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    • 专利摘要:
    coating of a medical device, isolated polymer assembly, method of coating a medical device and manufacturing process of a copolymer, wherein substrates may be coated with the n-vinylpyrrolidone and aryl ketone copolymers; The processes are described for making high molecular weight copolymers with ketones randomly dispersed in the copolymer.
    公开号:BR112013005754B1
    申请号:R112013005754-8
    申请日:2011-09-02
    公开日:2019-01-29
    发明作者:Shivpal S. Sandhu；Alan Rhodes；Simon Jon Onis
    申请人:Biointeractions Ltd；
    IPC主号:
    专利说明:

    "COATING OF A MEDICAL DEVICE, INSULATED POLYMER ASSEMBLY, WATER SOLUTION, METHOD OF COATING OF A MEDICAL DEVICE, PROCESS OF MANUFACTURING OF A COPOLYMER AND COPOLYMER" Field of application generally refers to, generally, the field of application medical devices and polymers to the same.
    History Medical devices can benefit from coatings that increase biocompatibility and other surface properties. Coatings provide desirable surface properties without sacrificing the mechanical properties of the underlying substrate.
    Summary One embodiment of the present patent application is a copolymer of N-vinylpyrrolidone and diaryl ketone monomers. Diaryl ketone monomeric units are randomly dispersed along the length of the copolymer. In contrast, to a conventional method of synthesis that places the diaryl ketone subunits in groups such that the copolymer is not formed. These copolymers have been discovered to provide coatings with desirable properties.
    The N-vinylpyrrolidone and diaryl ketone copolymer may be produced in a water-soluble form, with an average molecular weight of more than about 100,000, with at least about 60% by weight of N-vinylpyrrolidone, and with no more than about 5 wt% diaryl ketone monomer. The water soluble nature of the copolymer contributes to the hydrophilicity of coatings made with the copolymer. The molecular weight of more than about 100,000 provides performance characteristics that are distinct from lower molecular weight.
    Another embodiment of the present patent application relates to a coating composed of the N-vinylpyrrolidone copolymer and diaryl ketone monomers with the diaryl ketone monomer units randomly dispersed over the length of the copolymer.
    Another embodiment of the present patent application relates to a method of producing N-vinylpyrrolidone copolymer and diaryl ketone monomers where the diaryl ketone monomer units are randomly dispersed over the length of the copolymer. These copolymers have been discovered to provide coatings with desirable properties.
    Another embodiment of the present patent application relates to a method of manufacturing a coating comprising the N-vinylpyrrolidone copolymer and diaryl ketone monomers with the diaryl ketone monomer units randomly dispersed over the length of the copolymer. The diaryl ketone ketones in the copolymer are activated to make covalent crosslinks to then form crosslinked layers. The water soluble nature of the copolymer contributes to the hydrophilicity of coatings made with the copolymer. The molecular weight of the copolymer of more than about 100,000 provides significant control distances between crosslinks.
    Brief Description of the Figures Figure 1A illustrates the structure of N-vinylpyrrolidone; Figure 1B illustrates the structure of 4-benzoylphenyl methacrylate; and Figure IC represents the polymerization of N-vinylpyrrolidone and 4-benzoylphenyl methacrylate.
    DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A water-soluble N-vinylpyrrolidone (NVP) copolymer and monomers with diaryl ketone monomer units randomly dispersed over the length of the copolymer are disclosed. The copolymer was synthesized with the approaches described herein. The water soluble copolymer may be additionally crosslinked. In general, the cross-linked copolymer or copolymer may be used as lubricable coatings for medical devices.
    The term water soluble means that 1 L of water will dissolve at least 1 g of the polymer. The term polymer refers to a molecule consisting of repeated subunits. Subunits are indicated as "mers". The terms "monomer unit" or "monomer unit" are used interchangeably with the term "mer". Polymers may be formed by polymerization of monomers. Monomers undergo chemical reactions with each other to form covalent bonds. The monomers used may be the same or different. "Copolymer" refers to a polymer derived from two or more monomer units, as opposed to a homopolymer in which only one monomer is used. The term "random" means that the probability of finding a given monomeric unit at any given given current location is substantially independent of the nature of the adjacent units. The term "group" indicates that the generically repeated chemical entity (for example an alkyl group) may have any substituent that is consistent with the binding structure of said group. For example, where the term "alkyl group" is used, this term not only includes unsubstituted linear, branched and cyclic alkyl such as methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, dodecyl and the like; having heteroatom substituents such as 3-ethoxypropyl, 4- (N-ethylamino) butyl, 3-hydroxypentyl, 2-thiolhexyl, 1,2,3-tribromopropyl and the like. However, as is consistent with that nomenclature, no substitution would be included within the term that would alter the fundamental binding structure of the base group.
    An example of an aryl ketone is benzophenone, which is a diaryl ketone. Figure 1A illustrates the structure of NVP, Figure 1B illustrates the structure of 4-benzoylphenyl methacrylate, and Figure 1C illustrates the copolymer formed from the polymerization of these two monomer units. The diaryl ketone is a group having a carbonyl group in which carbon of the carbonyl group is attached directly to two carbon atoms that are part of aromatic rings. For example, the simplest (monomeric) diaryl ketone is benzophenone, also called diphenyl ketone. Other diaryl ketones are, for example, anthraquinone, anthrone, and heterocycles similar to anthrone and their substituted derivatives. Additional diaryl ketones are 2-hydroxybenzophenone, 3-hydroxybenzophenone, 4-hydroxybenzophenone, 2,2'-dihydroxybenzophenone, 2,4-dihydroxybenzophenone, 3,4-dihydroxybenzophenone, 4,4'-dihydroxybenzophenone, 2,3,4-trihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2-aminobenzophenone, 3-aminobenzophenone, 4-aminobenzophenone, 3,4-diaminobenzophenone, 4,4 '-diaminobenzophenone, 4- (bromomethyl) benzophenone, 2-benzoylbenzoic acid, 3-benzoylbenzoic acid, 4-benzoylbenzoic acid, 4-benzoylbenzoyl chloride, 4-isocyanatobenzophenone, benzophenone-3,3', 4,4'-dianhydride tetracarboxylic acid, 3-bromo-2 ', 5-dichloro-2-hydroxybenzophenone, 2-hydroxy-2', 3,5-trichlorobenzophenone, 3-bromo-5-chloro-2-hydroxybenzophenone, 5-bromo-2'-chloro-2 -hydroxybenzophenone, 4'-chloro-5-fluoro-2-hydroxybenzophenone, 2 ', 5-dichloro-2-hydroxybenzophenone, 5-bromo-2-hydroxybenzophenone, 4-fluoro-4'-hydroxybenzophenone, 2-amino-4' -bromobenzophenone, 2-amino-5-chlorobenzophenone, 4-amino-3-nitroben zophenone, 2'-chloro-2-hydroxy-4-methylbenzophenone, 2'-chloro-2-hydroxy-5-methylbenzophenone, 2-hydroxy-5-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-amino-4- methylbenzophenone, benzoin, 4,4'-dimethoxybenzoin, 4-chlorobenzoin, benzyl 4-hydroxyphenyl ketone, benzyl 2,4-dihydroxyphenyl ketone, 2-phenyl-2 ', 4', 6'-trihydroxyacetophenone. The monomers may have an aryl ketone group or other pendant groups.
