Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02258077 2005-11-21
28371-47
HYDROPHILIC INTERPENETRATING POLYMER NETWORK COAT~TG FOR
MEDICAL DEVICES
The present invention relates to medical devices which present an elongate
shaft hang an
outer surface coating for insertion into a passageway in a human or animal
body and is
principally, but not exclusively, concerned with surface coated catheters:
Many medical devices incorporate elongate shafts such as tubes which are
intended for
insertion into and through passageways of a living body such as those of the
urethral tract
and the cardiovascular system. The most common type of this general grouping
of medical
~o devices are known as catheters. Exemplary catheters include those
designated for
urological, angioplasty and valwloplasty uses, that is, adapted respectively
for insertion into
the urethra, the lumen of a blood vessel and heart passageway of a living
body, normally a
human body.
is Because of the intended use of such medical devices certain parameters need
to be satisfied
by the material from which the elongate shaft is manufactured. The material
must fulfil such
requirements as softness, good kink resistance, good dimensional stability,
processability,
for example ease to form and glue, and the possibility to be sterilised by
radiation, steam,
ethylene oxide or other means. There is further the need for the material to
accept a surface
Zo treatment which will impart desired surface properties to the medical
device such as
lubricity, hydrophilicity and blood compatibility. To this latter end, the
chemistry of the
substrate material is critical since this affects the possibility to coat the
substrate.
For many years now polyvinyl chloride (PVC) has been used to manufacture
medical
Zs devices having elongate shafts for insertion into a body passageway such as
catheters due to
PVC fulfilling the requirements mentioned in the preceding paragraph.
For instance, prior European patent application publication No. 0493093 (Astra
Meditec
AB) makes known a process for manufacturing a PVC urinary catheter having a
hydrophilic
so outer surface coating which exhibits a low coefficient of friction when
wetted. The process
involves forming a hydrophilic surface coating on the PVC catheter by
sequentially applying
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97/01121
2
a solution containing between 0.05-40% (weightlvolume, that is, kg/1) of an
isocyanate
compound and a solution of polyvinylpyrrolidone (PVP) containing between 0.5-
50%
(weight/volume) to the outer surface of the catheter, for example by dipping,
and then
curing the hydrophilic coating at an elevated temperature advantageously in
the presence of
a water-containing gas such as ambient air.
The suitability of PVC for medical devices such as catheters, however, is now
being
questioned on environmental grounds and further because of the toxicity of the
plasticisers
added to PVC. Moreover, coating PVC catheters by, for example, the process of
European
patent application publication No. 0093093 results in an appreciable shrinkage
of the PVC
catheters in the longitudinal direction, typically 6-7% of the original
length, due to the
operating temperatures used in the coating process. The obvious disadvantage
of such
appreciable shrinkage is the wastage of material in the sense that PVC
catheters of longer
length than finally required have to be used to account for the shrinkage. In
addition,
is quality control of the coating process is made more complicated than would
be ideal by this
marked degree of shrinkage.
There is therefore a need for a medical device which presents a hydrophilic
surface coated
non-PVC elongate shaft for insertion into a body passageway which experiences
no
zo appreciable shrinkage on application of the hydrophilic surface coating.
To this end, the present invention provides a method for the manufacture of a
medical
device which presents a hydrophilic surface coated elongate shaft for
insertion into a body
passageway comprising the steps of having the elongate shaft formed from a
thermoplastic
zs elastomer material selected from the group consisting of a polyether block
amide and a
styrene block copolymer and forming the hydrophilic coating on the elongate
shaft by
applying sequentially to the surface of the elongate shaft a solution
comprising between
0.05 to 40% (weight to volume) of an isocyanate compound and a solution
containing
between 0.5 and 50% (weight to volume) of polyvinylpyrrolidone and curing at
an elevated
3o temperature.
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97/01121
3
The use of a polyether block amide or a styrene block copolymer results in an
elongate shaft
which undergoes substantially no shrinkage in the longitudinal direction as
compared to
PVC on application of the hydrophilic coating as well as providing an elongate
shaft with
the normal properties required for insertion thereof into a body passageway.
