U.S. patent application number 12/440775 was filed with the patent office on 2010-03-25 for coating formulation for medical coating.
This patent application is currently assigned to DSM IP ASSETS B.V.. Invention is credited to Peter Bruin, Aylvin Jorge Angelo Athanasius Dias, Marnix Rooijmans, Rudolfus Antonius Theodorus Maria Van Benthem, Edith Elizabeth M. Van Den Bosch.
Application Number | 20100076546 12/440775 |
Document ID | / |
Family ID | 38739926 |
Filed Date | 2010-03-25 |
United States Patent
Application |
20100076546 |
Kind Code |
A1 |
Dias; Aylvin Jorge Angelo
Athanasius ; et al. |
March 25, 2010 |
COATING FORMULATION FOR MEDICAL COATING
Abstract
The invention relates to a coating formulation for preparing a
medical coating, which coating formulation comprises (a) at least
one multifunctional polymerizable compound according to formula
(I), wherein G is a residue of a polyfunctional compound having at
least n functional groups, wherein each R.sub.1 and each R.sub.2
independently represents hydrogen or a group selected from
substituted and unsubstituted hydrocarbons which optionally contain
one or more heteroatoms, and wherein n is an integer having a value
of at least 2; and (b) at least one initiator. ##STR00001##
Inventors: |
Dias; Aylvin Jorge Angelo
Athanasius; (Maastricht, NL) ; Van Den Bosch; Edith
Elizabeth M.; (Riemst, BE) ; Bruin; Peter;
(Veldhoven, NL) ; Rooijmans; Marnix; (Born,
NL) ; Van Benthem; Rudolfus Antonius Theodorus Maria;
(Limbricht, NL) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
DSM IP ASSETS B.V.
Heerlen
NL
|
Family ID: |
38739926 |
Appl. No.: |
12/440775 |
Filed: |
September 13, 2007 |
PCT Filed: |
September 13, 2007 |
PCT NO: |
PCT/EP2007/007985 |
371 Date: |
November 24, 2009 |
Current U.S.
Class: |
623/1.46 ;
427/508; 427/520; 524/389; 524/391; 525/450; 525/471; 528/220;
528/229; 528/361; 600/585; 604/265 |
Current CPC
Class: |
Y10T 428/31935 20150401;
A61L 29/14 20130101; C23C 14/06 20130101; Y10T 428/1393 20150115;
C23C 14/22 20130101; C08G 65/33324 20130101; A61L 2420/06 20130101;
C08G 2650/50 20130101; C09D 135/00 20130101; Y10T 428/31504
20150401; C09D 5/00 20130101; Y10T 428/31725 20150401; A61L 31/14
20130101; A61L 31/10 20130101; A61L 29/085 20130101; C08G 65/3322
20130101; C09D 4/06 20130101; A61L 31/10 20130101; A61L 29/10
20130101; A61L 2420/02 20130101; C09D 135/02 20130101; Y10T
428/24975 20150115; Y10T 428/31562 20150401; C08L 33/26 20130101;
C08L 33/26 20130101 |
Class at
Publication: |
623/1.46 ;
528/220; 528/229; 528/361; 525/450; 525/471; 524/389; 524/391;
427/508; 427/520; 604/265; 600/585 |
International
Class: |
A61F 2/82 20060101
A61F002/82; C08G 4/00 20060101 C08G004/00; C08G 12/00 20060101
C08G012/00; C08G 63/06 20060101 C08G063/06; C08L 67/04 20060101
C08L067/04; C08L 61/00 20060101 C08L061/00; C08K 5/05 20060101
C08K005/05; C08F 2/46 20060101 C08F002/46; A61M 25/00 20060101
A61M025/00; A61M 25/09 20060101 A61M025/09 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 13, 2006 |
EP |
06019148.3 |
May 15, 2007 |
EP |
07009702.7 |
May 15, 2007 |
EP |
07009703.5 |
Claims
1. Coating formulation for preparing a medical coating, which
coating formulation comprises (a) at least one multifunctional
polymerizable compound according to ##STR00007## wherein G is a
residue of a polyfunctional compound having at least n functional
groups; wherein each R.sub.1 and each R.sub.2 independently
represents hydrogen or a group selected from substituted and
unsubstituted hydrocarbons which optionally contain one or more
heteroatoms, preferably hydrogen or a C1-C20 hydrocarbon, more
preferably hydrogen or a C1-C20 alkyl; and wherein n is an integer
having a value of at least 2, preferably 2-100, more preferably
2-8, in particular 2 or 3; (b) at least one initiator.
2. Coating formulation according to claim 2, wherein G comprises at
least one heteroatom.
3. Coating formulation according to claim 1, wherein the
multifunctional polymerizable compound according to formula (1) has
a number average molecular weight (Mn) of 500 g/mol or more.
4. Coating formulation according to claim 1, wherein the
multifunctional polymerizable compound according to formula (1) has
a number average molecular weight (Mn) of 2000 g/mol or less.
5. Coating formulation according to claim 1, wherein the
multifunctional polymerizable compound according to formula (1) is
soluble in a polar solvent.
6. Coating formulation according to claim 1, wherein G is a residue
of a hydrophilic polyfunctional compound, preferably chosen from
the group consisting of polyethers, polyesters, polyurethanes,
polyepoxides, polyamides, poly(meth)acrylamides,
poly(meth)acrylics, polyoxazolidones, polyvinyl alcohols,
polyethylene imines, polypeptides and polysaccharides, such as
cellulose or starch or any combination of the above, more
preferably a polymer comprising at least one polyethyleneglycol or
polypropylene glycol block.
7. Coating formulation according to claim 1, wherein R.sub.1.dbd.H
and R.sub.2.dbd.H.
8. Coating formulation according to claim 1, wherein R.sub.1 is
CH.sub.3 and H.
9. Coating formulation according to claim 1, further comprising at
least one functional component (c), preferably a functional polymer
(c).
10. Coating formulation according to claim 9, wherein the
functional polymer (c) is a hydrophilic polymer, preferably chosen
from the group consisting of poly(lactams), for example
polyvinylpyrollidone (PVP), polyurethanes, homo- and copolymers of
acrylic and methacrylic acid, polyvinyl alcohol, polyvinylethers,
maleic anhydride based copolymers, polyesters, vinylamines,
polyethylene imines, polyethyleneoxides, poly(carboxylic acids),
polyamides, polyanhydrides, polyphosphazenes, cellulosics, for
example methyl cellulose, carboxymethyl cellulose, hydroxymethyl
cellulose, and hydroxypropylcellulose, heparin, dextran,
polypeptides, for example collagens, fibrins, and elastin,
polysacharrides, for example chitosan, hyaluronic acid, alginates,
gelatin, and chitin, polyesters, for example polylactides,
polyglycolides, and olycaprolactones, polypeptides, for example
collagen, albumin, oligo peptides, polypeptides, short chain
peptides, proteins, oligonucleotides, and mixtures thereof.
11. Coating formulation according to claim 9, wherein the
hydrophilic polymer is a polyelectrolyte chosen from the group
consisting of polyacrylamide-co-acrylic acid sodium salt,
polyacrylic acid sodium salt, polymethacrylic acid sodium salt,
polyacrylamido-2-methyl-1-propanesulfonic acid sodium salt,
poly(4-styrene sulfonic acid) sodium salt,
poly(acrylamide-co-dialkyl ammonium chloride), quaternized
poly[bis-(2-chloroethyl)ether-alt-1,3-bis[3-(dimethylamino)propyl]ureal
and poly(diallyldimethylammonium chloride), polyallylammonium
phosphate, poly(diallyldimethylammonium chloride), poly(sodium
trimethyleneoxyethylene sulfonate),
poly(dimethyldodecyl(2-acrylamidoethyl)ammonium bromide), poly(2-N
methylpyridiniumethylene iodine), polyvinylsulfonic acids, salts of
poly(vinyl)pyridines, polyethyleneimines, and polylysines, and
mixtures thereof.
12. Coating formulation further comprising an ionic compound,
preferably a polyelectrolyte as defined in claim 10 or a low
molecular salt.
13. Coating formulation according to claim 1, further comprising at
least one surfactant.
14. Coating formulation according to claim 1, further comprising a
polar solvent.
15. Coating system for preparing a lubricious coating, said coating
system comprising a coating formulation according to claim 10, and
a wetting fluid comprising an ionic compound, preferably a
polyelectrolyte or a low molecular weight salt.
16. Medical coating obtainable by curing a medical coating
formulation according to claim 1.
17. Medical coating according to claim 16, which medical coating is
a hydrophilic medical coating.
18. Lubricious medical coating obtainable by wetting a hydrophilic
medical coating according to claim 17 applying a wetting fluid.
19. Lubricious medical coating according to claim 18, wherein the
wetting fluid comprises an ionic compound, preferably a
polyelectrolyte or a low molecular weight salt.