    The copolymer may consist essentially of NVP and aryl ketone monomer units, or may further comprise additional monomers. In this context, the term essentially refers to having at least about 90% by weight of NVP in the copolymer, with the remaining 10% being aryl ketones or hydrophilic subunits. The configurations include a water soluble copolymer with more than about 50% or about 60% by weight NVP monomer units and not more than 5% or 10% aryl ketone monomer units; those skilled in the art will recognize that all ranges and values within the explicitly stated ranges are contemplated. The copolymers may be prepared with less than 0.5% aryl ketone monomer units (e.g. benzophenone); those skilled in the art will recognize that immediately that all ranges and values within explicitly stated ranges are contemplated, for example, from about 0.2% to about 0.05% to about 0.25%.
    In some embodiments, the water soluble copolymer is no more than about 5% by weight of an aryl ketone (or diaryl ketone) monomer unit; those skilled in the art will readily recognize that all ranges and values within the explicitly stated ranges are contemplated, for example, from about 1% to about 5% or less than about 0.5%. The molecular weight of the copolymer may be, for example, at least 100,000; those skilled in the art will readily recognize that all ranges and values within the explicitly stated ranges are contemplated, for example, from about 100,000 to about 1,500,000, or about 900,000 to about 1,200,000. The rest of the copolymer may be NVP, or NVP may be present in a range from about 10 wt.% To about 99 wt.%, With other established subunits providing the equilibrium, for example, at least 60% NVP monomer units . The embodiments comprise the coatings formed of said copolymers.
    Monomers for the copolymer may have active centers comprising vinyl groups that form free radicals and undergo polymerization. Examples of active centers are acrylate groups and methacrylate groups. The monomers may have additional substituents to form acrylate and methacrylate derivatives. Examples of said substituents are hydroxyls and alkyls. Additional monomers include methyl methacrylate, ethyl methacrylate, n-alkyl methacrylates, methyl ethyl acrylate, ethyl acrylate, n-alkyl acrylates, and hydroxyethyl methacrylate.
    Monomer groups may have other substituent groups. Examples include poly (ethylene glycol) groups, poly (propylene glycol) groups, poly (alkylene oxide) groups, silyl groups, trimethoxysilyl groups, sulfonic acid groups, ammonium sulfatoethyl groups, acid groups methylpropanesulfonic, polyhexanide groups and chlorohexidine groups. Other examples of substituents include sulfate groups, sulfabetaine groups, phosphorylcholine groups, zwitterionic groups, 2-methacryloyloxyethyl phosphorylcholine (MPC), carboxylic acids, heparin, heparin methacrylate, alcohols and hydroxyls. Other monomeric units are defined in U.S. Patent Nos. 6,007,833, 6,849,669, 7,138,541 and 7,459,489, which are incorporated herein by reference for all intents and purposes in the event of conflict with the present specification.
    The term alkyl, unless otherwise specified, refers to a linear, branched or cyclic saturated hydrocarbon, and specifically includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl pentyl, cyclopentyl isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The alkyl group may be optionally substituted by any appropriate group, including but not limited to one or more groups selected from halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, acid phosphonic, phosphate or phosphonate, whether unprotected or protected as necessary, as is known to those skilled in the art.
    All of these groups may optionally be derivatized with substituent groups. Suitable substituent groups which may be present in a given "substituted" group, including for example halogens such as fluorine, chlorine, bromine and iodine, cyano, H, a hydroxyl group, ester group, ether group, a carbamate, an acidic group oxo carboxylic, an oxo carbon group, an oxo carboxylic acid group, an oxo group, a ketone group; nitro; azide; sulfhydryl; alkanoyl - for example C1-6 alkanoyl alkanoyl group such as acetyl and the like; carboxamido; alkyl, alkenyl and alkynyl groups including groups having one or more unsaturated bonds, alkoxy groups having one or more oxygen bonds; aryloxy such as phenoxy, alkylthio groups, alkylsulfinyl groups; alkylsulfonyl groups, aminoalkyl groups such as groups having one or more N atoms; carbocyclic aryl; aryloxy such as phenoxy; aralkyl having 1 to 3 separate or fused rings; aralkoxy having 1 to 3 separate or fused rings, or a heteroaromatic, heterocyclic, or heteroalicyclic group with 1 to 4 separate or fused rings, for example with one or more N atoms, or S atoms, for example coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, piperidinyl, morpholine and pyrrolidinyl. In some embodiments, substituents may include groups that include 0, S, Se, N, P, Si, C and have from 2 to about 150 atoms. In some embodiments it is useful to limit the size of any substituent to for example less than about 150, less than about 100, less than about 50, or less than about 20 atoms.
    In some embodiments, suitable substituent groups include these and other N-containing compounds, for example amines, amides, amidium ions, amine imides, amine oxides, aminium ions, aminonitrenes, nitrenes, aminoxides, nitriles, nitrile imides. Other suitable substituent groups refer to these and other S-containing compounds, for example sulfonic acid, sulfate, sulfonates, sulfamic acids, sulfanes, sulfates, sulfenamides, sulfenes, sulfenic acids, sulfenium ions, sulfenyl groups, sulfenylium ions, nitrenes sulfenyl, sulfenyl radicals, sulfides, sulfilimines, sulfimides, sulfimines, sulfanamides, sulfinamidines, sulfins, sulfinic acids, sulfinic anhydrides, sulfinimines, sulfinylamines, sulfolipids, sulfonamides, sulfonamidines, sulfonadiimines, sulfones, sulfonic acids, sulfonamide, sulfonic compounds , sulfontaleines, sulphonylamines, sulphoxides, sulphoximides, sulphoximines, sulfur diimides, thiols, thioacetals, thioaldehydes, thioaldehydes S-oxides, thioanhydrides, thiocyanates, thioethers, thiohemiacetal, thiocytones thiocytones thiocytones thiocyanates In some embodiments, suitable substituent groups include these and other compounds containing O, for example, as ROH (alcohol), RCOOH (carboxylic acids), RCHO (aldehydes), RR'C = 0 (ketones), ROR (ethers) and RCOOR '(esters), with R denoting a bond or atomic element. In some embodiments, suitable substituent groups include these and other P-containing compounds, for example, phosphanes, phosphanilidenes, phosphatidic acids, phosphates, phosphine oxides, phosphines, phosphinic acids, phosphonidenes, phosphonium acid, phosphoglycerides, phospholipids, phosphonic acids, phosphonitriles, phosphonium compounds, phosphonium ilides, phosphono, phosphonous acids, phosphoramides and phosphoranes. Carbon is useful for producing the substituents and the number of carbon atoms in a heteroatomic structure may be, for example, between 1 and n-1 when between 2 and n are used to form a substituent with, for example, 0, P In some embodiments, it is useful to limit the size of these substituents to, for example, less than about 150, less than about 100, less than about 50, or less than about 20 atoms.
