WO2016090863A1 - 基于海洋生物物质的高透氧性材料及其制备方法与应用 - Google Patents

基于海洋生物物质的高透氧性材料及其制备方法与应用 Download PDF

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WO2016090863A1
WO2016090863A1 PCT/CN2015/080218 CN2015080218W WO2016090863A1 WO 2016090863 A1 WO2016090863 A1 WO 2016090863A1 CN 2015080218 W CN2015080218 W CN 2015080218W WO 2016090863 A1 WO2016090863 A1 WO 2016090863A1
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silicon
containing substance
substance
acid
permeable material
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PCT/CN2015/080218
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English (en)
French (fr)
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王宝泉
李青
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青岛中皓生物工程有限公司
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Priority to CA2970702A priority Critical patent/CA2970702C/en
Priority to US15/535,311 priority patent/US20170329053A1/en
Priority to EP15867518.1A priority patent/EP3231838B1/en
Priority to AU2015361791A priority patent/AU2015361791B2/en
Publication of WO2016090863A1 publication Critical patent/WO2016090863A1/zh

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    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
    • G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
    • G02B1/041—Lenses
    • G02B1/043—Contact lenses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/34—Silicon-containing compounds
    • C08K3/36—Silica
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/54—Silicon-containing compounds
    • C08K5/541—Silicon-containing compounds containing oxygen
    • C08K5/5415—Silicon-containing compounds containing oxygen containing at least one Si—O bond
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/54—Silicon-containing compounds
    • C08K5/541—Silicon-containing compounds containing oxygen
    • C08K5/5415—Silicon-containing compounds containing oxygen containing at least one Si—O bond
    • C08K5/5419—Silicon-containing compounds containing oxygen containing at least one Si—O bond containing at least one Si—C bond
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/54—Silicon-containing compounds
    • C08K5/544—Silicon-containing compounds containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
    • G—PHYSICS
    • G02—OPTICS
    • G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
    • G02C7/00—Optical parts
    • G02C7/02—Lenses; Lens systems ; Methods of designing lenses
    • G02C7/04—Contact lenses for the eyes
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00—Characterised by the use of proteins; Derivatives thereof
    • C08J2389/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08J2389/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2483/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen, or carbon only; Derivatives of such polymers
    • C08J2483/04—Polysiloxanes
    • C08J2483/06—Polysiloxanes containing silicon bound to oxygen-containing groups

Definitions

  • the invention belongs to the field of medical device materials, in particular to a high oxygen permeability material based on marine biological materials and a preparation method and application thereof.
  • Contact lens is a sophisticated ophthalmic medical device, the main purpose is to correct vision, maintain natural face, medical and so on.
  • the oxygen permeability of contact lenses commonly used oxygen gas permeability coefficient (DK) or oxygen transfer coefficient (DK / t) is represented, wherein, D is the diffusion coefficient of O 2 in the material, K is the solubility coefficient of O 2 in the material, DK is the product of D and K, the unit is banrrer, and t is the center thickness of the lens in millimeters (mm).
  • DK/t value must be greater than 24 banrrers/mm.
  • DK/t When worn overnight, DK/t must be greater than 87 banrrers/mm, but there is 4% corneal edema. Only when DK/t>125 banrrers/mm can it be extended without wearing related symptoms caused by hypoxia.
  • the contact lens can be worn continuously for 7 days, 30 days or longer, which can reduce the trouble caused by the daily wear type and provide possibilities for the treatment of the eye such as sustained release and controlled release of the drug.
  • Oxygen permeability is the primary factor in determining whether a lens is suitable for day wear or extended wear. Most consumers will consider whether it is suitable for extended wear when choosing a contact lens. Therefore, high oxygen permeability contact lens has great market demand. .
  • the DK/t values of the current common hydrogel contact lenses still need to be improved.
  • the object of the present invention is to overcome the poor defects such as oxygen permeability of the existing contact lens, and to provide a high oxygen permeability material based on marine biological materials, and a preparation method and application thereof.
  • the present invention provides a highly oxygen permeable material comprising a silicon-containing substance and a biologically active substance in a crosslinking agent. And compounded in the presence of the silicon-containing substance having a siloxy group, the biologically active substance being selected from at least one of alginic acid, collagen, hyaluronic acid, and a salt thereof.
  • the present invention provides a method for preparing a highly oxygen permeable material, the method comprising: mixing a silicon-containing substance with a biologically active substance under acidic conditions, and then obtaining the obtained mixture in the presence of a crosslinking agent Crosslinking.
