WO2017012578A1 - 用于眼部疾病光治疗的材料 - Google Patents

用于眼部疾病光治疗的材料 Download PDF

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Publication number
WO2017012578A1
WO2017012578A1 PCT/CN2016/090980 CN2016090980W WO2017012578A1 WO 2017012578 A1 WO2017012578 A1 WO 2017012578A1 CN 2016090980 W CN2016090980 W CN 2016090980W WO 2017012578 A1 WO2017012578 A1 WO 2017012578A1
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Prior art keywords
photosensitizer
group
matrix material
medical
medical device
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PCT/CN2016/090980
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English (en)
French (fr)
Inventor
隋信策
魏永吉
解江冰
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Eyebright Medical Technology Beijing Co Ltd
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Eyebright Medical Technology Beijing Co Ltd
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Priority to EP16827269.8A priority Critical patent/EP3351219A4/en
Priority to JP2018503474A priority patent/JP6823044B2/ja
Priority to US15/746,746 priority patent/US11925686B2/en
Publication of WO2017012578A1 publication Critical patent/WO2017012578A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/0079—Methods or devices for eye surgery using non-laser electromagnetic radiation, e.g. non-coherent light or microwaves
    • 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
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
    • A61N2005/0645—Applicators worn by the patient
    • A61N2005/0647—Applicators worn by the patient the applicator adapted to be worn on the head
    • A61N2005/0648—Applicators worn by the patient the applicator adapted to be worn on the head the light being directed to the eyes

Definitions

  • the present invention relates to a medical material for phototherapy, in particular an ophthalmic material for phototherapy of ocular diseases and a preparation method thereof.
  • eye diseases such as eyelid disease, lacrimal disease, conjunctival disease, corneal disease, sclera, uveal disease, cataract, posterior cataract, glaucoma, vitreous lesion, lens disease, iridopathy, retinal disease, macular degeneration Pathological diseases, eyelid diseases, eye injuries, refractive of the eyes, eye muscle diseases, eye tumors, etc., especially some diseases in the eye, can cause the patient to be unclear or even blind, causing a huge life for the patient. Inconvenience and pain.
  • Laser-driven phototherapy has achieved remarkable results in cancer treatment, and its advantages in non-invasiveness, non-toxicity, and high efficiency have attracted more and more attention in the field of ophthalmology in recent years.
  • the prior art phototherapy uses a near-infrared light that penetrates the skin to activate the photodynamic or photothermal effect of the nanomaterial to act on the tumor site to achieve the purpose of killing the tumor cells. According to the mechanism of action that occurs after laser irradiation of materials, it can be divided into photodynamic therapy and photothermal therapy.
  • Photodynamic therapy also known as photochemotherapy, is based on the interaction of light, photosensitizer and oxygen.
  • the photosensitizer acts to absorb photons and is in an excited state, and then transfer the energy to the surrounding oxygen.
  • Singlet oxygen On the one hand, singlet oxygen can cause ischemia by causing vascular obstruction caused by acute microvascular damage in the diseased tissue, and on the other hand, it can directly kill the diseased tissue cells, thereby achieving the purpose of local treatment.
  • Photothermal therapy also known as photophysical therapy, is similar to photodynamic therapy and is a laser medical technique for treating local lesions in humans.
  • Photothermal therapy is based on a photothermal conversion agent. Under the illumination of a specific wavelength of laser light, the photothermal reagent can efficiently convert light energy into heat energy and generate high temperature to kill diseased tissue cells. DNA, RNA and protein synthesis can be inhibited when the temperature of the diseased tissue reaches 43 °C. The safety margin of normal cells is 45 °C.
  • photothermal therapy and photodynamic therapy are ideal treatments, both of which have local lethal effects on the lesion and are non-invasive treatments that rely on lasers.
  • Patent WO2013/027222 reports chlorophyll photosensitizers for the treatment of eye diseases; patent CN103083133 reports a fundus phototherapy system based on gold nanorods; patent WO97/33619 reports a photodynamics through the eye Method for improving vision; Patent WO 98/25648 reports a photosensitizing compound for preparing photodynamic therapy for ocular diseases; WO 98/25610 reports a green porphyrin photosensitizer for treating posterior cataract Drugs; and so on.
  • photodynamic therapy and photothermal therapy are limited by photosensitizers and cannot be widely used.
  • the photosensitizers used in traditional photodynamic therapy and photothermal therapy including photodynamic photosensitizers and photothermal photosensitizers, all need to be made into liquid medicaments, which can enter the bloodstream after intravenous injection or the like, or directly into the diseased tissue, or directly Injection into the diseased tissue, when the treatment is over, the photosensitizer needs to be excreted by degradation or metabolism.
  • Conventional photodynamic therapy and photothermal therapy greatly limit the range and type of photosensitizer selection because of the need to consider the safety and metabolism of photosensitizers.
  • the photosensitizer used eventually enters the human body and has certain toxicity.
  • the photosensitizer is generally not used alone, and needs to cooperate with other drugs or compounds to enter the human body in the form of a solution, a suspension or an emulsion. These compounds interacting with the photosensitizer will also have certain toxicity and increase the therapeutic risk.
  • the photosensitizer needs to be injected into the body from the vein, and the injection speed is required to be fast, the removal speed is also fast, and the organ tissues such as the heart and blood vessels of the patient need to withstand the discomfort caused by the rapid injection of the photosensitizer during the treatment;
  • laser irradiation can be turned on for effective treatment, so high requirements are imposed on the timing and duration of administration, which brings difficulty to the treatment process.
  • the invention provides medical materials for photodynamic therapy and photothermal therapy, which can solve the drawbacks of traditional photodynamic therapy and photothermal therapy.
  • the invention also provides a process for the preparation of the above materials and uses thereof.
  • the invention provides a medical material for phototherapy (including photodynamic therapy and photothermal therapy), in particular, an ophthalmic material for treating an ocular disease, comprising: a base material and at least one photosensitizer, wherein The photosensitizer is dispersed in the matrix material by copolymerization or doping, or adhered to the surface of the base material by surface grafting, modification or coating to form the medical material of the present invention.
  • the present invention is used for treating eye diseases. Ophthalmic material.
  • the material of the invention combines the photosensitizer with the base material, so that the photosensitizer is fixed inside or on the surface of the base material, and the material is implanted into the lesion by surgery, and when the lesion is to be treated, the laser of the selected wavelength is irradiated thereto. When the treatment is over, only the laser needs to be removed. Since the photosensitizer is bound inside or on the surface of the material and cannot enter the other tissues of the human body via blood or other body fluids freely, the toxicity of the photosensitizer itself can be neglected, and the selection range of the photosensitizer is no longer limited.
  • the material provided by the present invention can be pre-implanted into tissues or sites that may be afflicted with other operations (such as ocular surgery), on the one hand, can play a preventive role, on the other hand, when the tissue or part is once In the case of onset, laser treatment is also required without further surgery; more particularly, the material provided by the present invention has a repetitive effect, and when the laser treatment is completed, the photosensitizer is still eliminated in the lesion because it is not eliminated.
  • the site develops a posterior lesion again or more, the laser treatment may be received again or in multiple times without multiple injections of the photosensitizer, and the treatment is reproducible.
  • the present invention relates to medical materials for phototherapy, particularly ophthalmic materials for phototherapy of ocular diseases, including:
  • At least one photosensitizer selected from the group consisting of photodynamic and/or photothermal photosensitizers
  • the combination of the photosensitizer and the matrix material is selected from the group consisting of:
  • the photosensitizer participates in the polymerization during the molding of the matrix material
  • the photosensitizer is added to the matrix material by physical dispersion during the molding of the matrix material;
  • the photosensitizer is surface-grafted, surface-modified to the surface of the formed substrate;
  • the photosensitizer is fixed to the surface of the formed base material by surface coating.
  • the matrix material is a material comprising a polymerizable monomer.
  • the matrix material may be any suitable material, optionally comprising a polymerizable monomer.
  • the matrix material is a formed material, but contains a polymerizable group on the surface of the material.
  • a polymerizable group for example: vinyl, allyl, butene, acryloxy, methacryloxy, acrylamido, methacrylamido, vinyl ether Alkyl, alkynyl, hydroxy, decyl, amino, imino, carboxy, anhydride, aldehyde, isocyanate, siloxane, epoxy, cyclonitro, and the like.
  • the matrix material is a formed material, which may be any material that can be coated with the photosensitizer.
  • the photosensitizer may contain a polymerizable group in the molecular structure, for example, vinyl, allyl, butene, acryloxy, methacryloxy, acrylamide, A Acrylamide group, vinyl ether group, alkynyl group, hydroxyl group, mercapto group, amino group, imino group, carboxyl group, acid anhydride, aldehyde group, isocyanate group, siloxane group, epoxy group, ring nitrogen group, and the like.
  • a polymerizable group in the molecular structure for example, vinyl, allyl, butene, acryloxy, methacryloxy, acrylamide, A Acrylamide group, vinyl ether group, alkynyl group, hydroxyl group, mercapto group, amino group, imino group, carboxyl group, acid anhydride, aldehyde group, isocyanate group, siloxane group, epoxy group, ring nitrogen group, and the like.
