U.S. patent application number 15/037591 was filed with the patent office on 2016-10-06 for reducing the deterioraton of wetted hydrophilic coatings comprising water subjected to sterilization by radiation.
The applicant listed for this patent is DSM IP ASSETS B.V.. Invention is credited to Johannes Wilhelmus BELT, Pieter GIJSMAN.
Application Number | 20160287757 15/037591 |
Document ID | / |
Family ID | 53179004 |
Filed Date | 2016-10-06 |
United States Patent
Application |
20160287757 |
Kind Code |
A1 |
BELT; Johannes Wilhelmus ;
et al. |
October 6, 2016 |
REDUCING THE DETERIORATON OF WETTED HYDROPHILIC COATINGS COMPRISING
WATER SUBJECTED TO STERILIZATION BY RADIATION
Abstract
A method of reducing the deterioration of a wetted hydrophilic
coating comprising water at the time of sterilization by radiation
is provided. The method comprises the step of reducing the amount
of oxygen in an atmosphere in contact with the wetted hydrophilic
coating in addition to any reduction in oxygen provided by oxygen
scavengers that may be present in the wetted hydrophilic
coating.
Inventors: |
BELT; Johannes Wilhelmus;
(Echt, NL) ; GIJSMAN; Pieter; (Echt, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DSM IP ASSETS B.V. |
Heerlen |
|
NL |
|
|
Family ID: |
53179004 |
Appl. No.: |
15/037591 |
Filed: |
November 20, 2014 |
PCT Filed: |
November 20, 2014 |
PCT NO: |
PCT/EP2014/075194 |
371 Date: |
May 18, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2/081 20130101;
A61L 31/14 20130101; A61L 2300/428 20130101; B65B 55/16 20130101;
A61L 2/087 20130101; B65B 55/08 20130101; A61L 29/041 20130101;
A61L 31/143 20130101; A61L 29/14 20130101; B65D 81/2069 20130101;
A61L 31/10 20130101; A61L 2420/02 20130101; B65D 81/266 20130101;
A61L 29/085 20130101; A61L 2400/10 20130101; A61B 50/30 20160201;
A61L 2420/06 20130101; A61L 29/143 20130101 |
International
Class: |
A61L 29/08 20060101
A61L029/08; A61L 29/14 20060101 A61L029/14; B65D 81/20 20060101
B65D081/20; B65B 55/08 20060101 B65B055/08; B65B 55/16 20060101
B65B055/16; A61L 29/04 20060101 A61L029/04; A61L 2/08 20060101
A61L002/08 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 20, 2013 |
EP |
13193707.0 |
Nov 20, 2013 |
EP |
13193715.3 |
Claims
1. A method of reducing the deterioration of a wetted hydrophilic
coating comprising water at the time of sterilization by radiation
comprising the step of reducing the amount of oxygen in an
atmosphere in contact with the wetted hydrophilic coating in
addition to any reduction in oxygen provided by oxygen scavengers
that may be present in the wetted hydrophilic coating, wherein the
wetted hydrophilic coating comprises at least 70 wt % water, based
on the total weight of the wetted hydrophilic coating.
2. The method of claim 1, wherein the wetted hydrophilic coating is
formed by bringing a wetting agent into contact with a hydrophilic
coating, and wherein the hydrophilic coating is formed by curing a
hydrophilic coating composition, the hydrophilic coating
composition comprising at least 70 wt % of hydrophilic polymers,
based on the total dry weight of the hydrophilic coating
composition.
3. The method of claim 1 wherein the amount of oxygen in the
atmosphere in contact with the wetted hydrophilic coating is
reduced below 15% by volume of the atmosphere in contact with the
wetted hydrophilic coating.
4. The method of claim 1 wherein the step of reducing the amount of
oxygen in the atmosphere in contact with the wetted hydrophilic
coating comprises replacing at least some of the oxygen in the
atmosphere in contact with the wetted hydrophilic coating with an
alternative gas.
5. The method of claim 1 further comprising the step of
incorporating a radical scavenger in the wetted hydrophilic
coating.
