a phenomenon such as peeling of the coating film did not occur. All. Thereafter, the coating surface was planarized in the same manner as in Example 1- (3). The result was a drug coated stent with a smooth surface. At this time, it was possible to form a coating layer having a smooth surface even at the boundary where the difference between the coating layer inside and outside the stent.
  • Example 1 is a photograph of the surface of the stent after undergoing the surface coating step (Example 1_ (2)) in Example 1, the left side of which is 200 times magnification, and the right side of which is 5000 times magnification. As shown in Figure 1 it can be seen that the uniform particles of about 400nm size uniformly deposited on the surface. Therefore, it can be seen that the stent can be uniformly coated with nanoparticles by the production method of the present invention.
  • FIG. 2 is a photograph of the surface of the stent after the surface planarization step (Example 1_ (3)) in Example 1, the left side of which is a 200 times magnification photograph, and the right side is a magnification 5000 times photograph. After the surface planarization as shown in Figure 2, it can be seen that the stent surface is sintered into a uniform film to have a smooth surface. .
  • Example 3 shows the stent surface of the stent prepared in Example 1 after being expanded with a balloon (BIO SENSOR), which is a 200 times magnification photograph.
  • FIG. 4 is a photograph showing the polymer coating on the inside and the outside of the stent strut of the stent prepared in Example 2.
  • FIG. The left side is a differential scanning micrograph of the inner coating and the right side of the outer coating, each magnification 5000 times.
  • the outer coating is thicker than the inside of the stent. Therefore, it can be seen that the thickness of the coating formed on the inside and outside of the stent can be adjusted according to the manufacturing method of the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Materials For Medical Uses (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

L'invention concerne un procédé de production d'un stent imprégné de médicaments, ainsi qu'un stent produit par la mise en oeuvre de ce procédé. Le procédé selon l'invention consiste : (a) à préparer un stent ; (b) à revêtir par atomisation le stent obtenu lors de l'étape (a) au moyen d'un liquide de revêtement dans lequel des polymères biodégradables et des médicaments sont dissous dans un solvant ; et (c) à exposer le stent, sur lequel à été formée une couche de revêtement lors de l'étape (b), à des vapeurs de solvant organique pour recuire la surface revêtue. Le procédé selon l'invention permet de produire un stent imprégné de médicaments qui ne laisse pas de résidus à long terme de médicaments dans la partie du corps où il est utilisé, et qui présente une surface pourvue d'une couche de revêtement plate et uniforme. Les surfaces interne et externe du stent selon l'invention peuvent notamment être revêtues partiellement différemment, ce qui permet d'obtenir une stabilité maximisée dans le corps humain.
PCT/KR2011/000943 2010-02-11 2011-02-11 Procédé de production de stent imprégné de médicaments et stent ainsi produit WO2011099813A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020100012781A KR101140002B1 (ko) 2010-02-11 2010-02-11 약물 코팅 스텐트 제조방법 및 스텐트
KR10-2010-0012781 2010-02-11

Publications (2)

Publication Number Publication Date
WO2011099813A2 true WO2011099813A2 (fr) 2011-08-18
WO2011099813A3 WO2011099813A3 (fr) 2012-01-05

Family

ID=44368328

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2011/000943 WO2011099813A2 (fr) 2010-02-11 2011-02-11 Procédé de production de stent imprégné de médicaments et stent ainsi produit

Country Status (2)

Country Link
KR (1) KR101140002B1 (fr)
WO (1) WO2011099813A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160008758A (ko) * 2014-07-15 2016-01-25 주식회사 엠아이텍 스텐트
CN112336508A (zh) * 2020-11-26 2021-02-09 刘艳娟 一种骨科用肢体石膏涂覆系统

