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WO2008005752A2 - Modification des surfaces d'articles polymères par réaction d'addition de michael - Google Patents

Modification des surfaces d'articles polymères par réaction d'addition de michael Download PDF

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Publication number
WO2008005752A2
WO2008005752A2 PCT/US2007/072119 US2007072119W WO2008005752A2 WO 2008005752 A2 WO2008005752 A2 WO 2008005752A2 US 2007072119 W US2007072119 W US 2007072119W WO 2008005752 A2 WO2008005752 A2 WO 2008005752A2
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WO
WIPO (PCT)
Prior art keywords
medical device
group
functional group
coating
coating polymer
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Application number
PCT/US2007/072119
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English (en)
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WO2008005752A3 (fr
Inventor
Joseph C. Salamone
Wenyan Yan
Yu-Chin Lai
Weihong Lang
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Bausch & Lomb Incorporated
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Publication date
Priority claimed from US11/480,243 external-priority patent/US20080003259A1/en
Priority claimed from US11/479,227 external-priority patent/US20080003252A1/en
Application filed by Bausch & Lomb Incorporated filed Critical Bausch & Lomb Incorporated
Priority to EP07812327A priority Critical patent/EP2035050A2/fr
Publication of WO2008005752A2 publication Critical patent/WO2008005752A2/fr
Publication of WO2008005752A3 publication Critical patent/WO2008005752A3/fr

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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
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Definitions

  • the present invention relates to modification of surfaces of polymeric articles by the Michael addition reaction.
  • the present invention relates to medical devices having surfaces modified by the Michael addition reaction.
  • a known method for modifying the surface hydrophilicity of a relatively hydrophobic ophthalmic device, such as a contact lens, is through the use of a plasma treatment.
  • Plasma treatment techniques are disclosed, for example, in PCT Publications WO 96/31792 to Nicolson et al., WO 99/57581 to Chabrececk et al., and WO 94/06485 to Chatelier et al.
  • photoinitiator molecules are covalently bound to the surface of the article after the article has been subjected to a plasma treatment which provides the surface with functional groups.
  • a layer of polymerizable macromonomer is then coated onto the modified surface and heat or radiation is applied to graft polymerize the macromonomer to form the hydrophilic surface.
  • heat or radiation is applied to graft polymerize the macromonomer to form the hydrophilic surface.
  • photoinitiators it may be difficult to provide an effective number of photoinitiators on the surface to effect a strong attachment of the resulting polymer.
  • the present invention provides a method for modifying surfaces of polymeric articles by the Michael addition reaction (sometimes also referred to in the art as "Michael reaction”).
  • Michael addition reaction sometimes also referred to in the art as "Michael reaction”
  • the present invention also provides such polymeric articles having surfaces comprising attached polymeric materials.
  • the polymeric articles are medical devices that can provide higher level of performance quality and/or comfort to the users.
  • the present invention provides a medical device having a polymer coating on a surface of the medical device.
  • the polymer coating comprises a hydrophilic polymer coating.
  • the hydrophilic polymer coating is attached directly or indirectly to the surface of the medical device.
  • the coating comprises a coating polymer covalently attached directly or indirectly to the surface of the medical device.
  • the coating polymer is attached to the surface of the medical device by the Michael addition reaction.
  • the medical device and the coating polymer have complementary functional groups that participate in the Michael addition reaction.
  • the medical devices are ophthalmic devices.
  • the medical devices are contact lenses.
  • the medical devices have reduced contact angles compared to those that do not have a polymeric coating of the present invention.
  • the present invention provides a method of making a medical device that has a hydrophilic surface.
  • the method comprises: (a) providing the medical device having a medical-device surface functional group; (b) providing a polymer having a hydrophilic moiety and a polymer functional group capable of interacting with said medical-device surface functional group in the Michael addition reaction; and (c) contacting the medical device with the polymer at a condition sufficient to produce the medical device having an increased surface hydrophilicity.
  • the present invention provides a method for modifying surfaces of polymeric articles by the Michael addition reaction.
  • the present invention also provides such polymeric articles having surfaces comprising attached polymeric materials.
  • the polymeric materials are attached to the surfaces of the polymeric articles by the Michael addition reaction, which is the nucleophilic addition to the ⁇ - ⁇ double bond conjugate to an electron-withdrawing group.
  • a coating polymeric material of the present invention comprises one or more ⁇ - ⁇ double bonds conjugate to electron-withdrawing groups (such as carbonyl or sulfonyl group), and the surfaces of the polymeric article comprise a plurality of nucleophilic groups.
  • the surfaces of the polymeric article comprise a plurality of ⁇ - ⁇ double bonds conjugate to electron-withdrawing groups (such as carbonyl or sulfonyl group), and a coating polymeric material of the present invention comprises one or more nucleophilic groups.
  • electron-withdrawing groups such as carbonyl or sulfonyl group
  • nucleophilic groups are amines, thiols, hydroxyl, hydroxylamines, hydrazines, guanadines, imines, phosphines, and carbanions.
  • the nucleophilic groups comprise the primary amine group (-NH 2 ), the secondary amine groups (-NHR), the tertiary amine groups (-NR 1 R 2 ), wherein R, R 1 , and R 2 are monovalent groups, such as, for example, monovalent d-1 0 aliphatic hydrocarbon groups or alkylaryl groups, or aromatic tertiary amino groups (such as pyridine); and the coating polymeric material comprises the acrylate group.
  • the nucleophilic group comprises a tertiary amino group
  • the attachment reaction is advantageously carried out in the presence of a hydrogen donor.
  • the polymeric material of the article comprises the nucleophilic groups, some of which are exposed on the surface of the article.
  • the nucleophilic groups are created on the surface of the polymeric article, such as by implantation of reactive moieties at the surface of such an article, which reactive moieties comprise such nucleophilic groups or by reaction of the surface material with a reagent to result in such nucleophilic groups.
  • ⁇ - ⁇ double bonds conjugate to electron- withdrawing groups are formed on the surfaces of the polymeric article by reacting the same with reactive compounds having such double bonds.
  • the polymeric article is a medical device.
  • the medical device is an ophthalmic device.