6. The method of claim 5 wherein the step of incorporating a
radical scavenger in the wetted hydrophilic coating is performed by
wetting a hydrophilic coating with a wetting agent comprising the
radical scavenger.
7. The method of claim 1 further comprising the step of enclosing
an article comprising the wetted hydrophilic coating in a gas
impermeable packaging.
8. The method of claim 7 wherein the step of reducing the amount of
oxygen in the atmosphere in contact with the wetted hydrophilic
coating comprises incorporating an oxygen scavenging packaging
component inside the gas impermeable packaging or as part of the
gas impermeable packaging itself.
9. The method of claim 1 further comprising the step of sterilizing
an article comprising the wetted hydrophilic coating with radiation
by gamma rays or electron beam.
10. The method of claim 1 wherein the wetted hydrophilic coating is
wetted by a wetting agent comprising from 1 wt % to 20 wt % of a
component selected from the group consisting of glycerol,
monoacetin, diacetin, diacetone alcohol, diethyleneglycol,
triethyleneglycol, tetraethyleneglycol, propyleneglycol and
dipropyleneglycol.
11. A method of sterilizing a packaged article comprising the step
of sterilizing with radiation a package comprising an article and a
gas impermeable packaging enclosing the article, the article
comprising a wetted hydrophilic coating, the wetted hydrophilic
coating comprising water, and the package comprising an amount of
oxygen that is less than an amount of oxygen that would have been
present in the package if oxygen scavengers that may be present in
the wetted hydrophilic coating were alone acting on ambient air at
the time of packaging within the gas impermeable packaging, wherein
the wetted hydrophilic coating comprises at least 70 wt % water,
based on the total weight of the wetted hydrophilic coating.
12. (canceled)
13. (canceled)
14. A package comprising a. an article comprising a wetted
hydrophilic coating, the wetted hydrophilic coating comprising
water, wherein the wetted hydrophilic coating comprises at least 70
wt % water, based on the total weight of the wetted hydrophilic
coating, b. a gas impermeable packaging enclosing the article, and
c. an atmosphere within the gas impermeable packaging and in
contact with the wetted hydrophilic coating that has an amount of
oxygen that is less than an amount of oxygen that would have been
present if oxygen scavengers that may be present in the wetted
hydrophilic coating were alone acting on ambient air at the time of
packaging within the gas impermeable packaging.
15. The package of claim 14, wherein the wetted hydrophilic coating
further comprises a radical scavenger.
16. The package of claim 14, wherein the wetted hydrophilic coating
comprises at least 90 wt % water.
17. The package of claim 15, wherein the wetted hydrophilic coating
comprises at least 90 wt % water.
18. The method of claim 2 wherein the step of reducing the amount
of oxygen in the atmosphere in contact with the wetted hydrophilic
coating comprises replacing at least some of the oxygen in the
atmosphere in contact with the wetted hydrophilic coating with an
alternative gas.
19. The method of claim 18 further comprising the step of
incorporating a radical scavenger in the wetted hydrophilic
coating.
20. The method of claim 5, wherein the radical scavenger is vitamin
C or a compound comprising a thiosulfate anion.
21. The method of claim 19, wherein the radical scavenger is
vitamin C or a compound comprising a thiosulfate anion.
22. The method of claim 21 further comprising the step of enclosing
an article comprising the wetted hydrophilic coating in a gas
impermeable packaging.
Description
FIELD
[0001] The field of the invention is the sterilization and
stabilization of wetted hydrophilic coatings.
BACKGROUND
[0002] Many medical devices, such as guide wires, intermittent and
(cardio)vascular catheters or other medical tubing, syringes, and
membranes require some sort of lubrication in order to facilitate
insertion into or removal from the body. Pain or soft tissue damage
can occur upon insertion or removal of the medical device if the
medical device is not properly lubricated.