  • the photosensitizer is selected from the group consisting of ruthenium monophthalocyanine (monomethine phthalocyanine), ruthenium phthalocyanine (trimethyl phthalocyanine), quinone dicarbocyanine (pentamethine phthalocyanine), ruthenium tricarbonate (seven Amethine cyanine, tri-carbon cyanine dye, benzoquinone phthalocyanine dye, squaraine dye, chlorophyll derivative, pheophytin, pheophorbide a and its derivatives, chlorin e6 And its derivatives, purpurin 18, chlorin p6 and its derivatives, chlorin f and its derivatives, protoporphyrin and its derivatives, hematoporphyrin derivatives (HpD), porphine sodium , cancer photoporphyrin (PSD-007), nano gold, nano tungsten oxide, nano copper sulfide, nano iron oxide,
  • the photosensitizer is preferably selected from the group consisting of nano gold, purple pigment 18, fluorescein O-acrylate, and fluorescein O-methacrylate, and water-soluble or fat modified or modified based on the above photosensitizer. Soluble derivative.
  • the concentration (or mass fraction) of the photosensitizer in the matrix material can be reasonably controlled, and the active oxygen or high temperature heat generated by the laser irradiation at the selected wavelength can effectively kill the cells in the lesion site, and preserve the normal cells from loss; It is also necessary to minimize the effect of the photosensitizer on the performance of the original material.
  • the photosensitizer is contained in an amount of less than 1%, preferably less than 0.5%, more preferably less than 0.1%, based on the total weight of the material.
  • the matrix material is selected from the group consisting of hydrophobic acrylates, acrylate hydrogels, silica gels, silicone hydrogels, fluorosilicon acrylates, polystyrene and polymethyl methacrylate, polycarbonates. , polysiloxane, or a mixture thereof.
  • the invention further relates to a method of preparing a medical material according to the invention comprising the steps of:
  • the invention further relates to another method of preparing the medical material of the invention comprising the steps of:
  • a photosensitizer which is an optional auxiliary agent such as a polymerizable monomer, and then performing polymerization such as graft polymerization or surface modification.
  • the invention further relates to another method of preparing the medical material of the invention comprising the steps of:
  • the mixed raw material is processed and formed, for example, by extrusion molding, injection molding, blow molding, foaming, calendering, or spinning.
  • the invention further relates to a medical device comprising the aforementioned medical material of the invention.
  • the medical device in particular the ophthalmic medical device, is preferably selected from the group consisting of an implant such as an intraocular lens for preventing and/or treating a posterior cataract, a contact lens, a Ortho-K CL, an iris Retractor, endoscope, artificial cornea, intracorneal ring, capsular tension ring, intracorneal lens, glaucoma drainage valve, drug delivery carrier, intraocular filler, external medical device in contact with body tissue, such as skin medical device, Glasses, goggles, medical device lenses, telescopes, sight glasses and fundus fillings.
  • an implant such as an intraocular lens for preventing and/or treating a posterior cataract, a contact lens, a Ortho-K CL, an iris Retractor, endoscope, artificial cornea, intracorneal ring, capsular tension ring, intracorneal lens, glaucoma drainage valve, drug delivery carrier, intraocular filler, external medical device in contact with body tissue, such as skin medical device, Glasses, goggles
  • the invention further relates to the use of the medical material of the invention in the preparation of a medical device, such as an ophthalmic medical device.
  • the present invention also relates to a method of treating a disease associated with a medical device comprising the medical material of the present invention, wherein the related disease is, for example, all diseases which can be treated using phototherapy (including photodynamic therapy and photothermotherapy), for example, a tumor. , eye diseases, skin diseases, cardiovascular diseases, etc.
  • phototherapy including photodynamic therapy and photothermotherapy
  • the matrix material of the present invention is selected from a matrix material comprising a polymerizable monomer or any suitable matrix material that is preferably biocompatible.
  • the polymerizable monomer is selected from a hydrophilic polymerizable monomer or a hydrophobic polymerizable monomer.
  • the matrix material may be a homopolymer of a polymerizable monomer Or a copolymer of a plurality of monomers.
  • the matrix material is a soft material, for example selected from polymeric materials having a glass transition temperature of less than 20 ° C, such as polyacrylates, silica gels, polyurethanes, or hydrogels, or foamed materials.
  • the matrix material is selected from the group consisting of polymerizable matrix materials, preferably comprising a biocompatible polymerizable monomer.
  • the matrix material when the photosensitizer is dispersed in the matrix material to obtain the material of the invention, the matrix material preferably comprises a matrix material which is biocompatible, optionally a polymerizable matrix material.
  • the base material or photosensitizer comprises a polymerizable group such as vinyl, allyl, butene, Acryloxy, methacryloxy, acrylamide, methacrylamide, vinyl ether, alkynyl, hydroxy, decyl, amino, imino, carboxyl, anhydride, aldehyde, isocyanate, silicon
  • a polymerizable group such as vinyl, allyl, butene, Acryloxy, methacryloxy, acrylamide, methacrylamide, vinyl ether, alkynyl, hydroxy, decyl, amino, imino, carboxyl, anhydride, aldehyde, isocyanate, silicon
  • the matrix material is preferably a biocompatible matrix material.
  • the matrix material is selected from any suitable matrix material that is biocompatible.
  • the matrix material may be, but is not limited to, silicone hydrogel, fluorosilicon acrylate, silicone, polystyrene, methyl methacrylate, siloxane, methyl siloxane. , phenylsiloxane, vinyl siloxane, acrylate siloxane, methacrylate siloxane, or a mixture of the foregoing.
  • the matrix material of the present invention may also be a polymer selected from the group consisting of polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, polyacrylic acid, polymethacrylic acid, Polyhydroxy acrylate, polyhydroxy methacrylate, polystyrene, polyethylene, polypropylene, polyvinyl ether, polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone, polysiloxane Alkane, polyurethane, polyetheretherketone, polycarbonate, polyamide (nylon), polyethylene terephthalate, polybutylene terephthalate, polyoxymethylene, polyvinyl chloride, ABS, polysulfone And polytetrafluoroethylene, polysaccharide, collagen, natural polymer or the like, or a derivative of the above polymer, or a copolymer of the above polymer, or a mixture thereof.
  • a polymer selected from
  • the matrix material may also be a hydrogel, including but Not limited to: collagen, gelatin, keratin, elastin, vegetable protein, reticular hard protein and quaternized protein, or poly-polysaccharide, heparin, chondroitin sulfate, hyaluronic acid, gum arabic, agar, horn Alanine, pectin, guar and alginate, or modified starch, modified cellulose, carboxymethyl starch, starch acetate, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyl Ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, etc., or polyvinyl acetate, polymethyl vinyl ether, polyvinyl alcohol, polyethylene glycol, polyoxyethylene, polyacrylamide (PAM) Hydrolyzed polyacrylamide (HPAM), polyvinylpyrrolidone (PVP), polyethyleneimine (PEI), or a blend of
  • the polymerizable monomer contained in the matrix material is selected from the group consisting of methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, butyl acrylate, trifluoroethyl methacrylate, and trifluoroacrylate.
  • Ethyl ester hydroxyethyl methacrylate, hydroxyethyl acrylate, vinyl pyrrolidone, phenyl ethyl methacrylate, phenyl ethyl acrylate, phenoxyethyl methacrylate, phenoxyethyl acrylate, A Benzyl acrylate, benzyl acrylate, ethoxyethoxyethyl methacrylate, ethoxyethoxyethyl acrylate, ethoxyethyl methacrylate, ethoxyethyl acrylate, two Ethylene glycol methacrylate, butylene glycol dimethacrylate, hexanediol dimethacrylate, styrene, methyl styrene, divinyl benzene, hydroxymethyl cellulose, sodium hyaluronate, Collagen, and silanes and siloxanes, for example, include:
  • the polymerizable monomer contained in the matrix material is selected from the group consisting of silicone, methylsiloxane, phenylsiloxane, vinylsiloxane, acrylate silicone, and A acrylate based siloxane, or a mixture of the foregoing.
  • the photosensitizer of the present invention is selected from a photodynamic type photosensitizer or a photothermal type photosensitizer.
  • the photosensitizer of the present invention is any photosensitizer having an activated laser source having a wavelength in the range of from 300 to 1100 nanometers.
  • the wavelength range of the laser light source is selected from 500 to 1000 nm; preferably, the wavelength range of the laser light source is selected from 600 to 900 nm; preferably, the wavelength range of the laser light source is selected from 700 to 900 nm or the wavelength range of the laser light source is selected from 800. ⁇ 1100 nm.
  • the material containing the photodynamic type photosensitizer is irradiated with laser light of a selected wavelength (for example, 300 to 1100 nm), and the photosensitizer in the material is excited to generate cytotoxic active oxygen. It can kill the cells in the lesion and achieve the therapeutic effect.