The present
invention therefore enables a catheter to be provided which addresses the
aforementioned
disadvantages of PVC based catheters leading to inter alia less wastage of
starting materials
and the possibility to use TV monitors for quality control.
While the background section of prior European patent application publication
No.
io 0566755 (Cordis Corp.) makes it known that the use of a polyether block
amide in the
manufacture of medical device tubing intended for insertion into a body
passageway is
known per se, European patent application publication No. 0566755 goes on to
teach that
undesirable blooming develops in such tubing material after it has been stored
for a length
of time which can interfere with the adherence of a coating thereto, for
example a coating
is for imparting lubricity to the tubing. The solution to the blooming problem
according to
European patent application publication No. 0566755 is to blend the polyether
block amide
with a polyetheramide component having substantially no ester linkages.
No such problem with adherence of the hydrophilic coating to a polyether block
amide
2o manifests itself when the method according to the present invention is
followed despite the
fact that blooming is sometimes observed after some months storage. This can
be attributed
to the manner in which the hydrophilic coating is applied to the elongate
shaft in the method
according to the invention.
is The polyether block amide used in the invention is believed to have a
structure as follows:
HO-[-C-PA-C-O-PE-O-J~-H
O O
CA 02258077 1998-12-10
WO 97/49437 PCTlSE97/01121
4
wherein PA is a polyamide, PE is a polyether and n is an integer greater than
I which
represents the number of blocks of copolymer molecular repeating units within
the
molecular formula of the copolymer. Representative polyether block amide
materials
include the Pebax~ polymers (Elf Atochem S. A.).
In an embodiment of the invention the styrene block copolymer is a styrene-
ethylene/butylene-styrene block copolymer, for example Evoprene~ G (Evode
Plastics
Ltd.).
io Application of the isocyanate solution to the elongate shaft surface
results in a coating
having unreacted isocyanate groups being formed on the elongate shaft surface.
Application of the polyvinylpyrrolidone solution to the elongate shaft surface
then results in
a hydrophilic polyvinylpyrrolidone-polyurea interpoiymer coating being formed
on the
elongate shaft surface. Curing of this hydrophilic coating binds the
isocyanate compounds
is together to form a stable non-reactive network that binds the hydrophilic
polyvinylpyrrolidone. To advantage, curing takes place in the presence of a
water-
containing gas, for example ambient air, to enable the isocyanate groups to
react with the
water to yield an amine which rapidly reacts with other isocyanate groups to
form a urea
cross-link.
In an embodiment of the invention the method further comprises the steps of
evaporating
the solvent of the isocyanate solution prior to application of the
polyvinyipyrrolidone
solution and evaporating the solvent of the polyvinylpyrrolidone solution
prior to curing of
the hydrophilic coating. This may for example be done by air drying.
2s
In an embodiment of the invention the isocyanate compound comprises at least
two
unreacted isocyanate groups per molecule. The isocyanate may be selected from
2,4-
toluene diisocyanate and 4,4'-diphenylmethane diisocyanate, or a pentamer of
hexamethylene diisocyanate and toluene diisocyanate of cyanurate type, or
trimerized
3o hexamethylene diisocyanate biuret or mixtures thereof.
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97/01121 -
The solvent for the isocyanate compound is preferably one which does not react
with
isocyanate groups. The preferred solvent is methylene chloride but it is also
possible to use
ethyl acetate, acetone, chloroform, methyl ethyl ketone and ethylene
dichloride, for
s example.
The isocyanate solution may advantageously contain between 0.5 to 10% (weight
to
volume) of the isocyanate compound, and may preferably contain between 1 to 6%
(weight
to volume) of the isocyanate compound. Generally, the isocyanate solution only
needs to be
~o in contact with the surface briefly, for example S to 60 sec.
To enhance adherence of the hydrophilic coating to the elongate shaft surface
the elongate
shaft may be swelled beforehand in a suitable solvent. Another way is to
choose a solvent
for the isocyanate solution which has the ability to swell or dissolve the
elongate shaft
is surface which is to be coated.