[0003] Many medical devices are coated with a hydrophilic coating
that must be wetted with a liquid to attain the sufficient level of
lubrication. A hydrophilic coating is typically provided as a
coating on a surface of a medical device. The act of wetting a
hydrophilic coating is performed by causing the hydrophilic coating
to retain a wetting agent. Upon being wetted with a wetting agent,
a hydrophilic coating may absorb at least two times its weight of
the wetting agent and be rendered lubricious. A hydrophilic coating
that does not absorb at least two times its weight of wetting agent
will likely be insufficiently lubricous. The wetting agent may be
any number of water or oil-based products, for example those
disclosed in WO2006037321, assigned to Coloplast A/S, or
WO2013017547, assigned to DSM IP Assets B.V.
[0004] Water-based wetting agents are often preferred by users.
Unlike oil-based wetting agents, such as those that contain more
than 50% by weight of propylene glycol or glycerol, water-based
wetting agents do not have the disadvantage of leaving an oily
residue on surfaces that come in contact with the wetted
hydrophilic coating, such as a user's fingers. Furthermore,
although a hydrophilic coating that is wetted with an oil-based
wetting agent generally has good lubricious properties and dry-out
time, improved lubricity can often be realized when a hydrophilic
coating is wetted with a water-based wetting agent. Dry-out time is
the amount of time that the wetted hydrophilic coating can retain
suitable lubricious properties.
[0005] A hydrophilic coating may be wetted in a number of ways,
depending on the composition of the wetting agent and the medical
device design. For example, the hydrophilic coating may be wetted
by submersing the hydrophilic coating in the wetting agent,
spraying the wetting agent on the hydrophilic coating, running
wetting agent over the hydrophilic coating for a short period of
time, injecting the wetting agent into a packaging containing an
article comprising a hydrophilic coating, or applying the wetting
agent to the hydrophilic coating in the form of a gas, for instance
in a high humidity environment.
[0006] The hydrophilic coating may be wetted immediately prior to
use. Wetting immediately prior to use requires access to a wetting
agent, for instance, a water source. Moreover, wetting immediately
prior to use requires handling of the medical device at the risk of
contacting the medical device with bacteria.
[0007] Because of the disadvantages with wetting the hydrophilic
coating on a medical device immediately prior to use, numerous
medical devices have been introduced that are sterile, pre-wetted,
and individually packaged for immediate use. The use of so-called
"ready-to-use" products may reduce the risk of contact with
bacteria, and allows for the medical device to be used when access
to a wetting agent is not practical or possible. A ready-to-use
product typically comprises a wetted hydrophilic coating wherein
the wetted hydrophilic coating comprises at least 70 wt %, or more
preferably at least 90 wt % of wetting agent, based on the total
weight of the wetted hydrophilic coating (i.e. the combined weight
of the wetting agent and the hydrophilic coating). A product that
does not possess a wetted hydrophilic coating that is sufficiently
lubricious is not a ready-to-use product. An example of a
ready-to-use product is described in U.S. Pat. No. 7,380,658,
hereby incorporated by reference in its entirety.
[0008] In addition to numerous benefits, ready-to-use products
present numerous challenges. One challenge faced is to avoid a
reduction in the lubricious properties, durability, or dry-out time
of the hydrophilic coating as a result of sterilization. Certain
sterilization techniques, such as sterilization with radiation, are
known to potentially degrade the beneficial properties of a wetted
hydrophilic coating. Consequently, various attempts have been made
to reduce the damaging effects of sterilization on the beneficial
properties of a hydrophilic coating wetted with a wetting agent
comprising water prior to sterilization.
[0009] For example, a known technique described in WO/2000/030696,
assigned to Coloplast A/S, involves wetting a hydrophilic coating
on a medical device with an aqueous wetting agent comprising a
hydrophilic polymer prior to sterilizing the medical device.
However, the presence of polymers in the water phase can leave
sticky residues on fingers and clothes. Moreover, an insufficiently
cross-linked additional coating layer may be formed that is not
acceptably durable.