    A variety of substituents are contemplated, so that some possible combinations of the claimed configurations may be unstable or impractical to realize. A person of ordinary skill in the art may select stable compounds presented within the genus of compounds based on disclosure. Therefore, in general, substituents are limited to those that result in adequate valence for the particular element substituted without formation of a charged compound or radical (except for titratable charged groups, stable zwitterionic forms and triple neutral radicals with unpaired orbitals). with full valences), as may be conventionally determined by one of ordinary skill in the art.
    The copolymer is composed of N-vinylpyrrolidone (NVP) and monomers with a pendant aryl ketone group, with the aryl ketone monomer units being randomly distributed in the copolymer. Conventional mixing and polymerization of monomeric NVP and monomeric aryl ketones is not effective for the synthesis of such copolymer. It has been found, however, that such copolymer can be synthesized using the approaches described herein. For example, dissolving the polymerization initiator in the NVP monomer has been found to be useful in preparing the copolymer with randomly distributed aryl ketone monomer units. In addition, it has been found to be useful to dissolve the aryl ketone monomer in NVP. But these approaches, alone or in combination, were not sufficient to prepare the desired copolymer as indicated in examples 2 and 4 below. The desired copolymer can, however, be manufactured by adding such solutions in a controlled manner to a larger solution, with polymerization in progress, as illustrated in Examples 3 and 5 below. The copolymers thus formed were soluble in water and other aqueous solutions, sometimes with other molecular weights of about 1,000,000. Copolymers can be made to provide coatings with unexpected and surprisingly favorable properties including: thin, lubricable, and durable coatings.
    More specifically, a 4-benzoylphenyl methacrylate (an aryl ketone monomer unit) was synthesized (Example 1) and mixed in a solvent with NVP. An initiator was dissolved in NVP and added to the mixture of monomer units. The initiator began polymerization but produced poly (4-benzoylphenyl methacrylate) polymer was produced instead of the NVP-co-aryl ketone copolymer (Example 2). Consequently, this approach does not work even when the initiator is dissolved in NVP.
    In contrast, in Example 3, the primer was dissolved in NVP to form a first solution and aryl ketone was dissolved in NVP in a second solution. A third solution of NVP in water was prepared and heated. The first solution was added to the third to form a mixture. The second solution was slowly added dropwise to the mixture. A water soluble copolymer of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate) was formed. In addition, a higher high molecular weight of about 1,000,000 was achieved.
    Similarly, Example 4 demonstrates how the formation of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-methoxypolyethylene glycol 550 methacrylate) was unsuccessful even when the various components were dissolved in NVP and mixed. In this case, methoxypolyethylene glycol 550 methacrylate polymerized with itself instead of producing a copolymer. But poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-methoxypolyethylene glycol 550 methacrylate) was successfully produced (Example 5), when procedures similar to the process described in Example 2 were adapted.
    These approaches are generally suitable for the formation of N-vinylpyrrolidone (NVP) copolymer and monomers with a pendant aryl ketone group, as evidenced by several examples: poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl) methacrylate) in example 2; poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-methoxypolyethylene glycol 550 methacrylate) in example 5, poly [N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co- (2- methacryloyloxy) ethyl dimethyl- (3-sulfopropyl) ammonium hydroxide] in example 6; ammonia poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate- (3-methacryloylamino) propyl dimethyl- (3-sulfopropyl) hydroxide] in example 7; co-4-benzoylphenyl methacrylate-co-2-methacryloyloxyethyl phosphorylcholine) in example 8. poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-ammonia sulfateethyl methacrylate) in example 9; 2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-acrylic acid) in example 10, poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-dimethylaminoethyl methacrylate) in example 11; N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-2-hydroxyethyl methacrylate) in example 12 and poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-polyhexanide methacrylate) ) in Example 13. These copolymers and their derivatives further comprising additional groups or substitutions are embodiments of the invention, as are the coatings thereof. "Azobisisobutyronitrile" (AIBN) is an initiator for the Other copolymer polymerization are also suitable, as is recognized by those skilled in the art.
    Another embodiment of the invention is a coating or layer comprising a copolymer as defined herein, for example an N-vinylpyrrolidone (NVP) copolymer and monomers with a pendant aryl ketone group. Said copolymers may form lubricable and resistant coatings. Example 3 describes the synthesis of said copolymer. Polymers made from the same precursors, however, did not exhibit these characteristics and the properties of an example 2 polymer coating were considered quite poor compared to the example 3 copolymer (See examples 14 and 15).
    In addition, the copolymer coatings had excellent flexibility and were highly lubricable. The coefficient of friction can be defined as the force required to move the sample by means of a constant force clamp divided by the force that is applied by the clamp. For example, if the force required to pull a sample through a clamp, which has a force of 400 g applied to it, is 100 g, then the coefficient of friction is 0.25. The coefficients of friction for the copolymer coatings range from 0.5 to 0.005 depending on the substrate used. The coating reduces the coefficient of friction by 50 to 99.5% compared to the uncoated sample; those skilled in the art will immediately recognize that all ranges and values within the explicitly stated ranges are contemplated, for example, a reduction of about 60%, about 90%, or from about 80% to about 99%. , 5%.
    Embodiments include a coating comprising covalently cross-linked copolymers as set forth herein, the coating being hydrophilic, highly flexible and durable. Highly flexible means that a coating of about 50 to about 200 µm thick applied to a substrate will not crack with observation with the naked eye. Contact angle is the angle at which the liquid / vapor interface encounters a solid surface, with smaller contact angles representing a more hydrophilic (wettable) surface. Typical contact angles for water on surfaces coated with the present invention are from about 0 ° to about 30 °; those skilled in the art will readily recognize that all ranges and values within explicitly stated ranges are contemplated, for example, from about 0.1 to about 20 °.
    Durability can be assessed by pretending a coated substrate and then subjecting the coated article to a wet abrasion test.
    For example, rub the wet coated article between the index finger and thumb using firm pressure for at least 20 cycles. If the dye does not fade, or the coating resumes color to a similar intensity, the coating passes the durability assessment. If the dye fades and does not regain color, then the coating has not adhered sufficiently and will detach from the substrate (as in example 14).