  • the ophthalmic device is a contact lens.
  • the medical device comprises a siloxanyl-based polymer.
  • siloxanyl-based means comprising a silicon-oxygen-silicon bond. Suitable siloxanyl-based polymers are disclosed below.
  • the present invention provides medical devices comprising hydrophilic surfaces and/or reduced dehydration rates and methods for making these devices.
  • a method of making a medical device that has a hydrophilic surface comprises: (a) providing the medical device having a medical-device surface functional group; (b) providing a polymer having a hydrophilic moiety and polymer functional group that is capable of interacting with said medical-device surface functional group in the Michael addition reaction; and (c) contacting the medical device with the polymer at a condition sufficient to produce the medical device having an increased surface hydrophilicity.
  • the step of providing the medical device having a medical-device surface functional group comprises creating the surface functional group by implantation of moieties that comprise the surface functional group. The implantation is effected at or in the surface of the medical device.
  • the step of providing the medical device having a medical- device surface functional group comprises creating the surface functional group by reacting the material of the surface of the medical device with a suitable reagent to form the surface functional group.
  • the suitable reagent is an oxidizing agent.
  • the step of reacting comprises exposing the surface to plasma containing an oxidizing agent, such as an oxygen-containing species, ammonia, or amine.
  • One class of coating materials includes a macromonomer having the formula of
  • G and G' are groups that comprise at least an ethylenically unsaturated group
  • L is a direct bond or a divalent linkage group that comprises a hydrocarbon group or a heterohydrocarbon group
  • M represents a hydrophilic monomeric unit
  • n is a positive integer in the range from about 2 to about 1000. In some embodiments, n is in the range from about 2 to about 800, or from about 2 to about 600, or from about 10 to about 600, or from about 20 to about 600, or from about 20 to 500.
  • L is a direct bond.
  • L comprises a C M O linear saturated or unsaturated hydrocarbon group, a C 3- io branched saturated or unsaturated hydrocarbon group, or a 0 3 -1 0 cyclic saturated or unsaturated hydrocarbon group.
  • L also can include one or more atoms selected from the group consisting of O, N, S, and combinations thereof.
  • G' can be absent, and a macromonomer of the present invention has a formula of G' (M) n - (H)
  • G, L, M, and n have the meanings as disclosed above, and E comprises a C- 1 - 10 linear or branched hydrocarbon group, or a C 3- I 0 cyclic saturated, or unsaturated hydrocarbon group, or a heteroatom.
  • G and G' are independently selected from the group consisting of acrylate, methacrylate, sinapate (or 3,5-dimethoxy-4- hydroxycinnamate), cinnamate (or 3-phenylacrylate), senecioate (or 3,3- dimethylacrylate), crotonate, maleate, fumarate, itaconate, vinyl, allyl, and styryl groups.
  • (M) n represents oligomeric or polymeric chain comprising units of N-vinylpyrrolidone.
  • (M) n represents oligomeric or polymeric chain comprising units of polyhydric alcohols (such as glyceryl methacrylate or glyceryl acrylate), dimethyl methacrylamide, dimethyl acrylamide (“DMA”), 2-hydroxyethyl methacrylate (“HEMA”), 2- hydroxyethyl acrylate, erythritol (meth)acrylate, xylitol (meth)acrylate, sorbitol (meth)acrylate, or derivatives thereof.
  • polyhydric alcohols such as glyceryl methacrylate or glyceryl acrylate
  • DMA dimethyl acrylamide
  • HEMA 2-hydroxyethyl methacrylate
  • 2- hydroxyethyl acrylate 2- hydroxyethyl acrylate
  • erythritol (meth)acrylate erythr
  • (M) n represents oligomeric or polymeric chain comprising units of one of the foregoing monomers and units of an alkylene oxide (such as ethylene oxide or propylene oxide).
  • M include acrylic acid, methacrylic acid, and Zwitterionic monomer such as ⁇ 3-(methacryloylamino)propyi ⁇ dimethyl(3- sulfopropyl)ammonium hydroxide inner salt.
  • the macromonomer is a methacrylate- or acrylate-terminated poly(N-vinylpyrrolidone). Poly(N-vinylpyrrolidone) is sometimes herein abbreviated as "PVP". Such a macromonomer is represented by the following formula.
  • G 1 and G 2 are independently selected from the group consisting of acrylate and methacrylate; G 2 can be absent in some embodiments; and L, M, and have the meanings disclosed above.
  • the present invention provides a method for making an ethylenically unsaturated hydrophilic macromonomer.
  • the method comprises reacting an oligomer or polymer having a first functional group with a compound having a second functional group that is capable of reacting with the first functional group, wherein the compound comprises an ethylenically unsaturated group.
  • An acrylate- or methacrylate-terminated PVP can be prepared by reacting acryloyl chloride or methacryloyl chloride with monohydroxy- or dihydroxy-terminated PVP in the presence of a weak base, such as a tertiary amine or an alkali carbonate.
  • a weak base such as a tertiary amine or an alkali carbonate.
  • an acrylate-terminated PVP is prepared according to the following reaction.
  • R is a direct bond or a divalent group selected from the group consisting of C-1-10 saturated and unsaturated hydrocarbon groups, C M0 saturated and unsaturated hydrocarbon groups having one or more heteroatoms therein, C3- 10 cyclic hydrocarbon groups, C3-10 heterocyclic groups, C ⁇ -36 aryl groups, and C 6-36 heteroaryl groups.
  • R is a C M0 alkyl group.
  • R is methylene, dimethylene, trimethylene, or tetra methylene.
  • hydroxy-terminated PVP can be reacted with glycidyl acrylate or glycidyl methacylate to yield acrylate- or methacrylate-terminated PVP.
  • methacrylate-terminated PVP can be prepared according to the following reaction, wherein R has the meaning disclosed above.
  • hydroxyl-terminated PVP can be reacted with 2-isocyantoethyi acrylate or 2-isocyanato methacylate to yield acrylate- or methacrylate-terminated PVP.
  • methacrylate-terminated PVP is prepared according to the following reaction, wherein R has the meaning disclosed above.