[0010] Another known technique described in WO/2007/137699,
assigned to DSM IP Assets B.V., involves the use of a compound
selected from the group consisting of aliphatic compounds,
alicyclic compounds and antioxidants for protecting a hydrophilic
coating wetted with water. This technique may provide insufficient
protection from the damaging effects of radiation at certain doses
of radiation, such as greater than 30 kGy.
[0011] Therefore, an improved way of protecting a hydrophilic
coating wetted with a wetting agent comprising water prior to
sterilization from the damaging effects of radiation is
desired.
SUMMARY
[0012] Without wishing to be bound by any theory, the inventors
suspect that the damage caused by radiation sterilization of wetted
hydrophilic coatings comprising water results from the presence of
oxygen. Radicals formed in the wetted hydrophilic coating by the
radiation combine with oxygen to deteriorate the wetted hydrophilic
coating. Oxygen is present in the wetted hydrophilic coating
comprising water itself, and in an atmosphere in contact with the
wetted hydrophilic coating. The inventors have discovered that the
effects of oxygen in the atmosphere in contact with the wetted
hydrophilic coating cannot be ignored.
[0013] In accordance with the invention, the deterioration of a
wetted hydrophilic coating comprising water at the time of
sterilization by radiation is reduced by reducing the amount of
oxygen in an atmosphere in contact with the wetted hydrophilic
coating in addition to any reduction in oxygen provided by oxygen
scavengers that may be present in the wetted hydrophilic coating,
wherein the wetted hydrophilic coating comprises at least 70 wt %,
or more preferably at least 90 wt % water, based on the total
weight of the wetted hydrophilic coating. As opposed to the prior
art, which sought to avoid the damaging effects of sterilization
solely by addressing the content of the wetted hydrophilic coating,
the inventors have discovered that the oxygen in the atmosphere
contacting the wetted hydrophilic coating may be controlled to
reduce the damaging effects of radiation sterilization.
[0014] Further embodiments of the invention relate to a method of
sterilizing a packaged article comprising the step of sterilizing
with radiation a package comprising an article and a gas
impermeable packaging enclosing the article, the article comprising
a wetted hydrophilic coating, the wetted hydrophilic coating
comprising water, and the package comprising an amount of oxygen
that is less than an amount of oxygen that would have been present
in the package if oxygen scavengers that may be present in the
wetted hydrophilic coating were alone acting on ambient air at the
time of packaging within the gas impermeable packaging, wherein the
wetted hydrophilic coating comprises at least 70 wt %, or more
preferably at least 90 wt % water, based on the total weight of the
wetted hydrophilic coating.
[0015] A further embodiment of the invention relates to a method of
packaging an article comprising the steps of providing an article
comprising a hydrophilic coating; wetting the hydrophilic coating
with a wetting agent comprising water, thereby forming a wetted
hydrophilic coating; reducing the amount of oxygen in an atmosphere
in contact with the wetted hydrophilic coating in addition to any
reduction in oxygen provided by oxygen scavengers that may be
present in the wetted hydrophilic coating; and enclosing the
article in a gas impermeable packaging, wherein the wetted
hydrophilic coating comprises at least 70 wt %, or more preferably
at least 90 wt % water, based on the total weight of the wetted
hydrophilic coating.
[0016] Another embodiment of the invention is a package comprising
an article comprising a wetted hydrophilic coating, the wetted
hydrophilic coating comprising water; a gas impermeable packaging
enclosing the article, and an atmosphere within the gas impermeable
packaging and in contact with the wetted hydrophilic coating that
has an amount of oxygen that is less than an amount of oxygen that
would have been present if oxygen scavengers that may be present in
the wetted hydrophilic coating were alone acting on ambient air at
the time of packaging within the gas impermeable packaging, wherein
the wetted hydrophilic coating comprises at least 70 wt %, or more
preferably at least 90 wt % water, based on the total weight of the
wetted hydrophilic coating.
[0017] In such embodiments, the article is preferably a medical
device, such as a catheter, guidewire, syringe, or contact
lens.
[0018] Further embodiments of the invention are elucidated in the
following detailed description.
