WO2011059216A2 - Stent médical revêtu d'un agent photosensibilisant, et sa méthode d'élaboration - Google Patents

Stent médical revêtu d'un agent photosensibilisant, et sa méthode d'élaboration Download PDF

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WO2011059216A2
WO2011059216A2 PCT/KR2010/007890 KR2010007890W WO2011059216A2 WO 2011059216 A2 WO2011059216 A2 WO 2011059216A2 KR 2010007890 W KR2010007890 W KR 2010007890W WO 2011059216 A2 WO2011059216 A2 WO 2011059216A2
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stent
photosensitizer
coated
medical
coating
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PCT/KR2010/007890
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Korean (ko)
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WO2011059216A9 (fr
WO2011059216A3 (fr
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나건
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가톨릭대학교 산학협력단
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Priority claimed from KR1020100061082A external-priority patent/KR101200210B1/ko
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Publication of WO2011059216A2 publication Critical patent/WO2011059216A2/fr
Publication of WO2011059216A9 publication Critical patent/WO2011059216A9/fr
Publication of WO2011059216A3 publication Critical patent/WO2011059216A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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 medical stent coating composition that can be used for photodynamic therapy, a medical stent coated with the composition and a method of manufacturing the same.
  • Surgical surgery is the most classic method of treating cancer, and the type, location, metastasis, and condition of the patient before surgery. Considering other factors, the best way is to relieve cancer or tumor tissue.
  • surgical therapy has a problem that the normal tissue around the extent to be removed to a certain extent to remove the cancer, there is a hassle that must be accompanied by reconstruction or rehabilitation treatment after surgery. Therefore, various therapies have been mixed to minimize the problems associated with the reconstruction and rehabilitation of patients by additional removal of normal tissue around the tumor.
  • chemotherapy which involves taking anticancer drugs as pills or injecting them by intramuscular or intravenous injection.
  • Such chemotherapy is a systemic therapy that acts as a mechanism of action by which the anticancer agent rotates throughout the bloodstream, inhibiting the synthesis of nucleic acid, the body of genes in cancer cells, or impairing the function of cellular components.
  • the anticancer agent damages not only cancer cells but also normal cells, causing side effects such as bone marrow disorder, gastrointestinal disorder, hair loss, immune disorder, etc. in almost all patients.
  • radiation therapy is a topical treatment that uses high-energy radiation to kill cancer cells, rather than killing them immediately, destroying their nuclei, causing them to lose their division and proliferation functions, preventing them from splitting anymore, It is a way to die and die.
  • radiation therapy is the cheapest in terms of cost among various chemotherapy, the radiation is limited to two times due to its serious side effects.
  • PDT photodynamic therapy
  • Photodynamic therapy a technique attempted from around 1400 BC, was initially used to treat various diseases using only light, but recently, a photosensitizer and a material that can act sensitively to light.
  • a technique using a technology that can be applied to the treatment of diseases by using a laser to excite the sensitizer it has recently spread worldwide.
  • porphyrin-based compounds are widely used as photosensitizers used in photodynamic therapy. Porphyrin-based compounds not only selectively accumulate in cancer cells but also display fluorescence or phosphorescence due to the characteristics of the compounds. In the case of metalloporphyrin, which has a metal bound to porphyrin, it can exhibit various characteristics depending on the type of metal bound to the tumor cells using magnetic resonance imaging (MRI) contrast agent. It may also be used for early diagnosis.
  • MRI magnetic resonance imaging
  • photosensitizers for photodynamic therapy must satisfy the following requirements. That is, it must have a high quantum yield of the reactant, be non-toxic to the object, preferentially capable of absorbing electromagnetic radiation near the red or infrared region of the spectrum, as well as selectively attaching it to the tumor.
  • the current photodynamic therapy using the photosensitizers was to induce selective attack or death of cancer cells or tumors by administering the photosensitizers to the subjects by intravenous injection and then irradiating with appropriate light.
  • current photodynamic therapy is not used in bulky tumors due to the restriction of light transmission, and in particular, side effects of phototoxicity have been found due to the slow metabolism of photosensitizers in the human body.
  • concentration of the photosensitizer in the tumor is low, it does not show an effective therapeutic effect.
  • the present inventors can use the photodynamic therapy without transdermal or oral administration for the photodynamic therapy which is superior to the conventional method, and the optical sensitizer can be attached to the medical stent for a long time so that the therapeutic effect can be maintained for a long time.
  • the present invention has been completed by developing a novel stent coating composition for epidemiological treatment.