20. Lubricious medical coating obtainable by curing a coating
formulation and wetting the obtained coating, wherein a coating
system according to claim 15 is used.
21. Medical, hydrophilic or lubricious coating comprising a polymer
network comprising a multifunctional polymerizable compound (a) as
defined in claim 1.
22. Use of a multifunctional polymerizable compound according to
formula (1) in a medical coating.
23. Article comprising at least one medical, hydrophilic medical or
lubricious medical coating according to claim 16.
24. Article according to claim 23, wherein the article is a medical
device or component.
25. Medical device or component according to claim 24 comprising a
catheter, medical tubing, guidewire, a stent or a membrane.
26. Method of forming on a substrate a medical, hydrophilic or
lubricious coating, the method comprising applying a coating
formulation according to claim 1 to at least one surface of the
article; allowing the coating formulation to cure by exposing the
formulation to electromagnetic radiation thereby activating the
initiator; and, in case of a lubricious coating, subsequently
wetting the coating in a wetting fluid.
Description
[0001] The invention relates to a coating formulation for preparing
a medical coating, a medical coating obtainable by curing said
coating formulation, a hydrophilic coating, a lubricious coating
obtainable by wetting said hydrophilic coating, a coating system,
use of a multifunctional polymerizable compound in a medical
coating, an article comprising at least one medical, hydrophilic or
lubricious coating and a method of forming on a substrate a
medical, hydrophilic or lubricious coating.
[0002] People have continually attempted to impart certain
functional properties to a surface by applying coatings to it. Many
medical devices, such as urinary and cardiovascular catheters,
syringes, membranes, imaging devices, drug-eluting devices, stents
and implants therefore have a coating applied to the outer and/or
inner surface. For instance, a hydrophobic surface may be made
hydrophilic by applying a hydrophilic coating to it. Anti-microbial
properties may be provided by including active substances, for
example metal ions and/or other anti-microbial agents in the
coating. Similarly, drug-eluting coatings and imaging coatings may
be obtained by including drugs and imaging materials in the
coating, respectively.
[0003] For most medical applications robustness of the coating is
one of the most important requirements. In order to achieve
sufficient robustness, multifunctional polymerizable compounds are
frequently applied in the coating formulation, which are
polymerized upon curing in the presence of an initiator. Apart from
improved robustness, the use of a multifunctional polymerizable
compound may offer a controllable network which will allow tuned
release of active substances, for example metal ions, other
anti-microbial agents and drugs. In particular for functional
coatings, good results have been achieved by physically or
covalently entrapping functional components, e.g. functional
polymers, into a network of a multifunctional polymerizable
compound that provides the necessary adherence to the surface. In
that way the functional, e.g. imaging, drug-eluting, protecting or
lubricious properties of the functional component are mostly well
maintained. When the functional component is a functional polymer,
these coatings are often referred to as interpenetrating networks
or IPNs. IPNs thus consist of a functional polymer that provides
the desired properties to the coating and a multifunctional
polymerizable compound that is polymerized in order to form a
network of polymers.
[0004] The inventors have found that many coatings comprising a
multifunctional polymerizable compound show inferior coating
performance. Typically such coatings tend to degrade within a given
time, particularly in a hydrated environment causing increase in
extractables or leachables. Such extractables or leachables may
comprise low molecular and/or polymeric compounds and/or particles
which may be vital to the function of the coating. The extractables
or leachables may have for example an antimicrobial,
anti-thrombogenic, imaging, bioactive, and/or signalling function.
Degradation of said coatings typically results in loss of
properties such as ability to hydrate and maintain hydration, loss
of lubricious properties, loss of patient comfort, loss of imaging
properties, increased risk of infection due to the residue being
left on the tissue surface, uncontrolled release and co-elution
problems for biologically active components, and/or lack of
mechanical robustness, as demonstrated by the fact that parts of
the coating are easily removed from the coated article upon
rubbing.
[0005] The problem to be solved is therefore to provide a coating
formulation which comprises a multifunctional polymerizable
compound and an initiator, and which results in robust and
consistent coatings.
[0006] It has now surprisingly been found that such coating
formulations can be obtained by using a multifunctional
polymerizable compound according to formula (1)
##STR00002##
wherein G is a residue of a polyfunctional compound having at least
n functional groups, wherein each R.sub.1 and each R.sub.2
independently represent hydrogen or a group selected from
substituted and unsubstituted hydrocarbons which optionally contain
one or more heteroatoms, preferably hydrogen or a C1-C20
hydrocarbon, more preferably hydrogen or a C1-C20 alkyl; and
wherein n is an integer having a value of at least 2, preferably
2-100, more preferably 2-8, in particular 2 or 3.
[0007] The invention thus relates to a coating formulation for
preparing a medical coating, which coating formulation
comprises:
[0008] (a) at least one multifunctional polymerizable compound
according to formula (1)
##STR00003##
[0009] wherein G is a residue of a polyfunctional compound having
at least n functional groups, wherein each R.sub.1 and each R.sub.2
independently represent hydrogen or a group selected from
substituted and unsubstituted hydrocarbons which optionally contain
one or more heteroatoms, preferably hydrogen or a C1-C20
hydrocarbon, more preferably hydrogen or a C1-C20 alkyl; and
wherein n is an integer having a value of at least 2, preferably
2-100, more preferably 2-8, in particular 2 or 3; and
[0010] (b) at least one initiator.
[0011] It has surprisingly been found that the coating formulation
according to the invention results in better coating performance
compared to conventional coating formulations.
[0012] The multifunctional polymerizable compound (a) may be used
in more than 0%, based on the total weight of the dry coating, for
example more than 1%, or more than 2%. The multifunctional
polymerizable compound can be present in the coating formulation up
to 100%, 90%, 80%, 70%, 60% or 50, based on the total weight of the
dry coating. The skilled person can vary the amount of
multifunctional polymerizable compound within the above ranges to
obtain the desired properties for his application.
[0013] Hereinafter all percentages of components given in the
application are based on the total weight of the dry coating.
[0014] Generally multifunctional polymerizable compound (a) has a
number average molecular weight (Mn) of 500 g/mol or more,
preferably 750 g/mol or more, more preferably 1000 g/mol or more.
Generally multifunctional polymerizable compound (a) has a number
average molecular weight (Mn) of 100,000 g/mol or less, preferably
10,000 g/mol or less, more preferably 6,000 g/mol or less, in
particular 2,000 g/mol or less. Multifunctional polymerizable
compounds with an Mn within the preferred ranges show a favorable
cross-link density, i.e. open enough to give room to functional
components and dense enough to provide sufficient mechanical
robustness.
[0015] Apart for multifunctional polymerizable compound (a) as
defined above, i.e. with n.gtoreq.2, the composition may also
comprise species according to formula (1) wherein n=1, i.e.
molecules comprising only one reactive moiety. These
mono-functional molecules may also be part of the network formed
after curing. The average number of reactive moieties per molecule
according to formula (1) is preferably in the range of about 1.2 to
about 64, more preferably in the range of about 1.2 to about 16,
most preferably in the range of about 1.2 to about 8.
[0016] In one embodiment of the invention multifunctional
polymerizable compound (a) is soluble in a polar solvent. Within
the context of the invention this means that according to this
embodiment at least 1 g, preferably at least 3 g, more preferably
at least 5 g, in particular at least 10 g of multifunctional
polymerizable compound (a) can be dissolved in 100 g of the polar
solvent at 25.degree. C. Examples of suitable polar solvents
include water and C1-C6 alcohols, in particular methanol, ethanol,
propanol, isopropanol, butanol, isobutanol and t-butanol.
[0017] In one embodiment of the invention multifunctional
polymerizable compound (a) comprises at least one moiety containing
a heteroatom. Within the context of the invention a heteroatom is
understood to be a non-carbon, non-hydrogen atom. Examples of
suitable hereoatoms include oxygen atoms (O), nitrogen atoms (N),
sulfur atoms (S) and phosphor atoms (P).
[0018] In one embodiment of the invention G is a residue of a
hydrophilic polyfunctional compound, preferably chosen from the
group consisting of polyethers, polyesters, polyurethanes,
polyepoxides, polyamides, poly(meth)acrylamides,
poly(meth)acrylics, polyoxazolidones, polyvinyl alcohols,
polyethylene imines, polypeptides and polysaccharides, such as
cellulose or starch or any combination of the above, more
preferably a polymer comprising at least one polyethylene glycol or
polypropylene glycol block. The use of a hydrophilic polyfunctional
compound is particularly advantageous if the coating needs to have
hydrophilic and/or lubricious properties.
[0019] In multifunctional polymerizable compound (a) of formula (1)
R.sub.1 preferably represents hydrogen, CH.sub.3 or CH.sub.2OH.
Particularly suitable are multifunctional polymerizable compounds
wherein R.sub.1 and R.sub.2 both represent hydrogen or wherein
R.sub.1 represents CH.sub.3 and R.sub.2 represents hydrogen.