DETAILED DESCRIPTION
[0019] As mentioned above, the prior art of reducing the
deterioration of wetted hydrophilic coatings subject to
sterilization by radiation has failed to suitably address the role
that oxygen in the atmosphere in contact with the wetted
hydrophilic coating plays in coating deterioration when the wetted
hydrophilic coating comprises substantial amounts of water.
[0020] The prior art has recognized some reduction in deterioration
may occur from employing components that may have oxygen and
radical scavenging capabilities in the wetted hydrophilic coating,
but a sufficient level of deterioration reduction was not obtained.
For example, WO/2007/137699 mentions Vitamin C, which may act as
both an oxygen scavenger and a radical scavenger. However,
WO/2007/137699 notes that when a hydrophilic coating wetted with a
wetting agent consisting essentially of water and Vitamin C is
sterilized with 25 kGy of gamma radiation, as shown in Examples B
and C of WO/2007/137699, "some improvement was observed compared to
sterilization in pure water, but . . . a desirable dry-out time was
not realized." Additionally, the improvement exhibited with a
wetting agent consisting essentially of water and 2 wt % vitamin C
exhibited coloration after sterilization.
[0021] The inventors now theorize that the oxygen and/or radical
scavenging abilities of the vitamin C are exhausted prior to
sterilization. By reducing the amount of oxygen in an atmosphere in
contact with the wetted hydrophilic coating beyond the reduction in
oxygen that would otherwise be provided by any oxygen scavengers
that may be present in the wetted hydrophilic coating, the oxygen
scavenger and radical scavenger are able to perform their functions
sufficiently prior, during, and after sterilization. Additionally,
potentially less oxygen scavenger and/or radical scavenger are
needed in the wetted hydrophilic coating, thereby allowing for
components, such as additional water, that perform the sole
function of providing lubricity to the wetted hydrophilic coating
or have a lower raw material cost.
[0022] In accordance with the invention, the deterioration of a
wetted hydrophilic coating comprising water at the time of
sterilization by radiation is reduced by reducing the amount of
oxygen in an atmosphere in contact with the wetted hydrophilic
coating in addition to any reduction in oxygen provided by oxygen
scavengers that may be present in the wetted hydrophilic coating,
wherein the wetted hydrophilic coating comprises at least 70 wt %,
or more preferably at least 90 wt % water, based on the total
weight of the wetted hydrophilic coating.
[0023] A hydrophilic coating is typically provided on a surface of
an article. A hydrophilic coating may be provided in a number of
ways, such as extrusion, molding, or curing. In the case of curing,
a hydrophilic coating composition is cured to form a hydrophilic
coating. A hydrophilic coating composition is typically present as
a liquid, but may also be present as a paste or some other form.
Radiation curing may be performed by curing with heat and/or light,
such as UV light. Preferably, the hydrophilic coating is formed by
curing a hydrophilic coating composition by radiation comprising UV
light.
[0024] A typical hydrophilic coating may be obtained by providing
on a surface of an article, said surface may or may not being
already primed by a primer, a hydrophilic coating composition and
curing the hydrophilic coating composition. A typical hydrophilic
coating composition comprises a hydrophilic polymer, a solvent, and
an initiator. Examples of hydrophilic polymers are
polyvinylpyrrolidone (PVP), polyacrylamide, polyelectrolytes, and
poly(ethylene oxide). Hydrophilic polymers may also comprise
reactive groups, such as (meth)acrylate groups) or photo-active
groups, in addition to a hydrophilic portion. The reactive groups
contribute to the formation of a polymer network when the
hydrophilic coating composition is cured to form a hydrophilic
coating. The initiator is typically a photoinitiator. One or more
supporting monomers, oligomers, or polymers having reactive
moieties to support the hydrophilic polymer or other components or
additives, such as plasticizers or surfactants, may also be
present. A solvent may be, for example, water, methanol or ethanol.