  • such a methacrylate- or acrylate- terminated PVP can be further modified to produce amino-terminated PVP, for example, according to the following scheme.
  • vinyl-, allyl-, or styryl-terminated PVP can be prepared by reacting hydroxy-terminated PVP with vinyl, allyl, or styryl isocyanate, respectively.
  • vinyl-terminated can be prepared from hydroxyl-terminated PVP and vinyl isocyanate according to the following reaction, wherein R has the meaning disclosed above.
  • a maleate- or itaconate-terminated PVP can be prepared by reacting maleic anhydride or itaconic anhydride with hydroxyl-terminated PVP.
  • fumarate-terminated PVP can be prepared by reacting fumaric acid with hydroxyl-terminated PVP.
  • maleate-terminated PVP can be prepared according to the following reaction, wherein R has the meaning disclosed above.
  • a macromonomer comprising hydrophilic moieties other than, or in addition to N-vinylpyrrolidone can be prepared in a method similar to one of those disclosed above.
  • hydrophilic monomers comprising such other hydrophilic moieties include glyceryl (meth)acrylate, dimethyl (meth)acrylamide, 2-hydroxyethyl (meth)acrylate, erythritol (meth)acrylate, xylitol (meth)acrylate, sorbitol (meth)acrylate, derivatives thereof, combinations thereof, and mixtures thereof.
  • a macromonomer of the present invention can comprise units of one or more hydrophilic monomers disclosed above.
  • a contact lens comprises surface amino group
  • the coating polymer comprises acrylate- terminated polyvinylpyrrolidone
  • the surface-modified contact lens is produced according to Scheme 1 , wherein n is a positive integer. In one embodiment, n can range from about 5 to about 1000, or from about 10 to 800, or from about 10 to about 600, or from about 20 to about 500.
  • R is a direct bond or a divalent group selected from the group consisting of C1- 10 saturated and unsaturated hydrocarbon groups, CM O saturated and unsaturated hydrocarbon groups having one or more heteroatoms therein, C3-10 cyclic hydrocarbon groups, C3-10 heterocyclic groups, C 6 - 3 6 aryl groups, and C ⁇ -36 heteroaryi groups.
  • the medical devices have increased surface lubricity.
  • the medical devices of the present invention provide higher level of performance quality and/or comfort to the users due to their hydrophilic or lubricious surfaces.
  • the medical devices are contact lenses, such as extended-wear contact lenses. Hydrophilic surfaces of such contact lenses substantially prevent or limit the adsorption of tear lipids and proteins on, and their eventual absorption into, the contact lenses, thus preserving the clarity of the contact lenses, and in turn preserving their performance quality and providing a higher level of comfort to the wearer.
  • the present invention provides a medical device having a hydrophilic polymer coating that is attached to a surface of the medical device by the Michael addition reaction at surface functional groups.
  • the hydrophilic polymer coating comprises a plurality of hydrophilic moieties, which may be the same or different, and a polymer functional group that is capable of reacting with the surface functional groups in the Michael addition reaction.
  • such a polymer functional group comprises an ⁇ - ⁇ double bond conjugate to an electron-withdrawing group.
  • such an electron-withdrawing group is a carbonyl group.
  • such an electron-withdrawing group is a sulfonyl group.
  • the coating polymer comprises monomeric units selected from the group consisting of N,N-dimethylacrylamide, polymerizable polyhydric alcohols, polymerizable alkylene oxides, polymerizable carboxylic acids, derivatives thereof, combinations thereof, and mixtures thereof.
  • n is a positive integer.
  • n can range from about 5 to about 1000, or from about 10 to 800, or from about 10 to about 600, or from about 20 to about 500, and R is as previously defined.
  • the polymerizable polyhydric alcohols comprise a material other than polymerizable poly(alkylene glycol) (or poly(oxyalkylene)) and derivatives thereof.
  • the polymerizable polyhydric alcohols are other than polymerizable poly(ethylene glycol) or polymerizable poly(propylene glycol).
  • Non-limiting examples of such polymerizable polyhydric alcohols include glycerol (meth)acrylate, erythritol (meth)acrylate, xylitol (meth)acrylate, sorbitol (meth)acrylate, derivatives thereof, combinations thereof, r or mixtures thereof.
  • the term "(meth)acrylate” means methacrylate or acrylate.
  • the (meth)acrylate is mono(meth)acrylate.
  • di(meth)acrylate or a mixture of mono(meth)acrylate and di(meth)acrylate may be used.
  • the coating polymer comprises polysaccharides (such as hyaluronic acid or hydroxypropylmethyl cellulose) that have a terminal functional group that is capable of participating in the Michael addition reaction.
  • polysaccharides such as hyaluronic acid or hydroxypropylmethyl cellulose
  • the coating polymer comprises a macromonomer having a formula of
  • the coating polymer can comprise carboxylic acids that are selected from alkenoic acids comprising 4 to and including 10 carbon atoms.
  • the alkenoic acids are selected from the group consisting of maleic acid, fumaric acid, itaconic acid, derivatives thereof (such as maleic anhydride, fumaric anhydride, or itaconic anhydride), combinations thereof, and mixtures thereof.
  • carboxylic acids also includes compounds that are capable of being converted into carboxylic acids, such as, for example, vinyldimethyloxozalone ("VDMO").
  • the coating polymer is attached to the surface of the medical device through an intermediate compound or linking compound or an intermediate polymer (or also herein sometimes called "linking polymer") that has functional groups capable of interacting with functional groups on the surface of the medical device and functional groups of the coating polymer.
  • the intermediate compound acts to couple the coating polymer to the surface of the medical device through the Michael addition reaction.
  • the intermediate compound or polymer can comprise terminal amino groups, which are capable of forming bonds with functional groups on the surface of the medical device and with the conjugate unsaturated bond at the end of the hydrophilic coating polymer.
  • the intermediate compound or polymer has a terminal amino group, it may be desirable to have no other functional groups in such intermediate compound or polymer that can react with the terminal amino group.
