IE20030294U1 - Coating for biomedical devices - Google Patents
Coating for biomedical devicesInfo
- Publication number
- IE20030294U1 IE20030294U1 IE2003/0294A IE20030294A IE20030294U1 IE 20030294 U1 IE20030294 U1 IE 20030294U1 IE 2003/0294 A IE2003/0294 A IE 2003/0294A IE 20030294 A IE20030294 A IE 20030294A IE 20030294 U1 IE20030294 U1 IE 20030294U1
- Authority
- IE
- Ireland
- Prior art keywords
- polymeric
- coating
- monomer
- molecular weight
- hydrophilic
- Prior art date
Links
- 238000000576 coating method Methods 0.000 title claims description 72
- 239000011248 coating agent Substances 0.000 title claims description 71
- 241000894007 species Species 0.000 claims abstract description 51
- 239000000178 monomer Substances 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 238000009472 formulation Methods 0.000 claims abstract description 12
- 230000001902 propagating Effects 0.000 claims abstract description 5
- 229920000642 polymer Polymers 0.000 claims description 56
- 239000000758 substrate Substances 0.000 claims description 34
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 32
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 29
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 29
- RWCCWEUUXYIKHB-UHFFFAOYSA-N Benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 21
- 239000008199 coating composition Substances 0.000 claims description 19
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 17
- 239000003999 initiator Substances 0.000 claims description 13
- -1 aryl ketones Chemical class 0.000 claims description 8
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
- RLUFBDIRFJGKLY-UHFFFAOYSA-N (2,3-dichlorophenyl)-phenylmethanone Chemical compound ClC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1Cl RLUFBDIRFJGKLY-UHFFFAOYSA-N 0.000 claims description 3
- JNELGWHKGNBSMD-UHFFFAOYSA-N Xanthone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3OC2=C1 JNELGWHKGNBSMD-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- 230000000977 initiatory Effects 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 229920001477 hydrophilic polymer Polymers 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 8
- 239000004677 Nylon Substances 0.000 description 6
- 229920001778 nylon Polymers 0.000 description 6
- 239000004814 polyurethane Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229920003250 poly(2-hydroxyethyl methacrylate) Polymers 0.000 description 5
- 229920002635 polyurethane Polymers 0.000 description 5
- WOBHKFSMXKNTIM-UHFFFAOYSA-N 2-hydroxyethyl 2-methylacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SSZWOQANOUHNLV-UHFFFAOYSA-N 2-cyclohexylpropan-2-ol Chemical compound CC(C)(O)C1CCCCC1 SSZWOQANOUHNLV-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000003431 cross linking reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000003019 stabilising Effects 0.000 description 3
- 241001190717 Hea Species 0.000 description 2
- 229940063557 Methacrylate Drugs 0.000 description 2
- 229920003082 Povidone K 90 Polymers 0.000 description 2
- IQPQWNKOIGAROB-UHFFFAOYSA-N [N-]=C=O Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000007598 dipping method Methods 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- BHBPJIPGXGQMTE-UHFFFAOYSA-N ethane-1,2-diol;2-methylprop-2-enoic acid Chemical compound OCCO.CC(=C)C(O)=O.CC(=C)C(O)=O BHBPJIPGXGQMTE-UHFFFAOYSA-N 0.000 description 2
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 229920001888 polyacrylic acid Polymers 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920000098 polyolefin Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002522 swelling Effects 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 1
- 210000001124 Body Fluids Anatomy 0.000 description 1
- 206010069853 Device difficult to use Diseases 0.000 description 1
- 210000001847 Jaw Anatomy 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000001464 adherent Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000001680 brushing Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000002783 friction material Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000003702 immature single positive T cell Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001976 improved Effects 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 230000001050 lubricating Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical group 0.000 description 1
- 238000007540 photo-reduction reaction Methods 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Abstract
abstractable hydrogen radicals, the formulation including a hydrophilic polymeric component comprising at least two polymeric species of differing molecular weights, an unsaturated hydrophilic monomer capable of free-radical polymerisation in the presence of a radical and a UV activatable compound capable of abstracting hydrogen radicals from the surface to be coated and from a polymeric specie of the hydrophilic polymeric component so as to initiate and promote the cross-linkage of the monomer to the surface and of the monomer or a propagating monomer chain to a polymeric specie of the polymeric component, and a suitable solvent to give the formulation a desired viscosity.