  • the method of the invention comprises the steps of:
  • step (1) the mixture obtained in step (1) is crosslinked in the presence of a crosslinking agent for 2-5h;
  • the silicon-containing substance is used in an amount of from 1 to 10 parts by weight, based on 100 parts by weight of the bioactive substance, and the crosslinking agent is used in an amount of from 0.01 to 5 parts by weight.
  • the present invention provides a highly oxygen permeable material produced by the method of the second aspect.
  • the present invention provides the use of the high oxygen permeability material of the first or third aspect, or the method of the second aspect, in the preparation of a contact lens, a corneal stent material or a corneal substitute.
  • the present invention obtains a high oxygen permeability material which can meet the requirements of prolonging the wearing of high oxygen permeability and has good wearing comfort (high water content), and long-wearing contact lens and control
  • the research and development of therapeutic dosage forms for the release of corneal diseases has important practical significance and broad application prospects.
  • the highly oxygen-permeable material of the present invention has good biocompatibility and high safety performance due to the use of marine biomaterials having good biocompatibility (alginic acid, collagen, hyaluronic acid, and salts thereof).
  • the high oxygen permeability material provided by the present invention is composed of a silicon-containing substance and a biologically active substance compounded in the presence of a crosslinking agent, wherein the silicon-containing substance has a siloxy group, and the biologically active substance is selected from the group consisting of alginic acid. At least one of collagen, hyaluronic acid, and a salt thereof. Among them, at least some (or all) of the biologically active substances are cross-linked to each other.
  • the silicon-containing substance is preferably used in an amount of from 1 to 10 parts by weight based on 100 parts by weight of the biologically active substance.
  • the collagen may be various common collagens, may be collagen derived from mammals, or may be collagen derived from other sources, preferably fish collagen, more preferably having a molecular weight of 8- Collagen of 350 kDa, most preferably type I collagen.
  • the hyaluronic acid preferably has a molecular weight of from 80 to 2000 kDa.
  • a salt of alginic acid, collagen or hyaluronic acid may also be used to obtain the highly oxygen-permeable material of the present invention, and more preferably, the biologically active substance is selected from the group consisting of alginic acid, sodium alginate, and potassium alginate. At least one of collagen, hyaluronic acid, sodium hyaluronate, and potassium hyaluronate.
  • the silicon-containing substance may be various silicon-containing substances having a siloxy group which are commonly used in the preparation of contact lenses in the art.
  • the silicon-containing substance is selected from the group consisting of silica gel and 3-aminopropyl group. At least one of trimethoxysilane, tetraethoxysilane, and dimethyldiethoxysilane.
  • the particle diameter of the silica gel is preferably from 200 to 800 mesh.
  • the highly oxygen permeable material of the present invention is a composite of a silicon-containing substance and a biologically active substance in the presence of a crosslinking agent.
  • the crosslinking agent is preferably used in an amount of from 0.01 to 5 parts by weight, more preferably from 0.1 to 3 parts by weight, per 100 parts by weight of the biologically active substance.
  • the crosslinking agent may be a substance commonly used in the art to crosslink the biologically active substance.
  • the crosslinking agent is calcium chloride, and/or 1-ethyl-3-(3- A mixture of dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide (EDC/NHS, the molar ratio of the two is usually 1:0.1-2).
  • the method for preparing a highly oxygen permeable material provided by the present invention comprises: mixing a silicon-containing substance with a biologically active substance under acidic conditions, and crosslinking the obtained mixture in the presence of a crosslinking agent.
  • the silicon-containing substance is preferably used in an amount of from 1 to 10 parts by weight based on 100 parts by weight of the biologically active substance.
  • the collagen may be various common collagens, may be collagen derived from mammals, or may be collagen derived from other sources, preferably fish collagen, more preferably having a molecular weight of 8- Collagen of 350 kDa, most preferably type I collagen.
  • the step of mixing the silicon-containing substance with the biologically active substance is carried out at a temperature of 0 to 20 °C.
  • the hyaluronic acid preferably has a molecular weight of from 80 to 2000 kDa.
  • a salt of alginic acid, collagen or hyaluronic acid may also be used to obtain the highly oxygen-permeable material of the present invention, and more preferably, the biologically active substance is selected from the group consisting of alginic acid, sodium alginate, and potassium alginate. At least one of collagen, hyaluronic acid, sodium hyaluronate, and potassium hyaluronate.