  • a contact lens comprises surface carboxylic group
  • the coating polymer comprises acrylate-terminated poly(vinylpyrrolidone)
  • the linking compound is ethylene diamine
  • n can range from about 5 to about 1000, or from about 10 to 800, or from about 10 to about 600, or from about 20 to about 500
  • R is a direct bond or a divalent group selected from the group consisting of CM O saturated and unsaturated hydrocarbon groups, Ci- io saturated and unsaturated hydrocarbon groups having one or more heteroatoms therein, C 3 -10 cyclic hydrocarbon groups, C 3 -10 heterocyclic groups, C ⁇ -36 aryl groups, and C 6 -36 heteroaryl groups.
  • the medical device has a polymer coating consisting or consisting essentially of units of vinylpyrrolidone.
  • the surface treatment of the medical device can be carried out, for example, at about room temperature or under autoclave condition.
  • the medical device is immersed in a solution comprising the coating polymer.
  • the medical device is immersed in a solution comprising the coating polymer and the linking compound (or linking polymer).
  • the medical device comes into contact with the linking compound and the coating polymer substantially simultaneously.
  • the medical device is immersed in a solution comprising the linking compound.
  • the coating polymer is added to the solution in which the medical device is still immersed.
  • the solution is aqueous.
  • the solution comprises a polar organic solvent, such as methanol or ethanol.
  • the medical device comprises a polymeric material and the nucleophilic functional groups on the surface thereof are parts of units of the polymeric material.
  • hydrogel polymers of contact lens typically comprise hydrophilic monomeric units, such as 2-hydroxyethyl methacrylate, which provides nucleophilic hydroxyl surface groups.
  • a hydrogel polymer can comprise a suitable amount of a precursor of 2-aminoethyl methacrylate, which provides nucleophilic amino surface groups after the manufactured lens is neutralized.
  • the surface of the medical device can be treated with a plasma discharge or corona discharge to increase the population of reactive surface groups.
  • the type of gas introduced into the treatment chamber is selected to provide the desired type of reactive surface groups.
  • hydroxyl surface groups can be produced with a treatment chamber atmosphere comprising water vapor or alcohols.
  • Carboxyl surface groups can be generated with a treatment chamber comprising oxygen or air or another oxygen-containing gas.
  • Ammonia or amines in a treatment chamber atmosphere can generate amino surface groups.
  • Sulfur-containing gases, such as organic mercaptans or hydrogen sulfide can generate the mercaptan group on the surface.
  • a combination of any of the foregoing gases also can be used in the treatment chamber.
  • the surfaces of the polymeric article comprise a plurality of ⁇ - ⁇ double bonds conjugate to electron-withdrawing groups (such as carbonyl or sulfonyl group), and a coating polymeric material of the present invention comprises one or more nucleophilic groups.
  • the plurality of ⁇ - ⁇ double bonds conjugate to electron-withdrawing groups can be generated on the surfaces of the polymeric article by reacting the article with a compound that has a moiety that comprises such an ⁇ - ⁇ double bond.
  • a polymeric article the surfaces of which have a plurality of hydroxyl groups can be reacted with acryloyl chloride, methacryloyl chloride, fumaroyl chloride, or itaconyl chloride to generate a plurality of ⁇ - ⁇ double bonds conjugate to carbonyl electron-withdrawing groups.
  • the polymeric article thus treated can then be exposed to a hydrophilic coating polymeric material comprising at least a nucleophilic group to form a hydrophilic coating thereon, as shown in Scheme 4, wherein the hydrophilic coating comprises a plurality of polyethylene glycol units.
  • an acryloyl-functionalized contact lens as disclosed above, can be treated with hydrophilic poly(vinylpyrrolidone) to produce a hydrophilic coating as shown in Scheme 5.
  • Non-hydrogel materials are hydrophobic polymeric materials that do not contain water in their equilibrium state.
  • Typical non- r hydrogel materials comprise silicone acrylics, such as those formed from bulky silicone monomer (e.g., tris(trimethylsiloxy)silylpropyl methacrylate, commonly known as "TRIS" monomer), methacrylate end-capped poly(dimethylsiloxane) prepolymer, or silicones having fluoroalkyl side groups.
  • hydrogel materials comprise hydrated, cross-linked polymeric systems containing water in an equilibrium state. Hydrogel materials contain about 5 weight percent water or more (up to, for example, about 80 weight percent).
  • Non-limiting examples of materials suitable for the manufacture of medical devices, such as contact lenses, are herein disclosed.
  • Hydrogel materials for medical devices can comprise a hydrophilic monomer, such as, HEMA, methacrylic acid (“MAA”), acrylic acid (“AA”), methacrylamide, acrylamide, N,N'-dimethylmethacrylamide, or N,N'-dimethylacrylamide; copolymers thereof; hydrophilic prepolymers, such as poly(alkylene oxide) having varying chain length, functionalized with polymerizable groups; and/or silicone hydrogels comprising siloxane-containing monomeric units and at least one of the aforementioned hydrophilic monomers and/or prepolymers.
  • a hydrophilic monomer such as, HEMA, methacrylic acid (“MAA"), acrylic acid (“AA”), methacrylamide, acrylamide, N,N'-dimethylmethacrylamide, or N,N'-dimethylacrylamide
  • copolymers thereof hydrophilic prepolymers, such as poly(alkylene oxide) having varying chain length, functionalized with polymerizable groups
  • Hydrogel materials also can comprise a cyclic lactam, such as N-vinyl-2-pyrrolidone ("NVP"), or derivatives thereof.
  • NDP N-vinyl-2-pyrrolidone
  • Still further examples are the hydrophilic vinyl carbonate or vinyl carbamate monomers disclosed in U.S. Patent 5,070,215, and the hydrophilic oxazolone monomers disclosed in U.S. Patent 4,910,277.
  • Other suitable hydrophilic monomers will be apparent to one skilled in the art.
  • Silicone hydrogels generally have water content greater than about 5 weight percent and more commonly between about 10 to about 80 weight percent. Such materials are usually prepared by polymerizing a mixture containing at least one siloxane-containing monomer and at least one hydrophilic monomer. Typically, either the siloxane-containing monomer or the hydrophilic monomer functions as a crosslinking agent (a crosslinking agent or crosslinker being defined as a monomer having multiple polymerizable functionalities) or a separate crosslinker may be employed. Applicable siloxane-containing monomeric units for use in the formation of silicone hydrogels are known in the art and numerous examples are provided, for example, in U.S. Patents 4,136,250; 4,153,641 ; 4,740,533; 5,034,461 ; 5,070,215; 5,260,000; 5,310,779; and 5,358,995.