Description
The present invention relates to a coating for biomedical devices and in particular to such a
coating which facilitates the passage of the coated device through a body cavity or vessel.
Medical devices are commonly composed of plastic materials or metals. Generally the
surfaces of these materials are hydrophobic, and thus tend to be ‘non—slippery’ and likely
to damage tissue during the insertion, positioning and removal of the device, resulting in
the possible delay in the recovery of the patient. In recent times this consideration has
become an important requirement in the manufacture of biomedical devices.
The introduction and removal of a catheter during an angioplasty procedure involves
sliding a catheter through a narrow and tortuous body vessel. It is therefore of great
advantage that the friction between the catheter surface and contact tissue be minimised.
An effective way to reduce the friction between the surface of a biomedical device and the
body area into which it is introduced is through the use of low friction materials and/or
coatings, such as PTFE, glycerine or silicone fluids. However these and similar coatings
may present problems to the physician before and during insertion by making the device
difficult to handle. It is preferable that the coating would only become slippery following
insertion of the device into the patient’s body. Such coatings are known and are commonly
referred to as lubricious hydrophilic coatings or LHC’s, and only become slippery when
they come into contact with aqueous environments such as bodily fluids.
These coatings are applied to the medical device by the attachment of hydrophilic polymer
chains to the surface. One class of such coatings comprise hydrophilic polymers that
possess reactive end groups that can directly attach or graft onto the surface of the device.
US—A—4,100,309 describes a method for producing a flexible LHC by blending a
hydrophilic polymer with a polyurethane binder. US—A-5,776,611 employs isocyanate
chemistry to produce cross-linked hydrogels on the surfaces of devices. Both coatings
US—A—5,001,009 describes the
may be applied to metallic or polymeric substrates.
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preparation of a coating by blending polyvinylpyrrolidone and cellulose esters. The
coating can be cast from solution onto biomedical devices and implants such as catheters.
In all of these coating systems elevated temperature and aggressive solvents or surface
pretreatment are necessary to effect attachment of the coating to the device.
Amiji and Park, ACS Symp. Ser. (1994), 5_4_0, pp. 135-146 describe a poly(ethyleneoxide)
formulation tipped on one end with an isocyanate group for grafting to a polyurethane
catheter surface. Freij-Larsson and Wessien, Journal of Applied Polymer Sciences, (1993)
Q, pp. 345-352, reported similar findings using various substrates. Fujimoto et al., J.
Polymer Science, Polymer Chemistry Edition, (1993) 3_l, pp. 1035-1043, describe an
ozone pretreatment to produce a hydrophilic layer grafted onto pellethane. In their
technique they suggested the use of ozone to pre-treat the substrate in order to produce
sites for grafting of acrylamide, which they then polymerised in situ. However in all cases
high temperatures were required to bring about the reaction and this possibly causes
damage to the substrate.
Another known technique involves the mixing of a hydrophilic polymer and a supporting
polymer. This formulation is then applied to the surface of the medical device with the use
of a common solvent. The hydrophilic component produces the lubricious coating while
the stabilising polymer anchors the soluble polymer through molecular entanglements.
This technique is currently used in many commercially available coating formulations
including those manufactured and distributed by Hydromer, STS, and Surmodics.
The use of hydrogels as LHC’s is also known. Such coatings do not require any anchoring
or stabilising component as they are self stabilised through cross—links.
In order to minimise the heating times and temperatures involved in curing LHC’s,
methods have been developed which use UV radiation to produce such coatings which do
not require excessive heating of the substrate, as the reactions rely on low temperature
radiation. US—A—6,l 10,483 discloses a UV curable coating system which has a high degree
of flexibility, consisting of a hydrophilic polymer, a stabilising polymer and an active
agent. Such a system avoids the necessity of high cure temperatures to bring about the
reaction, but it still requires the use of aggressive solvents. Furthermore, there is a need for
several dipping cycles and drying temperatures of at least 50°C to remove the solvents
following the reaction.