    A coating material is formed on a substrate. A substrate generally has a surface on which the coating material may be deposited, and the substrate may comprise a plurality of layers wherein the surface refers to the uppermost layer. The substrate surface may be treated to prepare the surface for adhesion of the coating material. Prior to surface preparation, the surface may be cleaned and / or smoothed as appropriate. Suitable substrate surfaces may comprise any reasonable material. Some substrates of particular interest include, for example, stainless steel, metals, nitinol, engineering polymers, polyethylene, polypropylene, polytetrafluoroethylene, polyurethane, polyamide, polyether block amide, inorganic materials, polymeric substrates such as organic polymers, composites thereof. and combinations thereof along a surface and / or in layers of the substrate. The substrate may be a surface of a medical device, for example, a surface exposed to blood and / or for temporary or permanent use within the body. Examples of such medical devices are a stent (expandable stent), a guidewire, a pacemaker, a catheter, a medical balloon, a nasogastric feeding tube, a PICC line and an endotracheal tube. The catheters may be, for example, a urinary catheter, an infusion catheter and a drainage catheter. The term medical device as used herein is broad and includes medical diagnostic devices, for example, surfaces exposed to a biological sample or for diagnostic purposes.
    In general, any suitable coating process may be used to provide the copolymer to a substrate. Suitable coating approaches may include, for example, spin coating, spray coating, dip coating, painting and melting. Aryl ketones may be activated after the copolymer is present in the substrate to cross-link the copolymers to form a covalently cross-linked matrix. Light-based activation may be used, or any other suitable medium, for example heat. The coating material may be applied in various coating steps to provide greater control over the coating process. For example, multiple coatings per rotation may be performed to obtain the desired final coating thickness. The heat treatment described below may be applied after each coating step or after a plurality of coating steps. The solvents for the copolymers in the coating process may be aqueous or alcoholic, or a mixture thereof. Examples of alcohol include methanol, ethanol and 2-propanol. Additional solvents are water, dimethyl sulfoxide, tetrahydrofuran and dichloromethane. The method may comprise solvent evaporation and drying of the layer at a temperature ranging from about 15 to about 80 ° C; those skilled in the art will immediately recognize that all ranges and values within explicitly stated ranges are contemplated. The solvent may be aqueous, a term meaning a solvent that is at least 10% w / v of water, with the remainder of the solvents being liquid that are miscible with water. Solvent 20 may consist essentially of water and / or alcohol, with the term "essentially" in this context meaning that the liquid phase of the solvent is at least 90% v / v of water or alcohol and the remainder of the phase liquid does not substantially interfere with the coating process.
    The thickness of the coating may generally be a function of the coating process chosen. In some embodiments, the coating materials may have an average thickness between about 1 µm and about 1 mm; those skilled in the art will immediately recognize that all ranges and values within explicitly stated ranges are contemplated, for example, from about 10 pm to about 200 pm, or about 5 pm to about 20 pm.
    N-vinylpyrrolidone (NVP) copolymers and pendant aryl ketone monomers have been transformed into effective coatings on a variety of substrates including polyurethane (Examples 15 and 16), the polyether block polymers (Example 17) , polyamide (Example 18), and stainless steel (Example 19). The coatings were considered excellent, flexible, durable, lubricable and hydrophilic.
    Examples Example 1: Synthesis of 4-benzoylphenyl methacrylate.
    To a 100 ml round bottom flask equipped with a magnetic stirrer and addition funnel was added 4-hydroxybenzophenone (1g = 5.04 mmol) and CH 2 Cl 2 (35 ml). The mixture was cooled to 0 ° C and methacryloyl chloride (0.39 ml, 4.04 mmol) was added in a single portion. After 30 minutes, triethylamine (0.7 mL, 5.04 mmol) dissolved in CH 2 Cl 2 (10 mL) was added dropwise over 30 minutes. The mixture was stirred for a further 1 hour at 0 ° C and then at room temperature for 3 hours. After this time, the organic mixture was washed with 0.1% NaOH (3 x 100 mL) and water (5 x 100 mL). The combined organic layers were dried over MgSO4 and then concentrated in vacuo to yield a crude product. The crude product was purified by column chromatography (100% CH 2 Cl 2) to give the compound as a white solid (yield = 75%, 1g). Example 2: Failure synthesis of poly (N-vinyl-2-pyrrolidone-co- 4-benzoylphenyl methacrylate).
    This example demonstrates that simply combining a mixture of precursors does not generate the synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate). Instead, the result is a mixture of a variety of polymers, apparently as a result of varying reactivity ratios of precursors. In this case, poly (4-benzoylphenyl methacrylate) is apparently produced as evidenced by the resulting precipitates.
    To a 250 ml conical flask equipped with a magnetic stir bar, N-vinyl-2-pyrrolidone (NVP) (30 g), 4-benzoylphenyl methacrylate (0.1 g) and deionized water (70 g) were added. ml). The mixture was purged with N 2 for 20 minutes while heating to 70 ° C. After this time, azobisisobutyronitrile (AIBN) (0.1 g dissolved in NVP, 2 ml) was added in one portion to initiate polymerization. After approximately 5 minutes, the solution became cloudy and insoluble precipitates formed as a result of precipitation of poly (4-benzoylphenyl methacrylate) from the solution.
    Example 3: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate).
    It was added to a 250 ml conical flask equipped with a magnetic stir bar, NVP (30 g) and deionized water (70 ml). The mixture was purged with N 2 for 20 minutes while heating to 70 ° C. After this time, AIBN (0.1 g dissolved in NVP, 2 ml) was added in a single portion. About 8 minutes after the addition of AIBN, 4-benzoylphenyl methacrylate (0.1 g dissolved in NVP, 2 ml) was added dropwise over a 10 minute period. The polymerization was carried out for 1 hour, after which time the viscous mixture was cooled to room temperature and then dissolved in water (150 ml). The resulting polymer solution was clear, with no evidence of precipitation of poly (4-benzoylphenyl methacrylate). The polymer solution was dialyzed against water (10 L) for 16 hours and then freeze dried to afford the polymer as a white solid (yield = 32 g).
    Gel permeation chromatography (GPC) was performed on the white solid using a Perkin-Elmer 200 series GPC system equipped with PL-AQUAGEL-OH 40 and PL-AQUAGEL-OH 50 columns (300 x 7.5 mm), a PL-AQUAGEL-OH 5 pm guard column and a refractive index (RI) detector. Molecular weights were determined relative to polyethylene oxide / polyethylene glycol (Varian, Inc) standards using a mobile phase consisting of 0.02% NaN3 in water at a flow rate of 1.0 ml / min. at 30 ° C with a 50 pl sample injection. Normally, the measured molecular weights were in the range of 1,000,000 gmol-1.
    Example 4: Failure Synthesis of poly (N-vinyl-2-pyrrolidonaco-4-benzoylphenyl methacrylate-co-methoxypolyethylene glycol 550 methacrylate).