  • Examples of applicable siloxane-containing monomeric units include bulky polysiloxanylalkyl (meth)acrylic monomers.
  • the term "(meth)acrylic” means methacrylic or acrylic, depending on whether the term "meth” is present or absent.
  • An example of bulky polysiloxanylalkyl (meth)acrylic monomers are represented by the following Formula I:
  • X denotes -O- or -NR-; each Ri independently denotes hydrogen or methyl; each R 2 independently denotes a lower alkyl radical, phenyl radical or a group represented by
  • each R 2 independently denotes a lower alkyl, fluoroalkyl, or phenyl radical; and h is 1 to 10.
  • lower alkyl means an alkyl radical having 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, or hexyl radical.
  • a suitable bulky monomer is methacryloxypropyltris(trimethyl- siloxy)silane or tris(trimethylsiloxy)silylpropyl methacrylate (“TRIS").
  • silicon-containing monomers includes silicone-containing vinyl carbonate or vinyl carbamate monomers such as: 1 ,3- bis ⁇ 4-vinyloxycarbonyloxy)but-1-yl ⁇ tetramethyldisiloxane; 3-(trimethylsilyl)propyl vinyl carbonate; 3-(vinyloxycarbonylthio)propyl- ⁇ tris(trimethylsiloxy)silane ⁇ ; 3- ⁇ tris(trimethylsiloxy)silyl ⁇ propyl vinyl carbamate; 3- ⁇ tris(trimethylsiloxy)silyl ⁇ propyl allyl carbamate; 3- ⁇ tris(trimethylsiloxy)silyl ⁇ propyl vinyl carbonate; t- butyldimethylsiloxyethyl vinyl carbonate; trimethylsilylethyl vinyl carbonate; and trimethylsilylmethyl vinyl carbonate.
  • silicone-containing vinyl carbonate or vinyl carbamate monomers such as: 1 ,3- bis ⁇ 4-vinyloxycarbonyloxy)but
  • silicon-containing monomers includes silicone-containing vinyl carbonate or vinyl carbamate monomers such as: 1 ,3- bis ⁇ 4-vinyloxycarbonyloxy)but-1-yl ⁇ tetramethyl-disiloxane; 3-(trimethylsilyl)propyl vinyl carbonate; 3-(vinyloxycarbonylthio)propyl- ⁇ tris(trimethylsiloxy)silane ⁇ ; 3- ⁇ tris(tri-methyisiloxy)silyl ⁇ propyl vinyl carbamate; 3- ⁇ tris(trimethylsiloxy)silyi ⁇ propyl allyl carbamate; 3- ⁇ tris(trimethylsiloxy)silyl ⁇ propyl vinyl carbonate; t- butyldimethylsiloxyethyl vinyl carbonate; trimethylsilylethyl vinyl carbonate; and trimethylsilylmethyl vinyl carbonate.
  • silicone-containing vinyl carbonate or vinyl carbamate monomers such as: 1 ,3- bis ⁇ 4-vinyloxycarbony
  • Y 1 denotes -O-, -S- or -NH-;
  • R denotes a silicon-containing organic radical
  • R 3 denotes hydrogen or methyl
  • d is 1 , 2, 3 or 4.
  • Suitable silicon-containing organic radicals RSi include the following: -(CH 2 J n . Si[(CH 2 ) m ,CH 3 ] 3 ; -(CH 2 J n . Si[OSi(CH 2 ) m ,CH 3 ] 3 ;
  • R 5 denotes an alkyi radical or a fluoroalkyl radical having from 1 to and including 6 carbon atoms; e is 1 to 200; n' is 1 , 2, 3 or 4; and m' is 0, 1 , 2, 3, 4 or 5.
  • An example of a particular species within Formula Il is represented by Formula III.
  • silicon-containing monomer includes polyurethane- polysiloxane macromonomers (also sometimes referred to as prepolymers), which may have hard-soft-hard blocks like traditional urethane elastomers. They may be end-capped with a hydrophilic monomer such as HEMA.
  • silicone urethanes are disclosed in a variety or publications, including Lai, Yu-Chin, "The Role of Bulky Polysiloxanylalkyl Methacryates in Polyurethane- Polysiloxane Hydrogels," Journal of Applied Polymer Science, Vol. 60, 1193- 1199 (1996).
  • PCT Published Application No. WO 96/31792 discloses examples of such monomers, which disclosure is hereby incorporated by reference in its entirety.
  • Further examples of silicone urethane monomers are represented by Formulae IV and V:
  • D denotes an alkyl diradical, an alkyl cycloalkyl diradical, a cycloalkyl diradical, an aryl diradical or an alkylaryl diradical having 6 to 30 carbon atoms
  • G denotes an alkyl diradical, a cycloalkyl diradical, an alkyl cycloalkyl diradical, an aryl diradical or an alkylaryl diradical having 1 to 40 carbon atoms and which may contain ether, thio or amine linkages in the main chain;
  • a is at least 1 ;
  • A denotes a divalent polymeric radical of Formula Vl:
  • each R s independently denotes an alkyl or fluoro-substituted alkyl group having 1 to 10 carbon atoms which may contain ether linkages between carbon atoms; m' is at least 1 ; and p is a number which provides a moiety weight of 400 to 10,000; each of E and E' independently denotes a polymerizable unsaturated organic radical represented by Formula VII:
  • R 6 is hydrogen or methyl
  • R 7 is hydrogen, an alkyl radical having from 1 to and including 6 carbon atoms, or a -CO-Y-R 9 radical wherein Y is -O-, -S- or -NH-;
  • R 8 is a divalent alkylene radical having from 1 to and including 10 carbon r atoms
  • R 9 is a alkyl radical having from 1 to and including 12 carbon atoms
  • X denotes -CO- or -OCO-
  • Z denotes -O- or -NH-
  • Ar denotes a substituted or unsubstituted aromatic radical having from 6 to and including 30 carbon atoms
  • w is from 0 to and including 6; x is 0 or 1 ; y is 0 or 1 ; and z is 0 or 1.