[0020] Examples of suitable multifunctional polymerizable compounds
according to the invention are polyether based (meth)acrylamides,
for example polyethylene glycol diacrylamide and polyethylene
glycol dimethacrylamide. Commercially available polyether
multifunctional amines which can be used to produce multifunctional
(meth)acrylamide multifunctional polymerizable compounds include
poly(ethylene glycol) bis(3-aminopropyl) terminated, Mw=1500
(Aldrich); PEG diamine (purely ethylene oxide units) P2AM-2
(molecular weight 2K), P2AM-3 (3.4K), P2AM-6 (6K), P2AM-8 (8K) and
P2AM-10 (10K) (Sunbio), JEFFAMINE.RTM. D-230 polyetheramine,
JEFFAMINE.RTM. D-400 polyetheramine, JEFFAMINE.RTM. D-2000,
JEFFAMINE.RTM. D-4000, JEFFAMINE.RTM. XTJ-500 (ED-600),
JEFFAMINE.RTM. XTJ D501 (ED-900), JEFFAMINE.RTM. XTJ-502 (ED-2003),
JEFFAMINE.RTM. XTJ-590 diamine, JEFFAMINE.RTM. XTJ-542 diamine,
JEFFAMINE.RTM. XTJ-548 diamine, JEFFAMINE.RTM. XTJ-559 diamine,
JEFFAMINE.RTM. XTJ-556 diamine, JEFFAMINE.RTM. SD-231 (XTJ584),
JEFFAMINE.RTM. SD401 (XTJ-585), JEFFAMINE.RTM. T-403
polyetheramine, JEFFAMINE.RTM. XTJ-509 polyoxypropylenetriamine,
JEFFAMINE.RTM. T-5000 polyetheramine, and JEFFAMINE.RTM. ST-404
polyetheramine (XTJ-586).
[0021] The coating formulation according to the invention can be
cured in the presence of initiator (b). The term "to cure" includes
any way of treating the formulation such that it forms a firm or
solid coating. In particular "curing" is understood to refer to
physical or chemical hardening or solidifying by any method, for
example heating, cooling, drying, crystallization or curing as a
result of a chemical reaction, such as radiation-curing or
heat-curing. In the cured state all or part of the components in
the coating formulation may be cross-linked forming covalent
linkages between all or part of the components, for example by
using UV or electron beam radiation. However, in the cured state
all or part of the components may also be ionically bonded, bonded
by dipole-dipole type interactions, via Van der Waals forces or
hydrogen bonds.
[0022] The coating formulation according to the invention can for
example be cured using electromagnetic radiation, for example
visible or UV light, electro-beam, plasma, gamma or IR radiation,
in the presence of an initiator, for example a photo-initiator or
thermal initiator, to form the medical coating. Examples of
photo-initiators that can be used in the medical coating are
free-radical photo-initiators, which are generally divided into two
classes according to the process by which the initiating radicals
are formed. Compounds that undergo unimolecular bond cleavage upon
irradiation are termed Norrish Type I or homolytic
photo-initiators. A Norrish Type II photo-initiator interacts with
a second molecule, i.e. a synergist, which may be a low molecular
weight compound of a polymer, in the excited state to generate
radicals in a bimolecular reaction. In general, the two main
reaction pathways for Norrish Type II photo-initiators are hydrogen
abstraction by the excited initiator or photo-induced electron
transfer. The mechanisms are further explained in WO06/056482.
[0023] Examples of suitable Norrish Type I or free-radical
photo-initiators are benzoin derivatives, methylolbenzoin and
4-benzoyl-1,3-dioxolane derivatives, benzilketals,
.alpha.,.alpha.-dialkoxyacetophenones, .alpha.-hydroxy
alkylphenones, .alpha.-aminoalkylphenones, acylphosphine oxides,
bisacylphosphine oxides, acylphosphine sulphides, halogenated
acetophenone derivatives, and the like. Commercial examples of
suitable Norrish Type I photoinitiators are Irgacure 2959
(2-hydroxy-4'-(2-hydroxyethoxy)-2-methyl propiophenone), Irgacure
651 (benzildimethyl ketal or 2,2-dimethoxy-1,2-diphenylethanone,
Ciba-Geigy), Irgacure 184 (1-hydroxy-cyclohexylphenyl ketone as the
active component, Ciba-Geigy), Darocur 1173
(2-hydroxy-2-methyl-1-phenylpropan-1-one as the active component,
Ciba-Geigy), Irgacure 907
(2-methyl-1-[4-(methylthio)phenyl]-2-morpholino propan-1-one,
Ciba-Geigy), Irgacure 369
(2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-one as the
active component, Ciba-Geigy), Esacure KIP 150 (poly
{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one},
Fratelli Lamberti), Esacure KIP 100 F (blend of poly
{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one} and
2-hydroxy-2-methyl-1-phenyl-propan-1-one, Fratelli Lamberti),
Esacure KTO 46 (blend of
poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one},
2,4,6-trimethylbenzoyldiphenyl-phosphine oxide and
methylbenzophenone derivatives, Fratelli Lamberti), acylphosphine
oxides such as Lucirin TPO (2,4,6-trimethylbenzoyl diphenyl
phosphine oxide, BASF), Irgacure 819
(bis(2,4,6-trimethylbenzoyl)-phenyl-phosphine-oxide, Ciba-Geigy),
Irgacure 1700 (25:75% blend of
bis(2,6-dimethoxybenzoyl)2,4,4-trimethyl-pentyl phosphine oxide and
2-hydroxy-2-methyl-1-phenyl-propan-1-one, Ciba-Geigy), and the
like. Also mixtures of type I photo-initiators can be used.
[0024] Examples of Norrish Type II photo-initiators that can be
used in the medical coating formulation according to the invention
include aromatic ketones such as benzophenone, xanthone,
derivatives of benzophenone (e.g. chlorobenzophenone), blends of
benzophenone and benzophenone derivatives (e.g. Photocure 81, a
50/50 blend of 4-methyl-benzophenone and benzophenone), Michler's
Ketone, Ethyl Michler's Ketone, thioxanthone and other xanthone
derivatives like Quantacure ITX (isopropyl thioxanthone), benzil,
anthraquinones (e.g. 2-ethyl anthraquinone), coumarin, or chemical
derivatives or combinations of these photoinitiators.
[0025] Preferred is a photo-initiator that is water-soluble or can
be adjusted to become water-soluble. Polymeric photo-initiators may
also be used.
[0026] In one embodiment of the invention the coating formulation
further comprises a functional species (c), which is capable of
providing a function to a coating. Examples of such functional
species include functional polymers, e.g. hydrophilic polymers,
imaging materials, drugs, and anti-thrombogenic materials. If the
functional species is a functional polymer it may be synthetic or
bio-derived and can be a blend or a copolymer.
[0027] Within the context of the invention the term polymer is used
for a molecule comprising two or more repeating units. In
particular it may be composed of two or more monomers which may be
the same or different. As used herein, the term includes oligomers
and prepolymers. Usually polymers have a number average weight (Mn)
of about 500 g/mol or more, in particular of about 1000 g/mol or
more, although the Mn may be lower in case the polymer is composed
of relatively small monomeric units. Herein and hereinafter the Mn
is defined as the Mn as determined by light scattering.
[0028] In one embodiment of the invention the functional species
(c) is a hydrophilic polymer, which is capable of providing
hydrophilicity to a coating and may be synthetic or bio-derived and
can be a blend or a copolymer. As a hydrophilic polymer in
principle any polymer may be used that is suitable to provide a
hydrophilic coating. In particular, suitable is such a polymer that
is polymerisable, graftable and/or cross-linkable in the presence
of an initiator.
[0029] The presence of a hydrophilic polymer is particularly useful
in case a coating is required that is hydrophilic and, upon wetting
with a wetting fluid, lubricious.
[0030] For some medical applications, such as urinary or
cardiovascular catheters, such a coating preferably acts as a
lubricant to facilitate insertion of the device into and removal
from the body and/or to facilitate drainage of fluids from the
body. Lubricious properties are also required so as to minimize
soft tissue damage upon insertion or removal. Especially, for
lubrication purposes, such medical devices may have a hydrophilic
surface coating or layer which becomes lubricious and attains
low-friction properties upon wetting, i.e. applying a wetting fluid
for a certain time period prior to insertion of the device into the
body of a patient.
[0031] Within the context of the invention "lubricious" is defined
as having a slippery surface. A coating on the outer or inner
surface of a medical device, such as a catheter, is considered
lubricious if (when wetted) it can be inserted into the intended
body part without leading to injuries and/or causing unacceptable
levels of discomfort to the subject. In particular, a coating is
considered lubricious if it has a friction as measured on a Harland
FTS5000 Friction Tester (HFT) of 20 g or less, preferably of 15 g
or less, at a clamp-force of 300 g, a pull speed of 1 cm/s, and a
temperature of 22.degree. C. The protocol is as indicated in the
Examples.