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101585028B1 (ko) 2015-06-01 2016-01-14 (주)시지바이오 동맥류 치료용 고분자 코팅 스텐트 및 이의 제조 방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050010827A (ko) * 2002-05-20 2005-01-28 오르버스 메디칼 테크놀로지즈 인코포레이티드 약물 용리 이식성 의료 장치
US20050037052A1 (en) * 2003-08-13 2005-02-17 Medtronic Vascular, Inc. Stent coating with gradient porosity
US20080026034A1 (en) * 2006-07-26 2008-01-31 David Cook Therapeutic agent elution control process
KR20090090314A (ko) * 2006-10-20 2009-08-25 바이오센서스 인터내셔널 그룹, 리미티드 약물-전달 혈관내 스텐트 및 사용 방법

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504125B1 (en) * 2001-04-27 2009-03-17 Advanced Cardiovascular Systems, Inc. System and method for coating implantable devices

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050010827A (ko) * 2002-05-20 2005-01-28 오르버스 메디칼 테크놀로지즈 인코포레이티드 약물 용리 이식성 의료 장치
US20050037052A1 (en) * 2003-08-13 2005-02-17 Medtronic Vascular, Inc. Stent coating with gradient porosity
US20080026034A1 (en) * 2006-07-26 2008-01-31 David Cook Therapeutic agent elution control process
KR20090090314A (ko) * 2006-10-20 2009-08-25 바이오센서스 인터내셔널 그룹, 리미티드 약물-전달 혈관내 스텐트 및 사용 방법

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160008758A (ko) * 2014-07-15 2016-01-25 주식회사 엠아이텍 스텐트
KR101696809B1 (ko) * 2014-07-15 2017-01-16 주식회사 엠아이텍 스텐트
CN112336508A (zh) * 2020-11-26 2021-02-09 刘艳娟 一种骨科用肢体石膏涂覆系统

Also Published As

Publication number Publication date
KR20110093009A (ko) 2011-08-18
KR101140002B1 (ko) 2012-05-02
WO2011099813A3 (fr) 2012-01-05

Similar Documents

Publication Publication Date Title
Petlin et al. Plasma treatment as an efficient tool for controlled drug release from polymeric materials: A review
EP2897661B1 (fr) Revêtements par centrifugation par élution médicamenteuse et procédés d'utilisation
US7622135B2 (en) Coated stent
KR102410365B1 (ko) 기능성 내피 세포 층의 복구를 가능하게 하는 약물 용출 스텐트 및 이의 사용 방법
US20090043380A1 (en) Coatings for promoting endothelization of medical devices
US20100119578A1 (en) Extracellular matrix modulating coatings for medical devices
JP2012501219A (ja) 治療薬送達のための無機コーティングを有する医療用デバイス
CN101600463B (zh) 药物释放型血管内支架及其使用方法
EP2575917A2 (fr) Revêtement d'endoprothèses d'une couche de fils polymères entrelacés à mailles serrées
Cherian et al. Surface engineering at the nanoscale: A way forward to improve coronary stent efficacy
WO2017113634A1 (fr) Instrument médical pouvant être implanté en alliage à base de fer et son procédé de fabrication
US8728150B2 (en) Medical device loaded with formulation for targeted delivery of biologically active material/s and method of manufacture thereof
WO2011099813A2 (fr) Procédé de production de stent imprégné de médicaments et stent ainsi produit
JP2004222953A (ja) 生体留置用ステント
US20100092534A1 (en) Combination Local Delivery Using a Stent
US20150209483A1 (en) Bioabsorbable medical devices and methods of use thereof
US20100183501A1 (en) Medical Devices With Nanotextured Titanium Coating
US20120239140A1 (en) Medical product comprising an active coating
US20070118211A1 (en) Method for preparing drug eluting medical devices and devices obtained therefrom
KR102409251B1 (ko) 약제 용출형 스텐트
CN111760179A (zh) 一种血管外支架及其应用
WO2020134542A1 (fr) Dispositif d'élution de médicament et son procédé de fabrication
JP2016163619A (ja) 防食効果を利用したマグネシウムの分解速度制御
JP2015154921A (ja) 薬剤徐放性ステント
JP7170647B2 (ja) 薬物送達面積が増大したインプラント型装置

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11742505

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11742505

Country of ref document: EP

Kind code of ref document: A2