  • a preferred silicone hydrogel material comprises (in the bulk monomer mixture that is copolymerized) 5 to 50 percent, preferably 10 to 25, by weight of one or more silicone macromonomers, 5 to 75 percent, preferably 30 to 60 percent, by weight of one or more poly(siloxanylalkyl (meth)acrylic) monomers, and 10 to 50 percent, preferably 20 to 40 percent, by weight of a hydrophilic monomer.
  • the silicone macromonomer is a poly(organosiloxane) capped with an unsaturated group at two or more ends of the molecule.
  • the silane macromonomer is a silicon-containing vinyl carbonate or vinyl carbamate or a polyurethane-polysiloxane having one or more hard-soft-hard blocks and end- capped with a hydrophilic monomer.
  • a polymeric material of the present invention comprises an additional monomer selected from the group consisting of hydrophilic monomers and hydrophobic monomers.
  • Hydrophilic monomers can be nonionic monomers, such as 2- hydroxyethyl methacrylate (“HEMA”), 2-hydroxyethyl acrylate (“HEA”), 2-(2- ethoxyethoxy)ethyl (meth)acrylate, glyceryl (meth)acrylate, poly(ethylene glycol (meth)acrylate), tetrahydrofurfuryl (meth)acrylate, (meth)acrylamide, N 1 N'- dimethylmethacrylamide, N,N'-dimethylacrylamide("DMA”), N-vinyl-2-pyrrolidone (or other N-vinyl lactams), N-vinyl acetamide, and combinations thereof.
  • HEMA 2- hydroxyethyl methacrylate
  • HOA 2-hydroxyethyl acrylate
  • glyceryl (meth)acrylate poly(ethylene glycol (meth)
  • hydrophilic monomers can have more than one polymerizable group, such as tetraethylene glycol (meth)acrylate, triethylene glycol (meth)acryiate, tripropylene glycol (meth)acrylate, ethoxylated bisphenol-A (meth)acrylate, pentaerythritol (meth)acrylate, pentaerythritol (meth)acrylate, ditrimethylolpropane (meth)acrylate, ethoxylated trimethylolpropane (meth)acrylate, dipentaerythritol (meth)acrylate, alkoxylated glyceryl (meth)acrylate.
  • polymerizable group such as tetraethylene glycol (meth)acrylate, triethylene glycol (meth)acryiate, tripropylene glycol (meth)acrylate, ethoxylated bisphenol-A (meth)acrylate, pentaerythritol (me
  • hydrophilic monomers are the vinyl carbonate and vinyl carbamate monomers disclosed in U.S. Patent 5,070,215, and the hydrophilic oxazolone monomers disclosed in U.S. Patent 4,910,277. The contents of these patents are incorporated herein by reference.
  • the hydrophilic monomer also can be an anionic monomer, such as 2-methacryloyloxyethylsulfonate salts.
  • Substituted anionic hydrophilic monomers such as from acrylic and methacrylic acid, can also be utilized wherein the substituted group can be removed by a facile chemical process.
  • Non-limiting examples of such substituted anionic hydrophilic monomers include trimethylsilyl esters of (meth)acrylic acid, which are hydrolyzed to regenerate an anionic carboxyl group.
  • the hydrophilic monomer also can be a cationic monomer selected from the group consisting of 3- methacrylamidopropyl-N,N,N-trimethyammonium salts, 2-methacryloyloxyethyl- N,N,N-trimethylarnmonium salts, and amine-containing monomers, such as 3- methacrylamidopropyl-N,N-dimethyl amine.
  • Other suitable hydrophilic monomers will be apparent to one skilled in the art.
  • Non-limiting examples of hydrophobic monomers are CrC 2 O alkyl and C 3 -C 20 cycloalkyl (meth)acrylates, substituted and unsubstituted aryl (meth)acrylates (wherein the aryl group comprises 6 to 36 carbon atoms), (meth)acrylonitrile, styrene, lower alkyl styrene, lower alkyl vinyl ethers, and C 2 - C 10 perfluoroalkyl (meth)acrylates and correspondingly partially fluorinated (meth)acrylates.
  • Solvents useful in the surface treatment of the medical device, such as a contact lens include solvents that readily solubilize the polymers such as water, alcohols, lactams, amides, cyclic ethers, linear ethers, carboxylic acids, and combinations thereof.
  • Preferred solvents include tetrahydrofuran (“THF”), acetonitrile, N,N-dimethyl formamide (“DMF”), and water. The most preferred solvent is water.
  • PVP Hydroxyl-functionalized poly(vinylpyrrolidone)
  • PureVision® contact lenses (comprising silicone hydrogel, Bausch & Lomb Incorporated, Rochester, New York) were dried and then plasma treated sequentially with ammonia, butadiene, and ammonia to generate amine- containing groups on the surfaces of the lenses.
  • the lenses were placed in glass vials.
  • Freshly prepared methanol solution containing 16.8% (by weight) of acrylate PVP of Example 2 was then added to the glass vials, which were then set on a rotary machine for three days at room temperature.
  • the treated lenses were rinsed with Dl water and stored in borate buffer saline ("BBS").
  • Control lenses (only plasma treated) were extracted with isopropanol, rinsed with Dl water, and placed in BBS. After being desalinated, both control lenses and coated lenses were subjected to standard surface analysis by XPS, and water contact angles were measured on the lenses. The results are shown in Table 1.
  • the results show an increase in surface carbon and large decreases in surface nitrogen, oxygen, and silicon, indicating that the lens surfaces are covered with the coating polymer.
  • the water contact angle of coated lenses is smaller than that of control lenses, indicating that the coated lenses are more wettable and, thus, should be more lubricious.
  • the coated medical device has a water contact angle of less than about 50 degrees.
  • the water contact angle can be less than about 40 degrees, or less than about 30 degrees, or less than about 20 degrees.
  • Low contact angles can be obtained with hydrophilic coating polymers having an abundance of hydrophilic moieties.