  • a selected wavelength for example, 300 to 1100 nm
  • the material containing the photothermal type photosensitizer is irradiated with laser light of a selected wavelength (for example, 300 to 1100 nm), the photosensitizer in the material is excited, and the light energy is converted into heat.
  • the ambient temperature is raised to kill the diseased tissue cells. DNA, RNA and protein synthesis can be inhibited when the temperature of the diseased tissue reaches 43 ° C.
  • the safety limit of normal cells is 45 ° C. Therefore, in a preferred embodiment, the material containing the photothermal photosensitizer can generate heat under laser irradiation.
  • the elevated temperature is greater than 38 ° C, greater than 39 ° C, preferably greater than 40 ° C, preferably greater than 41 ° C, preferably greater than 42 ° C, preferably greater than 43 ° C, preferably greater than 44 ° C, preferably greater than 45 ° C, preferably greater than 46 ° C, preferably greater than 47 ° C, preferably greater than 50 ° C, but less than 55 ° C, preferably greater than 56 ° C, preferably greater than 57 ° C, preferably greater than 58 ° C, preferably greater than 59 ° C, preferably greater than 60 ° C, preferably greater than 61 ° C, preferably greater than 62 ° C, preferably greater than 63 ° C, preferably greater than 64 ° C, preferably greater than 65 ° C, and preferably less than 66 ° C, preferably less than 65 ° C, preferably less than 64 ° C, preferably less than 63 ° C, preferably less than 62 ° C,
  • the photosensitizer suitable for use in the present invention is selected from the group consisting of porphyrin, metal porphyrin, porphin, chlorophyll, ruthenium, fluorescein, phthalocyanine, metal phthalocyanine, phthalocyanine green, tricarbon cyanine, nano gold particles, metal nanoparticles a metal oxide nanoparticle, a metal sulfide nanoparticle, a metal carbide nanoparticle, a carbon nanotube, a graphene or the like, and a derivative product of the above compound, or a degradation product of the above compound, or a salt form of the above compound.
  • the photosensitizer is selected from the group consisting of ruthenium monophthalocyanine (monomethine phthalocyanine), ruthenium phthalocyanine (trimethyl phthalocyanine), quinone dicarbocyanine (pentamethine phthalocyanine), ruthenium tricarbonate (heptamethine) , a three-carbon cyanine dye, a benzofluorene hemi-cyanine dye, an anthocyanine dye, a phthalocyanine, a chlorophyll derivative, a pheophytin, a pheophorbide a and a derivative thereof, a chlorin e6 and Its derivatives, purpurin 18, chlorin p6 and its derivatives, chlorin e4 and its derivatives, chlorin f and its derivatives, protoporphyrin and its derivatives, benzoate green Porphyrin, metalloporphyrin, hematoporphyrin
  • the photosensitizer may be a photosensitizer having a wavelength range of 400 to 600 nm of an activated laser light source, such as fluorescein; and the photosensitizer may be a wavelength range of the activated laser source of 600 to 750 nm.
  • the photosensitizer contains a polymerizable group such as a vinyl group, an allyl group, a butene, an acryloyloxy group, a methacryloxy group, an acrylamide group, a methacrylamide group.
  • a polymerizable group such as a vinyl group, an allyl group, a butene, an acryloyloxy group, a methacryloxy group, an acrylamide group, a methacrylamide group.
  • vinyl ether group, alkynyl group, etc. can be copolymerized with the matrix material monomer, the photosensitizer molecule exists in the molecular chain of the matrix material in the form of a covalent bond, the photosensitizer is fixed in the matrix material, and cannot enter the blood freely. Or other body fluids, so the toxicity of the photosensitizer itself can be completely ignored.
  • the photosensitizer has a reactive group in the molecular structure, for example, a hydroxyl group, a thiol group, an amino group, an imino group, a carboxyl group, an acid anhydride, an aldehyde group, an isocyanate group, a siloxane group, an epoxy group, and a ring.
  • the nitrogen group, etc. may be grafted with a group on the side chain of the molecular material molecule, the photosensitizer molecule is bound to the molecular chain of the matrix material in a covalent bond, and the photosensitizer is immobilized inside or on the surface of the matrix material. Also, you are not free to enter blood or other body fluids.
  • the photosensitizer is dispersed or doped in a matrix material, and the photosensitizer molecule is bonded to the molecular chain of the matrix material by hydrogen bonding or van der Waals force, and the photosensitizer molecule is bound to In the matrix material, it is not free to enter blood or other body fluids.
  • the photosensitizer is dispersed in other auxiliaries by means of dissolution, suspension, emulsification, etc. (for example: cosolvents, emulsifiers, lubricants, hydrophilic coatings, drug loading, color masterbatch, ultraviolet absorption) Agent, cross-linking agent, coupling agent, pH adjuster, antistatic agent, mold release agent, etc.), and coated on the surface of the base material, the photosensitizer molecule and the matrix material molecular chain act by hydrogen bonding or van der Waals force When combined, the photosensitizer is bound to the surface of the substrate material and is not free to enter blood or other body fluids.
  • Agent cross-linking agent
  • coupling agent pH adjuster
  • antistatic agent antistatic agent
  • mold release agent etc.
  • the photosensitizer molecule in order to enhance the affinity between the photosensitizer molecule and the matrix material molecule, can be chemically modified without changing the photoactivity; the matrix material can also be activated, including It is not limited to plasma treatment, corona treatment, flame treatment, strong acid treatment, strong alkali treatment, and the like.
  • the material of the invention when the photosensitizer is polymerized with the matrix material to obtain the material of the invention, or when the photosensitizer is doped in the matrix material to obtain the material of the invention, the material of the invention may be prepared by a process comprising the following steps:
  • the materials of the invention can be prepared by a process comprising the following steps:
  • the materials of the invention can be prepared by a process comprising the following steps:
  • the mixed raw material is processed and formed, for example, by extrusion molding, injection molding, blow molding, foaming, calendering, or spinning.
  • the material of the present invention when the photosensitizer is immobilized on the surface of the base material by surface grafting or surface modification, the material of the present invention can be prepared by a method comprising the following steps:
  • the photosensitizer is added and dissolved, for example, the photosensitizer is dissolved with a suitable auxiliary agent such as a polymerizable monomer, and then subjected to polymerization such as graft polymerization or surface modification or transfer printing.
  • a suitable auxiliary agent such as a polymerizable monomer
  • the materials of the invention can be prepared by a process comprising the following steps:
  • a photosensitizer to dissolve it.
  • the photosensitizer is dissolved with a suitable adjuvant such as a polymerizable monomer;
  • the material of the invention when the photosensitizer is fixed to the surface of the substrate by surface coating, the material of the invention may be prepared by a process comprising the following steps:
  • a photosensitizer for example, a photosensitizer, is dissolved on a surface of a base material by dissolving it with a suitable auxiliary agent such as a polymerizable monomer.
  • the amount of the crosslinking agent may be 0.1-20% by weight of the polymerizable monomer, Choose 0.5-15%, especially 1-5%.
  • the ultraviolet absorber is used in an amount of from 0 to 10% by weight, preferably from 0 to 5%, particularly from 0 to 1%, of the polymerizable monomer.
  • the initiator is used in an amount of from 0.01 to 10% by weight, preferably from 0.01 to 5%, particularly from 0.05% to 1.0%, of the polymerizable monomer.
  • the materials of the present invention may comprise other optional components including, but not limited to, co-solvents, pigments, fillers, dispersants, curing agents, wetting agents, antifoaming agents, UV absorbers, anti-wear agents.
  • the material of the present invention can be applied to a desired substrate by conventional coating techniques such as conventional or airless spray coating, roll coating, brush coating, curtain coating, shower coating, and dip coating.
  • the materials of the present invention can be applied to the desired substrate by conventional printing techniques such as conventional letterpress, gravure, lithographic, screen printing, thermal transfer printing, xerographic, ink jet printing or 3D printing.
  • the material of the invention When the material of the invention is applied to a substrate, it can optionally be cured at room temperature or elevated temperature.
  • the invention further relates to a method of treating a disease with laser-driven phototherapy, wherein the method can be carried out using only the medical device prepared by the present invention.
  • the medical device obtained by preparing the material of the present invention is placed on a site to be treated, and the medical device obtained by the preparation of the material of the present invention having the photosensitizer can be used only for the treatment required for contact.
  • the medical device prepared by the invention has a photosensitizer, on the one hand: based on the interaction of light, photosensitizer and oxygen, the photosensitizer acts to absorb photons In the excited state, and then transfer the energy to the surrounding oxygen, generating a strong singlet oxygen; singlet oxygen can cause ischemia by vascular obstruction caused by acute microvascular damage in the diseased tissue, on the other hand Directly kill the diseased tissue cells to achieve the purpose of local treatment.
  • the medical device prepared by the invention has a photosensitizer, based on the photothermal conversion agent, the photothermal reagent can efficiently convert the light energy into heat energy and generate high temperature to kill at a specific wavelength of laser irradiation. Lesion tissue cells. DNA, RNA and protein synthesis can be inhibited when the temperature of the diseased tissue reaches 43 °C.