[0032] The term "wetted" is generally known in the art and--in a
broad sense--means "containing water". In particular the term is
used herein to describe a coating that contains sufficient water to
be lubricious. In terms of the water concentration, usually a
wetted coating contains at least 10 wt % of water, based on the dry
weight of the coating, preferably at least 50 wt %, based on the
dry weight of the coating, more preferably at least 100 wt % based
on the dry weight of the coating. For instance, in a particular
embodiment of the invention a water uptake of about 300-500 wt %
water is feasible. Examples of wetting fluids are treated or
untreated water, water-containing mixtures with for example organic
solvents or aqueous solutions comprising for example salts,
proteins or polysaccharides. In particular a wetting fluid can be a
body fluid.
[0033] Generally the functional, in particular hydrophilic polymer
has a number average molecular weight (Mn) in the range of about
8,000 to about 5,000,000 g/mol, and preferably is a polymer with a
Mn in the range of about 20,000 to about 3,000,000 g/mol and more
preferably in the range of about 200,000 to about 2,000,000 g/mol.
The Mn is the value as determined by light scattering.
[0034] The functional polymer may for instance be a prepolymer,
i.e. a polymer comprising one or more polymerisable groups, in
particular one or more radically polymerisable groups such as one
or more vinyl groups.
[0035] However, also a functional polymer which is free of such
polymerisable groups may be cured in the presence of an initiator,
in particular by the formation of grafts when the formulation is
exposed to light.
[0036] The functional, in particular hydrophilic, polymer may be
non-ionic or ionic or a mixture of non-ionic and ionic
polymers.
[0037] Non-ionic polymers include but are not limited to
poly(lactams), for example polyvinylpyrollidone (PVP),
polyurethanes, homo- and copolymers of acrylic and methacrylic
acid, polyvinyl alcohol, polyvinylethers, maleic anhydride based
copolymers, polyesters, vinylamines, polyethylene imines,
polyethylene oxides, poly(carboxylic acids), polyamides,
polyanhydrides, polyphosphazenes, cellulosics, for example methyl
cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, and
hydroxypropyl cellulose, heparin, dextran, polypeptides, for
example collagens, fibrins, and elastin, polysacharrides, for
example chitosan, hyaluronic acid, alginates, gelatin, and chitin,
polyesters, for example polylactides, polyglycolides, and
polycaprolactones, polypeptides, for example collagen, albumin,
oligo peptides, polypeptides, short chain peptides, proteins, and
oligonucleotides.
[0038] In particular for polyvinylpyrrolidone (PVP) and polymers of
the same class, a polymer having a molecular weight corresponding
to at least K15, more in particular K30, even more in particular
K80 is preferred. Particular good results have been achieved with a
polymer having a molecular weight corresponding to at least K90.
Regarding the upper limit, a K120 or less, in particular a K100 is
preferred. The K-value is the value as determinable by the Method
W1307, Revision 5/2001 of the Viscotek Y501 automated relative
viscometer. This manual may be found at
www.ispcorp.com/products/hairscin/index 3.html.
[0039] If an ionic polymer is used for (c) it may be a
polyelectrolyte chosen from the group as defined below for
component (d).
[0040] If a functional, in particular hydrophilic polymer (c) is
present, it may be used in more than 0 wt % of the coating
formulation, for example more than 1 wt %, more than 2 wt %, or
more than 10 weight %, based on the total weight of the dry
coating. The functional polymer can be present in the coating
formulation up to 99 wt %, however, more often the functional
polymer will be used up to 50, 60, 70, 80 or 90 wt %, based on the
total weight of the dry coating.
[0041] In one embodiment of the invention the coating formulation
according to the invention may comprise an ionic compound (d), such
as a low molecular weight salt or a polyelectrolyte, preferably a
polyelectrolyte, in order to further improve the dry-out time of a
hydrophilic coating. Herein "ionic" may also refer to "ionizable",
as long as at least part of the ionizable groups is in the ionized
form in the hydrophilic coating. Hereinafter such groups are named
after their ionized form. Herein polyelectrolytes are defined as a
high molecular weight linear, branched or cross-linked polymers
composed of macromolecules comprising constitutional units, in
which between 5 and 100% of the constitutional units are in the
ionized form in the hydrophilic coating. Herein a constitutional
unit is understood to be for example a repeating unit, for example
a monomer. A polyelectrolyte herein may refer to one type of
polyelectrolyte composed of one type of macromolecules, but it may
also refer to two or more different types of polyelectrolytes
composed of different types of macromolecules.
[0042] Polyelectrolytes can for example be used to improve the
dry-out time of a lubricious coating. Considerations when selecting
a suitable polyelectrolyte are its solubility and viscosity in
aqueous media, its molecular weight, its charge density, its
affinity with the supporting network of the coating and its
biocompatibility. Herein biocompatibility means biological
compatibility by not producing a toxic, injurous or immunological
response in living mammalian tissue. Preferably the
polyelectrolytes have a number average molecular weight (Mn) of
between 1,000 to 1,000,000 g/mol.
[0043] Examples of ionic groups that may be present in the
polyelectrolyte are ammonium groups, phosphonium groups, sulfonium
groups, carboxylate groups, sulfate groups, sulfinic groups,
sulfonic groups, phosphate groups, and phosphonic groups. Such
groups are very effective in binding water. In one embodiment of
the invention the polyelectrolyte also comprises metal ions. Metal
ions, when dissolved in water, are complexed with water molecules
to form aqua ions [M(H.sub.2O).sub.x].sup.n+, wherein x is the
coordination number and n the charge of the metal ion, and are
therefore particularly effective in binding water. Metal ions that
may be present in the polyelectrolyte are for example alkali metal
ions, such as Na.sup.+ or K.sup.+. When the polyelectrolyte
comprises quaternary ammonium groups, anions such as halogenides,
for example Cl.sup.-, Br.sup.-, I.sup.- and F.sup.-, and also
sulphates, nitrates, carbonates and phosphates may be present.
[0044] Suitable polyelectrolytes are for example salts of homo- and
copolymers of acrylic acid, methacrylic acid, maleic acid, fumaric
acid, and sulfonic acid, and quaternary ammonium salts and mixtures
and/or derivatives thereof. Examples of suitable polyelectrolytes
are polyacrylamide-co-acrylic acid sodium salt, polyacrylic acid
sodium salt, polymethacrylic acid sodium salt,
polyacrylamido-2-methyl-1-propanesulfonic acid sodium salt,
poly(4-styrene sulfonic acid) sodium salt,
poly(acrylamide-co-dialkyl ammonium chloride), quaternized
poly[bis-(2-chloroethyl)ether-alt-1,3-bis[3-(dimethylamino)propyl]urea],
polyallylammonium phosphate, poly(diallyldimethylammonium
chloride), poly(sodium trimethyleneoxyethylene sulfonate),
poly(dimethyldodecyl(2-acrylamidoethyl) ammonium bromide), poly(2-N
methylpyridiniumethylene iodine), polyvinylsulfonic acids, and
salts of poly(vinyl)pyridines, polyethyleneimines, and
polylysines.
[0045] The ionic compound may also be a low molecular weight salt.
In principle any salt can be used as long as it does not negatively
affect the performance of the coating composition or the
coating.
[0046] The coating formulation according to the invention may
comprise 0-90 wt %, 1-80 wt %, 5-50 wt %, or 10-30 wt % of an ionic
compound based on the total weight of the dry coating.
[0047] In one embodiment of the invention the coating formulation
comprises both a functional polymer (c), being a hydrophilic
polymer, and an ionic compound (d). In said embodiment the weight
to weight ratio of the ionic compound (d) to the hydrophilic
polymer (c) is preferably in the range of 1:9 to 9:1, more
preferably 1:30 to 1:1, even more preferably 1:10 to 1:5.
[0048] It has formerly been found that coatings comprising an ionic
compound, in particular a polyelectrolyte, are particularly
vulnerable to inferior coating performance. Therefore it is
surprising that the coating according to the invention show better
properties even in the presence of an ionic compound (d).
[0049] The invention relates to a coating formulation for preparing
a hydrophilic coating. In one embodiment of the invention coating
formulation refers to a liquid coating formulation, e.g. a solution
or a dispersion comprising a liquid medium. Herein any liquid
medium that allows application of the coating formulation on a
surface would suffice. The coating formulation thus further
comprises a liquid medium in a sufficient amount to disperse or
dissolve the other components of the formulation. The concentration
of the liquid medium is usually at least 25 wt. %, preferably at
least 40 wt. %, more preferably at least 68 wt. %, 75 wt. %, 80 wt.
%, or 85 wt. % of the total weight of the liquid coating
formulation. In view of handling properties (low viscosity) and/or
in order to facilitate the application of the composition such that
a coating with the desired thickness is obtained, the amount of
liquid medium in the composition is preferably relatively high. For
that reason the total solids content is preferably 20 wt % or
less.