  • another object of the present invention is to provide a medical stent and a method for manufacturing the stent comprising a layer coated with the composition for coating a stent according to the present invention.
  • Another object of the present invention is to provide a photodynamic therapy method using the medical stent according to the present invention.
  • the present invention provides a composition for stent coating for photodynamic therapy comprising a photosensitizer, a non-degradable polymer and an organic solvent.
  • the composition may further comprise a biodegradable polymer.
  • the photosensitizer when further comprising the biodegradable polymer, may be present in the form of a conjugate by the biodegradable polymer and the ester bond.
  • the photosensitizer is a porphyrin-based (phorphyrins) compounds, chlorins (chlorins) compounds, bacteriochlorins (bacteriochlorins) compounds, phthalocyanine (phtalocyanine) compounds, naphthalocyanines (naphthalocyanines) compounds
  • 5-aminolevulin ester-based (5-aminoevuline esters) compound may be selected from the group consisting of.
  • the biodegradable polymer is dextran, chondroitin sulfate, pullulan acetate, pullulan, chitosan and hyaluronic acid acid).
  • the non-degradable polymer may be selected from the group consisting of polyurethane, silicone and Teflon.
  • the organic solvent is dichloromethane, tetrahydrofuran (THF), ethanol, methanol, acetone, dimethyl formamide (dimethyl formamide: DMF), dimethyl sulfoxide : DMSO) and dioxane may be selected from the group consisting of.
  • the photosensitizer, biodegradable polymer and non-degradable polymer is 0.001 to 0.01% by weight of the photosensitizer, 0.1 to 1% by weight of the biodegradable polymer and non-degradable polymer with respect to the total weight of the composition It may be to contain 3 to 7% by weight.
  • the present invention also provides a medical stent coated with a photosensitizer comprising a layer coated with the coating composition according to the present invention.
  • the material of the stent may be selected from the group consisting of stainless steel, cobalt-chromium alloy, tantalum, nitimol and gold.
  • the stent may further include an inner film disposed inside the stent.
  • the material of the inner film may be selected from the group consisting of silicon, Teflon and urethane.
  • It provides a method for producing a medical stent coated with a photosensitizer, comprising the step of volatilizing the coating solvent.
  • the photosensitive agent is dissolved in the biodegradable polymer and the organic solvent before dissolving in the non-degradable polymer and the organic solvent to form a combination of the photosensitive agent and the biodegradable polymer It may further comprise a step.
  • the biodegradable polymer is dextran, chondroitin sulfate, pullulan acetate, pullulan, chitosan and hyaluronic acid acid) may be selected from the group consisting of.
  • the non-degradable polymer may be selected from the group consisting of polyurethane, silicone and Teflon.
  • the step of volatizing the solvent may be to include drying or heating at room temperature.
  • the photosensitizer is a porphyrin-based (phorphyrins) compounds, chlorins (chlorins) compounds, bacteriochlorins (bacteriochlorins) compounds, phthalocyanine (phtalocyanine) compounds, naphthalocyanines (naphthalocyanines) compounds
  • 5-aminolevulin ester-based (5-aminoevuline esters) compound may be selected from the group consisting of.
  • the organic solvent is dichloromethane, tetrahydrofuran (THF), ethanol, methanol, acetone, dimethyl formamide (dimethyl formamide: DMF), dimethyl sulfoxide : DMSO) and dioxane (dioxane) may be selected from the group consisting of.
  • the present invention provides a photodynamic therapy method using a medical sensit coated medical stent comprising inserting a medical stent according to the present invention into a lesion site of an individual except a human, and irradiating light to the stent.
  • the photodynamic therapy may be to treat cancer selected from the group consisting of stomach cancer, lung cancer, esophageal cancer, duodenum cancer, colon cancer, rectal cancer, colon cancer, uterine cancer and biliary tract cancer.
  • the medical stent according to the present invention is a non-degradable polymer that does not easily degrade in the body and a solution dissolved with an organic solvent capable of dissolving a photosensitizer is used as a stent coating composition for the stent coated with the composition,
  • the pharmacologically active photosensitive agent can be attached to the stent for a long time to induce an excellent therapeutic effect by irradiation of light even after a long time in vivo, and to selectively treat only the target cell.
  • Figure 1 shows a stent prepared in accordance with the method of the present invention coated with pheophoride a dissolved in dichloromethane solution, the left picture shows the stent before coating, the right picture shows the color sensitizer with a color development Only the bottom part of the coating is shown.