  • the material of the present invention and the medical device prepared by the invention completely get rid of the exogenous photosensitizer (without pre-administration of photosensitizer, etc.), the method of the invention does not need to add any additional reagents (including photosensitizers), and It has the advantages of non-invasiveness, non-toxicity and high efficiency.
  • the base material can be processed into an ophthalmic medical device with safety, biological phase Capacitive, functional, and matched mechanical properties, and can be sterilized.
  • the distribution of photosensitizers on the inside and on the surface of ophthalmic medical devices including but not limited to: overall uniform distribution, local distribution, band distribution, gradient distribution, scatter distribution, etc.
  • the photosensitizer in the ophthalmic medical device material can receive the laser of the selected wavelength again or more times, and each time the photosensitizer can be activated to generate active oxygen or high temperature heat, so that the medical device can be repeatedly performed.
  • the efficacy of laser treatment can be performed.
  • Example 1a Synthesis of methyl methacrylate-photosensitive agent copolymer
  • MMA methyl methacrylate monomer
  • ELDMA ethylene glycol dimethacrylate
  • AIBN initiator
  • Photosensitizer purple 18
  • the mold was sealed, and then placed in a 65 ° C water bath for polymerization for 24 hours, and then transferred to a 90 ° C oven for 24 hours to obtain a photoreceptor containing A polymethyl methacrylate material.
  • the molecular structural formula of the purpurin 18 is shown below.
  • the 18-molecular structure of the purple pigment contains a vinyl unsaturated double bond, it can be copolymerized with MMA and EGDMA to fix the photoactive porphyrin (tetrapyrrole ring structure) group in the PMMA molecular chain, and also because of EGDMA.
  • the presence of PMMA molecular chains can be cross-linked to form PMMA macromolecules of network structure.
  • the crosslinked polymer having a network structure can only be swollen in a solvent and cannot be dissolved, so that the photosensitizer (purple 18) molecule will be firmly fixed in the PMMA material and cannot enter the blood or other body fluid freely.
  • EGDMA ethylene glycol dimethacrylate
  • HDDMA hexanediol dimethacrylate
  • PEA phenylethyl acrylate
  • EOEOEMA ethoxyethoxyethyl methacrylate
  • TMSPMA Methacryloxypropyltris(trimethylsiloxy)silane
  • TTMSBPMA 1,3-bis(methacryloxypropyl)tetrakis(trimethylsiloxy)disiloxane
  • the molecular structure of the 18-molecular structure contains a vinyl unsaturated double bond, it can be copolymerized with a hydrogen-containing silicone oil and a vinyl silicone oil to fix a photoactive porphyrin (tetrapyrrole ring structure) group in the molecular chain of the silica gel. Therefore, the photosensitizer (purple 18) molecule will be firmly fixed in the silica gel material and will not be free to enter blood or other body fluids.
  • reaction conditions are basically the same as in Example 2a, and the differences are as follows:
  • Example 3a Synthesis of a polypropylene-photosensitive agent blend material
  • reaction conditions are basically the same as in Example 3a, and the differences are as follows:
  • HDPE high density polyethylene
  • TPU thermoplastic polyurethane
  • PA polyamide (nylon)
  • PET polyethylene terephthalate
  • PVC polyvinyl chloride
  • ABS acrylonitrile-butadiene-styrene copolymer
  • the structure of the photosensitizer molecule listed in the examples is as follows:

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Abstract

一种用于眼部疾病光治疗的材料，包括基体材料和光敏剂，其中，光敏剂以共聚或掺杂等方式分散在基体材料内部，或以表面接枝，或表面修饰，或表面涂覆等方式附着在基体材料表面。该材料在选定波长的激光照射下，可以杀死病变部位细胞，达到用于眼科疾病光治疗的功效。同时提供了该材料的制造方法及其在制备眼科医疗器材中的用途。

Description

用于眼部疾病光治疗的材料 技术领域
本发明涉及一种用于光疗法的医用材料，尤其是针对眼部疾病进行光疗法的眼科材料及其制备方法。
背景技术
各种眼部疾病，如眼睑病、泪器病、结膜病、角膜病、巩膜病、葡萄膜疾病、白内障、后发性白内障、青光眼、玻璃体病变、晶状体病变、虹膜病、视网膜疾病、黄斑变性、视路疾病、眼眶疾病、眼外伤、眼的屈光、眼部肌病、眼部肿瘤等，特别是一些眼内的疾病，可以导致患者视物不清甚至失明，给患者造成巨大的生活不便及痛苦。由于人眼独特的生理结构，很多疾病只能通过手术进行治疗，而人眼结构又非常复杂，且眼内组织非常精细微小，手术操作难度非常大，有时还需要进行二次手术，这也给患者带来极大不便和经济压力。
以激光驱动的光疗法在肿瘤治疗方面取得了显著的成绩，以其非侵袭性、无毒性、高效性等优势，近年来在眼科领域也越来越受到关注。现有技术的光疗法以穿透皮肤的近红外光激活纳米材料的光动力效应或光热效应来对肿瘤部位进行作用，达到杀死肿瘤细胞的目的。根据激光照射材料后发生的作用机理不同又可以分为光动力疗法和光热疗法。
光动力疗法,又可称为光化学疗法，以光、光敏剂和氧的相互作用为基础，光敏剂的作用是吸收光子而处于激发态，然后再将能量传递给周围的氧，生成活性很强的单线态氧。单线态氧一方面可以通过造成病变组织中微血管急性损伤引起血管阻塞引起局部缺血，另一方面可以直接杀死病变组织细胞，从而达到局部治疗的目的。
光热疗法，又可称为光物理疗法，同光动力疗法相似，也是治疗人体局部病变的一种激光医学技术。光热疗法以光热转换剂为基础，在特定波长的激光照射下，光热试剂能够高效地将光能转换成热能，产生高温以杀死病变组织细胞。当病变组织区域温度达到43℃时可以抑制DNA、RNA和蛋白质合成。正常细胞的安全界限为45℃。
光热疗法和光动力疗法都是理想的治疗方法，二者都具有对病变部位的局部杀伤力，并且都是依靠激光来进行的非侵入式治疗手段。
近年来，光动力疗法或光热疗法在眼科领域的研究也受到关注。专利WO2013/027222报道了用于治疗眼睛疾病的叶绿素光敏剂；专利CN103083133报道了一种基于金纳米棒的眼底病激光光热治疗系统；专利WO97/33619报道了一种通过对眼的光动力学治疗改善视力的方法；专利WO98/25648报道了一种用于制备眼部疾病光动力治疗药物的光敏性化合物；WO98/25610报道了一种用于治疗后发性白内障的绿卟啉类光敏剂药物；等等。
但是，传统的光动力疗法和光热疗法都受到光敏剂的限制而无法被广泛使用。传统的光动力疗法和光热疗法所使用的光敏剂，包括光动力型光敏剂和光热型光敏剂，最终都需要制成液体药剂，通过静脉注射等方式进入血液后进入病变组织，或直接注射进入病变组织，当治疗结束后，光敏剂需要通过降解或代谢等方式排出体外。传统的光动力疗法和光热疗法由于需要考虑光敏剂的安全性及代谢等问题，因此大大限制了光敏剂选择的范围和种类。虽然光动力疗法的毒副作用很小，但是所使用的光敏剂最终进入人体，具有一定的毒性。并且光敏剂一般无法单独使用，需要与其他药物或化合物共同作用，以溶液、悬混液或乳液的形式进入人体内，这些与光敏剂相互作用的化合物也将具有一定的毒性，增大治疗风险。另外，由于光敏剂需要从静脉注入体内，并且要求注射速度很快，清除速度也很快，病人的心脏和血管等器官组织在治疗过程中需要承受光敏剂快速注射所带来的不适；并且只有当光敏剂通过病变组织时，才能够开启激光照射进行有效的治疗，因此对给药时机和维持时间都提出较高的要求，为治疗过程带来难度。
发明内容
本发明提供了用于光动力治疗和光热治疗方法的医用材料，可以解决传统光动力疗法和光热疗法存在的弊端。本发明还提供上述材料的制备方法及其用途。
本发明提供的用于光疗法(包括光动力治疗和光热治疗方法)的医用材料，尤其地，用于治疗眼部疾病的眼科材料，包括：基体材料和至少一种光敏剂，其中通过将光敏剂以共聚或掺杂等方式分散在基体材料内部，或以表面接枝、修饰或涂覆等方式附着在基体材料表面，形成本发明医用材料，尤其地，本发明用于治疗眼部疾病的眼科材料。
本发明材料将光敏剂与基体材料结合，使得光敏剂固定在基体材料内部或表面，通过手术将所述材料植入病变部位，当需要对病变部位进行治疗时，对其照射选定波长的激光；当治疗结束后，仅需要移去激光。由于光敏剂被束缚在材料内部或表面，不能自由经由血液或其他体液进入人体其他组织中，因此光敏剂本身的毒性可以被忽略，而光敏剂的选择范围也不再受到局限。特别地，本发明提供的材料可以伴随其他手术(如眼部手术)被预先地植入到可能发病的组织或部位中，一方面可以起到预防的作用，另一方面当该组织或部位一旦发病，也无需再次进行手术即可接受激光治疗；更为特别地，本发明提供的材料具有重复作用的效果，当一次激光治疗完成后，由于光敏剂并不被消除而依然存在于病变部位，当该部位再次或多次发生后发性病变时，无需多次注射光敏剂即可再次或多次接受激光治疗，具有治疗的可重复性。
具体地，本发明涉及用于光治疗法的医用材料，尤其是用于光治疗眼部疾病的眼科材料，其包括：
·基体材料；
·至少一种光敏剂，选自光动力型和/或光热型光敏剂；
其中，光敏剂与基体材料的结合方式选自：
-光敏剂在基体材料成型过程中参与聚合；
-光敏剂在基体材料成型过程中通过物理分散添加到基体材料内；
-光敏剂以表面接枝、表面修饰方式固定在已成型的基体材料表面；和/或
-光敏剂以表面涂覆方式固定在已成型的基体材料表面。
当(1)光敏剂与基体材料的结合方式是光敏剂在基体材料成型过程中参与聚合时，基体材料是包含可聚合单体的材料。
当(2)光敏剂与基体材料的结合方式是光敏剂在基体材料成型过程中通过物理分散添加到基体材料内时，基体材料可以是任何合适的材料,任选包含可聚合单体。
当(3)光敏剂与基体材料的结合方式是光敏剂以表面接枝、表面修饰方式固定在已成型的基体材料表面时，基体材料是已成型的材料，但是在材料表面包含可聚合基团，例如：乙烯基、烯丙基、丁烯、丙烯酰氧基、甲基丙烯酰氧基、丙烯酰胺基、甲基丙烯酰胺基、乙烯醚 基、炔基、羟基、巯基、氨基、亚氨基、羧基、酸酐、醛基、异氰酸酯基、硅氧烷基、环氧基、环氮基，等。
当(4)光敏剂与基体材料的结合方式是光敏剂以表面涂覆方式固定在已成型的基体材料表面时，基体材料是已成型的材料，其可以是任何可被光敏剂涂覆的材料。
在本发明另一个实施方式中，光敏剂分子结构中可含有可聚合基团，例如：乙烯基、烯丙基、丁烯、丙烯酰氧基、甲基丙烯酰氧基、丙烯酰胺基、甲基丙烯酰胺基、乙烯醚基、炔基、羟基、巯基、氨基、亚氨基、羧基、酸酐、醛基、异氰酸酯基、硅氧烷基、环氧基、环氮基，等。
在本发明一个实施方式中，光敏剂选自吲哚单菁(一甲川菁)，吲哚碳菁(三甲川菁)，吲哚二碳菁(五甲川菁)，吲哚三碳菁(七甲川菁)，三碳花菁染料、、苯并吲哚半菁染料、吲哚方酸菁染料、叶绿素衍生物、脱镁叶绿素、脱镁叶绿酸a及其衍生物，二氢卟吩e6及其衍生物，紫红素18，二氢卟吩p6及其衍生物，二氢卟吩f及其衍生物，原卟啉及其衍生物，血卟啉衍生物(HpD)、卟吩姆钠、癌光啉(PSD-007)，纳米金、纳米钨氧化物、纳米铜硫化物、纳米铁氧化物、纳米镍碳化物、纳米钼氧化物、以及其它基于以上光敏剂修饰或改性的水溶性或脂溶性的衍生物。
在本发明另一个实施方式中，光敏剂优选选自纳米金、紫红素18、荧光素O-丙烯酸酯和荧光素O-甲基丙烯酸酯以及基于以上光敏剂修饰或改性的水溶性或脂溶性的衍生物。
光敏剂在基体材料中的浓度(或质量分数)可以被合理控制，在选定波长激光照射下产生的活性氧或高温热能够有效杀死病变部位细胞，而保全正常细胞不受损失；同时，还需兼顾最低程度降低光敏剂对原有材料使用性能的影响。例如，基于材料总重量，所含光敏剂含量为小于1％，优选小于0.5％，更优选小于0.1％。
在本发明另一个实施方式中，基体材料选自疏水型丙烯酸酯、丙烯酸酯水凝胶、硅胶、硅水凝胶、氟硅丙烯酸酯、聚苯乙烯和聚甲基丙烯酸甲酯、聚碳酸酯、聚硅氧烷，或其混合物。
本发明还涉及制备本发明所述医用材料的方法，包括下述步骤：
1)将可聚合单体与任选添加剂如交联剂、热引发剂和/或紫外吸收 剂混合；