The hydrophilic coating may be obtained by at least partially
evaporating the solvent from the hydrophilic coating composition
and then curing the hydrophilic coating composition with light,
such as UV light. Hydrophilic coating compositions are disclosed
in, for example, US2011046255 to DSM IP Assets BV, which is hereby
incorporated by reference in its entirety. A commercial example of
a hydrophilic coating composition that may be cured by radiation
comprising UV light to form a hydrophilic coating is a
ComfortCoat.RTM. product from DSM, such as TC43005.
[0025] A primer may be present to improve the adherence of the
hydrophilic coating to an article. The primer may be cured prior to
application and curing of a hydrophilic coating composition, or may
be cured at the same time as the hydrophilic coating composition is
cured.
[0026] A typical primer composition may comprise a supporting
monomer, oligomer, or polymer that provides the necessary adherence
to the article, an initiator, and a solvent. The initiator is
typically a photoinitiator. A hydrophilic polymer, such as
polyvinylpyrrolidone (PVP) and poly(ethylene oxide), may also be
present. The primer may be formed by at least partially evaporating
the solvent from the primer composition and then curing the primer
composition with UV light. Subsequently, a hydrophilic coating
composition may be applied on top of the primer and cured to form a
hydrophilic coating.
[0027] In an embodiment, a hydrophilic coating is formed by curing
a hydrophilic coating composition, the hydrophilic coating
composition comprising at least 70 wt %, preferably at least 80 wt
%, more preferably at least 90 wt % of hydrophilic polymers, based
on the total dry weight of the hydrophilic coating composition. By
dry weight it is meant the total weight of the hydrophilic coating
composition excluding any solvents.
[0028] A wetted hydrophilic coating may be formed in a number of
ways. The process of forming a wetted hydrophilic coating from a
hydrophilic coating is known as wetting the hydrophilic coating.
Wetting can be accomplished by, for example, bringing a wetting
agent present as a liquid into contact with a hydrophilic coating.
The contact may be established in a number of ways, for instance,
submerging the hydrophilic coating in the wetting agent or spraying
the hydrophilic coating with the wetting agent. Other methods of
wetting a hydrophilic coating may be performed with a wetting agent
present as a gas or vapor. For instance, a liquid wetting agent may
be present out of direct contact with the hydrophilic coating, but
the wetting agent wets the hydrophilic coating by traveling as a
gas or vapor. Similarly, a high humidity environment could be
present in a package containing an article comprising a hydrophilic
coating such that over time the hydrophilic coating is wetted. In a
wetting method where the wetting agent wets the hydrophilic coating
as a gas or vapor, components that may normally be included in the
wetting agent that cannot travel as a vapor or gas would need to be
incorporated into the wetted hydrophilic coating by other means,
such as inclusion in the hydrophilic coating itself. The thickness
of a typical wetted hydrophilic coating is generally more than 0.5
micron and less than 100 microns.
[0029] Sterilization is typically performed by radiation. Methods
of sterilization by radiation include sterilization by gamma rays,
x-rays, and electron beams. In the medical device area, gamma ray
or electron beam sterilization are generally preferred. In an
embodiment, sterilization is performed by gamma rays or electron
beam. In an embodiment, sterilization is performed by gamma rays or
electron beam at a dosage of greater than 25 kGy, preferably
greater than 30 kGy. Catheters are typically sterilized with a dose
of radiation of from 25 to 50 kGy, preferably 25 to 45 kGy.
[0030] Generally, chemical or other means of sterilization present
difficulties when sterilizing wetted hydrophilic coatings. Chemical
sterilization, such as sterilization with ethylene oxide, requires
the use of a gas that must contact the article that is being
sterilized. A vacuum is then applied to remove the gas. This vacuum
may adversely affect the wetted hydrophilic coating by removing
some of the liquid components of a wetting agent retained by the
wetted hydrophilic coating, thereby reducing the lubricity of the
wetted hydrophilic coating. Moreover, depending on the type of
packaging used, a chemical sterilization may not fully penetrate a
sealed package and consequently not sufficiently sterilize the
article.