US-A—6,077,698 discloses a chemical linking agent for attaching (any of a number of)
many different materials to a surface. The linking agent comprises an at least di—functional
photo active compound and at least one charged group to enhance water solubility. A
surface is coated with the material by forming an aqueous mixture of the material and
linking agent and activating the photoreactive groups to cross—link the material to the
surface.
US—A-5,702,754 discloses a coating comprising polyfunctional crosslinking agent
“sandwiched” covalently between a substrate and a hydrophilic polymer having organic
acid functional groups.
US-A-4,979,959 is directed to a method of improving the biocompatibility of a surface by
coating it with a linking moiety of structure A-X-B, in which A is a photochemically
reactive group capable of bonding covalently to a solid surface, B represents a different
reactive group capable of forming a convalent bond to a biocompatible agent and X
represents a relatively inert skeletal moiety joining groups A and B.
In US—A—4,835,003, it is disclosed that a PVP coating having a high molecular weight of at
least 800,000d provides improved lubricating characteristics.
W0 01/ 17575 discloses a method of coating a substrate by initiating a graft polymerisation
reaction on the substrate to generate reactive radical sites on the surface and contacting the
substrate with one or more monomers in a medium having different hydrophilicity from
the substrate to graft the monomer onto the substrate.
US—A—6,340,465 discloses a stable, lubricious, biocompatible coating composition
comprising a coupling agent, a polyfunctional polymer and at least one biocompatible
agent, wherein the coupling agent and the polymer interact to form a three—dimensional
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crosslinking network which can entrap the biocompatible agent. The polyfunctional
polymer disclosed has two or more functionalities. The biocompatible agent may be an
antithrombotic agent and in one embodiment, the biocompatible agent is a hydrophilic
polymer selected from the group consisting of PVP, PVP/vinyl acetate copolymer and
polyethylene oxide.
The present invention seeks to provide a method of coating a medical device which
provides a reliable, durable hydrophilic coating for the device.
Accordingly, the present invention provides a coating formulation for a substrate having
abstractable hydrogen radicals, the formulation including a hydrophilic polymeric
component comprising at least two polymeric species of differing molecular weights, an
unsaturated hydrophilic monomer capable of free-radical polymerisation in the presence of
a radical and a UV activatable compound capable of abstracting hydrogen radicals from
the surface to be coated and from a polymeric specie of the hydrophilic polymeric
component so as to initiate and promote the cross-linkage of the monomer to the surface
and of the monomer or a propagating monomer chain to a polymeric specie of the
polymeric component, and a suitable solvent to give the formulation a desired viscosity.
Preferably, the unsaturated hydrophilic monomer has at least two acrylate functional
groups. The at least two polymeric species may include different functional groups. For
example, the species may comprise chemically different polymers. The polymeric species
may comprise straight chain or branched chain polymers. Ideally, at least one polymeric
species comprises a relatively lower molecular weight polymer and at least one polymeric
species comprises a relatively higher molecular weight polymer. Molecular weights in the
range of 40kDa to lO0kDa are contemplated for the relatively lower molecular weight
polymer and molecular weights in the range of l00kDa to l500kDa are contemplated for
the relatively higher molecular weight polymer. Weight ratios of the lower molecular
weight polymer to the higher molecular weight polymer of at least about 1-3: 1-2 have
been found to give coatings with acceptable properties.
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In a preferred arrangement, the substrate to be coated comprises a surface of a biomedical
device and the formulation’s monomeric and polymeric components are biomedically
compatible.
The surface to be coated with the formulation of the invention will be one which contains
labile hydrogen atoms available for abstraction. Such materials include without limitation
nylon-based materials, polyurethanes, polyolefins and polyethyleneterephthalates.
Ideally, the UV activatable compound is selected from any of a group that use a hydrogen
abstraction mechanism to initiate polymerisation, including aryl ketones such as
benzophenone, xanthone and dichlorobenzophenone. Benzophenone is particularly
preferred since it is readily available and inexpensive. A particularly preferred monomer
for the coating formulation is acrylic acid, which has the functionality to react both with
the substrate and with the polymeric specie on initiation of the hydrogen abstraction
mechanism by the UV—activated initiator. Other monomeric species will also be suitable.