2)加入光敏剂，并使其溶解，然后聚合。
本发明还涉及制备本发明所述医用材料的另一方法，包括下述步骤：
1)将可聚合单体与任选添加剂如交联剂、热引发剂、紫外吸收剂等混合，然后聚合，得到基体材料；
2)加入任选用助剂如可聚合单体溶解的光敏剂，然后进行聚合如接枝聚合或表面修饰。
本发明还涉及制备本发明所述医用材料的另一方法，包括下述步骤：
1)将基体材料和光敏剂，以及任选添加剂如色母粒、稳定剂等，进行混合；
2)将混合后的原料加工成型，例如通过选自挤出、注塑、吹塑、发泡、压延、或纺丝等的方式加工成型。
本发明还涉及医疗设备，其包括前述本发明医用材料。
在本发明另一个实施方式中，医疗设备尤其是眼科医疗设备，优选选自：植入物如用于预防和/或治疗后发性白内障的人工晶状体、角膜接触镜、角膜塑形镜、虹膜拉钩、眼内镜、人工角膜、角膜内环、囊袋张力环、角膜内透镜、青光眼引流阀、药物缓释载体、眼内填充物、与身体组织接触的外用医疗装置，如皮肤医疗装置，眼镜、护目镜、医疗设备透镜、望远镜、观测镜和眼底填充物。
本发明还涉及本发明医用材料在制备医疗设备如眼科医疗设备中的用途。
本发明还涉及使用包含本发明医用材料的医疗设备进行治疗相关疾病的方法，其中所述相关疾病例如是可以使用光疗法(包括光动力治疗和光热治疗方法)治疗的所有疾病，例如：肿瘤、眼科疾病、皮肤病、心血管疾病等。
发明详述
本发明基体材料选自包含可聚合单体的基体材料或优选生物相容性好的任何合适的基体材料。其中，可聚合单体选自亲水型可聚合单体或疏水性可聚合单体。
在本发明一个实施方式中，基体材料可以是可聚合单体的均聚物 或多种单体的共聚物。
在本发明一个实施方式中，基体材料为软性的材料，例如选自玻璃化转变温度小于20℃的聚合物材料，如聚丙烯酸酯、硅胶、聚氨酯，或水凝胶，或发泡材料。
在本发明一个实施方式中，光敏剂与基体材料聚合获得本发明材料时，基体材料选自可聚合基体材料，优选包含生物相容性好的可聚合单体。
在本发明另一个实施方式中，当光敏剂分散在基体材料中获得本发明材料时，基体材料优选包含生物相容性好的基体材料，任选是可聚合的基体材料。
在本发明另一个实施方式中，当光敏剂以表面接枝、表面修饰方式固定在基体材料表面时，基体材料或光敏剂包含可聚合基团，例如：乙烯基、烯丙基、丁烯、丙烯酰氧基、甲基丙烯酰氧基、丙烯酰胺基、甲基丙烯酰胺基、乙烯醚基、炔基、羟基、巯基、氨基、亚氨基、羧基、酸酐、醛基、异氰酸酯基、硅氧烷基、环氧基、环氮基，等，其中基体材料优选是生物相容性好的基体材料。
在本发明另一个实施方式中，当光敏剂以表面涂覆方式固定在基体材料表面时，基体材料选自生物相容性好的任何合适的基体材料。
在本发明另一个实施方式中，基体材料可以是，但不仅限于：硅水凝胶、氟硅丙烯酸酯、硅酮、聚苯乙烯、甲基丙烯酸甲酯、硅氧烷、甲基硅氧烷、苯基硅氧烷、乙烯基硅氧烷、丙烯酸酯基硅氧烷、甲基丙烯酸酯基硅氧烷，或上述的混合物。
在本发明另一个实施方式中，本发明基体材料还可以是聚合物，其选自聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸羟基酯、聚甲基丙烯酸羟基酯、聚苯乙烯、聚乙烯、聚丙烯、聚乙烯醚、聚乙烯醇、聚醋酸乙烯酯、聚乙二醇、聚丙二醇、聚乙烯吡咯烷酮、聚硅氧烷、聚氨酯、聚醚醚酮、聚碳酸酯、聚酰胺(尼龙)、聚对苯二甲酸乙二醇酯、聚对苯二甲酸丁二醇酯、聚甲醛、聚氯乙烯、ABS、聚砜、聚四氟乙烯、多糖、胶原、天然高分子等，或上述聚合物的衍生物，或上述聚合物的共聚物，或上述的混合物。
在本发明另一个实施方式中，基体材料还可以是水凝胶，包括但 不局限于：胶原蛋白、明胶、角蛋白、弹性蛋白、植物蛋白、网状硬蛋白和季铵化蛋白等，或聚多糖、肝素、硫酸软骨素、透明质酸、阿拉伯胶、琼脂、角叉菜胺、果胶、瓜尔胶和海藻酸盐等，或改性淀粉、改性纤维素、羧甲基淀粉、醋酸淀粉、甲基纤维素、乙基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素等，或聚醋酸乙烯酯、聚甲基乙烯基醚、聚乙烯醇、聚乙二醇、聚氧乙烯、聚丙烯酰胺(PAM)、水解聚丙烯酰胺(HPAM))、聚乙烯吡咯烷酮(PVP)、聚乙烯亚胺(PEI)，或上述的共混物。
优选，基体材料中包含的可聚合单体选自甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸丁酯、甲基丙烯酸三氟乙酯、丙烯酸三氟乙酯、甲基丙烯酸羟基乙酯、丙烯酸羟基乙酯、乙烯基吡咯烷酮、甲基丙烯酸苯基乙酯、丙烯酸苯基乙酯、甲基丙烯酸苯氧基乙酯、丙烯酸苯氧基乙酯、甲基丙烯酸苄基酯、丙烯酸苄基酯、甲基丙烯酸乙氧基乙氧基乙酯、丙烯酸乙氧基乙氧基乙酯、甲基丙烯酸乙氧基乙酯、丙烯酸乙氧基乙酯、二甲基丙烯酸乙二醇酯、二甲基丙烯酸丁二醇酯、二甲基丙烯酸己二醇酯、苯乙烯、甲基苯乙烯、二乙烯基苯、羟甲基纤维素、透明质酸钠、胶原，以及硅烷及硅氧烷，例如包括：甲基三氯硅烷、二甲基二氯硅烷、甲基三乙氧基硅烷、甲基三甲氧基硅烷、苯基三甲氧基硅烷、(3,3,3-三氟丙基)甲基二甲氧基硅烷、乙烯基三乙氧基硅烷或乙烯基三甲氧基硅烷、甲基丙烯酰氧丙基三(三甲基硅氧烷基)硅烷、3-(甲基丙烯酰氧)丙基三甲氧基硅烷、二甲基硅氧烷和二苯基硅氧烷的嵌段共聚物，二乙烯封端的、乙烯基硅油、3-(异丁烯酰氧)丙基三甲氧基硅烷、烯丙基三乙氧基硅烷、烯丙基三(三甲硅氧基)硅烷、3-丙烯酰氧基丙基三甲氧基硅烷、六甲基环三硅氧烷、八甲基环四硅氧烷、混合环硅氧烷、三氟丙基甲基环三硅氧烷或四氟丁基甲基环四硅氧烷，或上述物质的混合物。
能用于本发明的其它可聚合单体包括：丁二烯、苯乙烯、α-甲基苯乙烯、苯乙烯磺酸钠、乙烯基甲苯、丙烯腈、甲基丙烯腈、α-氯代丙烯腈、乙基丙烯腈、甲基乙烯基醚、异丙基乙烯基醚、正丁基乙烯基醚、异丁基乙烯基醚、叔丁基乙烯基醚、2-乙基己基乙烯基醚、4-羟丁基乙烯基醚、1，4-丁二醇二乙烯基醚、二甘醇二乙烯基醚、乙烯基酯如，乙酸乙烯基酯、烷羟羧酸乙烯基酯、丙酸乙烯酯、丁酸乙烯 酯、异丁酸乙烯基酯、己酸乙烯基酯、2-乙基己糖酸乙烯酯以及癸酸乙烯基酯；烯丙基氯、甲基烯丙基氯、二氯乙烯、氯乙烯、氟乙烯、二氟乙烯、乙烯基磺酸钠、丁基乙烯基磺酸盐、苯基乙烯基砜、甲基乙烯基砜、N-乙烯基吡咯烷二酮、N-乙烯基噁唑烷二酮、丙烯醛、丙烯酰胺、甲基丙烯酰胺、N，N-二甲基(甲基)丙烯酰胺、羟甲基丙烯酰胺，N-丁氧基(甲基)丙烯酰胺、异丁氧基(甲基)丙烯酰胺等、等；其它的烯属不饱和羧酸及其酯如，二元与三元羧酸(如衣康酸等)的二烷基酯和三烷基酯，包括马来酸二(2-乙基己基)酯、马来酸二丁基酯、富马酸二甲酯、衣康酸二甲酯、柠康酸二乙基酯、乌头酸三甲基酯、中康酸二乙基酯、衣康酸二(2-乙基己基)酯、衣康酸二(2-氯乙基)酯、马来酸、马来酸酐、富马酸、衣康酸；以及烯烃如，二异丁烯、1-辛烯、1-癸烯、1-十六烯，或上述的混合物。
在本发明另一个实施方式中，基体材料中包含的可聚合单体选自硅氧烷、甲基硅氧烷、苯基硅氧烷、乙烯基硅氧烷、丙烯酸酯基硅氧烷、甲基丙烯酸酯基硅氧烷，或上述的混合物。
本发明光敏剂选自光动力型光敏剂或光热型光敏剂。在本发明另一个实施方式中，本发明光敏剂是被活化的激光光源的波长范围为300～1100纳米的任何光敏剂。优选，激光光源的波长范围选自500～1000纳米；优选，激光光源的波长范围选自600～900纳米；优选，激光光源的波长范围选自700～900纳米或激光光源的波长范围选自800～1100纳米。
在本发明一个实施方式中，本发明含有光动力型光敏剂的材料在选定波长(例如300～1100纳米)的激光照射下，材料中的光敏剂被激发，生成具有细胞毒性的活性氧，可以杀死病变部位细胞，达到治疗的效果。
在本发明另一个实施方式中，本发明含有光热型光敏剂的材料在选定波长(例如300～1100纳米)的激光照射下，材料中的光敏剂被激发，光能被转换成热，使周围环境温度升高以杀死病变组织细胞。当病变组织区域温度达到43℃时可以抑制DNA、RNA和蛋白质合成，正常细胞的安全界限为45℃，因此在优选的方案中，含有光热型光敏剂的材料在激光照射下能够发热，使温度升高4～20℃；在更优选的方案中，含有光热型光敏剂的材料在激光照射下能够发热，使环境温度 升高6～12℃；在更优选的方案中，含有光热型光敏剂的材料在激光照射下能够发热，使环境温度升高8～10℃。例如升高温度大于38℃，大于39℃，优选大于40℃，优选大于41℃，优选大于42℃，优选大于43℃，优选大于44℃，优选大于45℃，优选大于46℃，优选大于47℃，优选大于50℃，而小于55℃，优选大于56℃，优选大于57℃，优选大于58℃，优选大于59℃，优选大于60℃，优选大于61℃，优选大于62℃，优选大于63℃，优选大于64℃，优选大于65℃，而优选小于66℃，优选小于65℃，优选小于64℃，优选小于63℃，优选小于62℃，优选小于61℃，优选小于60℃，优选小于59℃，优选小于58℃，优选小于57℃，优选小于56℃，优选小于55℃，优选小于54℃，优选小于53℃，优选小于52℃，优选小于51℃，优选小于50℃，优选小于49℃，优选小于48℃，优选小于47℃，优选小于46℃。