  • Figure 2 shows the cytotoxicity according to the coating composition prepared according to an embodiment of the present invention, 2a immediately after treatment of the coating composition according to the invention for HeLa cells, NIH 3T3 cells and HCT cells It shows the results of confirming the cytotoxicity, 2b shows the results of confirming the cytotoxicity after 1 week, 2 weeks and 3-4 weeks after treatment with the coating composition according to the invention on NIH 3T3 cells , 2c shows the results of confirming the cytotoxicity of HCT cells after treatment with the coating composition according to the present invention, after one week, after two weeks, and after three to four weeks.
  • FIG. 3 is a view comparing the drug release of the photosensitizer / coating stent and the polymer-photosensitizer / coating stent prepared according to an embodiment of the present invention over a fluorescence image over time.
  • Figure 4 is a surface of the optical sensitizer / coating stent (PU / pheo-a) and the polymer-photo sensitizer / coating stent (PU / PAP) of the present invention prepared according to an embodiment of the present invention through an electron microscope This is a detailed comparison.
  • Figure 5 is the analysis of the degree of drug release of the stent according to the present invention, the photosensitizer / coating stent (5a) and the polymer-photosensitizer / coating stent (5b) of the present invention prepared according to an embodiment of the present invention
  • Figure 5 shows the drug release in the animal over time using a fluorescence image
  • Figure 5 (c) shows the formula of the intensity of the fluorescence graphically ( ⁇ : PU / pheo-a, ⁇ : PU / PAP )
  • Figure 6 is a result of showing the toxicity of the tumor tissue in the animal of the photosensitizer / coating stent and the polymer-photosensitizer / coating stent of the present invention prepared according to an embodiment of the present invention
  • 6a is an animal film
  • 6b was the group irradiated with the laser after the film was released for 4 weeks, and other groups were irradiated with the laser (50J / cm 2 ).
  • the army did not investigate.
  • the present invention can be used in photodynamic therapy without transdermal or oral administration for a superior photodynamic therapy compared to the prior art, and the photosensitizer can be attached to a medical stent for a long time to maintain the therapeutic effect for a long time.
  • a novel stent coating composition for treatment to increase the tumor selectivity to propose a new photodynamic therapy method using a photosensitizer to reduce side effects and obtain an excellent therapeutic effect.
  • the present invention relates to a coating composition of a novel medical stent that can be used for photodynamic therapy and a medical stent having a layer coated with the composition.
  • stents are medical devices used to expand blood vessels by treating them inside the blood vessels when the blood vessels are narrowed by various diseases occurring in the human body and abnormalities occur in the blood circulation.
  • balloon dilation which is inserted with a balloon catheter into blood vessels such as cardiovascular, aortic or cerebrovascular vessels to expand the coronary passage as the balloon is inflated.
  • it has also been used in the procedure of cross-inserting the stent for the treatment of various lesions such as cancer.
  • the present invention is characterized in that it provides a novel stent coating composition that can be applied to a medical stent in order to induce a photodynamic therapeutic effect more effectively than the conventional, the stent coating composition according to the present invention is optical It is characterized by the inclusion of sensitizers, non-degradable polymers and organic solvents.
  • photosensitizer examples include, but are not limited to, porphyrin compounds, chlorins compounds, bacteriochlorins compounds, phthalocyanine compounds, and naphthalocyanine compounds. naphthalocyanines compounds and 5-aminoevuline esters compounds can be used.
  • photosensitizer is a substance that exhibits a specific action when it comes into contact with light and oxygen.
  • a photosensitizer binds to oxygen in the body and exhibits cytotoxicity and destroys cells of interest.
  • the photosensitizer is non-toxic because it is in the base energy state when not exposed to light and thus does not exhibit toxicity to cells.
  • a photosensitizer when exposed to light of a certain wavelength, it is excited to a single energy state, and some of the excited photosensitizers return to a base energy state while emitting energy in the form of fluorescence, but most of them are ternary energy. Transition to state The photosensitizer then exhibits cytotoxicity through two pathways, type I and type II.
  • the photosensitizer in the ternary energy state transmits energy to the surrounding oxygen effectively and generates reactive oxygen, single oxygen, which causes cytotoxicity.
  • the produced singlet oxygen kills cells by chemically reacting and damaging cellular components such as unsaturated fatty acids, cholesterol, proteins, etc.
  • reactive oxygen species produced are generally highly reactive and have short half-lives for treatment purposes.
  • the distance between the site and the photosensitizer should be close, but effective cytotoxic effect can be obtained.