    To a 250 ml conical flask equipped with a magnetic stir bar was added NVP (27 g), methoxypolyethylene glycol 550 methacrylate (MPEG 550 methacrylate) (6 g) and deionized water (100 ml). The mixture was purged with N 2 for 20 minutes while heating to 70 ° C. After this time, AIBN (0.1 g dissolved in NVP, 2 ml) was added in one portion to initiate polymerization. The solution became viscous within 5 minutes and a gel formed within 8 minutes, so that 4-benzoylphenyl methacrylate could not be added. The reaction was terminated by the addition of deionized water (150 ml). The gelled polymer was dialyzed against water (10 L) for 16 hours and then lyophilized to give 5 g of product. The polymeric product was insoluble in water, ethanol, dimethyl sulfoxide, dimethylformamide and mixtures thereof, indicating that a crosslinked product had been produced. Evidently MPEG 550 methacrylate had homopolymerization and as a result of the present residual crosslinking agent in the monomer had formed an insoluble cross-linked gel.
    The polymer was characterized by infrared spectroscopy using a Perkin-Elmer Paragon 1000 FT-IR spectrometer. The samples were recorded as a thin film. The absence of a C = O absorption (amide) around 1650 cm -1 indicated that no NVP had been incorporated into the polymer.
    Example 5: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-methoxypolyethylene glycol 550 methacrylate).
    To a 250 ml conical flask equipped with a magnetic stir bar was added NVP (27 g) and deionized water (100 ml). The mixture was purged with N 2 for 20 minutes while heating to 70 ° C. After this time, AIBN (0.1 g dissolved in NVP, 2 ml) was added in a single portion. About 8 minutes after the addition of AIBN, 4-benzoylphenyl methacrylate (0.1 g dissolved in NVP, 2 ml) was added dropwise over a period of 10 minutes. Then MPEG 550 methacrylate (6 g) containing 4-benzoylphenyl methacrylate (0.03 g) (dissolved in NVP, 1 ml) was added dropwise over a period of 10 minutes. Careful control over the rate and addition time of MPEG 550 methacrylate ensured that the monomer did not undergo homopolymerization and did not crosslink to form a gel. Polymerization occurred for 1 hour while maintaining the reaction temperature at 70-75 ° C. After this time, the reaction was terminated by the addition of water (150 ml). The polymer solution was dialyzed against water (10 L) for 16 hours and then lyophilized to give the polymer as a white solid (yield = 30 g).
    FT-IR analysis of the white solid revealed the presence of strong absorption of about 1650 cm -1, which was attributed to the C = O (amide) of the polymeric NVP. An absorption of about 1100 cm -1 provided evidence of the presence of the polyethylene glycol (C-O-C) unit.
    Example 6: Synthesis of ammonia poly [N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate- (2-methacryloyloxy) ethyl dimethyl- (3-sulfopropyl) hydroxide] [2-42- (Methacryloyl) monomer Ammonium loxy) ethyl] dimethyl (3-sulfopropyl) hydroxide (MEDSAH) was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 5, except that MEDSAH (6 g) was dissolved in water (10 ml) containing 4-benzoylphenyl methacrylate (0.03 g) (dissolved in NVP, 1 ml). The polymer yield was 29 g.
    FT-IR analysis revealed the presence of strong absorption around 1650 cm-1, which was attributed to polymeric NVP C = O (amide) and S = O absorption around 1200 and 1000. cm-1 from MEDSAH.
    Example 7: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co- (3-methacryloylamino) propyl dimethyl- (3-sulfopropyl) ammonium hydroxide].
    Ammonium 3- (methacryloylamino) propyl] dimethyl- (3-sulfopropyl) hydroxide (MPDSAH) monomer was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 6. The polymer yield was 29 g.
    FT-IR analysis revealed the presence of strong absorption around 1650 cm-1, which was attributed to polymeric NVP C = O (amide) and S = O absorption around 1200 cm-1. 1 and 1000 cm -1 from MPDSAH.
    Example 8: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-2-methacryloyloxyethyl phosphorylcholine).
    2-Methacryloyloxyethyl phosphorylcholine (MPC) monomer was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 6. The polymer yield was 25 g.
    The FT-IR analysis revealed absorptions around 950, 1080 and 1260 cm-1, which was attributed to the MPC phosphate group and a strong absorption around 1650 cm-1, which was attributed to C = The (amide) of the polymeric NVP. Example 9: Synthesis of ammonium poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-sulfatoethyl methacrylate).
    Ammonium sulfateethyl methacrylate (SEM) was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 6. The polymer yield was 28 g.
    Example 10: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-acrylic acid).
    Acrylic acid (sodium salt) was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 6. Once polymerized, the pH was reduced to ~ 3 to form the free acid. The polymer yield was 26 g.
    Example 11: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-dimethylaminoethyl methacrylate).
    Dimethylaminoethyl methacrylate was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 5. The polymer yield was 29 g.
    Example 12: Synthesis of poly (N-vinyl-2-pyrrolidone-co-4-benzoylphenyl methacrylate-co-2-hydroxyethyl methacrylate).
    2-Hydroxyethyl methacrylate (HEMA) was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 5. The polymer yield was 30 g.
    Example 13: Synthesis of poly (N-vinyl-2-pyrrolidinone-co-4-benzoylphenyl methacrylate-co-polyhexanide methacrylate).
    Polyhexanide methacrylate was polymerized with NVP and 4-benzoylphenyl methacrylate following the procedure as described in Example 6. The polymer yield was 23 g.
    Example 14: Coating poly (urethane) tube with the polymer of Example 2.
    The polymer prepared in Example 2 was dissolved in an isopropyl alcohol (IPA) / water mixture to give a final polymer concentration of 3% w / v. A clean poly (urethane) tube was then immersed in the coating solution and left for approximately 30 seconds. After this time, the tube was slowly withdrawn from solution and dried at room temperature for at least 10 minutes. After drying, the coated poly (urethane) tube was exposed to a UV lamp (UVASPOT 1000F) for 3 minutes. After exposure to water, the coating was easily delaminated from the surface, indicating that no chemical crosslinking had occurred.
    Example 15: Coating poly (urethane) tube with the copolymer of Example 3.
    The copolymer prepared in Example 3 was dissolved in an IPA / water mixture to give a final polymer concentration of 3% w / v. A clean poly (urethane) tube was then immersed in the coating solution and left for approximately 30 seconds. After this time, the tube was slowly withdrawn from solution and dried at room temperature for at least 10 minutes. After drying, the coated poly (urethane) tube was exposed to a UV lamp (UVASPOT F1000) for 3 minutes to obtain a thin, durable and crosslinked coating which upon exposure to water became quite sliding.
    Example 16: Coating poly (urethane) tube with the copolymer of Example 5.