  • the silicon-containing substance may be various silicon-containing substances having a siloxy group which are commonly used in the preparation of contact lenses in the art.
  • the silicon-containing substance is selected from the group consisting of silica gel and 3-aminopropyl group. At least one of trimethoxysilane, tetraethoxysilane, and dimethyldiethoxysilane.
  • the particle diameter of the silica gel is preferably from 200 to 800 mesh.
  • the crosslinking agent is preferably used in an amount of 100 parts by weight of the bioactive substance. 0.01 to 5 parts by weight, more preferably 0.1 to 3 parts by weight.
  • the crosslinking agent may be a substance commonly used in the art to crosslink the biologically active substance.
  • the crosslinking agent is calcium chloride, and/or 1-ethyl-3-(3- A mixture of dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide (EDC/NHS, the molar ratio of the two is usually 1:0.1-2).
  • the crosslinking agent may be used in the form of a solution having a concentration in the solution of 0.05 to 3 mol/L.
  • the acidic conditions have a pH of from 3 to 6.
  • the silicon-containing substance is dispersed in an acid solution before the silicon-containing substance is mixed with the biologically active substance, wherein the acid solution has a hydrogen ion concentration of 10 -3 -10 -6 Mol/L.
  • a dispersion of 0.2-10 L (or 0.2-5 L) of the acid solution is usually employed.
  • the dispersion can be carried out in a conventional manner as long as the silicon-containing substance is sufficiently dispersed to facilitate the subsequent crosslinking step.
  • ultrasonic dispersion can be used (the frequency of ultrasonic dispersion is 35-50 kHz, and the time of ultrasonic dispersion can be 15-30min).
  • the silica gel may be subjected to impurity removal, and the manner of removing impurities may be various methods known in the art. More preferably, the method further comprises: treating the silicon-containing substance as follows (to remove the used silica gel) before dispersing the silicon-containing substance in the acid solution:
  • the silicon-containing substance treated in the step (1) is immersed in a mixture of a hydrochloric acid solution and ethanol at 20-50 ° C for 2-10 h, and washed with water until neutral.
  • the hydrogen ion concentration of the acid liquid is preferably from 1 to 10 mol/L.
  • the acid in the acid solution is preferably at least one of sulfuric acid, nitric acid and hydrochloric acid.
  • the concentration of hydrogen ions in the hydrochloric acid solution is 0.005-0.05 mol/L, and the volume ratio of the hydrochloric acid solution to the ethanol is 1:0.1-5.
  • the acid in the acid solution is at least one of acetic acid, sulfuric acid, nitric acid, and hydrochloric acid.
  • the acid in the acid solution, the acid in the acid solution used in the step (a), and the acid used in the step (b) may be the same or different.
  • the crosslinking conditions include: a temperature of 15-35 ° C, time It is 2-5h.
  • the method may further comprise defogging the mixture prior to crosslinking, and the method of removing the bubbles may be in the form of centrifugation or vacuuming, and those skilled in the art can select this. Let me repeat.
  • the method of preparing a highly oxygen permeable material comprises the steps of:
  • step (1) the mixture obtained in step (1) is crosslinked in the presence of a crosslinking agent for 2-5h;
  • the silicon-containing substance is used in an amount of from 1 to 10 parts by weight, based on 100 parts by weight of the bioactive substance, and the crosslinking agent is used in an amount of from 0.01 to 5 parts by weight.
  • the biologically active substance may be mixed with a silicon-containing substance in the form of a solution, and the concentration of the biologically active substance in the solution may be 5 to 200 mg/mL, for example, for alginic acid or a salt thereof, the concentration of the solution It may be 10-200 mg/mL; for collagen or a salt thereof, the concentration of the solution may be 5-50 mg/mL; for hyaluronic acid or a salt thereof, the concentration of the solution may be 10-40 mg/mL.
  • the silicon-containing substance and the biologically active substance used in the present invention can be obtained by a chemical synthesis method, and are also commercially available, and will not be described herein.
  • the present invention also provides a highly oxygen permeable material produced by the above method.
  • the present invention also provides the use of the above method, or a highly oxygen permeable material, in the preparation of contact lenses, corneal stent materials or corneal substitutes.
  • the crosslinking can be directly carried out in a mold (a contact lens, a corneal stent material or a corneal substitute), for example, The mixture obtained by mixing the silicon substance and the biologically active substance is directly placed in a mold, and a crosslinking agent is added to the mold for crosslinking, thereby obtaining a contact lens, a corneal stent material or a corneal substitute having a specific shape.