  • porphyrin-based compounds are extracted from silkworms, mulberry leaves, green algae, etc., and have a spectroscopic property suitable for use as a photosensitizer.
  • the red light (700 ⁇ 900nm) having a relatively large cell permeability has the property of causing an electron transition and there is a feature that can efficiently generate a triplet excited state accordingly.
  • chlorin compound (Chlorins) compound has a feature that is discharged to the body relatively quickly, has a low probability of causing phototoxicity and has a number of substituents capable of chemical change.
  • bacteriochlorins compounds phthalocyanine compounds, naphthalocyanines compounds, and 5-aminoevuline esters compounds also have properties suitable for use as photosensitizers.
  • the structural formulas of the photosensitizer compounds that can be used in the present invention are as shown below.
  • the stent coating composition according to the present invention may include a non-degradable polymer that does not decompose in vivo, the type of the non-degradable polymer, but is not limited to this, polyurethane, silicone or Teflon may be used
  • the non-degradable polymer used in the present invention is a bioactive material, that is, a photo-sensitizer that can cause a pharmacological effect on the stent, which is a medical device, so that the adhesion can be maintained for a long time without falling on the stent, It is possible to maximize the treatment efficiency by irradiation of light at a desired time in the target site by reducing the emission of the photosensitizer until it is introduced to the target site of the living body to irradiate light.
  • the medical stent coating composition according to the present invention may further include a biodegradable polymer, the biodegradable polymer that may be included in the composition according to the present invention as a polymer that can be degraded in vivo Types include, but are not limited to, dextran, chondroitin sulfate, pullulan acetate, pullulan, chitosan, and hyaluronic acid. Among them, one selected from among them can be used, and flulan acetate can be preferably used.
  • a photosensitizer for inducing a pharmacological effect on the stent is required for a long time due to the use of the biodegradable polymer compared to the case where only the photosensitizer is used. This can delay the drug in the potato crab, and further has the advantage of smoothing the coating surface of the stent.
  • any organic solvent may be used as long as it is a solvent capable of dissolving a photosensitizer, a biodegradable polymer, and a non-degradable polymer, and preferably, but not limited thereto, dichloromethane ( dichloromethane, tetrahydrofuran (THF), ethanol, methanol, acetone, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and dioxane (dioxane) Can be used.
  • dichloromethane dichloromethane, tetrahydrofuran (THF), ethanol, methanol, acetone, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and dioxane (dioxane)
  • dichloromethane dichloromethane, tetrahydrofuran (THF)
  • ethanol ethanol
  • methanol methanol
  • acetone dimethyl formamide
  • DMSO dimethyl
  • the stent coating composition for the photodynamic therapy according to the present invention is the optical sensitizer and the non-degradable polymer is 0.001 ⁇ 0.01% by weight of the photosensitizer and the non-degradable polymer 3-7 to the total weight of the composition It may contain in weight%.
  • the therapeutic effect due to the light sensitizer may be insignificant when irradiated with light, and when it exceeds 0.01% by weight, there is a problem that may cause side effects in the body.
  • the non-degradable polymer if the non-degradable polymer contains less than 3% by weight, the pharmacological photosensitive agent may be released without being attached to the stent for a long time, whereas 7% by weight If exceeded, the thickness of the coating may be thickened, which may affect the function of the stent, and may exist in a saturated state in the solvent, which may clump, causing various side effects in the cells of the body.
  • the biodegradable polymer when the biodegradable polymer further comprises in the composition, the biodegradable polymer may include 0.1 to 1% by weight based on the total weight of the composition, when the biodegradable polymer contains less than 0.1% by weight It is not possible to evenly and sufficiently coat the surface of the stent together with the photosensitizer and non-degradable material. If it exceeds 1% by weight, the thickness of the coating becomes thicker, which hinders the basic role of the stent. There is a problem that can not maintain a uniform coating form on the stent is weakened. Therefore, in order to induce maximum therapeutic effect due to the use of the coated stent using the coating composition according to the invention it is important to contain a photosensitizer, biodegradable polymer and non-degradable polymer within the above-described range.
  • the present invention can provide a medical stent coated with the coating composition according to the present invention
  • the medical sensitized coated medical stent according to the present invention is a photodynamic therapy using a light sensitizer and light : Medical device that can be used for PDT), preferably a non-vascular stent.