For example, N-vinylpyrrolidone would also be a suitable choice and indeed any
monomers having unsaturated linkages which produces a final, non—toxic, biocompatible
coating will be available for selection. In a preferred arrangement, the polarity of the
monomeric species will be a consideration since selection of a suitably polar monomer will
enable the monomer to also act as a solvent for the other components of the formulation,
thereby reducing the volume of other solvent required, if any.
The invention also provides a coating mixture for a biomedical device which has labile
hydrogen radicals available for abstraction, the mixture comprising acrylic acid monomer,
at least two hydrophilic polymeric species of differing molecular weight and a UV
activatable compound capable of abstracting labile hydrogen radicals from the surface to
be coated and from at least one of the polymeric species so that on activation of the UV
activatable compound, the components bond to the surface of the biomedical device to coat
it with a hydrophilic, interpenetrating matrix of polymers. Ideally, the UV activatable
benzophenone and the polymeric species comprise
compound comprises
polyvinylpyrrolidone.
leasuzsi
The system of the invention involves the in situ polymerization of a coating which
produces good direct covalent grafting of a hydrophilic polymer to an underlying substrate,
for example the surface of a medical device.
By utilizing the monomer as a solvent prior to curing, the use of another solvent or
solvents to facilitate the application of the LHC is minimized. UV light is conveniently
used to activate, polymerize and crosslink the coating in situ.
The coating formulations of the invention are applicable for coating any surface which
permits the abstraction of hydrogen radicals from the substrate by, for example,
benzophenone. Any material can be coated if it contains an active hydrogen such as that
which would be present in an amino group or an hydroxyl group.
Materials which do not have active such groups may be pre-treated in order to impart the
correct functionality to enable them to be coated with a coating formulation of the present
invention.
The coating of the invention is useful in particular for coating stent delivery systems,
guiding catheters, introducers and other biomedical device. Equally, it is applicable to
coating many other materials and any material which has abstractable hydrogen atoms at
its surface may be coated using these coatings.
The invention will now be described in more detail with reference to biomedical devices
and to the accompanying figures, in which: -
Figure 1 is a schematic representation of a coating according to the invention applied to a
medical device;
Figure 2 is a representation of one suggested reaction mechanism for the coating method
according to the present invention; and
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Figure 3 and 4 are charts showing results of durability tests and frictional tests carried out
on different coatings fonnulations.
The present invention relates to the design and development of a tuneable lubricious
hydrophilic polymer coating formulations and a method for its direct attachment to
substrates, including polymeric substrates.
The coating components include (i) blends of hydrophilic polymeric species of differing
chemistry and/or molecular weight, (ii) a liquid monomeric species and (iii) an initiator.
Ideally, the polymer blend and monomeric species are readily available, relatively
inexpensive and non-toxic materials. Polyvinylpyrrolidone (PVP) is particularly useful as
the polymeric species and acrylic acid is particularly useful as the monomeric species. An
aryl ketone initiator, such as benzophenone, is particularly suitable as the UV activatable
compound for promoting the formation of a coating.
It is believed that when the initiator is activated, the radical generated on the benzophenone
(a) initiate chain addition polymerisation of acrylic acid;
(b) abstract labile hydrogens from nylon and PVP chains to generate radicals to initiate
grafting reactions; and
(C) where a difunctional methacrylate monomer is supplied as a crosslinking agent,
initiate polymerisation of this agent leading to a degree of crosslinking.
The radicals generated on the polymer chain can couple with propagating polyacrylic acid
chain radicals to graft and terminate the polymerisation, probably giving rise to polyacrylic
acid chains of varying chain lengths and probably branches and crosslinks grafted on to the
polymer chains. Propagating chains emanating from the polymers can also couple with
each other to generate hydrophilic crosslinked structures. Thus the resulting coating will
comprise a complex matrix with an interpenetrating network structure.