[0031] In accordance with the invention, the wetted hydrophilic
coating comprises water. In embodiments, the wetted hydrophilic
coating comprises at least 70 wt %, more preferably at least 90 wt
% water, based on the total weight of the wetted hydrophilic
coating. In embodiments wherein the wetted hydrophilic coating is
wetted with a wetting agent comprising water, the amount of water
in the wetting agent may be at least 70 wt %, more preferably at
least 90 wt %, based on the total weight of the wetting agent. In
an embodiment, a wetting agent comprises at least 95 wt %
water.
[0032] In embodiments of the invention, a radical scavenger is
incorporated in the wetted hydrophilic coating. In principle any
known radical scavenger that is soluble in water could be used. In
the case that the wetted hydrophilic coating will be inserted into
the body, for instance in the case of a catheter, the radical
scavenger should be biocompatible. Biocompatible means that a
material has the ability to be in contact with a living system
without producing an adverse effect. In an embodiment where a
radical scavenger is present in a wetted hydrophilic coating, the
total concentration of radical scavenger in the wetting hydrophilic
coating is preferably from 0.01 to 2 wt %, based on the total
weight of wetted hydrophilic coating. In the case that a radical
scavenger is present in a wetting agent for wetting a hydrophilic
coating, the total concentration of radical scavenger in the
wetting agent is preferably from 0.01 to 2 wt %, based on the total
weight of wetting agent.
[0033] In an embodiment, a wetted hydrophilic coating and/or a
wetting agent comprises a radical scavenger and an oxygen
scavenger. Preferably, the radical scavenger is also an oxygen
scavenger. Preferably, the radical scavenger and oxygen scavenger
is vitamin c (ascorbic acid) or a compound comprising a thiosulfate
anion. Compounds comprising thiosulfate anions are, for example,
sodium thiosulfate, ammonium thiosulfate, barium thiosulfate,
calcium thiosulfate, magnesium thiosulfate, potassium thiosulfate
or hydrates thereof. Additional compounds comprising a thiosulfate
anion are lithium thiosulfate, iron thiosulfate, zinc thiosulfate,
tin thiosulfate, silver thiosulfate or hydrates thereof. In the
case that the wetted hydrophilic coating or wetting agent comprises
a thiosulfate anion, it is preferred that the wetted hydrophilic
coating or wetting agent is maintained at a pH of 6 or higher, more
preferably 7 or higher. In an embodiment, a buffer is present for
maintaining the pH at 6 or higher, preferably 6.5 or higher, and
more preferably 7 or higher. In the case that the radical scavenger
is also an oxygen scavenger and is present in a wetting agent for
wetting a hydrophilic coating, the total concentration of radical
scavenger that is also an oxygen scavenger in the wetting agent is
from 0.05 to 2 wt % based on the total weight of wetting agent,
more preferably 0.3 to 1.5 wt % based on the total weight of
wetting agent. In an embodiment, the total concentration of radical
scavenger that is also an oxygen scavenger in the wetting agent is
from 0.5 to 1.5 wt % based on the total weight of wetting
agent.
[0034] Suitable compounds that are radical scavengers but not
oxygen scavengers are, for example, alkyl hydroxybenzyl alcohols
(such as 5-di-tert-butyl-4-hydroxybenzyl alcohol), alkyl
hydroxybenzoic acids (such as 3,5-di-tert-butyl-4-hydroxybenzoic
acid), pyrogallol, alkylated hydroxytoluene (such as butylated
hydroxy toluene), and 2,6-ditertbutyl-4-ethyl-phenol. Commercially
available examples of such radical scavengers that are not oxygen
scavengers include Irganox.RTM. 1300, Irganox.RTM. 1098,
Irganox.RTM. 1076 and combinations thereof. If present, a compound
that is a radical scavenger but not an oxygen scavenger may be
present in an amount of from 0.05 to 1 wt %, based on the total
weight of wetting agent.