  • the present invention is also characterized in that it provides a method for producing a medical stent coated with a photosensitizer using the composition for coating a stent according to the present invention, preferably, the method, the organic solvent is a photosensitive agent and a non-degradable polymer Dissolving in; Coating the stent with a coating solvent in which the photosensitizer and the non-degradable polymer are dissolved; And volatilizing the coating solvent. More preferably, the photosensitizer is dissolved in the biodegradable polymer and the organic solvent before dissolving the photosensitizer in the non-degradable polymer and the organic solvent. And forming a conjugate of the biodegradable polymer.
  • the method for preparing a stent according to the present invention may dissolve a photosensitizer and a non-degradable polymer in an organic solvent.
  • the photosensitizer, the non-degradable polymer and the organic solvent are as described above, and the process of dissolving the photosensitizer and the non-degradable polymer in the organic solvent is added to the organic solvent to dissolve at the same time.
  • a non-degradable polymer is added to the organic solvent to prepare a dissolved solution, and then the solution can be mixed with a solution in which the photosensitizer is dissolved.
  • a process of forming a combination of the photosensitive agent and the biodegradable polymer by dissolving the photosensitive agent in the biodegradable polymer and the organic solvent is added before the step of dissolving the photosensitive agent and the non-degradable polymer in an organic solvent.
  • the photosensitizer and the biodegradable polymer may be added to the organic solvent and dissolved together.
  • the solution is prepared by dissolving the biodegradable polymer in the organic solvent.
  • DMAP 4-hydroxymethylbezoic acid
  • DCC 1,3-dicyclehexyl carbodiimide
  • the mixed solution in which the conjugate of the photosensitizer and the biodegradable polymer is dissolved may be obtained through lyophilization after dialysis, and the binder may be dissolved in the non-degradable polymer and the organic solvent.
  • the binder and the non-degradable polymer may be dissolved together under an organic solvent, and preferably, the binder and the non-degradable polymer may be dissolved by adding and mixing a solution in which the non-degradable polymer is dissolved.
  • the non-degradable polymer that can be used in the present invention may be polyurethane, silicone or Teflon, which is a polymer that does not decompose in vivo, and in one embodiment of the present invention, polyurethane was used.
  • the solution in which the photosensitizer and the non-degradable polymer are dissolved or the solution in which the photosensitizer and the biodegradable polymer are combined and the solution in which the non-degradable polymer is dissolved is coated with a stent for photodynamic treatment according to the present invention. It can be used as a composition for, and after coating the stent with the solution, through the process of volatilizing the coating solution can be prepared a medical stent coated with the photosensitizer according to the present invention.
  • the method of coating the stent with the coating composition according to the present invention may be carried out by immersing the stent in the composition, or spraying the composition on the stent, or the like, and may be preferably coated by dipping.
  • the coating solvent may be volatilized, wherein the method of volatilizing the solvent may be a method of naturally drying by air at room temperature or by heat treatment, in particular, dichloromethane as a solvent.
  • dichloromethane dichloromethane
  • THF tetrahydrofuran
  • ethanol methanol and acetone
  • DMF dimethyl formamide
  • DMSO dimethyl sulfoxide
  • dioxane dioxane
  • the material of the stent according to the present invention can be used if the material for all stents known in the art, preferably, but not limited to, made of stainless steel, cobalt-chromium alloy, tantalum, nitimol and gold One selected from the group can be used.
  • the stent prepared in accordance with the present invention can be prepared in the structure of any stent known in the art, preferably may be a stent having a structure further comprising an inner film disposed inside the stent, wherein The material of the inner film may be silicon, Teflon and urethane.
  • the optical sensitizer coated medical stent according to the present invention prepared by the method has a feature that can be used in the treatment of photodynamic therapy through the step of inserting in the lesion site of the subject except human, and irradiating light .
  • the present invention provides a photodynamic therapy method using a photosensitive agent coated medical stent, comprising inserting a medical stent coated with a photosensitizer according to the present invention to a lesion site of an individual except a human, and irradiating light to the stent.
  • a photosensitive agent coated medical stent comprising inserting a medical stent coated with a photosensitizer according to the present invention to a lesion site of an individual except a human, and irradiating light to the stent.
  • Photodynamic therapy using a medical sensitizer coated with a photosensitizer according to the present invention may be performed by first inserting the stent to be as close as possible to the lesion site of an individual except a human, and irradiating a predetermined amount of light for a predetermined time. .
  • the light intensity in the step of irradiating the light may be irradiated with a time and intensity sufficient to generate a singlet oxygen or free radicals from the photosensitizer material used in the present invention, preferably by using an endoscope Can be.
  • the photodynamic therapy method using the optical sensitizer-coated medical stent according to the present invention has no side effects compared to the conventional method of percutaneous administration or oral administration using the optical sensitizer and has the advantage of repeating the procedure several times.