  • silica gel was purchased from Qingdao Ocean Chemical Co., Ltd.; 3-aminopropyltrimethoxysilane was purchased from Sigma; sodium alginate was purchased from Qingdao Mingyue Seaweed Co., Ltd.; fish collagen was isolated from deep sea carp, and the molecular weight was 300- 350kDa (ie type I collagen); sodium hyaluronate was purchased from Solarbio with a molecular weight of 80-2000kDa; both EDC and NHS were purchased from Sigma with the numbers 39391 and 130672 respectively; the thickness of the contact lens was measured by a corneal thickness gauge. .
  • a contact lens was prepared in accordance with the method of Example 2, except that the "fish collagen” used was replaced by "porcine collagen (molecular weight: 8-10 kDa)", and the obtained contact lens had a thickness of 100 ⁇ m.
  • the parameters of the contact lens obtained in the above examples such as light transmittance, oxygen transmission coefficient (DK/t), water content, etc., were determined.
  • the specific methods refer to national standards (GB/T11417.5-2012 and GB/T11417.7). -2012), the results are shown in Table 1 below.
  • Example number Transmittance(%) DK/t(banrrers/mm) Water content (% by weight) Example 1 95 106 63 Example 2 93 129 70 Example 3 91 102 52 Example 4 87 81 47
  • the high oxygen permeability material obtained in the examples has high light transmittance, and the oxygen permeability coefficient satisfies the requirement of ideally extending the wear and the water content is high. Therefore, the highly oxygen permeable material of the present invention has high oxygen permeability and a high water content, thereby simultaneously having better comfort.

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Abstract

本发明公开了一种基于海洋生物物质的高透氧性材料，其由含硅物质和生物活性物质在交联剂的存在下复合而成，所述含硅物质具有硅氧基团，所述生物活性物质选自海藻酸、胶原蛋白、透明质酸以及它们的盐中的至少一种。本发明还公开了制备所述高透氧性材料的方法，包括：在酸性条件下，将含硅物质与生物活性物质混合，再将得到的混合物在交联剂的存在下进行交联。本发明还公开了高透氧性材料或方法在制备角膜接触镜、角膜支架材料或角膜替代物中的应用。本发明获得了可以满足延长配戴对高透氧性的要求而且具有良好配戴舒适性的高透氧性材料。此外，由于采用具有良好生物相容性的海洋生物物质，使得本发明的高透氧性材料的生物相容性好、安全性能高。