In order to shorten the necessary reaction times and curing times suitable
catalysts for
isocyanate curing may be added. These catalysts may be dissolved in either the
isocyanate
solution or the polyvinylpyrrolidone solution but are preferably dissolved in
the latter.
2o Different types of amines are especially useful, for example diamines, but
also for example
triethylenediamine. Preferably, an aliphatic amine is employed which is
volatisable at the
drying and curing temperatures used for the coating, and which furthermore is
non-toxic.
Examples of suitable amines are N, N'diethylethylendiamine,
hexamethylendiamine,
ethylendiamine, paradiaminobenzene, 1,3-propandiol-para-aminobenzoic acid
diester and
2s diaminobicyclo-octane.
Where the catalyst is in the polyvinylpyrrolidone solution, the proportion of
catalyst in the
solution is suitably between 0.1 to 50% by weight of the amount of
polyvinyipyrrolidone,
preferably between 0.1 to 10% by weight. Some of the above-mentioned amines,
so particularly the diamines, can also react with isocyanate and thereby
contribute to the cross-
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97101121
6
linking of the isocyanate compounds that give the desired strong adherence
between the
hydrophilic coating and the polymer surface.
The polyvinylpyrrolidone used preferably has a mean molecular weight of
between I 04 to
s 10~ with the most preferred mean molecular weight being about 105.
Polyvinylpyrrolidone
having such a molecular weight is commercially available, for example under
the trademark
Kollidon~ (BASF). Examples of suitable solvents for polyvinylpyrrolidone that
may be used
are methylene chloride (preferred), ethyl acetate, acetone, chloroform, methyl
ethyl ketone
and ethylene dichloride. The proportion of polyvinylpyrrolidone in the
solution is preferably
io between 0.5 to 10% (weight to volume) and most preferred between 2 to 8%
(weight to
volume). The polyvinylpyrrolidone in the solvent is applied by dipping,
spraying or the like
for a short period of time, e.g. during 5 to 50 sec.
Curing of the coating is preferably performed at a temperature of 50 to
130° C, in for
is example an oven, for a duration of between 5 to 300 min.
According to the invention there is further provided a medical device which
presents a
hydrophilic surface coated elongate shaft for insertion into a body passageway
manufactured by the method according to the invention.
According to the invention there is yet further provided a medical device
which presents an
elongate shaft for insertion into a body passageway, the elongate shaft being
made from a
polyether block amide or a styrene block copolymer and provided with a
hydrophilic outer
surface coating formed from an interpenetrating network of
polyvinylpyrrolidone and
2s polyurea.
According to the invention there is additionally provided a medical device
which presents an
elongate shaft for insertion into a body passageway, the elongate shaft being
made from a
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97/01121
7
polyether block amide or a styrene block copolymer and provided with a
polyvinyipyrrolidone hydrophilic outer surface coating having enhanced
osmolality.
In an embodiment of the invention the hydrophilic coating contains an
osmolality-increasing
compound, for instance an inorganic salt selected from sodium and potassium
chlorides,
iodides, citrates and benzoates. The osmolality-increasing compound may be
applied in the
manner detailed in prior European patent application publication No. 0217771.
In an embodiment of the invention the medical device is a catheter, for
example those
io designated for urological, angioplasty and valvuloplasty uses or the like.
In this case, the
polyether block amide or styrene block copolymer selected for the elongate
shaft
respectively has a hardness in the range 25 Sh D to 70 Sh D and 40 shore A to
70 shore D.
Where the medical device is a urinary catheter a hardness in the range 25 Sh D
to 45 Sh D
for polyether block amide and 40 shore A to 45 shore D for styrene block
copolymer is
is ideal with greater hardnesses being preferred for intravascular catheters.
According to the invention there is also provided the use of a styrene block
copolymer in
the manufacture of a medical device which presents an elongate shaft for
insertion into a
body passageway.
zo
The invention will now be illustrated but not limited by the following
examples.