  • the stent coated with the photosensitizer can be directly inserted into the lesion site requiring treatment or a region very close to the lesion site, there is an advantage that the treatment effect by the photosensitizer can be greatly enhanced.
  • the medical stent coated with the coating composition according to the present invention allows the photosensitizer, which is a photodynamic therapeutic material, to adhere to the stent for a long time due to the use of a non-degradable polymer. It is possible to reduce the emission and thus induce a therapeutic effect by irradiating light at the appropriate treatment point.
  • a drug that is, a photosensitizer
  • a coating composition containing a stent coated with the coating composition according to the present invention and an unmodified photosensitizer The release rate of) was observed in vitro and in vivo, and as a result, the release of the drug did not occur well over time when coated with the composition according to the present invention, whereas in the case of the control It was shown that the drug was not released to maintain the fluorescence, and this result was also the same result in vivo experiments using animals (see Experimental Example 2 and Experimental Example 4).
  • the inventors of the present invention when coated on the medical stent for the photodynamic therapy using the coating composition according to the present invention, even if a long time after injection in vivo, the sensitizing agent does not release the sensitizing effect exhibiting a pharmacological effect It can be seen that it is attached to the surface of the coating.
  • the stent according to the present invention is characterized in that after being inserted into an object for treatment, the coated state can be maintained for 3 to 4 months.
  • the coating composition according to the present invention has a feature that can evenly coat the surface of the medical stent.
  • a material causing a therapeutic effect by irradiation of light such as a photosensitizer, is evenly coated on the surface of the stent and is important in inducing an effective therapeutic effect. can do.
  • the surface of the stent after coating the surface of the stent with a coating composition and a coating composition using an unmodified photosensitizer according to the present invention, the surface of the stent over time was observed, In the case of coating with the composition of the present invention, the surface was very uniform, whereas in the case of the control group, the surface was irregular and a large number of large pores were observed (see Experimental Example 3).
  • the results of the coating composition according to the present invention can be very even coating the surface of the stent, it can be seen that the drug, that is, the photosensitizer is not released through the pores are not observed on the surface over time. .
  • the medical stent coated with the coating composition according to the present invention is characterized in that it can induce a therapeutic effect at a desired time point, and in particular, there is no need to adjust the release rate of the drug, and when not irradiated with laser or light It is characterized by not causing toxicity to cells.
  • the toxicity of cancer cells to a group irradiated with a laser and a group irradiated with a laser according to the time after inserting the film coated with the coating composition according to the present invention in an animal in a tumor-induced animal model.
  • the degree was analyzed.
  • cancer cells inserted into the film coated with the coating composition according to the present invention are more toxic to cancer cells than those using the film coated with the unmodified photosensitive agent. It appeared high and ultimately showed excellent anticancer activity (see Experimental Example 5).
  • cancer cells are irradiated with and without laser irradiation using a stent coated with a composition according to the present invention and a stent coated with a composition using an unmodified photosensitizer.
  • a stent coated with a composition according to the present invention and a stent coated with a composition using an unmodified photosensitizer.
  • the present inventors found that the stent for the photodynamic therapy coated with the composition for coating containing the photosensitizer, the biodegradable polymer, the non-degradable polymer and the organic solvent according to the present invention is particularly a non-degradable polymer. If the light sensitizer is attached to the stent for a long time due to its use, if only the light is irradiated after a long time, it may have an excellent therapeutic effect by causing cytotoxicity of the target cell, while not irradiating the light. Since it does not cause toxicity to cells, it can be seen that a more selective and efficient therapeutic effect can be obtained.
  • the disease that can be prevented or treated by the photodynamic therapy using the medical sensit coated with the photosensitive agent according to the present invention is not limited thereto, but may be cancer, and the cancer may be gastric cancer, esophageal cancer, duodenal cancer, or colon cancer. It may be, rectal cancer, colon cancer and biliary tract cancer.
  • the present inventors In order to prepare a medical stent coated with a photosensitizer, the present inventors first dissolved fluorinated acetate (100 mg), an acetylated biocompatible polymer material, in 5 ml of dehydrated DMSO solvent, and a photosensitive agent, pheophorbide a ( 10 mg of pheophorbide a) was mixed with catalyst 4-hydroxymethylbezoic acid (DMAP) and 1,3-dicyclohexylcarbodiimide (1,3-dicyclohexyl carbodiimide (DCC)) in 5 ml of DMSO solvent. Dissolved.