  • PureVision® contact lenses (comprising silicone hydrogel, Bausch & Lomb Incorporated, Rochester, New York) were plasma treated in succession with ammonia, butadiene, and ammonia.
  • the plasma-treated lenses were placed in a 5% (by weight) solution of acryloyl chloride in tetrahydrofuran overnight, followed by hydration.
  • the acryloyl chloride-treated lenses were placed in a 2% (by weight) solution of amino-terminated polyamidoamine (“PAMAM”) dendrimer (generation 4) in methanol/water (5/1 v/v) for 72 hours, and then were rinsed with distilled water and stored in borate buffered saline.
  • PAMAM amino-terminated polyamidoamine
  • Another batch of lenses serving as control lenses was not treated with the PAMAM dendrimer, were extracted with isopropanol, then rinses in deionized water and then stored in borate buffered saline.
  • the results show that treatment of Pure Vision® lenses with hydrophilic PAMAM dendrimer via Michael addition reaction produced a lower contact angle as compared to the control lenses or lenses that were not exposed to PAMAM.
  • the PAMAM-treated lenses also had a significantly lower surface silicon content and a significantly higher surface nitrogen content as compared to control lenses and lenses that were not exposed to PAMAM.
  • the lower contact angle and lower surface silicon content indicate that the PAMAM-treated lenses are much more wettable than control lenses or lenses that were not treated with PAMAM.
  • the present invention also provides a method for producing a medical device having improved hydrophilic surfaces.
  • the method comprises: (a) providing the medical device having a medical-device surface functional group; (b) providing a polymer having a hydrophilic moiety and a polymer functional group capable of interacting with said medical-device surface functional group through the Michael addition reaction; and (c) contacting the medical device with the polymer at a condition sufficient to produce the medical device having an increased surface hydrophilicity.
  • the interaction of the polymer functional group and the medical-device surface functional group involves a Michael addition reaction between said groups.
  • such an interaction involves the Michael addition reaction between the polymer functional group and a functional group of a linking compound (or linking polymer), and a second reaction between a second functional group of the linking compound (or linking polymer) and the medical-device surface functional group.
  • such an interaction involves the Michael addition reaction between the medical-device surface functional group and a functional group of a linking compound (or linking polymer), and a second reaction between a second functional group of the linking compound (or linking polymer) and the polymer functional group.
  • the medical device is contacted with the linking compound or polymer and the coating polymer substantially simultaneously.
  • the medical device may be contacted with the linking compound or polymer in a medium.
  • the coating polymer is subsequently added into the medium after an elapsed time to produce the finally treated medical device.
  • the step of contacting can be effected at ambient condition or under autoclave condition at about 120° C.
  • the temperature for treatment can range from ambient to about 120 0 C, or from slightly above ambient temperature to about 80 0 C.
  • the treatment time can range from about 10 seconds to about 5 days, or from about 1 minute to about 3 days, or from about 10 minutes to about 24 hours, or from about 10 minutes to about 4 hours, or from about 10 minutes r to about 2 hours.
  • the method further comprises the step of treating the surface of the medical device to increase a population of the medical-device surface functional groups before the step of contacting the medical device with the coating polymer or with the coating polymer and the linking polymer.
  • the step of treating the surface of the medical device is carried out in a plasma discharge or corona discharge environment.
  • a gas is supplied to the discharge environment to provide the desired surface functional groups.
  • Medical devices having a hydrophilic coating of the present invention can be used advantageously in many medical procedures.
  • contact lenses having a hydrophilic coating of the present invention and/or produced by a method of the present invention can be advantageously used to correct the vision of the natural eye.
  • Medical articles that are in contact with body fluid such as a wound dressing, catheters, implants (e.g., artificial hearts or other artificial organs), can be provided with a hydrophilic coating of the present invention to inhibit bacterial attachment and growth or to reduce a deposit of lipids or proteins thereon.
  • the coating polymer of any one of the methods disclosed herein comprises units selected from the group consisting of polymerizable poly(N-vinylpyrrolidone), polyhydric alcohols, polymerizable carboxylic acids, copolymers thereof, combinations thereof, and mixtures r thereof.
  • the present invention provides a method of making a medical device that has reduced affinity for bacterial attachment.
  • the method comprises: (a) forming the medical device comprising a polymeric material; (b) treating the medical device such that a surface thereof becomes more hydrophilic.
  • the method comprises: (a) forming the medical device comprising a polymeric material having a medical-device surface functional group; (b) contacting the medical device with a coating polymer having a hydrophilic moiety and a coating-polymer functional group that is capable of interacting with said medical-device surface functional group via the Michael addition reaction.
  • the interaction between the coating polymer and the surface of the medical device is direct.
  • the coating polymer also may interact indirectly with the surface of the medical device through another compound, such as a linking compound or polymer that comprises a first functional group capable of interacting with the medical-device surface functional group and a second functional group capable of interacting with the coating- polymer functional group.
  • a linking compound or polymer that comprises a first functional group capable of interacting with the medical-device surface functional group and a second functional group capable of interacting with the coating- polymer functional group.
  • One or both of the interactions are effected by the Michael addition reaction.
  • Non-limiting examples of materials for the medical device, the linking compound or polymer, and the coating polymer are disclosed above.
  • the medical device is formed by disposing precursors for the medical device material in a cavity of a mold, which cavity has the shape of the medical device, and polymerizing the precursors.
  • a solid block of a polymeric material is first produced, then the medical device is formed from such a solid block; e.g., by shaping, cutting, lathing, machining, or a combination thereof.
  • the medical devices produced in a method of the present invention can be contact lenses, intraocular lenses, corneal inlays, corneal rings, or keratoprotheses.

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Abstract

La présente invention concerne un appareil médical comprenant une qualité d'hydrophilie de surface améliorée qui comprend un enduit polymère comportant des unités de composé hydrophilique polymérisable qui est joint à la surface du dispositif médical par le biais d'une réaction d'addition de Michael. L'enduit polymère peut être appliqué à un dispositif médical comprenant un hydrogel. L'adhésion de l'enduit polymère peut être améliorée en augmentant la population des groupes fonctionnels de surface du dispositif médical avant de d'appliquer l'enduit polymère à ce dispositif.