适用于本发明的光敏剂选自卟啉、金属卟啉、卟吩、叶绿素、紫红素、荧光素、酞菁、金属酞菁、吲哚菁绿、三碳菁、纳米金颗粒、金属纳米粒子、金属氧化物纳米粒子、金属硫化物纳米粒子、金属碳化物纳米粒子、碳纳米管、石墨烯等，以及上述化合物的衍生产物，或上述化合物的降解产物，或上述化合物的盐形式。优选的方案中，光敏剂选自吲哚单菁(一甲川菁)，吲哚碳菁(三甲川菁)，吲哚二碳菁(五甲川菁)，吲哚三碳菁(七甲川菁)，三碳花菁染料、苯并吲哚半菁染料、吲哚方酸菁染料，酞菁、叶绿素衍生物、脱镁叶绿素、脱镁叶绿酸a及其衍生物，二氢卟吩e6及其衍生物，紫红素18，二氢卟吩p6及其衍生物，二氢卟吩e4及其衍生物，二氢卟吩f及其衍生物，原卟啉及其衍生物，苯并叶绿卟啉，金属卟啉、血卟啉衍生物(HpD)、卟吩姆钠、癌光啉(PSD-007)，纳米金、纳米钨氧化物、纳米铜硫化物、纳米铁氧化物、纳米镍碳化物、纳米钼氧化物、以及其它基于以上光敏剂修饰或改性的水溶性或脂溶性的衍生物。
在本发明另一个实施方式中，光敏剂可以是被活化的激光光源的波长范围为400～600nm的光敏剂，如荧光素；光敏剂可以是被活化的激光光源的波长范围为600～750nm的光敏剂，如紫红素18；光敏剂可以是被活化的激光光源的波长范围为700～900nm的光敏剂，如吲哚菁绿ICG；光敏剂可以是被活化的激光光源的波长范围为800～1100nm的光敏剂，如纳米金。
在本发明另一个实施方式中，光敏剂含有可聚合基团，例如：乙烯基、烯丙基、丁烯、丙烯酰氧基、甲基丙烯酰氧基、丙烯酰胺基、甲基丙烯酰胺基、乙烯醚基、炔基，等，可以与基体材料单体一起发生共聚反应，光敏剂分子以共价键形式存在于基体材料分子链中，光敏剂被固定在基体材料中，不能自由进入血液或其他体液中，因此光敏剂本身的毒性完全可以被忽略。
在本发明另一个实施方式中，光敏剂分子结构中含有活泼基团，例如：羟基、巯基、氨基、亚氨基、羧基、酸酐、醛基、异氰酸酯基、硅氧烷基、环氧基、环氮基，等，可以与基体材料分子侧链上的基团发生接枝反应，光敏剂分子以共价键形式与基体材料分子链结合在一起，光敏剂被固定在基体材料内部或其表面上，同样不能自由进入血液或其他体液中。
在本发明另一个实施方式中，光敏剂以共混或掺杂等方式分散在基体材料中，光敏剂分子与基体材料分子链以氢键或范德华力作用结合在一起，光敏剂分子被束缚在基体材料中，不能自由进入血液或其他体液中。
在本发明另一个实施方式中，光敏剂以溶解、悬浊、乳化等方式分散在其他助剂(例如：助溶剂、乳化剂、润滑剂、亲水涂层、载药、色母、紫外吸收剂、交联剂、偶联剂、pH调节剂、抗静电剂、脱模剂，等)中，并涂覆在基体材料的表面，光敏剂分子与基体材料分子链以氢键或范德华力作用结合在一起，光敏剂被束缚在基体材料的表面，不能自由进入血液或其他体液中。
在本发明另一个实施方式中，为了增强光敏剂分子与基体材料分子之间的亲和力，光敏剂分子可以在不改变光活性的前提下进行化学改性；基体材料也可以进行活化处理，包括但不局限于，等离子体处理、电晕处理、火焰处理、强酸处理、强碱处理等。
在本发明一个实施方式中，光敏剂与基体材料聚合获得本发明材料时，或当光敏剂掺杂在基体材料中获得本发明材料时，本发明材料可以通过包括下述步骤的方法制备：
1)将任选添加剂(如交联剂、热引发剂、紫外吸收剂等)与可聚合单体混合；
2)加入光敏剂，并使其溶解，然后聚合。
更具体地，本发明材料可以通过包括下述步骤的方法制备：
1)将引发剂、交联剂、紫外吸收剂、可聚合单体混合；
2)加入光敏剂，使其溶解；
3)将2)获得的反应体系放置于模具中；
4)进行聚合，例如水浴聚合。
更具体地，本发明材料可以通过包括下述步骤的方法制备：
1)将基体材料和光敏剂，以及任选添加剂如色母粒、稳定剂等，进行混合；
2)将混合后的原料加工成型，例如通过选自挤出、注塑、吹塑、发泡、压延、或纺丝等的方式加工成型。
在本发明另一个实施方式中，当光敏剂以表面接枝、表面修饰方式固定在基体材料表面时，本发明材料可以通过包括下述步骤的方法制备：
1)将可聚合单体与任选添加剂如交联剂、热引发剂和/或紫外吸收剂混合；
2)加入光敏剂，并使其溶解，例如将光敏剂用合适的助剂(例如可聚合单体)溶解，然后进行聚合，如接枝聚合或表面修饰或转移印刷。
更具体地，本发明材料可以通过包括下述步骤的方法制备：
1)将引发剂、交联剂、紫外吸收剂、可聚合单体混合；
2)将1)获得的反应体系转移至模具中；
4)进行聚合，例如水浴聚合；
5)干燥器内再次聚合；
6)加入光敏剂，使其溶解。例如，光敏剂用合适的助剂(例如可聚合单体)溶解；
7)将上述获得的体系再次聚合。
在本发明另一个实施方式中，当光敏剂以表面涂覆方式固定在基体材料表面时，本发明材料可以通过包括下述步骤的方法制备：
1)获得合适的基体材料；
2)将光敏剂，例如将光敏剂用合适的助剂(例如可聚合单体)溶解，涂覆在基体材料表面。
在本发明方法中，交联剂用量可为可聚合单体的0.1-20重量％，优 选0.5-15％，特别地1-5％。紫外吸收剂用量为可聚合单体的0-10重量％，优选0-5％，特别地0-1％。引发剂用量为可聚合单体的0.01-10重量％，优选0.01-5％，特别地0.05％-1.0％。
除了基体材料和光敏剂外，本发明材料可包含其它任选组分包括但不局限于：助溶剂、颜料、填料、分散剂、固化剂、润湿剂、消泡剂、紫外线吸收剂、抗氧化剂、灭菌剂、稳定剂、乳化剂、亲水涂层、载药、色母、交联剂、偶联剂、pH调节剂、抗静电剂、脱模剂，等等。
本发明中，可采用常规涂覆技术如常规或无空气喷涂、辊涂、刷涂、帘涂、淋涂以及浸涂方法将本发明材料涂敷在所要求的底材上。同时可采用常规印刷技术如常规凸版印刷、凹版印刷、平板印刷、丝网印刷、热转移印刷、静电复印、喷墨印刷或3D打印等方法将本发明材料涂覆在所要求的底材上。当本发明材料被涂覆在底材上后，可任选在室温或高温下固化。
本发明还涉及以激光驱动的光疗法治疗疾病的方法，其中该方法仅仅使用本发明所制备的医疗设备就可以进行。具体地，例如，将本发明所述材料制备获得的医疗设备置于所需治疗的部位上，可以仅仅通过本发明所述的具有光敏剂本发明所述材料制备获得的医疗设备接触所需治疗的部位(无需额外加入光敏剂)，在激光设备下，由于本发明所制备的医疗设备具有光敏剂，一方面：以光、光敏剂和氧的相互作用为基础，光敏剂的作用是吸收光子而处于激发态，然后再将能量传递给周围的氧，生成活性很强的单线态氧；单线态氧一方面可以通过造成病变组织中微血管急性损伤引起血管阻塞引起局部缺血，另一方面可以直接杀死病变组织细胞，从而达到局部治疗的目的。另一方面，由于本发明所制备的医疗设备具有光敏剂，以光热转换剂为基础，在特定波长的激光照射下，光热试剂能够高效地将光能转换成热能，产生高温以杀死病变组织细胞。当病变组织区域温度达到43℃时可以抑制DNA、RNA和蛋白质合成。
由此可见，本发明所述材料和本发明所制备的医疗设备彻底的摆脱外源性光敏剂(无需预先服用光敏剂等)，本发明方法无需添加任何额外的试剂(包括光敏剂)，并具有非侵袭性、无毒性、高效性等优势。
本发明还涉及如下技术方案：
1.基体材料可以被加工成眼科用医疗器械，具有安全性，生物相 容性，功能性，以及匹配的机械性能，并且可以被灭菌。
2.根据项1的基体材料加工方法，包括但不局限于：车削法、模压成型法、注塑法、离心浇铸法、3D打印法等。
3.根据项1的眼科医疗器械的灭菌方法，包括但不局限于：湿热灭菌、辐照灭菌、环氧乙烷灭菌等。
4.光敏剂在眼科医疗器械内部及表面上的分布，包括但不局限于：整体均匀分布，局部分布，带状分布，梯度分布，散点分布等。
5.眼科医疗器械材料中的光敏剂可以再次或多次接受选定波长激光的照射，并且每次照射光敏剂都可以被活化而产生活性氧或高温热，从而使该医疗器械具有可以重复进行激光治疗的功效。
具体实施方式
在下文中，将通过具体的实施例更加详细地描述本发明，但所提供的实施例仅是说明性的而并不意欲限制本发明。