Description

基于海洋生物物质的高透氧性材料及其制备方法与应用 技术领域
本发明属于医疗器械材料领域，具体地，涉及一种基于海洋生物物质的高透氧性材料及其制备方法与应用。
背景技术
角膜接触镜(简称接触镜)是一种精致的眼科医疗器械，主要用途是矫正视力、保持自然面容、医疗等。角膜接触镜的透氧能力常用氧气渗透系数(DK)或氧气传导系数(DK/t)来表示，其中，D为O2在材料中的扩散系数，K为O2在材料中的溶解系数，DK为D和K的乘积，单位为banrrer，t为镜片的中心厚度，单位为毫米(mm)。研究指出，要满足无角膜水肿的日戴要求，DK/t值必须大于24banrrers/mm。过夜佩戴时，DK/t必须大于87banrrers/mm，但存在4％的角膜水肿，只有当DK/t>125banrrers/mm时，才能保证延长佩戴时不会引起因缺氧引起的相关症状。可以连续佩戴7天、30天或者更长时间的接触镜，能减少日戴型所带来的麻烦，为药物的缓释、控释等眼部的治疗提供可能性。透氧能力是决定镜片是适合于日戴还是延长佩戴的首要因素，大多数的消费者在选择接触镜时会考虑是否适合延长佩戴，因此，高透氧性角膜接触镜有很大的市场需求。而目前常见的水凝胶接触镜的DK/t值仍有待提高。
发明内容
本发明的目的是克服现有的角膜接触镜透氧性等较差的缺陷，提供一种基于海洋生物物质的高透氧性材料及其制备方法与应用。
为了获得透氧性高、舒适性强的角膜接触镜，本发明的发明人进行了大量实验，结果发现，将海藻酸等海洋生物物质与具有硅氧基团的含硅物质作为原料制得的角膜接触镜的透氧性和舒适性均较佳，因此，第一方面，本发明提供了一种高透氧性材料，该高透氧性材料由含硅物质和生物活性物质在交联剂的存在下复合而成，其中，所述含硅物质具有硅氧基团，所述生物活性物质选自海藻酸、胶原蛋白、透明质酸以及它们的盐中的至少一种。
第二方面，本发明提供了一种高透氧性材料的制备方法，该方法包括：在酸性条件下，将含硅物质与生物活性物质混合，再将得到的混合物在交联剂的存在下进行交联。
优选地，本发明的方法包括如下步骤：
(1)将分散于氢离子浓度为10-3-10-6mol/L的酸溶液中的含硅物质与生物活性物质混合，所述含硅物质选自硅胶、3-氨基丙基三甲氧基硅烷、四乙氧基硅烷和二甲基二乙氧基硅烷中的至少一种，所述硅胶的粒径为200-800目，所述生物活性物质选自海藻酸、海藻酸钠、海藻酸钾、胶原蛋白、透明质酸、透明质酸钠和透明质酸钾的至少一种；
(2)在15-35℃下，将步骤(1)得到的混合物在交联剂的存在下交联2-5h；
其中，相对于100重量份的所述生物活性物质，所述含硅物质的用量为1-10重量份，所述交联剂的用量为0.01-5重量份。
第三方面，本发明提供了由第二方面所述的方法制得的高透氧性材料。
第四方面，本发明提供了第一方面或第三方面所述的高透氧性材料、或者第二方面所述的方法在制备角膜接触镜、角膜支架材料或角膜替代物中的应用。
通过上述技术方案，本发明获得了可以满足延长配戴对高透氧性的要求而且具有良好配戴舒适性(含水量高)的高透氧性材料，对长期佩戴型角膜接触镜以及缓控释角膜疾病治疗剂型的研发有重要的现实意义和广阔的应用前景。此外，由于采用具有良好生物相容性的海洋生物物质(海藻酸、胶原蛋白、透明质酸以及它们的盐)，使得本发明的高透氧性材料的生物相容性好、安全性能高。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
本发明提供的高透氧性材料由含硅物质和生物活性物质在交联剂的存在下复合而成，其中，所述含硅物质具有硅氧基团，所述生物活性物质选自海藻酸、胶原蛋白、透明质酸以及它们的盐中的至少一种。其中，至少部分(或全部)生物活性物质之间互相交联。
根据本发明，对含硅物质和生物活性物质的用量没有特别的要求，相对于100重量份的所述生物活性物质，所述含硅物质的用量优选为1-10重量份。
根据本发明，所述胶原蛋白可以为各种常见的胶原蛋白，可以为来源于哺乳动物的胶原蛋白，也可以为其他来源的胶原蛋白，优选为鱼类胶原蛋白，更优选为分子量为8-350kDa的胶原蛋白，最优选为I型胶原蛋白。
根据本发明，所述透明质酸的分子量优选为80-2000kDa。