[0050] The liquid medium may be a single liquid medium or a
mixture. It is chosen such that the components can be dissolved or
at least dispersed therein. In particular for dissolving or
dispersing the functional polymer, if present, it is preferred that
the liquid medium comprises a polar solvent. In particular, a
liquid is considered polar if it is soluble in water. Preferably it
comprises water and/or an organic solvent soluble in water, for
example an alcohol, acetone, methylethyl ketone, tetrahydrofuran,
dichloromethane, and aqueous mixtures or emulsions thereof,
preferably an alcohol, more preferably a C1-C4 alcohol, in
particular methanol and/or ethanol. In case of a mixture, the ratio
water to organic solvent, in particular one or more alcohols, may
be in the range of about 25:75 to 75:25, in particular 40:60 to
60:40, more in particular 45:55 to 55:45.
[0051] The invention also relates to a medical coating obtainable
by applying coating formulation according to the invention to a
substrate and curing it. The invention further relates to a
hydrophilic coating and to a lubricious coating obtainable by
wetting said hydrophilic coating applying a wetting fluid, and to
the use of a multifunctional polymerizable compound according to
formula (1) in a medical coating. Further the invention relates to
a medical, hydrophilic or lubricious coating comprising a polymer
network comprising multifunctional polymerizable compound (a). In
the medical, hydrophilic or lubricious coating multifunctional
polymerizable compound (a) is present in its polymerized form, i.e.
at least part of the vinyl groups have reacted. In the context of
the application "multifunctional polymerizable compound (a)" also
refers to the reacted (i.e. polymerized) multifunctional
polymerizable compound. Further the invention relates to an
article, in particular a medical device or a medical device
component comprising at least one medical, hydrophilic or
lubricious coating according to the invention and to a method of
forming on a substrate the medical, hydrophilic or lubricious
coating according to the invention, wherein the coating formulation
according to the invention is applied to at least one surface of
the substrate, wherein the coating formulation is allowed to cure
by exposing the formulation the electromagnetic radiation or heat
thereby activating the initiator, and wherein, in case of a
lubricious coating, the coating is subsequently wetted in a wetting
fluid.
[0052] In an embodiment of the invention the medical coating
comprises a multifunctional polymerizable compound (a) and at least
one functional polymer (c). In the coating formulation which is
used to produce said functional coating, the weight ratio of
functional polymer (c) to multifunctional polymerizable compound
(a) may for example vary between 5:95 and 95:5. In one embodiment
of the invention the multifunctional polymerizable compound and the
polyelectrolyte(s) are covalently linked and/or physically bound to
each other to form a polymer network after curing.
[0053] In an embodiment of the invention the functional coating
comprises a multifunctional polymerizable compound (a), a
functional (e.g. non-ionic hydrophilic) polymer (c) and a
polyelectrolyte (d). In the coating formulation which is used to
produce said hydrophilic coating, the weight ratio of the sum of
polyelectrolyte and non-ionic hydrophilic polymer to
multifunctional polymerizable compound may for example vary between
5:95 and 95:5. In one embodiment of the invention the
multifunctional polymerizable compound, the non-ionic hydrophilic
polymer, and the polyelectrolyte are covalently linked and/or
physically bound to each other to form a polymer network after
curing.
[0054] The invention also relates to a coating system for preparing
a lubricious coating, said coating system comprising a coating
formulation according to the invention and a wetting fluid
comprising an ionic compound, preferably a polyelectrolyte or a low
molecular weight salt.
[0055] The invention also relates to a medical, hydrophilic or
lubricious coating comprising a multifunctional polymerizable
compound comprising a polymer network comprising multifunctional
polymerizable compound (a). Said coating may further comprise a
functional species (c), e.g. a functional polymer and an ionic
species (d), which may originate from the coating formulation or
from a wetting fluid.
[0056] In an embodiment of the invention the coating formulation
according to the invention further comprises at least one
surfactant, which can improve the surface properties of the
coating. Surfactants constitute the most important group of
detergent components. Generally, these are water-soluble
surface-active agents comprised of a hydrophobic portion, usually a
long alkyl chain, attached to hydrophilic or water solubility
enhancing functional groups. Surfactants can be categorized
according to the charge present in the hydrophilic portion of the
molecule (after dissociation in aqueous solution): ionic
surfactants, for example anionic or cationic surfactants, and
non-ionic surfactants. Examples of ionic surfactants include Sodium
dodecylsulfate (SDS), Sodium cholate,
Bis(2-ethylhexyl)sulfosuccinate Sodium salt,
Cetyltrimethylammoniumbromide (CTAB), Lauryldimethylamine-oxide
(LDAO), N-Laurylsarcosine Sodium salt and Sodium deoxycholate
(DOC). Examples of non-ionic surfactants include Alkyl
Polyglucosides such as TRITON.TM. BG-10 Surfactant and TRITON
CG-110 Surfactant, Branched Secondary Alcohol Ethoxylates such as
TERGITOL.TM. TMN Series, Ethylene Oxide/Propylene Oxide Copolymers,
such as TERGITOL L Series, and TERGITOL XD, XH, and XJ Surfactants,
Nonylphenol
[0057] Ethoxylates such as TERGITOL NP Series, Octylphenol
Ethoxylates, such as TRITON X Series, Secondary Alcohol
Ethoxylates, such as TERGITOL 15-S Series and Specialty
Alkoxylates, such as TRITON CA Surfactant, TRITON N-57 Surfactant,
TRITON X-207 Surfactant, Tween 80 and Tween 20.
[0058] Typically 0.001 to 1 wt % of surfactant is applied,
preferably 0.05-0.5 wt %, based on the total weight of the dry
coating.
[0059] One or more other additives which may be present in the
coating formulation according to the invention are for example
amine compounds, for example diallylamine, diisopropylamine,
diethylamine, and diethylhexylamine; antioxidants; water-soluble
radical stabilizers; UV absorbers; light stabilizers; (silane)
coupling agents; coating surface improvers; heat polymerization
inhibitors; leveling agents; surfactants; colorants, for example a
pigment or a dye; discolorants; preservatives; dispersing agents;
plasticizers; lubricants; solvents; fillers; wettability improvers;
urea; and chain transfer agents. The colorant can be a pigment or
dye.
[0060] The medical coating according to the invention can be coated
on an article. The medical coating can be coated on a substrate
which may be selected from a range of geometries and materials. The
substrate may have a texture, such as porous, non-porous, smooth,
rough, even or uneven. The substrate supports the medical coating
on its surface. The medical coating can be on all areas of the
substrate or on selected areas. The medical coating can be applied
to a variety of physical forms, including films, sheets, rods,
tubes, molded parts (regular or irregular shape), fibers, fabrics,
and particulates. Suitable surfaces for use in the invention are
surfaces that provide the desired properties such as porosity,
hydrophobicity, hydrophilicity, colorisability, strength,
flexibility, permeability, elongation abrasion resistance and tear
resistance. Examples of suitable surfaces are for instance surfaces
that consist of or comprise metals, plastics, ceramics, glass
and/or composites. The medical coating may be applied directly to
the said surfaces or may be applied to a pretreated or coated
surface where the pretreatment or coating is designed to aid
adhesion of the medical coating to the substrate.
[0061] In one embodiment of the invention the medical coating
according to the invention is coated on a biomedical substrate. A
biomedical substrate refers, in part, to the fields of medicine,
and the study of living cells and systems. These fields include
diagnostic, therapeutic, and experimental human medicine,
veterinary medicine, and agriculture. Examples of medical fields
include opthalmology, orthopedics, and prosthetics, immunology,
dermatology, pharmacology, and surgery; nonlimiting examples of
research fields include cell biology, microbiology, and chemistry.
The term "biomedical" also relates to chemicals and compositions of
chemicals, regardless of their source, that (i) mediate a
biological response in vivo, (ii) are active in an in vitro assay
or other model, e.g., an immunological or pharmacological assay, or
(iii) can be found within a cell or organism. The term "biomedical"
also refers to the separation sciences, such as those involving
processes of chromatography, osmosis, reverse osmosis, and
filtration. Examples of biomedical articles include research tools,
industrial, and consumer applications. Biomedical articles include
separation articles, implantable articles, and ophthalmic articles.
Ophthalmic articles include soft and hard contact lenses,
intraocular lenses, and forceps, retractors, or other surgical
tools that contact the eye or surrounding tissue. A preferred
biomedical article is a soft contact lens made of a
silicon-containing hydrogel polymer that is highly permeable to
oxygen. Separation articles include filters, osmosis and reverse
osmosis membranes, and dialysis membranes, as well as bio-surfaces
such as artificial skins or other membranes. Implantable articles
include catheters, and segments of artificial bone, joints, or
cartilage. An article may be in more than one category, for
example, an artificial skin is a porous, biomedical article.