  • Fluranacetate a photosensitive agent prepared in ⁇ -1>, was dissolved in THF, and then mixed with THF, and then mixed with 5% polyurethane solution, which is a bioinert polymer, to prepare a mixed solution. Thereafter, the stainless steel stent was immersed in the mixed solution for 1 minute, and then dried in air at room temperature for 30 to 60 minutes until all of the volatile organic solvents THF were volatilized and coated with a photosensitive agent pheophorbide a.
  • a stent was prepared and the stent of the present invention prepared by the above method is shown in FIG. 1.
  • the experimental group used a stent (PU / PAP) coated with a mixed solution containing 5% polyurethane solution, which is a bioinert polymer, after dissolving Pluranacetate combined with a photosensitizer in THF.
  • a stent (PU / pheo-a) coated with a solution of an unmodified photosensitizer i.e., a photosensitizer with no biocompatible polymer bound in a solvent
  • a 5% polyurethane solution which is a bioinert polymer.
  • the concentration of the photosensitizer used in the experimental group and the control group was 40 ug / ml, and the amount of the photosensitizer coated at the time of one coating was 4 ug / ml per 1 cm 2 .
  • Example 1 a phthalocyanine compound is used as a photosensitizer, a tantalum material is used as a stent material, and a immersion time is set to 10 minutes in the process of immersing and coating a tantalum material stent.
  • a phthalocyanine-coated medical stent was prepared in the same manner as in Example 1 except that the volatilization process was heated and evaporated for 30 minutes at a temperature of 100 ° C. In this case, dichloromethane was used instead of THF in Example 1 as a volatile organic solvent.
  • the following experiment was performed to evaluate whether or not the cytotoxicity for the medical stent of the present invention coated with the photosensitizer prepared in Example 1. That is, HeLa (cervical cancer cells), NIH3T3 and HCT-8 (human colon cancer cells), which are various cancer cells, are cultured by dispensing 6 x 6 cells in 6 wells and then coated with a photosensitizer of the present invention. The PAP and the control stent PU / pheo-a were carefully placed and then incubated for 1 hour. After irradiating the laser at 670nm wavelength and incubated for 2 hours more, the degree of cytotoxicity was analyzed by trypan blue method.
  • the particles of the tryptop blue reagent used in the present experimental example can be introduced into the cell through the cell membrane by the cell membrane diffusion method, and the living cells are recombined with the trypan blue reagent by exocytosis using ATP energy.
  • Dead cells which are discharged to the outside but cannot generate energy, are dyed blue because no exocytosis occurs.
  • the cells used for these experiments were diluted in medium without serum to approximately 200-2,000 cells / ml, then treated with 0.4% trypan blue solution and allowed to stand for 5 minutes before the number of unstained live cells and stained dead. The cells were compared and analyzed, and the cytotoxicity of each drug release was also analyzed after coating of the stent.
  • the photosensitizer is attached to the stent for a long time due to the use of a bioinert substance urethane, and thus, drug release, that is, release of the photosensitizer does not occur, resulting in cytotoxicity after 4 weeks of laser irradiation. It was confirmed.
  • the prepared stent and the control stent in 37 °C PBS after KODAK image Fluorescence was observed using a station apparatus.
  • the bioinert substance used in the preparation of the stent of the present invention that is, the biodegradable urethane does not occur well, the release of the drug by a role that can maintain the photosensitive agent as a therapeutic material for a long time coated on the stent Due to the pharmacological or therapeutic effects in vivo it was found that it can be induced continuously.
  • the present inventors further analyzed by using an electron microscope to observe the surface of the medical stent according to the present invention prepared in Example 1. That is, after coating the stent PU / PAP and the control stent PU / pheo-a of the present invention prepared in Example 1 in the coating solvent, the photosensitive agent is released from the stent immediately after the coating and for 2 months Were respectively confirmed by an electron microscope.
  • the coating method of the stent according to the present invention can not only reduce the release of the drug due to the use of the bioinert polymer, but also very evenly coat the surface of the stent.
  • the inventors of the present invention provide the PU stent according to the present invention to determine whether the medical stent according to the present invention prepared in Example 1 can actually delay the drug release time in vivo through animal experiments using an animal model.
  • / PAP and control stent PU / pheo-a in the form of a film respectively, using a Balb / c nude mouse (5 weeks old) to implant the film in the subcutaneous layer surgically to observe the release of the photosensitizer over time saw.
  • the control stent PU / pheo-a is rapidly falling in the degree of fluorescence from the past one week, while the stent PU / PAP of the present invention is well maintained in vivo fluorescence even for a month appear.