本发明中，海藻酸、胶原蛋白或透明质酸的盐也可以用于获得本发明的高透氧性材料，更优选地，所述生物活性物质选自海藻酸、海藻酸钠、海藻酸钾、胶原蛋白、透明质酸、透明质酸钠和透明质酸钾的至少一种。
根据本发明，所述含硅物质可以为本领域常用于制备角膜接触镜的各种具有硅氧基团的含硅物质，优选情况下，所述含硅物质选自硅胶、3-氨基丙基三甲氧基硅烷、四乙氧基硅烷和二甲基二乙氧基硅烷中的至少一种。所述硅胶的粒径优选为200-800目。
根据本发明的实施方式，本发明的高透氧性材料在交联剂的存在下，由含硅物质和生物活性物质复合而成。相对于100重量份的所述生物活性物质，所述交联剂的用量优选为0.01-5重量份，更优选为0.1-3重量份。所述交联剂可以为本领域常用的可以使所述生物活性物质发生交联的物质，优选地，所述交联剂为氯化钙，和/或1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺与N-羟基琥珀酰亚胺的混合物(EDC/NHS，二者的摩尔比通常为1：0.1-2)。
本发明提供的制备高透氧性材料的方法包括：在酸性条件下，将含硅物质与生物活性物质混合，再将得到的混合物在交联剂的存在下进行交联。
根据本发明，对含硅物质和生物活性物质的用量没有特别的要求，相对于100重量份的所述生物活性物质，所述含硅物质的用量优选为1-10重量份。
根据本发明，所述胶原蛋白可以为各种常见的胶原蛋白，可以为来源于哺乳动物的胶原蛋白，也可以为其他来源的胶原蛋白，优选为鱼类胶原蛋白，更优选为分子量为8-350kDa的胶原蛋白，最优选为I型胶原蛋白。为了保持胶原蛋白的活性，当采用胶原蛋白与含硅物质复合获得高透氧性材料时，含硅物质与生物活性物质混合的步骤在0-20℃的温度下实施。
根据本发明，所述透明质酸的分子量优选为80-2000kDa。
本发明中，海藻酸、胶原蛋白或透明质酸的盐也可以用于获得本发明的高透氧性材料，更优选地，所述生物活性物质选自海藻酸、海藻酸钠、海藻酸钾、胶原蛋白、透明质酸、透明质酸钠和透明质酸钾中的至少一种。
根据本发明，所述含硅物质可以为本领域常用于制备角膜接触镜的各种具有硅氧基团的含硅物质，优选情况下，所述含硅物质选自硅胶、3-氨基丙基三甲氧基硅烷、四乙氧基硅烷和二甲基二乙氧基硅烷中的至少一种。所述硅胶的粒径优选为200-800目。
根据本发明，相对于100重量份的所述生物活性物质，所述交联剂的用量优选为 0.01-5重量份，更优选为0.1-3重量份。所述交联剂可以为本领域常用的可以使所述生物活性物质发生交联的物质，优选地，所述交联剂为氯化钙，和/或1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺与N-羟基琥珀酰亚胺的混合物(EDC/NHS，二者的摩尔比通常为1：0.1-2)。所述交联剂可以以溶液的形式使用，所述交联剂在溶液中的浓度可以为0.05-3mol/L。
优选地，所述酸性条件的pH值为3-6。
根据本发明的优选实施方式，在将含硅物质与生物活性物质混合之前，使所述含硅物质分散在酸溶液中，其中，所述酸溶液的氢离子浓度为10-3-10-6mol/L。对于每摩尔(克)的含硅物质，通常采用0.2-10L(或0.2-5L)的酸溶液进行分散。所述分散可以采用常规的方式进行，只要使含硅物质充分分散，从而有利于后续的交联步骤即可，例如可以采用超声分散(超声分散的频率为35-50kHz，超声分散的时间可以为15-30min)。当所述含硅物质为硅胶时，为了使获得的高透氧性材料具有更佳的舒适性和透光性，可以对硅胶进行除杂，除杂的方式可以为本领域公知的各种方式，更优选地，所述方法还包括：在将所述含硅物质分散在酸溶液中之前，将所述含硅物质进行如下处理(以对使用的硅胶进行除杂)：
(a)在50-100℃下将含硅物质用酸液处理2-10h，再用水洗涤至中性；
(b)在20-50℃下，将步骤(1)处理后的含硅物质置于盐酸溶液和乙醇的混合液中浸泡2-10h，用水洗涤至中性。
步骤(a)中，所述酸液的氢离子浓度优选为1-10mol/L。所述酸液中的酸优选为硫酸、硝酸和盐酸中的至少一种。
步骤(b)中，所述盐酸溶液和乙醇的混合液中，盐酸溶液中氢离子的浓度为0.005-0.05mol/L，盐酸溶液和乙醇的体积比为1:0.1-5。
本发明中，所述酸溶液中的酸为醋酸、硫酸、硝酸和盐酸中的至少一种。所述酸溶液中的酸、步骤(a)使用的酸液中的酸和步骤(b)中使用的酸可以相同或不同。