    The copolymer prepared in Example 5 was dissolved in an IPA / water mixture to give a final polymer concentration of 3% w / v. A clean poly (urethane) tube was then immersed in the coating solution and left for approximately 30 seconds. After this time, the tube was slowly withdrawn from solution and dried at room temperature for at least 10 minutes. Once dried, the poly (urethane) lining tube was exposed to a UV lamp (UVASPOT 1000F) for 3 minutes to obtain a thin, durable and cross-linked lining, which upon exposure to water became quite sliding. The coating also demonstrated excellent flexibility. Example 17: PEBAX tube coating with the copolymer of Example 5.
    The copolymer prepared in Example 5 was dissolved in an IPA / water mixture to give a final polymer concentration of 3% w / v. A clean PEBAX tube was then dipped into the coating solution and left for approximately 30 seconds. After this time, the tube was slowly withdrawn from solution and allowed to dry at room temperature for at least 10 minutes. After drying, the coated PEBAX tube was exposed to a UV lamp (UVASPOT 1000F) for 3 minutes to obtain a thin, durable and crosslinked coating which upon exposure to water became quite slippery. This coating also demonstrated excellent flexibility. PEBAX is a trade name of a block copolymer obtained by polycondensation of a carboxylic acid polyamide (PA6, PA11, PA12) with an alcohol terminating polyether (PTMG, PEG).
    Example 18: Coating the poly (amide) tube with the copolymer of Example 5.
    The copolymer prepared in Example 5 was dissolved in an IPA / water mixture to obtain a final polymer concentration of 3% w / v. A clean poly (amide) tube was then immersed in the coating solution and left for approximately 30 seconds. After this time, the tube was slowly withdrawn from solution and dried at room temperature for at least 10 minutes. Once dried, the coated poly (amide) tube was exposed to a UV lamp (UVASPOT 1000F) for 3 minutes to obtain a thin, durable and crosslinked coating which upon exposure to water became quite sliding. This coating also demonstrated excellent flexibility.
    Example 19: Coating of stainless steel guidewire with the copolymer of Example 5.
    A commercially available polyester, such as DYNAPOL® L4 90, was dissolved in THF at a concentration of 3% w / v. A clean stainless steel guidewire was then dipped into the solution and left for about 30 seconds. After this time, the guidewire was slowly withdrawn from the solution and dried in an oven at 60 ° C for 30 minutes to obtain a polyester coated guidewire.
    The copolymer prepared in Example 5 was dissolved in an IPA / water mixture to give a final polymer concentration of 3% w / v. The coated polyester guidewire was then immersed in the coating solution and left for approximately 30 seconds. After this time, the tube was slowly withdrawn from solution and allowed to dry at room temperature for at least 10 minutes. After drying, the coated guidewire was exposed to a UV lamp (UVASPOT 1000F) for 3 minutes to obtain a thin, durable and crosslinked coating, which upon exposure to water became quite slippery. This coating also demonstrated excellent flexibility. Additional Disclosure The above configurations are intended to be illustrative and not limiting. Additional configurations are included in the claims. Furthermore, while the present invention has been described with reference to particular embodiments, those skilled in the art will recognize that changes in shape and detail may be made without departing from the essence and object of the invention. Any incorporation by reference of the above documents is limited so that no subject matter is incorporated that is contrary to the disclosure herein.
    A coating for a medical device comprising hydrophilic layer containing covalently crosslinked copolymers by photoinitiation of diaryl ketones pending over the copolymers, with the copolymers prior to photoiniciation being polymerized from a plurality of monomers comprising N-vinylpyrrolidone and of vinyl diaryl ketone monomers, having an average molecular weight of more than about 100,000, at least about 60% by weight of N-vinylpyrrolidinone, not more than about 5% by weight of diaryl ketone monomer providing the pending diary ketones; and a random distribution of the diary ketones.
    An isolated set of polymers comprising copolymers polymerized from monomers comprising N-vinylpyrrolidone monomer and a diaryl ketone vinyl monomer, with the copolymers having an average molecular weight of more than about 100,000, at least about 60%. by weight of N-vinyl pyrrolidone, not more than about 5% by weight of diaryl ketone monomer, and a random distribution of diaryl ketone in the copolymer.
    A method of coating a medical device comprising exposing a medical device to copolymers with an average molecular weight of more than about 100,000, at least about 60% by weight of N-vinylpyrrolidinone, diaryl ketone monomer in no more than about 5% by weight and a random distribution of diaryl ketone in the copolymer, and a source of ultraviolet radiation to activate benzophenone to form crosslinks to create a covalently cross-linked layer on a medical device surface.
    A process of manufacturing a copolymer comprising preparing a solution of N-vinylpyrrolidinone in aqueous solution, adding a free radical polymerization initiator dissolved in N-vinylpyrrolidinone with the solution, adding a monomer of vinyl aryl ketone dissolved in N-vinylpyrrolidinone with solution and polymerization of the monomers to form a random copolymer of N-vinylpyrrolidinone and the diaryl ketone monomer.
    A copolymer comprising hydrophilic monomer units and aryl and / or diaryl ketone monomer units, and a polyethylene chair, wherein the copolymers have an average molecular weight of more than about 100,000, at least about 60% by weight. hydrophilic monomer units by weight, not more than about 5% by weight of diaryl ketone monomer units, and a random distribution of the diaryl ketone monomer units along the polyethylene chain of the copolymer.
    A process of manufacturing a copolymer comprising preparing a solution of a hydrophilic monomer in aqueous solution, adding a free radical polymerization initiator dissolved in the hydrophilic monomer to the solution, adding a diaryl ketone dissolved in the hydrophilic monomer into the solution, and polymerizing the monomers to form a random copolymer of the hydrophilic monomer and the diaryl ketone monomer.
    A hydrophilic coating on a medical device comprising covalently cross-linked diaryl ketone polyethylene copolymers in the copolymers, wherein the copolymer comprises hydrophilic monomeric units and diaryl ketone vinyl monomeric units having an average molecular weight of more than about 100,000 and at least about 60% by weight of hydrophilic monomer units, not more than about 5% by weight of diaryl ketone monomeric units providing the pendant diaryl ketones and a random distribution of the diaryl ketones along the polyethylene chain.
    A method of coating a medical device comprising exposing a medical device to copolymers having an average molecular weight of more than about 100,000, at least about 60% by weight of N-vinylpyrrolidinone monomer. diaryl ketone present in no more than about 5% by weight and a random distribution of diaryl ketone in the copolymer, and activation of diaryl ketone in the copolymer to form crosslinking to create a covalently cross-linked layer on a medical device surface.
    A medical device comprising a copolymer or coating as defined herein, wherein the medical device includes a medical device as defined herein.