实施例1：
实施例1a:甲基丙烯酸甲酯-光敏剂共聚材料的合成
在250ml烧杯中，分别加入98.0g甲基丙烯酸甲酯单体(MMA)，2.0g二甲基丙烯酸乙二醇酯(EGDMA)，0.12g引发剂(偶氮二异丁腈，AIBN)，0.04g光敏剂(紫红素18)，充分搅拌均匀后，转移至成型模具中。向单体溶液中通入氮气后，将模具进行密封，然后放入65℃水浴中进行聚合反应24小时，再将模具转移至90℃烘箱中继续保温24小时，即可得到含有紫红素18光敏剂的聚甲基丙烯酸甲酯材料。紫红素18的分子结构式如下所示。由于紫红素18分子结构式中含有乙烯基不饱和双键，可以与MMA和EGDMA发生共聚反应，从而将具有光活性的卟啉(四吡咯环结构)基团固定在PMMA分子链中，又由于EGDMA的存在，可以将PMMA分子链进行交联生成网络结构的PMMA大分子。具有网络结构的交联聚合物在溶剂中只能被溶胀，而不能被溶解，因此光敏剂(紫红素18)分子将被牢牢固定在PMMA材料中，不能自由进入血液或其他体液中。
Figure PCTCN2016090980-appb-000001
紫红素18。
实施例1a-1x:
反应条件与实施例1a基本相同，不同之处如下：
Figure PCTCN2016090980-appb-000002
Figure PCTCN2016090980-appb-000003
MMA：甲基丙烯酸甲酯
EA：丙烯酸乙酯
EMA：甲基丙烯酸乙酯
BA：丙烯酸丁酯
EGDMA：二甲基丙烯酸乙二醇酯
BDDMA：二甲基丙烯酸丁二醇酯
HDDMA：二甲基丙烯酸己二醇酯
TFEMA：甲基丙烯酸三氟乙酯
HEMA：甲基丙烯酸羟基乙酯
HEA：丙烯酸羟基乙酯
PEA：丙烯酸苯基乙酯
PEMA：甲基丙烯酸苯基乙酯
POEA：丙烯酸苯氧基乙酯
BMA：甲基丙烯酸苄基乙酯
EOEMA：甲基丙烯酸乙氧基乙酯
EOEOEMA：甲基丙烯酸乙氧基乙氧基乙酯
HFIPMA：甲基丙烯酸六氟异丙酯
TMSPMA：甲基丙烯酰氧丙基三(三甲基硅氧烷基)硅烷
TTMSBPMA：1,3-二(甲基丙烯酰氧丙基)四(三甲基硅氧基)二甲硅醚
MAA：甲基丙烯酸
St：苯乙烯
MSt：甲基苯乙烯
DVB：二乙烯基苯。
实施例2：
实施例2a:硅胶-光敏剂共聚材料的合成
在250ml烧杯中，将0.04g紫红素18(光敏剂)加入到双组份硅橡胶体系中(MED-6820，购自Nusil)，充分搅拌均匀并脱除气泡后， 转移至成型模具中。将模具进行密封，然后放入150℃烘箱中进行聚合反应30分钟，即可得到含有紫红素18光敏剂的硅胶材料。由于紫红素18分子结构式中含有乙烯基不饱和双键，可以与含氢硅油和乙烯基硅油发生共聚反应，从而将具有光活性的卟啉(四吡咯环结构)基团固定在硅胶分子链中，因此光敏剂(紫红素18)分子将被牢牢固定在硅胶材料中，不能自由进入血液或其他体液中。
实施例2a-2q:
反应条件与实施例2a基本相同，不同之处如下：
Figure PCTCN2016090980-appb-000004
实施例3：
实施例3a:聚丙烯-光敏剂共混材料的合成
准确称量5Kg聚丙烯粒料(PP，R370Y，购自韩国SK)和2g紫红素18粉末(光敏剂)先进行预混，然后将预混好的PP/紫红素18混 合原料加入双螺杆挤出机中，进行共混挤出造粒，即可得到含有紫红素18光敏剂的聚丙烯材料。紫红素18被共混到聚丙烯材料中，由于聚丙烯材料特有的结晶结构，因此紫红素18分子将被牢牢固定在聚丙烯材料中，不能自由进入血液或其他体液中。
实施例3a-3o:
反应条件与实施例3a基本相同，不同之处如下：
Figure PCTCN2016090980-appb-000005
PP：聚丙烯
HDPE：高密度聚乙烯
LDPE：低密度聚乙烯
TPU：热塑性聚氨酯
PA：聚酰胺(尼龙)
PET：聚对苯二甲酸乙二醇酯
PEEK：聚醚醚酮
POM：聚甲醛
PC：聚碳酸酯
PS：聚苯乙烯
PVC：聚氯乙烯
ABS：丙烯腈-丁二烯-苯乙烯共聚物
PMMA：聚甲基丙烯酸甲酯
PSU：聚砜
PTFE：聚四氟乙烯
其中，实施例所列出光敏剂分子结构式如下：
Figure PCTCN2016090980-appb-000006
Figure PCTCN2016090980-appb-000007
以上所述仅为本发明的优选实施例，并不用于限制本发明，显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。

Claims (13)

  1. 用于光治疗的医用材料，尤其是用于光治疗眼部疾病的眼科材料，其包括：
    ·基体材料；
    ·至少一种光敏剂，选自光动力型和/或光热型光敏剂；
    其中，光敏剂与基体材料的结合方式选自：
    -光敏剂在基体材料成型过程中参与聚合；
    -光敏剂在基体材料成型过程中通过物理分散添加到基体材料内；
    -光敏剂以表面接枝、表面修饰方式固定在基体材料表面；和/或
    -光敏剂以表面涂覆方式固定在基体材料表面。
  2. 根据权利要求1的医用材料，其中光敏剂选自吲哚单菁(一甲川菁)，吲哚碳菁(三甲川菁)，吲哚二碳菁(五甲川菁)，吲哚三碳菁(七甲川菁)，三碳花菁染料、苯并吲哚半菁染料、吲哚方酸菁染料、叶绿素衍生物、脱镁叶绿素、脱镁叶绿酸a及其衍生物，二氢卟吩e6及其衍生物，紫红素18，二氢卟吩p6及其衍生物，二氢卟吩f及其衍生物，原卟啉及其衍生物，血卟啉衍生物(HpD)、卟吩姆钠、癌光啉(PSD-007)，纳米金、纳米钨氧化物、纳米铜硫化物、纳米铁氧化物、纳米镍碳化物、纳米钼氧化物、以及其它基于以上光敏剂修饰或改性的水溶性或脂溶性的衍生物，及其混合物。
  3. 根据前述权利要求任一项的医用材料，其中光敏剂选自纳米金、紫红素18、荧光素O-丙烯酸酯和荧光素O-甲基丙烯酸酯以及基于以上光敏剂修饰或改性的水溶性或脂溶性的衍生物。
  4. 根据前述权利要求任一项的医用材料，其中光敏剂含有可聚合基团，例如选自：乙烯基、烯丙基、丁烯、丙烯酰氧基、甲基丙烯酰氧基、丙烯酰胺基、甲基丙烯酰胺基、乙烯醚基、炔基、羟基、巯基、氨基、亚氨基、羧基、酸酐、醛基、异氰酸酯基、硅氧烷基、环氧基和环氮基，及其混合物。
  5. 根据前述权利要求任一项的医用材料，其中基于材料总重量，所含光敏剂含量为小于1重量％，优选小于0.5重量％，更优选小于0.1重量％。
  6. 根据前述权利要求任一项的医用材料，其中基体材料选自疏水 型丙烯酸酯、丙烯酸酯水凝胶、硅胶、硅水凝胶、氟硅丙烯酸酯、聚苯乙烯和聚甲基丙烯酸甲酯、聚碳酸酯、聚硅氧烷，及其混合物。
  7. 制备前述权利要求1-6任一项的医用材料的方法，包括下述步骤：
    1)将可聚合单体与任选添加剂如交联剂、热引发剂和/或紫外吸收剂混合；
    2)加入光敏剂，并使其溶解，然后聚合。
  8. 制备前述权利要求1-6任一项的医用材料的方法，包括下述步骤：
    1)将可聚合单体与任选添加剂如交联剂、热引发剂和/或紫外吸收剂混合，然后聚合，得到基体材料；
    2)加入任选用助剂如可聚合单体溶解的光敏剂，然后进行聚合如接枝聚合或表面修饰。
  9. 制备前述权利要求1-6任一项的医用材料的方法，包括下述步骤：
    1)将基体材料和光敏剂，以及任选添加剂如色母粒、稳定剂，进行混合；
    2)将混合后的原料加工成型，例如通过选自挤出、注塑、吹塑、发泡、压延、或纺丝的方式加工成型。
  10. 医疗设备，其包括前述权利要求1-6任一项的医用材料。
  11. 根据权利要求10所述设备，其是眼科医疗设备，优选选自：植入物如用于预防和/或治疗后发性白内障的人工晶状体、角膜接触镜、角膜塑形镜、虹膜拉钩、眼内镜、人工角膜、角膜内环、囊袋张力环、角膜内透镜、青光眼引流阀、药物缓释载体、眼内填充物、与身体组织接触的外用医疗装置，如皮肤医疗装置，眼镜、护目镜、医疗设备透镜、望远镜、观测镜和眼底填充物。
  12. 前述权利要求1-6任一项的医用材料在制备医疗设备，尤其地眼科医疗设备，中的用途。
  13. 根据权利要求12所述用途，其中医疗设备选自：植入物如用于预防和/或治疗后发性白内障的人工晶状体、角膜接触镜、角膜塑形镜、虹膜拉钩、眼内镜、人工角膜、角膜内环、囊袋张力环、角膜内透镜、青光眼引流阀、药物缓释载体、眼内填充物、与身体组织接触 的外用医疗装置，如皮肤医疗装置，眼镜、护目镜、医疗设备透镜、望远镜、观测镜和眼底填充物。
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