  • the fluorescence intensity after 35 days was about 20% in the control group, whereas the PU / PAP according to the present invention maintained the fluorescence intensity of about 3 times 60% of the control group. Appeared.
  • the method for manufacturing a medical stent according to the present invention through the above results is that the drug, that is, the photosensitizer is released so easily that it is difficult to obtain a pharmacological effect at a desired time in a desired place, and the improvement of the conventional technique.
  • bio-inert material eg Yonde Polyurethane
  • biopolymer eg Yonde Polyurethane
  • Example 1 PU / PAP and control PU / pheo-a stent film of the present invention were planted at the site where the tumor was induced, and then irradiated with lasers (50 J / cm) for release of the drug in the body immediately after planting and 4 weeks after planting. 2 ). All groups were also compared with no laser irradiation.
  • the PU / PAP according to the present invention can reduce the drug release than the control PU / pheo-a, and the therapeutic effect on cancer cells is induced only when the laser is not irradiated It was found that cancer cells are more toxic than the control group.
  • the inventors of the present invention when manufacturing a medical stent using a bioinert polymer together with a photosensitizer and a biocompatible polymer, the photosensitizer causing the pharmacological effect due to the use of the bioinert polymer may be attached to the stent for a long time.
  • the function is improved compared to conventional photodynamic stents As a result, the disease could be treated more effectively.

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Abstract

La présente invention concerne un stent médical revêtu d'un agent photosensibilisant, ainsi qu'une méthode d'élaboration d'un tel stent, et plus spécifiquement une composition de revêtement d'un stent pour thérapie photodynamique, ladite composition comprenant un agent photosensibilisant, un polymère non dégradable et un solvant organique, un stent médical revêtu d'un agent photosensibilisant, comportant une couche revêtue de la composition de revêtement, une méthode d'élaboration du stent et une méthode de thérapie photodynamique exploitant ledit stent. Un stent médical revêtu de la composition pour revêtement selon la présente invention est élaboré par dissolution d'un agent photosensibilisant et d'un polymère non dégradable dans un solvant organique ; revêtement d'un stent par un solvant de revêtement où sont dissous l'agent photosensibilisant et le polymère non dégradable ; et évaporation du solvant de revêtement. D'excellents effets de traitement peuvent être induits in vivo même après une durée importante dans la mesure où un agent photosensibilisant, qui est une matière pharmaceutiquement active, adhère au stent pendant une longue durée par le biais d'un polymère non dégradable, et le patient peut être libéré immédiatement après l'opération dans la mesure où seules des cellules cibles peuvent être traitées sélectivement en fonction de l'irradiation, et où les effets secondaires in vivo sont peu importants par rapport aux thérapies photodynamiques connues par administration transdermique ou orale ; il est de plus possible de répéter plusieurs fois les opérations.
PCT/KR2010/007890 2009-11-10 2010-11-09 Stent médical revêtu d'un agent photosensibilisant, et sa méthode d'élaboration WO2011059216A2 (fr)

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KR20090108060 2009-11-10
KR10-2009-0108060 2009-11-10
KR1020100061082A KR101200210B1 (ko) 2009-11-10 2010-06-28 광감작제가 코팅된 의료용 스텐트 및 이의 제조방법
KR10-2010-0061082 2010-06-28

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5419760A (en) * 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
KR100230588B1 (ko) * 1992-11-20 1999-12-01 팜 윌리암 엔. 감광제함유 광역학적 요법제
US20050079200A1 (en) * 2003-05-16 2005-04-14 Jorg Rathenow Biocompatibly coated medical implants
KR20070002408A (ko) * 2005-06-30 2007-01-05 삼성전자주식회사 전하발생분산액 및 이를 이용한 전자사진장치용 감광체의제조 방법
US20070160646A1 (en) * 2004-03-01 2007-07-12 Terumo Kabushiki Kaisha Stent coated by a compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100230588B1 (ko) * 1992-11-20 1999-12-01 팜 윌리암 엔. 감광제함유 광역학적 요법제
US5419760A (en) * 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
US20050079200A1 (en) * 2003-05-16 2005-04-14 Jorg Rathenow Biocompatibly coated medical implants
US20070160646A1 (en) * 2004-03-01 2007-07-12 Terumo Kabushiki Kaisha Stent coated by a compound
KR20070002408A (ko) * 2005-06-30 2007-01-05 삼성전자주식회사 전하발생분산액 및 이를 이용한 전자사진장치용 감광체의제조 방법

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