根据本发明，对所述交联的条件没有特别的要求，只要能够使所述生物活性物质发生交联即可，但优选地，所述交联的条件包括：温度为15-35℃，时间为2-5h。
根据本发明，所述方法还可以包括在交联之前对混合物进行除气泡，除气泡的方式可以为离心的方式，也可以为抽真空的方式，本领域技术人员能够对此进行选择，本文不再赘述。
根据本发明的一种优选实施方式，所述制备高透氧性材料的方法包括如下步骤：
(1)将分散于氢离子浓度为10-3-10-6mol/L的酸溶液中的含硅物质与生物活性物质混合，所述含硅物质选自硅胶、3-氨基丙基三甲氧基硅烷、四乙氧基硅烷和二甲基二乙氧基硅烷中的至少一种，所述硅胶的粒径为200-800目，所述生物活性物质选自海藻酸、海藻酸钠、海藻酸钾、胶原蛋白、透明质酸、透明质酸钠和透明质酸钾的至少一种；
(2)在15-35℃下，将步骤(1)得到的混合物在交联剂的存在下交联2-5h；
其中，相对于100重量份的所述生物活性物质，所述含硅物质的用量为1-10重量份，所述交联剂的用量为0.01-5重量份。
本发明中，所述生物活性物质可以以溶液的形式与含硅物质混合，所述生物活性物质在溶液中的浓度可以为5-200mg/mL，例如，对于海藻酸或其盐，溶液的浓度可以为10-200mg/mL；对于胶原蛋白或其盐，溶液的浓度可以为5-50mg/mL；对于透明质酸或其盐，溶液的浓度可以为10-40mg/mL。
本发明使用的含硅物质和生物活性物质可以通过化学合成方法得到，也可以商购获得，在此不再赘述。
本发明还提供了由上述方法制得的高透氧性材料。
此外，本发明还提供了上述方法、或者高透氧性材料在制备角膜接触镜、角膜支架材料或角膜替代物中的应用。
在使用本发明的上述方法制备角膜接触镜、角膜支架材料或角膜替代物时，可以直接使交联在(角膜接触镜、角膜支架材料或角膜替代物的)模具中进行，例如，可以将含硅物质与生物活性物质混合得到的混合物直接置于模具中，再往模具中添加交联剂进行交联，即可获得具有特定形状的角膜接触镜、角膜支架材料或角膜替代物。
以下将通过实施例对本发明进行详细描述。
以下实施例中，硅胶购自青岛海洋化工有限公司；3-氨基丙基三甲氧基硅烷购自Sigma；海藻酸钠购自青岛明月海藻有限公司；鱼胶原蛋白分离自深海鳕鱼，分子量为300-350kDa(即I型胶原蛋白)；透明质酸钠购自Solarbio，分子量为80-2000kDa；EDC与NHS均购自Sigma，货号分别为39391和130672；角膜接触镜的厚度采用角膜测厚仪测得。
实施例1
(1)在70℃下将硅胶(300-400目)用浓硫酸(98重量％)处理2h后，用蒸馏水 清洗多次至中性，再经0.01M盐酸溶液：无水乙醇＝1:1(v/v)，在37℃下处理2h，用蒸馏水清洗多次至中性，20℃干燥24h备用；
(2)取0.01g经步骤(1)处理后的硅胶置于2mL的醋酸溶液(pH 4)中超声(40kHz)分散20min后，加入到浓度为25mg/mL的海藻酸钠的溶液(4mL)中，涡旋混合均匀，离心除气泡；取300μL滴加到角膜接触镜的模具中，将塞子缓慢塞住，从边缘缝隙中滴加0.2mol/L的CaCl2溶液10μL，轻旋塞子，置于25℃下2h，即得厚度为100μm的角膜接触镜。
实施例2
(1)在80℃下将硅胶(800目)用浓硫酸(98重量％)处理5h后，用蒸馏水清洗多次至中性，再经0.01M盐酸溶液：无水乙醇＝1:5(v/v)，在50℃下处理2h，用蒸馏水清洗多次至中性，20℃干燥24h备用；
(2)取0.008g经步骤(1)处理后的硅胶置于2mL的醋酸溶液(pH 6)中超声(40kHz)分散20min后，加入到浓度为20mg/mL的鱼胶原蛋白的溶液(5mL)中，涡旋混合均匀，离心除气泡；取300μL滴加到角膜接触镜的模具中，将塞子缓慢塞住，从边缘缝隙中滴加0.05mol/L的EDC/NHS混合液10μL，轻旋塞子，置于20℃下4h，即得厚度为100μm的角膜接触镜。
实施例3
(1)在4℃下将1mg的3-氨基丙基三甲氧基硅烷分散(40kHz超声分散20min)到3mL的醋酸溶液(pH 3)中，继而加入到10mL透明质酸钠的溶液(浓度为10mg/mL)中，在冰浴状态下涡旋混合10min，离心除气泡，取混合液100μL滴加到角膜接触镜的模具中，将塞子缓慢塞住，从边缘缝隙中滴加1mol/L的EDC/NHS混合液10μL，轻旋塞子，置于15℃下5h，即得厚度为100μm的角膜接触镜。
实施例4
按照实施例2的方法制备角膜接触镜，不同的是，使用的“鱼胶原蛋白”由“猪胶原蛋白(分子量为8-10kDa)”代替，获得的角膜接触镜的厚度为100μm。