Examine 1
zs A diisocyanate (named Desmodur II,) is dissolved in methylene chloride to a
concentration
of 2% (weight/volume). A urinary catheter formed exclusively or essentially
exclusively
from Pebax~ (hereinafter a "urinary Pebax~ catheter") with a hardness of 70
shore D is
dipped in this solution for 15 seconds and is then dried at ambient
temperature for 60
seconds. The catheter is then dipped for 1 second in a solution containing 6%
so (weight/volume) of polyvinylpyrrolidone (K90; mean molecular weight 360
000) dissolved
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97/01121
8
in methylene chloride. The catheter is then allowed to dry at ambient
temperature for 60
seconds and is finally cured for 50 minutes at 100 °C. The catheter is
finally allowed to cool
to room temperature and is then rinsed in water. The catheter has a slippery
and adherent
surface when wet.
s
The experiment was repeated with variations in the dipping time in the
isocyanate bath
ranging from 5 seconds to 1 minute, but no advantage was obtained by
increasing the
dipping time.
~o Example 2
A diisocyanate (named Desmodur IL) is dissolved in ethyl acetate to a
concentration of 2%
(weight/volume). A urinary Pebax~ catheter with a hardness of 35 shore D is
dipped in this
solution for 15 seconds and is then dried at ambient temperature for 60
seconds. The
i5 catheter is then dipped for 1 second in a solution containing 6%
(weight/volume) of
polyvinylpyrrolidone (K90; mean molecular weight 360 000) dissolved in ethyl
lactate
(50%) and ethyl acetate {50%). The catheter is then allowed to dry at ambient
temperature
for 60 seconds and is finally cured for 50 minutes at 80 °C. The
catheter is finally allowed to
cool to room temperature and is then rinsed in water. The catheter has a
slippery and
zo adherent surface when wet.
Eaamole 3
2s A diisocyanate (named Desmodur II,) is dissolved in methylene chloride
(75%) and tri
chloro ethylene (25%) to a concentration of 2% (weight/volume). A urinary
Pebax~
catheter with a hardness of 63 shore D is dipped in this solution for 15
seconds and is then
dried at ambient temperature for 60 seconds. The catheter is then dipped for 1
second in a
solution containing 6% (weight/volume) of polyvinylpyrrolidone {K90; mean
molecular
so weight 360 000) dissolved in methylene chloride (75%) and tri chloro
ethylene (25%). The
CA 02258077 1998-12-10
WO 97/49437 PCT/SE97/01121
9
catheter is then allowed to dry at ambient temperature for 60 seconds and is
finally cured
for 50 minutes at 100 °C. The catheter is finally allowed to cool to
room temperature and is
then rinsed in water. The catheter has a slippery and adherent surface when
wet.
s Example 4
A diisocyanate (named Desmodur II,) is dissolved in ethyl acetate to a
concentration of 2%
{weight/volurne). A urinary catheter manufactured from Evoprene~ G with a
hardness of 65
shore A is dipped in this solution for 15 seconds and is then dried at ambient
temperature
io for 60 seconds. The catheter is then dipped for 1 second in a solution
containing 6%
(weightlvolume) of polyvinylpyrrolidone (K90; mean molecular weight 360 000)
dissolved
in methylene chloride. The catheter is then allowed to dry at ambient
temperature for 60
seconds and is finally cured for 50 minutes at 100 °C. The catheter is
finally allowed to cool
to room temperature and is then rinsed in water. The catheter has a slippery
and adherent
is surface when wet.
The urinary catheters prepared according to the examples show low fi7ction,
good kink
resistance, good dimension stability and possibility to be sterilised.
Moreover, the
longitudinal shrinkage of the catheters as a result of the coating process was
less than 1% of
zo the original length.
While the examples refer to the manufacture of urinary catheters it is to be
understood that
the invention is not restricted to this sole application but is equally
applicable to other forms
of catheters and moreover other constructions falling within the broad class
of medical
Zs devices having an elongate shaft. adapted for insertion into a body
passageway as whole, for
instance transurethral devices for treating erectile dysfunction and wound
drains for
insertion into body passageways in the form of wound cavities.