Examples of cell culture articles are glass beakers, plastic petri
dishes, and other implements used in tissue cell culture or cell
culture processes. A preferred example of a cell culture article is
a bioreactor micro-carrier, a silicone polymer matrix used in
immobilized cell bioreactors, where the geometry, porosity, and
density of the particulate micro-carrier may be controlled to
optimize performance. Ideally, the micro-carrier is resistant to
chemical or biological degradation, to high impact stress, to
mechanical stress (stirring), and to repeated steam or chemical
sterilization. In addition to silicone polymers, other materials
may also be suitable. This invention may also be applied in the
food industry, the paper printing industry, hospital supplies,
diapers and other liners, and other areas where hydrophilic,
wettable, or wicking articles are desired.
[0062] The medical device can be an implantable device or an
extracorporeal device. The devices can be of short-term temporary
use or of long-term permanent implantation. In certain embodiments,
suitable devices are those that are typically used to provide for
medical therapy and/or diagnostics in heart rhythm disorders, heart
failure, valve disease, vascular disease, diabetes, neurological
diseases and disorders, orthopedics, neurosurgery, oncology,
opthalmology, and ENT surgery.
[0063] Suitable examples of medical devices include, but are not
limited to, a stent, stent graft, anastomotic connector, synthetic
patch, lead, electrode, needle, guide wire, catheter, sensor,
surgical instrument, angioplasty balloon, wound drain, shunt,
tubing, infusion sleeve, urethral insert, pellet, implant, blood
oxygenator, pump, vascular graft, vascular access port, heart
valve, annuloplasty ring, suture, surgical clip, surgical staple,
pacemaker, implantable defibrillator, neurostimulator, orthopedic
device, cerebrospinal fluid shunt, implantable drug pump, spinal
cage, artificial disc, replacement device for nucleus pulposus, ear
tube, intraocular lens and any tubing used in minimally invasive
surgery.
[0064] Articles that are particularly suited to be used in the
present invention include medical devices or components such as
catheters, guidewires, stents, syringes, metal and plastic
implants, contact lenses, medical tubing, and extracorporeal
devices.
[0065] The coating formulation can be applied to the substrate by
for example dip-coating. Other methods of application include
spray, wash, vapor deposition, brush, roller, curtain, spin coating
and other methods known in the art.
[0066] The thickness of the medical coating according to the
invention may be controlled by altering soaking time, drawing
speed, viscosity of the coating formulation and the number of
coating steps. Typically the thickness of a medical coating on a
substrate ranges from 0.05-300 .mu.m, preferably 0.1-200 .mu.m.
[0067] To apply the medical coating on the substrate, a primer
coating may be used in order to provide a binding between the
medical coating and the substrate. The primer coating is often
referred to as the primary coating, base coat or tie coat. Said
primer coating is a coating that facilitates adhesion of the
medical coating to a given substrate, as is described in for
example WO02/10059. The binding between the primer coating and the
medical coating may occur due to covalent or ionic links, hydrogen
bonding, physisorption or polymer entanglements. These primer
coatings may be solvent based, water based (latexes or emulsions)
or solvent free and may comprise linear, branched and/or
cross-linked components. Typical primer coatings that could be used
comprise for example polyether sulfones, polyurethanes, polyesters,
including polyacrylates, as described in for example U.S. Pat. No.
6,287,285, polyamides, polyethers, polyolefins and copolymers of
the mentioned polymers.
[0068] In particular, the primer coating comprises a supporting
polymer network, the supporting network optionally comprising a
functional, for example hydrophilic, polymer entangled in the
supporting polymer network as described in WO2006/056482 A1. The
information with respect to the formulation of the primer coating
is herewith incorporated by reference.
[0069] A primer layer as described in WO2006/056482 A1 is in
particular useful for improving adherence of a coating comprising a
hydrophilic polymer such as a polylactam, in particular PVP and/or
another of the above identified hydrophilic polymers, on a surface
having about the same or a lower hydrophilicity.
[0070] One embodiment of the invention relates to an article--in
particular a medical device, more in particular a
catheter--comprising a coating, which coating comprises at least
two layers: an inner and an outer layer, of which the inner layer
(i.e. a layer between the outer layer and the surface) is a primer
layer, comprising a supporting polymer network which is composed of
a supporting polymer selected from the group consisting of
polyethers, polyesters, polyurethanes, polyepoxides, polyamides,
poly(meth)acrylamides, poly(meth)acrylics, polyoxazolidones,
polyvinyl alcohols, polyethylene imines, polypeptides and
polysaccharides, such as cellulose or starch or any combination of
the above, more preferably a polymer comprising at least one
polyethylene glycol or polypropylene glycol block, including
copolymers comprising a polyether and/or polythioether moiety, and
the outer layer is a functional layer comprising a multifunctional
polymerizable compound (a) according to the invention, optionally a
hydrophilic polymer, and optionally a surfactant. The hydrophilic
polymer may advantageously be chemically coupled (cross-linked
and/or grafted) to each other, to the multifunctional polymerizable
compound and/or the primer layer.
[0071] In an embodiment of the invention the surface of the article
is subjected to oxidative, photo-oxidative and/or polarizing
surface treatment, for example plasma and/or corona treatment in
order to improve the adherence of the coating which is to be
provided. Suitable conditions are known in the art.
[0072] Application of the formulation of the invention may be done
in any manner. Curing conditions can be determined, based on known
curing conditions for the photo-initiator and polymer or routinely
be determined.
[0073] In general, curing may be carried out at any suitable
temperature depending on the substrate, as long as the mechanical
properties or another property of the article are not adversely
affected to an unacceptable extent.
[0074] Intensity and wavelength of the electromagnetic radiation
can routinely be chosen based on the photo-initiator of choice. In
particular, a suitable wavelength in the UV, visible or IR part of
the spectrum may be used.
[0075] The invention will be further illustrated by the following
examples.
EXAMPLES
1. Synthesis of Multifunctional Polymerizable Compounds
1.1 Synthesis of Peg-Diacrylate; PEGDA
##STR00004##
[0076] PEG.sub.4000DA
[0077] PEG (150 g, 75 mmol OH, Biochemika Ultra from Fluka [95904],
#427345/1, OH-value: 28.02 mg KOH/g, 499.5 meq/kg, Mn: 4004 mol/g)
was dissolved at 45.degree. C. in 350 mL of dry toluene (Merck, pro
analysis, dried on molsieves (4 .ANG.)) under nitrogen atmosphere,
Irgacure 1035 (0.2 g .about.0.15 w %, Ciba Specially Chemical) was
added as a radical stabilizer. The PEG/toluene solution was
distilled azeotropically overnight (50.degree. C./70 mbar) leading
the condensing toluene over 4 .ANG. mol sieves. It is important to
determine accurately the hydroxyl value for each batch of PEG by OH
titration (see analysis) to calculate the amount of acryloyl
chloride (Merck, for synthesis, stored at 5.degree. C. and used as
received) to be added and to determine the conversion during the
reaction.
[0078] Triethylamine (9.10 grams, 90 mmol, Aldrich, 99.5%, kept
under nitrogen atmosphere and is used as received) was added to the
reaction mixture, followed by the drop wise addition over 1 h of
acryloyl chloride (8.15 grams, 90 mmol, (Merck, for synthesis, is
stored at 5.degree. C. and used as received) dissolved in 50 mL of
dry toluene. The Acryloyl chloride and triethyl amine used should
be colorless liquids. The reaction mixture was stirred for 2 to 4
hours at 45.degree. C. under nitrogen atmosphere. During the
reaction the temperature was kept at 45.degree. C. to prevent
crystallization of PEG.
[0079] To check the conversion a sample was withdrawn from the
reaction mixture, dried and dissolved in deuterated chloroform,
trifluoro acetic anhydride (TFAA) was added and a .sup.1H-NMR
spectrum was recorded. TFAA reacts with any remaining hydroxyl
groups to form a trifluoro acetic ester, which can be easily
detected using .sup.1H-NMR spectroscopy (see analysis). When the
conversion was <98% (.+-.0.5%) an additional 10 mmol of acryloyl
chloride and triethylamine were added to the reaction mixture
allowing it to react for one additional hour.
[0080] At a conversion >98% (.+-.0.5%) the warm solution was
quickly filtrated to remove triethyl amine HCl salts. Approximately
300 mL of toluene was removed under vacuum (50.degree. C., 20
mbar). The remaining solution was kept at 45.degree. C. in a heated
dropping funnel and added drop wise to a 1 L of diethyl ether
(cooled on an ice bath, Merck). The ether suspension was cooled for
1 additional hour before the PEG diacrylate product was obtained by
filtration. The product was dried overnight at room temperature
under reduced air atmosphere (300 mbar). Yield: 80-90% as white
crystals.