The purpose of blending polymers of different chemical species and/or molecular weight is
to optimise the hydrophilicity of the coating when wetted, as illustrated in Figure 1. As
shown in that figure, the final coating on the surface of the medical device has polymeric
species of differing lengths extending away from it. This provides a means by which water
may be trapped between the polymeric species when the surface is wetted, lending it
hydrophilic and lubricious characteristics. The final coating will in fact be a chemically
heterogeneous system or interpenetrating network, but will nevertheless predominantly
comprise of a “layer” A constituted of the former monomer covalently attached to the
underlying surface of the medical device D. An outer layer B comprises the different
polymeric species covalently linked to the former monomer of layer A. Since the layer B
is comprised of polymer of different species and/or molecular weights, the result is that the
outer layer comprises a matrix or network of differing chain length or differing degrees of
molecular cross-linkage and entanglements of the polymers in the layer. Side reactions
further complicate the chemical nature of the coating. For example cross—linking may
occur between polymers. All these effects combine to give a coating which can swell on
exposure to an aqueous enviromnent to give the coated device a desired lubricity. By
altering the components of the system, lubricity, coating strength, durability and
hydrophilicity can be adjusted to provide suitable characteristics for a particular device or
use. Furthermore, the viscosity of the coating formulation can be modified as desired by
choice of the components and solvents.
Typically but not exclusively, the surface to be coated is itself a polymer. The coating is
covalently grafted or bonded to it by providing conditions under which the monomeric
species binds covalently first to the surface and subsequently to the polymeric species, so
that the monomer acts as a bridge or link between the surface and the polymeric material.
Differing co-polymeric species of differing length will exist on the surface on termination
of the reaction, depending on the number of monomers which polymerise together prior to
linkage of a polymeric species to the monomer or polymerised monomer chain, as well as
on the chemical nature of the polymer(s) in the mixture.
The purpose of the liquid monomer is to provide a coating which is covalently linked to the
underlying surface and on which to covalently attach and anchor the hydrophilic polymeric
species, e.g, PVP. In rendering the invention to practise, acrylic acid was used as the
liquid monomer which on curing immobilised the PVP on the substrate, as illustrated
schematically in Figure 1.
Without wishing to be limited to any particular reaction mechanism, Figure 2 nevertheless
illustrate some of the proposed reactions which are likely to occur in the formation of the
coating. Other reactions and side reactions are also likely to occur to differing extents
depending on the nature of the materials chosen and the reaction conditions selected. It is
believed that the final coating is a complex, interpenetrating network capable of swelling
on exposure to an aqueoues environment to impart desired lubricious characteristics to the
coated article.
Benzophenone is one suitable initiator for the acrylic acid polymerisation. It can also
covalently bond the polymer directly to the substrate (i.e. the medical device) polymer
through hydrogen abstraction, although in practice this reaction will proceed more slowly
and the predominant reaction is that of the covalent linkage of the monomer to the
substrate followed by reaction with the polymeric species.
Coatings were prepared by dissolving a desired polyvinylpyrrolidone (PVP) blend in
propanol and adding the monomer and initiator (e.g. acrylic acid and benzophenone) in
appropriate quantities. The solution was then mixed further before filtration and stored in
tinted glass containers.
It is an advantage of the coating of the present invention that the liquid monomer itself
contributes as a solvent for the dissolution of the polymeric species, thereby reducing the
amount of extraneous solvent in the coating.
The substrate (for example a medical device) is coated by known means. Normally, the
area to be coated is cleaned or otherwise treated, e.g., with alcohol, before being immersed
in the coating solution. The substrate is then removed from the coating solution and
transferred to a curing chamber where the coating is cured by exposure to light or heat,
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typically UV light, for a period sufficient for the initiator to catalyse the polymerisation.
Thereafter, any remaining extraneous solvent is allowed to dry off the surface.
Upon contact with blood, the hydrophilic polymeric coating swells as it absorbs water and
creates an aqueous lubricious coating about the coated device, lowering friction between it
and the vessel wall and thus reducing damage to the vasculature.
The coating formulation of the invention offers the possibility of using different molecular
weights of hydrophilic PVP’s or other polymers and the in situ polymerisation of monomer
acrylic acid/polymers. The initiator, such as benzophenone, has the dual role when used in
excess of abstracting hydrogen radicals from the polymer of the medical device surface
and from the monomer, when bound to the surface, to promote polymerisation of further
polymers. It can likewise abstract radicals from the PVP chains to initiate grafting
reactions.