PCT/US2007/072119 2006-06-30 2007-06-26 Modification des surfaces d'articles polymères par réaction d'addition de michael WO2008005752A2 (fr)

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US11/480,243 US20080003259A1 (en) 2006-06-30 2006-06-30 Modification of surfaces of polymeric articles by Michael addition reaction
US11/479,227 US20080003252A1 (en) 2006-06-30 2006-06-30 Functionalized hydrophilic macromonomers and medical devices incorporating same

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Cited By (13)

* Cited by examiner, † Cited by third party
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WO2010096649A1 (fr) 2009-02-21 2010-08-26 Tyco Healthcare Group Lp Dispositifs médicaux présentant des surfaces activées
WO2014149544A1 (fr) 2013-03-15 2014-09-25 Johnson & Johnson Vision Care, Inc. Lentille de contact contenant de la silicone présentant une quantité réduite de silicium sur la surface
US9486311B2 (en) 2013-02-14 2016-11-08 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US10195018B2 (en) 2013-03-21 2019-02-05 Shifamed Holdings, Llc Accommodating intraocular lens
US10350056B2 (en) 2016-12-23 2019-07-16 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
WO2019185302A1 (fr) 2018-03-27 2019-10-03 Mercene Labs Ab Revêtement et apprêt
US10548718B2 (en) 2013-03-21 2020-02-04 Shifamed Holdings, Llc Accommodating intraocular lens
US10736734B2 (en) 2014-08-26 2020-08-11 Shifamed Holdings, Llc Accommodating intraocular lens
US10987214B2 (en) 2017-05-30 2021-04-27 Shifamed Holdings, Llc Surface treatments for accommodating intraocular lenses and associated methods and devices
US11141263B2 (en) 2015-11-18 2021-10-12 Shifamed Holdings, Llc Multi-piece accommodating intraocular lens
US11266496B2 (en) 2017-06-07 2022-03-08 Shifamed Holdings, Llc Adjustable optical power intraocular lenses
CN116635492A (zh) * 2020-12-30 2023-08-22 康沃特克科技公司 医疗器材的官能化
US12167960B2 (en) 2016-12-23 2024-12-17 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same

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US6440571B1 (en) * 1999-05-20 2002-08-27 Bausch & Lomb Incorporated Surface treatment of silicone medical devices with reactive hydrophilic polymers
US20020120333A1 (en) * 2001-01-31 2002-08-29 Keogh James R. Method for coating medical device surfaces
WO2003063926A1 (fr) * 2002-02-01 2003-08-07 Sustech Gmbh & Co. Kg Prepolymeres en etoile pour la production de revetements ultraminces formant des hydrogels
AU2005234905B2 (en) * 2004-04-21 2008-07-31 Alcon Inc. Curable colored inks for making colored silicone hydrogel lenses

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US9555154B2 (en) 2009-02-21 2017-01-31 Covidien Lp Medical devices having activated surfaces
EP2398523A1 (fr) * 2009-02-21 2011-12-28 Tyco Healthcare Group LP Dispositifs médicaux présentant des surfaces activées
EP2398523A4 (fr) * 2009-02-21 2014-04-16 Covidien Lp Dispositifs médicaux présentant des surfaces activées
WO2010096649A1 (fr) 2009-02-21 2010-08-26 Tyco Healthcare Group Lp Dispositifs médicaux présentant des surfaces activées
US10709549B2 (en) 2013-02-14 2020-07-14 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US10350057B2 (en) 2013-02-14 2019-07-16 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US9486311B2 (en) 2013-02-14 2016-11-08 Shifamed Holdings, Llc Hydrophilic AIOL with bonding
US11540916B2 (en) 2013-02-14 2023-01-03 Shifamed Holdings, Llc Accommodating intraocular lens
US9250357B2 (en) 2013-03-15 2016-02-02 Johnson & Johnson Vision Care, Inc. Silicone-containing contact lens having reduced amount of silicon on the surface
WO2014149544A1 (fr) 2013-03-15 2014-09-25 Johnson & Johnson Vision Care, Inc. Lentille de contact contenant de la silicone présentant une quantité réduite de silicium sur la surface
US10195018B2 (en) 2013-03-21 2019-02-05 Shifamed Holdings, Llc Accommodating intraocular lens
US10548718B2 (en) 2013-03-21 2020-02-04 Shifamed Holdings, Llc Accommodating intraocular lens
US11583390B2 (en) 2014-08-26 2023-02-21 Shifamed Holdings, Llc Accommodating intraocular lens
US10736734B2 (en) 2014-08-26 2020-08-11 Shifamed Holdings, Llc Accommodating intraocular lens
US12251303B2 (en) 2014-08-26 2025-03-18 Shifamed Holdings, Llc Accommodating intraocular lens
US11141263B2 (en) 2015-11-18 2021-10-12 Shifamed Holdings, Llc Multi-piece accommodating intraocular lens
US10350056B2 (en) 2016-12-23 2019-07-16 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
US11065109B2 (en) 2016-12-23 2021-07-20 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
US12167960B2 (en) 2016-12-23 2024-12-17 Shifamed Holdings, Llc Multi-piece accommodating intraocular lenses and methods for making and using same
US10987214B2 (en) 2017-05-30 2021-04-27 Shifamed Holdings, Llc Surface treatments for accommodating intraocular lenses and associated methods and devices
US11266496B2 (en) 2017-06-07 2022-03-08 Shifamed Holdings, Llc Adjustable optical power intraocular lenses
WO2019185302A1 (fr) 2018-03-27 2019-10-03 Mercene Labs Ab Revêtement et apprêt
EP3655247B2 (fr) † 2018-03-27 2024-10-09 Mercene Coatings AB Revêtement et apprêt
US10975246B2 (en) 2018-03-27 2021-04-13 Mercene Coatings Ab Coating and primer
EP3655247B1 (fr) 2018-03-27 2021-01-13 Mercene Coatings AB Revêtement et apprêt
CN116635492A (zh) * 2020-12-30 2023-08-22 康沃特克科技公司 医疗器材的官能化

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