[0081] NMR: 300 MHz .sup.1H-NMR spectrum of PEG.sub.4000DA in
CDCl.sub.3 (TMS). 6.40 (doublet, 2H), 6.15 (multiplet, 2H), 5.8
(doublet, 2H), CH.sub.2.dbd.CH-- and CH.sub.2.dbd.CH--; 4.3
(triplet, 4H), --(C.dbd.O)OCH.sub.2--; 3.75 (triplet, 4H),
--(C.dbd.O)OCH.sub.2CH.sub.2--; 3.65 (multiplet, 370H),
--OCH.sub.2CH.sub.2O--.
[0082] The NMR pattern confirmed the formation of
PE.sub.4000DA.
[0083] The IR pattern confirmed the formation of
PEG.sub.4000DA.
[0084] The synthesis and characterization of PEG.sub.2000DA was
similar to synthesis and characterization of PE.sub.4000DA. Instead
of PE.sub.4000 (M.sub.r 3500-4500; Biochemika Ultra from Fluka),
PEG.sub.2000 (M.sub.r 1900-2200; Biochemika Ultra from Fluka) was
used.
1.2 Synthesis of PEG-Diacrylamide; PEG(AM).sub.2
##STR00005##
[0086] 20 g (13.3 mmol) of PEG-diamine (M.sub.n 1500 g/mol;
Aldrich) was azeotropically distilled in 400 mL of toluene under
nitrogen, removing about 100 mL of toluene. The solution was cooled
at room temperature under nitrogen and then cooled in an ice bath.
50 mL of dichloromethane (Merck) were added. 4.04 g (39.7 mmol) of
triethylamine was added dropwise followed by the dropwise addition
of 3.48 g (39.7 mmol) of acryloyl chloride (used without further
purification). The reaction proceeded overnight under nitrogen. The
solution was cooled in an ice bath to precipitate
NEt.sub.3.cndot.HCl salts and was then filtrated. After adding 1%
(w/w) Irganox 1035, the filtrate was concentrated under vacuum. The
concentrate was redissolved in 75 mL of dichloromethane, followed
by precipitation in 1.5 L ice cold diethyl ether. The product was
collected by filtration and subsequent washing with diethyl
ether.
[0087] .sup.1H-NMR (CDCl.sub.3, 22.degree. C.) .delta. (TMS)=6.7
ppm (2H, --NH--); 6.2 & 6.1 ppm (4H, CH.sub.2.dbd.CH--); 5.6
ppm (2H, CH.sub.2.dbd.CH--); 3.6 ppm (164H,
--O--CH.sub.2--CH.sub.2-- and --O--CH.sub.2--CH.sub.2--CH.sub.2--);
1.8 ppm (4H, --O--CH.sub.2--CH.sub.2--CH.sub.2--).
[0088] The NMR spectrum confirmed the formation of PEG(AM).sub.2.
From the integration of the NMR peaks at 6.2 and 6.1 ppm,
respectively 1.8 ppm, about 99% of the PEG-diamine was estimated to
be converted into PEG(AM).sub.2.
[0089] The IR spectrum confirmed the formation of
PEG(AM).sub.2.
1.3 Synthesis of PEG-Dimethacrylamide; PEG(MAM).sub.2
##STR00006##
[0091] Synthesis: similar to synthesis of PEG-diacrylamide.
[0092] Instead of acryloyl chloride, methacryloyl chloride (Acros)
was used.
[0093] .sup.1H-NMR (CDCl.sub.3, 22.degree. C.) .delta. (TMS)=6.8
ppm (2H, --NH--); 5.7 & 5.3 ppm (4H, CH.sub.2.dbd.C); 3.6 ppm
(164H, --O--CH.sub.2--CH.sub.2-- and
--O--CH.sub.2--CH.sub.2--CH.sub.2--); 1.95 ppm (CH.sub.3
methacrylamide); 1.8 ppm (4H,
--O--CH.sub.2--CH.sub.2--CH.sub.2--).
[0094] The NMR pattern confirmed the formation of PEG(MAM).sub.2.
From the integration of the NMR peaks at 5.7 and 5.3 ppm,
respectively 1.8 ppm, about 90% of the PEG-diamine was estimated to
be converted into PEG(MAM).sub.2.
[0095] The IR pattern confirmed the formation of
PEG(MAM).sub.2.
1.4 Synthesis of PTGL1000 (T-H).sub.2
[0096] In a dry inert atmosphere toluene diisocyanate (TDI or T,
Aldrich, 95% purity, 87.1 g, 0.5 mol), Irganox 1035 (Ciba Specialty
Chemicals, 0.58 g, 1 wt % relative to hydroxy ethyl acrylate (HEA
or H)) and tin(II) 2-ethyl hexanoate (Sigma, 95% purity, 0.2 g, 0.5
mol) were placed in a 1 liter flask and stirred for 30 minutes. The
reaction mixture was cooled to 0.degree. C. using an ice bath. HEA
(Aldrich, 96% purity, 58.1 g, 0.5 mol) was added dropwise in 30
min, after which the ice bath was removed and the mixture was
allowed to warm up to room temperature. After 3 h the reaction was
complete.
Poly(2-methyl-1,4-butanediol)-alt-poly(tetramethyleneglycol) (PTGL,
Hodogaya, Mn=1000 g/mol, 250 g, 0.25 mol) was added dropwise in 30
min. Subsequently the reaction mixture was heated to 60.degree. C.
and stirred for 18 h, upon which the reaction was complete as
indicated by GPC (showing complete consumption of HEA), IR
(displayed no NCO related bands) and NCO titration (NCO content
below 0.02 wt %).
2. Formulations
TABLE-US-00001 [0097] TABLE 1 Primer formulation Example 1 and
Comparative Experiment A: Compound Amount (%, w/w) PTGL.sub.1000
(TDI-HEA).sub.2 20 Ethanol (Merck, 96%, extra pure PH 79.6 EUR, BP)
Irgacure 2959 (Aldrich) 0.4
TABLE-US-00002 TABLE 2 Primer formulation Examples 3 and 4 and
Comparative Experiment C: Compound Amount (g) Amount (%, w/w)
PTGL.sub.1000 (TDI-HEA).sub.2 29.82 5.04 PVP 1.3 M (Povidone,
Sigma-Aldrich) 5.25 0.89 Ethanol 555.52 93.84 Irgacure 2959 1.40
0.23
TABLE-US-00003 TABLE 3 Coating formulation Example 1 and
Comparative Experiment A: Compound Amount (%, w/w) Multifunctional
polymerizable compound: 20 PEG(AM).sub.2 (Example 1) PEGDA (Comp.
Exp. A) Ethanol 79.6 Irgacure 2959 (Aldrich) 0.4
TABLE-US-00004 TABLE 4 Coating formulation Example 2 and
Comparative Experiment B: Compound Amount (%, w/w) Multifunctional
polymerizable compound: 2 PEG(AM).sub.2 (Example 2) PEGDA (Comp.
Exp. B) PVP 1.3 M 2 Methanol (Merck pa) 47.96 Water 47.96 Irgacure
2959 0.04 Tween 80 (surfactant, Merck) 0.04
TABLE-US-00005 TABLE 5 Coating formulation Examples 3 and 4 and
Comparative Experiment C: Amount Compound (g) Amount (%, w/w)
Multifunctional polymerizable compound: 10 4.71 [4.71]
PEG(AM).sub.2 (Example 3) PEG(MAM).sub.2 (Example 4) PEGDA (Comp.
Exp. C) PVP 1.3 M 6.66 3.14 [3.14] Poly(acrylamide-co-acrylic
acid).Na.sup.+ 3.34 1.58 [1.57] 20% (w/w) acrylamide/14.5% (w/w)
Na.sup.+ (Aldrich) Methanol 95.92 45.24 [45.20] Water 95.92 45.24
[45.20] Irgacure 2959 0.2 0.09 [0.09] [Tween 80] [0.2] [0.09]
[0098] For the primer formulations as well as for the coating
formulations the compounds were dissolved in the solvent under
stirring at room temperature. To obtain the coating formulation, a
formulation containing all of the compounds indicated above except
the multifunctional polymerizable compound was prepared the day
before the start of the experiment. The experiment was started with
the dissolution of the multifunctional polymerizable compound in
this formulation (within one hour the multifunctional polymerizable
compound was dissolved).
3. Methods
3.1. NMR Measurements
[0099] Nuclear magnetic resonance (NMR) measurements were performed
on a Varian Inova 300 spectrometer.
[0100] NMR experiments were performed at 22.degree. C. for the
synthesized multifunctional polymerizable compounds dissolved in
deuterated chloroform.
3.2. FTIR Measurements
[0101] Fourier transformed infrared (FTIR) measurements were
performed by means of a Perkin Elmer Spectrum One spectrophotometer
using the Spectrum software.
[0102] The synthesized multifunctional polymerizable compounds were
analysed in the form of potassium bromide (Uvasol; Merck)
pills.
3.3. Coating on PET Film
Example 1 and Comparative Experiment A
[0103] The primer coating formulation according to Table 1 was
coated on 120 .mu.m PET foil using Meyenbar # 12 resulting in a dry
film thickness of approximately 550 nm. The primer coating
formulation was cured with 1.10 J/cm.sup.2 using a D-lamp in air.