By blending hydrophilic polymer species of different molecular weights the hydrophilic
character of the coating can be modified in order to achieve a desired or optimum lubricity.
The hydrophilic component adheres to the substrate by becoming embedded in an adherent
polymer matrix film which is attached through chemical binding to the surface of the
substrate.
The direct covalent attachment of the embedding monomer matrix to the substrate by the
abstraction of hydrogen from the substrate and the subsequent grafting of the polymer
provides a durable and flexible coating.
The hydrophilic coating formulation comprises a number of components which contribute
to the application and curing of the coating and the performance of the final product. Use
of solvents has been minimised through the use of a monomeric component which prior to
curing, acts as a solvent for the other components present and during curing acts as a
grafting agent to ensure stability by covalently interlinking to both the surface being coated
and to the coating polymer. Preferred monomers include N—vinyl—2—pyrrolidones and
acrylic acid and other monomers will also be suitable. Any monomeric compounds
containing unsaturated linkages may be used. Monomeric compounds containing
active/extractable hydrogen atoms tend to form coatings that are less stable due to lower
occurrence of grafting to the substrate. The polarity of the monomer used is also important
in relation to its ability to act as an active solvent for the system. Though acting as a
solvent prior to cure, during cure the monomer is employed in grafting the coating to the
surface of the substrate. The monomers can auto-polymerise to form the coating and
predominantly will also graft to the polymeric substances, which serve as viscosity
modifiers prior to cure and which enhance lubriciousnes post cure.
A mixture of any suitable monomers may be used.
The UV activatable agent or initiator can be one of many of a group which rely on
hydrogen abstraction mechanisms to act as initiators. These include aryl ketones including
benzophenone, xanthone and dichlorobenzophenone. As mentioned above, one suggested
mechanism for grating is shown schematically in Figure 2, using benzophenone as the
initiator.
Initially the UV excitation of the benzophenone is followed by photoreduction of the
substrate (in this case a nylon catheter) via the extraction of the hydrogen atoms. This
leaves free radicals on the surface of the substrate which act as sites for covalent bonding
of a monomer molecule. Polymerisation of the monomer with itself and/or with the
hydrophilic polymer then occurs and the resultant coating is bound to the substrate through
covalent bonds.
The use of a polymeric species allows for control of the hydrophilicity (thus lubricity),
formulation viscosity and the coating thickness. The use of hydrophilic polymers such as
polyvinylpyrrolidone (PVP) and polyethylene—oxide is preferred but others can be used or
mixtures of different polymeric species may be used. The presence of active hydrogens
along such polymeric materials improves the stability of the coating through the formation
of bonds as described above.
E 030294’
Crosslinking agent such as ethylene glycol dimethacrylate (EGDMA) can optionally be
incorporated to improve the coating stability and to control swelling of the coating.
Solvents can also be incorporated into the formulation to control the coating thickness.
However, solvents such as acetone themselves provide active hydrogens and therefor
inhibit the reaction.
The coating formulation of the invention will be suitable for coating any surface which
includes susceptible hydrogen atoms, including but not limited to nylon—based materials,
polyurethanes, polyolefins, polyethyleneterephthalates and the like. The coating can be
applied to the surface by any method known to the skilled person, including dipping,
brushing or spraying.
EXAMPLES
Coating formulations were prepared in accordance with Table 1.
Example PVP K90 PVP29/32 Acrylic Acid Benzophenone Propanol
(Grams) (Grams) (Grams) (Grams) (mls)
1 7.5 2.5 0.6664 0.3328 440
2 5 5 0.6664 0.3328 440
TABLE 1
The molecular weight of PVP is often expressed in terms of the Fikentscher K—value that is
derived from the solution viscosity as shown in Table 2.
Viscosity in H20 K — Value Mn (Number Ave) Mw (Weight Ave)
cSt (%PVP)
7 (20) 13-19 10,000 12,000
(20) 26-34 40,000 55,000
50 (10) 50-62 220,000 400,000
400 (10) 80-100 630,000 1,280,000
7000 (10) 115-125 1,450,000 2,800,000
TABLE 2
Table 2 illustrates the relationship between K-Value and the number and weight average
molecular weights (From GAF (ISP) Technical Bulletin 2302-203 SM 1290 “PVP
polyvinylpyrrolidone polymers 1990”.