测试例1
测定以上实施例获得的角膜接触镜的各个参数，如透光率、氧气传导系数(DK/t)、含水量等，具体方法参照国家标准(GB/T11417.5-2012和GB/T11417.7-2012)，结果如下表1所示。
表1
实施例编号 透光率(％) DK/t(banrrers/mm) 含水量(重量％)
实施例1 95 106 63
实施例2 93 129 70
实施例3 91 102 52
实施例4 87 81 47
从表1所示的结果可以看出，实施例获得的高透氧性材料的透光率高、氧气传导系数满足理想延长佩戴的要求且含水量较高。因此，本发明的高透氧性材料具有高透氧性，且其含水量较高，从而同时具有较佳的舒适性。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。

Claims (16)

  1. 一种高透氧性材料，其特征在于，该高透氧性材料由含硅物质和生物活性物质在交联剂的存在下复合而成，其中，所述含硅物质具有硅氧基团，所述生物活性物质选自海藻酸、胶原蛋白、透明质酸以及它们的盐中的至少一种。
  2. 根据权利要求1所述的高透氧性材料，其中，相对于100重量份的所述生物活性物质，所述含硅物质的用量为1-10重量份。
  3. 根据权利要求1或2所述的高透氧性材料，其中，所述胶原蛋白的分子量为8-350kDa。
  4. 根据权利要求1或2所述的高透氧性材料，其中，所述透明质酸的分子量为80-2000kDa。
  5. 根据权利要求1或2所述的高透氧性材料，其中，所述含硅物质选自硅胶、3-氨基丙基三甲氧基硅烷、四乙氧基硅烷和二甲基二乙氧基硅烷中的至少一种，所述硅胶的粒径优选为200-800目。
  6. 根据权利要求1-5中任意一项所述的高透氧性材料，其中，相对于100重量份的所述生物活性物质，所述交联剂的用量为0.01-5重量份。
  7. 根据权利要求1-6中任意一项所述的高透氧性材料，其中，所述交联剂为氯化钙，和/或1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺与N-羟基琥珀酰亚胺的混合物。
  8. 制备权利要求1-7中任意一项所述的高透氧性材料的方法，其特征在于，该方法包括：在酸性条件下，将含硅物质与生物活性物质混合，再将得到的混合物在交联剂的存在下进行交联。
  9. 根据权利要求8所述的方法，其中，所述酸性条件的pH值为3-6。
  10. 根据权利要求8或9所述的方法，其中，在将含硅物质与生物活性物质混合之前，使所述含硅物质分散在酸溶液中，其中，所述酸溶液的氢离子浓度为10-3-10-6mol/L。
  11. 根据权利要求10所述的方法，其中，所述含硅物质为硅胶，所述方法还包括：在将所述含硅物质分散在酸溶液中之前，将所述含硅物质进行如下处理：
    (a)在50-100℃下将含硅物质用酸液处理2-10h，再用水洗涤至中性；
    (b)在20-50℃下，将步骤(1)处理后的含硅物质置于盐酸溶液和乙醇的混合液中浸泡2-10h，用水洗涤至中性。
  12. 根据权利要求10或11所述的方法，其中，所述酸溶液中的酸为醋酸、硫酸、硝酸和盐酸中的至少一种。
  13. 根据权利要求8所述的方法，其中，所述交联的条件包括：温度为15-35℃，时间为2-5h。
  14. 制备权利要求1所述的高透氧性材料的方法，其特征在于，所述方法包括如下步骤：
    (1)将分散于氢离子浓度为10-3-10-6mol/L的酸溶液中的含硅物质与生物活性物质混合，所述含硅物质选自硅胶、3-氨基丙基三甲氧基硅烷、四乙氧基硅烷和二甲基二乙氧基硅烷中的至少一种，所述硅胶的粒径为200-800目，所述生物活性物质选自海藻酸、海藻酸钠、海藻酸钾、胶原蛋白、透明质酸、透明质酸钠和透明质酸钾的至少一种；
    (2)在15-35℃下，将步骤(1)得到的混合物在交联剂的存在下交联2-5h；
    其中，相对于100重量份的所述生物活性物质，所述含硅物质的用量为1-10重量份，所述交联剂的用量为0.01-5重量份。
  15. 由权利要求8-14中任意一项所述的方法制得的高透氧性材料。
  16. 权利要求8-14中任意一项所述的方法、或者权利要求1-7和15中任意一项所述的高透氧性材料在制备角膜接触镜、角膜支架材料或角膜替代物中的应用。
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