Subsequently the coating formulations of Table 3 were coated on the
primer. The coatings were left for 1 min to dry at 25.degree. C.
and were exposed to a single UV pass with 1.10 J/cm.sup.2 using a
D-lamp in air. The resulting coating thickness was 2 .mu.m.
3.4. Dip-Coating
Examples 3 and 4 and Comparative Experiment C
[0104] Dip-coating was performed with a Harland PCX coater. The
intensity of the lamps was measured by means of a Harland UVR 335
(also known as IL 1400) equipped with an International Light
detector SED 005#989. Input optic: W#11521, filter
wbs320#27794.
[0105] Commercially available medical grade PVC tubing (14 French;
Raumedic) was used. The tubing was sealed at the bottom end in
order to prevent the coating formulation to reach the inside of the
tubing during dipping. A guide wire was inserted in the tubing to
fix the tubing and to attach it in the holder of the coater. The
tubing was cleaned with lens tissues (Whatman) immersed in a 96%
(w/v) aqueous ethanol solution (Merck). The assembly was
subsequently dipped in the primer and the topcoat formulations
using the coater. The intensity of the lamps was 60 mW/cm.sup.2 on
average. The instruction manual of International Light was applied
to measure the intensity of the lamps, which is available on the
internet: www.intl-light.com. The tubing was dipped in the primer
formulation for 10 seconds, moved up with a speed of 0.3 cm/s and
cured for 15 seconds with a total dose of 0.9 J/cm.sup.2. The
tubing was then dipped in the topcoat formulation for 10 seconds,
moved up with a speed of 1.5 cm/s and cured for 360 seconds with a
total dose of 21.6 J/cm.sup.2. After drying for a night at room
temperature, the lubricity, wear resistance and dry-out time of the
coatings were determined.
3.5. Determination of Lubricity and Wear Resistance of Coatings
Examples 3 and 4 and Comparative Experiment C
[0106] A Harland FTS 5000 friction tester was used. Friction tester
pads were used from Harland Medical Systems, P/N 102692, FTS 5000
Friction Tester Pads, 0.125*0.5*0.125, 60 durometer.
[0107] A guide wire was inserted in the tubing to fix the tubing
and to attach it in the holder of the friction tester. If the test
was to be run wet, the clamp was positioned over the container such
that the clamp pads were submerged. The holder was moved down such
that the (coated) tubing was also immersed in the water. After
immersing for one minute the clamp was closed and fixed the tubing
with a clamp force of 300 g. The holder moved up for 10 cm and the
friction force was measured during the moving-up. The following
parameters were applied: 25 testing cycles, pulling speed 1.0 cm/s,
acceleration time 2.0 s. When compounds were leaching out of the
coating, the clamp pads of the friction tester were cleaned before
each testing cycle.
[0108] The dry-out time can be determined by measuring the
lubricity (as friction in g) as a function of time. In the test to
measure the dry-out time 5 testing cycles were applied with a time
interval of 300 s. All other parameters are the same as in the
lubricity test.
3.6. Stability Tests
(Example 1 and Comparative Experiment A): Effect of Multifunctional
Polymerizable Compound on Rub Resistance
[0109] In order to test the stability of the coating formulations
of Example 1 and Comparative Example A the following test was
performed.
[0110] The films prepared according to 3.3. were incubated in
standard phosphate buffer solutions ("PBS buffers") for 110 hours
at 45.degree. C. The rub resistance was immediately checked after
annealing using a single index finger tip using 5 drops of water.
The results are shown in Table 6.
3.7. Stability Tests
(Example 2 and Comparative Experiment B): Effect of Multifunctional
Polymerizable Compound on Stability Upon Incubating the Coating
[0111] In order to test the stability of the coating formulations
of Examples 1-2 the following test was performed.
[0112] Coating formulations according to Table 3 were incubated at
a temperature of respectively 50, 20, and -20.degree. C. The amount
of respectively PEGDA and PEG(AM).sub.2 were monitored using liquid
chromatography-UV (LC-UV). The results are given in Tables 7 and
8.
3.8. Stability Tests
(Examples 3 and Comparative Experiment C): Effect of
Multifunctional Polymerizable Compound on the Lubricity of the
Lubricious Coating Upon Incubating the Coating Formulation
[0113] In order to test the stability of the coating formulations
used to prepare the lubricious coating the following test was
performed
[0114] Coating formulations according to Table 5, comprising
respectively PEGDA and PEG(AM).sub.2, were incubated at 50.degree.
C. in a closed container for 0 and 2 days (PEGDA) and 0, 2 and 7
days (PEG(AM).sub.2). Tubings were coated with the resulting
coating formulations according to the method described in 3.4.
[0115] The tubings coated with the coating formulation comprising
PEGDA were tested twice in a series (catheter still immersed in
water). After the 25 cycles of the first test the coated tubing was
kept in the water for 10 minutes before starting the second test
consisting of 25 cycles. The results are given in FIG. 1.
[0116] The tubings coated with the coating formulation comprising
PEG(AM).sub.2 were tested only once. The results are given in FIG.
2.
4. Results
4.1. Example 1 and Comparative Experiment A
Stability of the Coating Determined by Rub Tests
TABLE-US-00006 [0117] TABLE 6 Example 1 and Comparative Experiment
A: stability of coatings comprising PEG(AM).sub.2 and PEGDA,
respectively. Multifunctional polymerizable Primer compound Rubbing
performance Example 1 Table 1 PEG(AM).sub.2 - sComparative Table 1
PEGDA + Experiment A
Table 6 shows that the coating according to Example 1, prepared
form a coating formulation containing PEG(AM).sub.2, Irgacure 2959
and ethanol is much more stable against rubbing than an equivalent
coating containing PEGDA instead of PEG(AM).sub.2
4.2. Example 2 and Comparative Experiment B
Stability of the Multifunctional Polymerizable Compound in the
Coating Formulations
TABLE-US-00007 [0118] TABLE 7 Example 2: Stability of PEG(AM).sub.2
expressed in wt % of PEG(AM).sub.2 in formulation. Incubation time
(days) T = 50.degree. C. T = 20.degree. C. T = -20.degree. C. 1 1.9
1.9 1.9 14 2.1 1.8 2.0 27 2.1 2.0 2.2 41 1.9 1.9 1.9 54 1.9 1.9
1.9
TABLE-US-00008 TABLE 8 Comparative Experiment B: Stability of PEGDA
expressed in wt % of PEGDA in formulation. Incubation time (days) T
= 50.degree. C. T = 20.degree. C. T = -20.degree. C. 1 2.0 2.0 2.0
14 1.8 1.8 1.8 27 1.7 1.8 1.8 41 1.6 1.6 1.6 54 1.1 1.2 1.4 80 0.9
1.1 1.3
Comparison of the results in Tables 7 and 8 clearly show the
improved stability of the coating formulation comprising
PEG(AM).sub.2.
4.3. Examples 3 and 4 and Comparative Experiment C
4.3 1. Appearance of Coatings
[0119] Curing fresh formulations containing PEG(AM).sub.2 (Example
3), PEG(MAM).sub.2 (Example 4) and PEGDA (Comparative Experiment C)
resulted in clear coatings. Upon incubating the coating
formulations containing PEGDA at 50.degree. C. in a closed
container, the resulting coatings became more and more opaque. The
coating made from the formulation containing PEG(AM).sub.2 and
PEG(MAM).sub.2 remained clear upon incubating the formulation at
50.degree. C. This shows the improved stability of the coating
formulation.
4.3.2. Lubricity and Wear Resistance
[0120] FIG. 1 (Comparative Experiment C) shows that the lubricity,
expressed as the friction force (the higher the friction force, the
lower the lubricity), is significantly reduced after incubating the
coating formulations comprising PEGDA used for preparing the
lubricious coatings for 2 days at 50.degree. C. (closed triangles):
friction forces in the range 40-80 g were measured. In fact, for
the coatings prepared from a PEGDA containing coating formulation
parts of the coating were removed by the clamp pads of the friction
tester during the first cycles of the first test series. As a
result, the coatings were damaged. The second test of the test
series after 2 days of incubation therefore resulted in even higher
friction forces (open triangles) in the range 70-140 g. This was
not observed for the coatings prepared from the fresh coating
formulation (0 days incubation) (closed and open squares): friction
forces of approximately 10 g were measured in both test series.
[0121] FIG. 2 (Example 3) shows much more favorable results for the
lubricious coatings prepared from the formulation containing
PEG(AM).sub.2. Even the coatings prepared from coating compositions
incubated at 2 or 7 days still feature a high lubricity (low
friction force): in all measurements the friction force was below
10 g. All coatings stayed intact during the friction test. The
incubation of the formulation had no influence on the wear
resistance of the resulting coating.
* * * * *
References