The PVP was added slowly to the propanol with stirring at room temperature until all the
PVP had gone into solution. Next, the acrylic acid and benzophenone were added and
stirring was continued until all components were in solution. Thereafter, the solution was
filtered providing a stock coating solution. The solution was protected from light during
preparation and subsequent storage. The stock solution was filtered. This solution can be
stored, protected from light, for up to three weeks.
An article to be coated, such as a nylon catheter, is firstly end-sealed to prevent coating
solution from entering into the lumen of the catheter. The sealed shaft is then cleaned by
wiping with a solvent such as propanol. The shaft is lowered into the prepared stock
coating solution and withdrawn sufficiently slowly to allow excess coating to flow off.
The dipped article is held at room temperature for about 3 minutes to allow it to drip and
thereafter, it is moved into a UV chamber. Once the shaft has been dipped, great care is
taken to avoid touching the surface, thereby damaging the final coating. The UV chamber
includes a UV source operating at about 365nm. Following a residence in the chamber of
about 3 minutes, the coating cures and the shaft is withdrawn and allowed to cool for about
3 minutes. At the end of the cooling cycle, any remaining propanol solvent will have
evaporated off and the coating is complete and dry. Once the shaft has cooled, it is passed
to downstream processing steps which include a visual inspection of the coated surface to
ensure its integrity and removal of the sealed tip so that the lumen is once again open.
The coating formulations were used to coat lengths of nylon tubing according to the
method described above. The coated lengths were each inspected visually to assess the
gross appearance of the coating and its smoothness and integrity. In addition, a manual
assessment of the coating was made by rubbing the coated tubing twice between the
fingers and assessing the lubricity and durability of the coating of Examples 1 and 2 of
Table 1. The results of the visual and manual inspections are set out in Table 3.
IE 05029;‘
Example Feel 2"“ Run Lubricity Durability Comments
1 Pass Pass 1 2 Feels Good and Lub
2 Pass Fail Feels Good and Lub
Lub = Lubricions
TABLE 3
The lubricity characteristics of the coatings were measured using a calibrated test rig set up
to measure the initial frictional force in grams exerted as tubing pre—wetted in water at
room temperature is drawn through a jaw pair. Durability of the coating was assessed by
measuring initial frictional forces over iterative drawings. Figures 3 and 4 are respectively
plots of the durability and initial frictional forces measured for the different coating
formulations and Table 4 details the result of the lubricity and durability studies for
Examples 1 and 2.
th cycle
1st cycle 10th cycle Energy
Example peak (g) peak (g) 1st Energy (g/m) Durability (g/m)
1 63.2 128.6 512.2 878.4 366.2
2 60.2 595.4 572.4 5111.8 3484.4
TABLE 4
Example 1 was selected as the best performing sample in both frictional durability studies
and hand evaluation.
In the preferred embodiment of the invention described above, the two critical components
relating to the curing and performance of the coating are the acrylic acid and
benzophenone.
The following ranges of these components, based on solutions of 2.156% PVP K90 and
0.7197 % PVP K29/32 in isopropanol, are suitable for use in the present invention.
Benzophenone range 0.0088% to 0.01%
lE030294'
Acrylic Acid Range 0.0l77143% to 0.02%.
These ranges, which are Wt/volume, are also suitable for other solutions of the polymers.
Additions of PVP Weight ranged from 0.025% to 25.0%. The molecular weight of the PVP
is an important factor due to its effect on the solution viscosity). Molecular Weight
combinations of loW and high molecular Weight species are preferred).
Further examples 3 to 13 of formulations suitable for use in the present invention are set
out in the attached Table 5.