    A method, copolymer, coating or process wherein (i) a copolymer coating has a coefficient of friction not greater than about 0.2 or which reduces the coefficient of friction by more than about 50%; Those skilled in the art will readily recognize that all ranges and values within the explicitly stated ranges are contemplated and / or (ii) wherein the diaryl ketone is benzophenone and / or (iii) wherein the diaryl ketone monomer comprises a methacrylate group or an acrylate and / or (iv) group wherein the diaryl ketone of the copolymers is selected from the group consisting of 2-hydroxybenzophenone, 3-hydroxybenzophenone, 4-hydroxybenzophenone, 2,2'-dihydroxybenzophenone, 2,4-di -hydroxybenzophenone, 3,4-dihydroxybenzophenone, 4,4'-dihydroxybenzophenone, 2,3,4-trihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone, 2,2 ', 4,4' -tetrahydroxybenzophenone, 2-aminobenzophenone, 3-aminobenzophenone, 4-aminobenzophenone, 3,4-diaminobenzophenone, 4,4'-diamonibenzophenone, 4- (bromomethyl) benzophenone, 2-benzoylbenzoic acid, 3-benzoylbenzoic acid, benzoylbenzoic, 4-benzoylbenzoyl chloride, 4-isocyanatobenzophenone, benzophenone-3,3'-4,4'-tetracarboxylic dianhydride, 3-bromo -2 ', 5-dichloro-2-hydroxybenzophenone, 2-hydroxy-2', 3,5-trichlorobenzophenone, 3-bromo-5-chloro-2-hydroxybenzophenone, 5-bromo-2'-chloro-2-hydroxybenzophenone, 4'-Chloro-5-fluoro-2-hydroxybenzophenone, 2 ', 5-dichloro-2-hydroxybenzophenone, 5-bromo-2-hydroxybenzophenone, 4-fluoro-4'-hydroxybenzophenone, 2-amino-4'-bromobenzophenone, 2-amino-5-chlorobenzophenone, 4-amino-3-nitrobenzophenone, 2'-chloro-2-hydroxy-4-methylbenzophenone, 2'-chloro-2-hydroxy-5-methylbenzophenone, 2-hydroxy-5-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-amino-4-methylbenzophenone, benzoin, 4,4'-dimethoxybenzoin, 4-chlorobenzoin, benzyl 4-hydroxyphenyl ketones, benzyl 2,4-dihydroxyphenyl ketone, 2-phenylphenyl 2 ', 4', 6'-trihydroxyacetophenone and / or (v) wherein the diaryl ketone monomer comprises a polymerizable group selected from the group consisting of acrylate groups, methacrylate groups, and methyl methacrylate groups and / or (vi) ), wherein the plurality of monomers further comprises one or more monomers selected from tir from the group consisting of poly (ethylene glycol) methacrylate, poly (propylene glycol) methacrylate, poly (ethylene glycol) methyl ether methacrylate, poly (ethylene glycol) ethyl ether methacrylate, 3-trimethoxysilyl methacrylate, vinyl sulfonic acid (sodium salt ), ammonium sulfateethyl methacrylate, 2-acryloylamido-2-methylpropanesulfonic acid monomer, [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (MEDSAH), [3- (methacryloylamino) propyl] -dimethyl Ammonium (3-sulfopropyl) hydroxide (MPDSAH), 2-methacryloyloxyethyl phosphoricoline (MPC), acrylic acid (sodium salt), dimethylaminoethyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), polyhexanide methacrylate and chlorhexidine methacrylate and / or vii) wherein the plurality of monomers further comprises a monomer comprising a pendant group of polyethylene glycol and / or (viii), wherein the plurality of monomers further comprises a monomer comprising a pendant group ending in a sulfonate group and / or (ix) wherein the plurality of monomers further comprises a monomer comprising a silyl pendant group and / or (x) 1, wherein the plurality of monomers further comprises a monomer comprising a zwitterionic group and / or ( xi) wherein the plurality of monomers further comprises a monomer comprising a hydroxyl group and / or (xii), wherein the copolymers, prior to photoinitiation, consist essentially of the N-vinylpyrrolidinone polymerization product and the diaryl ketone monomer.
    Legend of the Figures Figure IA TI => N-Vinylpyrrolidone Figure 1B T2 4 => Benzoylphenyl methacrylate copolymer.
    权利要求:
    Claims (25)
    [1]
    1. A "medical device coating", characterized in that it comprises a hydrophilic layer comprising covalently crosslinked copolymers by pendant diaryl ketones photoinitiation with the copolymers prior to photoinitiation being polymerized from a plurality of monomers comprising N-vinyl pyrrolidone and vinyl diaryl ketone monomers, having an average molecular weight of more than approximately 100,000, at least approximately 60% by weight of N-vinylpyrrolidinone, not more than approximately 5% by weight of diaryl ketone vinyl monomer providing pending and a random distribution of diaryral ketones.
    [2]
    "Medical device coating" according to claim 1, characterized in that the vinyl diaryl ketone monomer comprises a methacrylate group or an acrylate group.
    [3]
    A "medical device coating" according to claim 1 or 2, characterized in that the copolymer diaryl ketone is selected from the group consisting of 2-hydroxybenzophenone, 3-hydroxybenzophenone, 4-hydroxybenzophenone, 2,2 'dihydroxybenzophenone, 2,4-dihydroxybenzophenone, 3,4-dihydroxybenzophenone, 4,4'-dihydroxybenzophenone, 2,3,4-trihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2-aminobenzophenone, 3-aminobenzophenone, 4-aminobenzophenone, 3,4-diaminobenzophenone, 4,4'-diaminobenzophenone, 4- (bromomethyl) benzophenone, 2-benzoyl acid, 3-benzoyl, 4-benzoyl acid, 4-benzoylbenzoyl acid, 4-isocyanatobenzophenone chloride, benzophenone-3 ', 4,4'-tetracarboxylic acid dichloride, 3-bromo-2', 5-dichloro-2-hydroxybenzophenone, 2-hydroxy-2 ', 3,5-trichlorobenzophenone, 3-bromo-5-chloro-2-hydroxybenzophenone, 5-bromo-2'-chloro-2-hydroxybenzophenone, 4'-chloro-5-fluoro-2-hydroxybenzophenone 2 ', 5-dichloro-2-hydr oxybenzophenone, 5-bromo-2-hydroxybenzophenone, 4-fluoro-4'-hydroxybenzophenone, 2-amino-4'-bromobenzophenone, 2-amino-5-chlorobenzophenone, 4-amino-3-nitrobenzophenone, 2'-chloro-2 -hydroxy-4-methylbenzophenone, 2'-chloro-2-hydroxy-5-methylbenzophenone, 2-hydroxy-5-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-amino-4-methylbenzophenone, benzoin, 4,4 ' dimethoxybenzoin, 4-chlorobenzoin, benzyl 4-hydroxyphenyl ketone, benzyl 2,4-dihydroxyphenyl ketone, 2-phenyl-2 ', 4', 6'-trihydroxyacetophenone.