Example Polymer A Polymer B Ratio Polymer C Initiator Solvent
PVPa PVPb 3:1 Acrylic Acid Benzephenone AA
7.5g 2.5g (AA) (0.000l%wt) Isopropanol 440mls
(75% wt) (25%)
MW 40kDa MW 360kDa
PVPa PVPb 1:1 Acrylic Acid Benzephenone AA
.0g 5.0g (AA) (0.000l%Wt) Isopropanol 440mls
(50%) (50%)
MW 40kDa MW 360kDa
PEO a PEO b 322 N—Vinyl 2 Benzephenone NV2P
6.0g 4.0g Pyrrolidone (0. lg) Isopropanol220m1s
(60%Wt) (40%wt) (NV2P) H20 (dist.) 220mls
MW l00kDa MW 300kDa
PEO a PEO b 3:2 N-Vinyl 2 Benzephenone NV2P in
6.0g 4.0g Pyrrolidone (0. lg) Isopropanol 220mls
(60%wt) (40%Wt) (N V2P) H20 (dist) 220mls
MW 40kDa MW 1500kDa
PVP PEO b 3:2 N—Vinyl 2 Benzephenone NVZP in
6.0g 4.0g Pyrrolidone (0. lg) Isopropanol 220mls
(6O%Wt) (4O%Wt) (NVZP) H20 (dist.) 220mls
MW 40kDa MW l00kDa
PEO a PEO b 3:2 Methyl meth Benzephenone MMA in
6.0g 4.0g acrylate (0. lg) Isopropanol 220mls
(60%Wt) (40%Wt) H20 (dist.) 220mls
MW l00kDa MW l000kDa
PEO a PEO b 3:2 Hydroxy Benzephenone HEA in
6.0g 4.0g ethyl (0. lg) Isopropanol 220mls
(60%Wt) (40%Wt) acrylate H20 (dist.) 220mls
MW l00kDa MW 1000kDa (HEA)
PHEMA PVP 3:2 Acrylic acid Hydroxy AA in
6.0g 4.0g (AA) cyclohexyl Isopropanol 440mls
(60%Wt) (40%Wt) phenyl ketone
MW l00kDa MW 300kDa (0. lg)
PVP PHEMA 3:2 Acrylic Acid Benzephenone AA
6.0g 4.0g (AA) (0.0001%Wt) Isopropanol 440mls
(60%Wt) (40%wt)
MW 40kDa MW l00kDa
E03029;
PVP a PVP b 3 :2 N-Vinyl 2 Hexamethylen NV2P
6.0g 4.0g Pyrrolidone e disocyanate Isopropanol 440mls
(60%wt) (40%wt) (NV2P) (0.0001%wt)
Mw 40kDa Mw 360kDa
11 PVP a PVP b 3:2 Acrylic Acid Hydroxy AA
6.0g 4.0g (AA) cyclohexyl Isopropanol 440mls
(60%wt) (40%wt) phenyl ketone
MW 40kDa Mw 360kDa (0. 1 g)
12 PEO PHEMA 3:2 Acrylic Acid Hydroxy AA
6.0g 4.0g (AA) cyclohexyl Isopropanol 220mls
(60%wt) (40%wt) phenyl ketone H20 (dist) 220mls
Mw 100kDa Mw l00OkDa (0. lg)
13 PVP a PVP b 3:2 N—Vinyl 2 Benzephenone NV2P
6.0g 4.0g Pyrrolidone (0.000l%wt) lsopropanol 440mls
(60%wt) (40%wt) (NV2P)
Mw 40kDa MW 360kDa
TABLE 5
Polymer A: Hydrophilic polymer
Polymer B: Amphiphilic polymer
Polymer C: Hydrophilic monomer
Typical Ratio’s Polymer A Polymer B
(50-75%) (25 — 50%)
PHEMA Poly hydroxy ethyl meth acrylate
PVP Polyvinyl methacrylate
PEO Poly ethylene oxide
PU Polyurethane (Hydrophilic/Hydrophobic) species
It will of course be understood that the invention is not limited to the specific details herein
described, which are given by way of example only and that Various alterations and
modifications may be made without departing from the scope of the invention.
MACLACHLAN & DONALDSON,
Applicants’ Agents,
Merrion Square,
DUBLIN 2.
Claims (1)
- Claim 1 substantially as herein described in the Examples.
Publications (2)
Publication Number | Publication Date |
---|---|
IE20030294U1 true IE20030294U1 (en) | 2004-10-20 |
IES83703Y1 IES83703Y1 (en) | 2004-12-15 |
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