    [4]
    A "medical device coating" according to any one of the preceding claims, characterized in that the plurality of monomers further comprises one or more monomers selected from the group consisting of poly (ethylene glycol) methacrylate, poly (propylene glycol). ) methacrylate, poly (ethylene glycol) methyl ether methacrylate, poly (ethylene glycol) ethyl ether methacrylate, propyl 3-trimethoxysilyl methacrylate, vinyl sulfonic acid (sodium salt), ammonium methacrylate sulfate, 2-acrylamido-2-methylpropanesulfonic acid [2 - (methacryloyloxy) ethyl] ammonium (3-sulfopropyl) ammonium hydroxide (MEDSAH), [3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) (MPDSAH), 2-methacryloyloxyethyl monomer phosphoricoline (MPC), acrylic acid (sodium salt), dimethylaminoethyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), polyhexanide methacrylate and chlorohexidine methacrylate.
    [5]
    A "medical device coating" according to any one of the preceding claims, characterized in that the plurality of monomers further comprises one or more monomers selected from methyl methacrylate, ethyl methacrylate, n-alkyl methacrylate, methyl acrylate, ethyl acrylate, n-alkyl acrylates and Hydroxyethyl Methacrylate.
    [6]
    "Medical device coating" according to claim 5, characterized in that one or more selected monomers include an n-alkyl acrylate or an n-alkyl methacrylate, in which the n-alkyl group is a propyl group; butyl, pentyl or hexyl.
    [7]
    A "medical device coating" according to any one of the preceding claims, characterized in that the plurality of monomers further comprises a monomer comprising a polyethylene glycol pendant group, a pendant group terminating at a sulfonate group, a pendant silyl group , a zwitterionic group or a hydroxyl group.
    [8]
    "MEDICAL DEVICE COATING" according to any one of claims 1 to 3, characterized in that the copolymers prior to photoinitiation consist essentially of the polymerization product of N-vinyl pyrrolidinone and the diaryl vinyl monomer. -ketone
    [9]
    A "medical device coating" according to claim 1, characterized in that the vinyl diaryl ketone monomer is 4-5 benzoyl phenyl methacrylate, and the plurality of monomers further comprise methoxy polyethylene glycol methacrylate.
    [10]
    "Medical device coating" according to Claim 9, characterized in that the plurality of monomers further comprise butyl methacrylate and / or butyl acrylate.
    [11]
    "Medical device coating" according to any one of the preceding claims, characterized in that the medical device is selected from the group consisting of a stent, a guidewire, a pacemaker, a catheter, a medical balloon. , a nasogastric feeding tube, a CCIP (Peripheral Insertion Central Catheter) line, and an endotracheal tube.
    [12]
    Water-soluble "INSULATED POLYMER SET", characterized in that it comprises copolymers polymerized from monomers comprising N-vinyl pyrrolidone and a diaryl ketone vinyl monomer, with the copolymers having an average molecular weight of more than approximately 100,000, at least at least about 60 wt% N-vinylpyrrolidinone, no more than about 5 wt% diaryl ketone monomer, and a random distribution of the diaryl ketone in the copolymer.
    [13]
    Water-soluble "POLYMER INSULATED SET" according to claim 12, characterized in that it is crosslinkable by exposure to an ultraviolet source to activate the diaryl ketone to form covalent crosslinks.
    [14]
    The water-soluble "POLYMER ISOLATED SET" according to claim 12 or 13, characterized in that the vinyl diaryl ketone monomer is 4-benzoylphenyl methacrylate and the copolymer further comprises the methoxy methoxy polyethylene glycol monomer.
    [15]
    The water-soluble "POLYMER ISOLATED SET" according to claim 14, characterized in that the copolymer further comprises the butyl methacrylate monomer (s) and / or butyl acrylate.
    [16]
    "Aqueous solution", characterized in that it comprises the isolated set of water-soluble polymers according to any one of claims 12 to 15.
    [17]
    Aqueous solution according to claim 16, further comprising isopropanol.
    [18]
    18. "Medical device coating method", characterized in that it comprises coating of a medical device with copolymers having an average molecular weight of more than approximately 100,000, at least approximately 60% by weight of vinyl monomer N-vinylpyrrolidinone. diaryl ketone present in no more than approximately 5% by weight, and a random distribution of diaryl ketone in the copolymer, and exposure of the coated device to an ultraviolet radiation source to activate the diaryl ketone, to form crosslinks to create a covalently cross-linked layer over a surface of the medical device.
    [19]
    A "MEDICAL DEVICE COATING METHOD" according to claim 18, characterized in that the copolymers prior to photoinitiation consist essentially of the polymerization product of N-vinylpyrrolidinone and the diaryl ketone vinyl monomer.
    [20]
    A "medical device coating method" according to claim 18 or 19, characterized in that the medical device is selected from the group consisting of a stent, guidewire, pacemaker, catheter, a nasogastric feeding tube, a CCIP (Peripheral Insertion Central Catheter) line and an endotracheal tube.
    [21]
    "MEDICAL DEVICE COATING METHOD" according to any one of claims 18 to 20, characterized in that the copolymers are coated onto the medical device in a solvent selected from the group consisting of methanol, ethanol, 2-propanol water, tetrahydrofuran, and mixtures thereof, with the method further comprising evaporating the solvent and drying the layer at a temperature ranging from about 15 to about 80 ° C.
    [22]
    22. "A copolymer manufacturing process", comprising preparing a solution of N-vinylpyrrolidinone in aqueous solution, adding a free radical polymerization initiator dissolved in N-vinylpyrrolidinone to the solution and adding a diaryl vinyl monomer. ketone dissolved in N-vinylpyrrolidinone with the solution, and polymerization of the monomers to form a random copolymer of N-vinylpyrrolidinone and the diaryl ketone vinyl monomer.
    [23]
    The process of manufacturing a copolymer according to claim 22, wherein the monomer comprises an acrylate group or a methacrylate group.
    [24]
    The process of making a copolymer according to claim 22 or 23, wherein the vinyl diaryl ketone monomer comprises 4-benzoylphenyl methacrylate, dimethyl sulfoxide and dichloromethane.
    [25]
    "Copolymer", characterized in that it is produced by the process as defined in any one of claims 22 to 24.
    类似技术:
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    法律状态:
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-07-17| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2018-11-21| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2019-01-29| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 02/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    2019-10-01| B25G| Requested change of headquarter approved|Owner name: BIOINTERACTIONS LTD (GB) |
    优先权:
    申请号 | 申请日 | 专利标题
    US12/877,233|US8541498B2|2010-09-08|2010-09-08|Lubricious coatings for medical devices|
    US12/877,233|2010-09-08|
    PCT/GB2011/001291|WO2012032283A1|2010-09-08|2011-09-02|Lubricious coatings for medical devices|
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