[0035] The radical scavenger may be incorporated into the wetted
hydrophilic coating in a number of ways. For example, the radical
scavenger may be present as a wetting agent that is used to wet the
hydrophilic coating, may be present in the hydrophilic coating
itself, or in both. If present in the wetting agent, the radical
scavenger may be incorporated in the wetting agent by simple
mixing. If present in the hydrophilic coating, the radical
scavenger may be incorporated in the hydrophilic coating
composition.
[0036] Further oxygen scavengers may be present in the wetted
hydrophilic coating provided that they are biocompatible.
[0037] In an embodiment, a further water soluble organic component
and/or water soluble polymer is incorporated into the wetted
hydrophilic coating or present in a wetting agent. Such components
may be, for example, polyvinylpyrrolidone, acrylic acid or acrylic
acid copolymers, polyacrylamides, polyethylene glycol, and/or
polyelectrolytes such as salts of (meth)acrylic acid copolymers,
for example, poly(acrylamide-co-acrylic acid) salt.
[0038] Further alcohols may be present in the wetted hydrophilic
coating and/or wetting agent in limited amounts. In an embodiment,
the wetted hydrophilic coating and/or wetting agent comprises a
component selected from the group consisting of glycerol, glycerol
esters, glycerol ethers, glycols, glycolesters and glycolethers.
Suitable examples of components are glycerol, monoacetin, diacetin,
diacetone alcohol, diethyleneglycol, triethyleneglycol,
tetraethyleneglycol, propyleneglycol or dipropyleneglycol. If
present, it is preferred that such components are present at from 1
wt % to 20 wt %, more preferably from 2 wt % to 10 wt %, more
preferably from 4 wt % to 10 wt %, based on the total weight of the
wetting agent.
[0039] In embodiments of the invention, further components that may
be present in the wetted hydrophilic coating and/or wetting agent
are preservatives, surfactants, buffers, antibiotics, and/or
anti-microbial compounds. Examples of preservatives are methyl
paraben, ethyl paraben, propyl paraben, salts of sulfite such as
sodium sulfite, sorbic acid, calcium propionate, benzoic acid,
salts of hydrosulfite such as sodium hydrogen sulfite, sodium
bisulfite, sodium benzoate, erythorbic acid, and salts of nitrate
such as potassium nitrate. In the case that the a buffer is
present, for instance to stabilize the pH of the wetting agent, the
buffer keeps the pH above 4, preferably above 6, more preferably
from 6.5 to 8, and more preferably about 7.
[0040] In accordance with the invention, the amount of oxygen in an
atmosphere in contact with the wetted hydrophilic coating is
reduced in addition to any reduction in oxygen provided by oxygen
scavengers that may be present in the wetted hydrophilic coating.
The atmosphere in contact with the wetted hydrophilic coating means
the gas surrounding and in contact with the wetted hydrophilic
coating at the time of sterilization. For example, the atmosphere
may be contained within a gas impermeable package or within a
sterilization apparatus.
[0041] An oxygen scavenger present in the wetted hydrophilic
coating will, depending on type and amount, generally provide some
reduction in the oxygen in the atmosphere in contact with the
wetted hydrophilic coating. As mentioned above, an oxygen scavenger
may also be a radical scavenger, for example vitamin C. However,
deterioration of the wetted hydrophilic coating may be improved by
a reduction in the amount of oxygen in an atmosphere in contact
with the wetted hydrophilic coating in addition to any reduction in
oxygen provided by oxygen scavengers that may be present in the
wetted hydrophilic coating. In an embodiment, the amount of oxygen
in the atmosphere in contact with the wetted hydrophilic coating is
reduced below 15%, more preferably below 10%, and even more
preferably below 5% by volume of the atmosphere in contact with the
wetted hydrophilic coating.
[0042] For present commercial purposes, wetted hydrophilic coatings
that are sterilized are preferably present on articles packaged in
a gas impermeable packaging. These individually packaged articles
are typically medical devices, such as catheters. However, it is
possible that the articles are not individually packaged. In such a
case, the oxygen in the atmosphere can be reduced by wholly or
partially substituting the oxygen in the sterilization chamber with
another gas, such as nitrogen, carbon dioxide, argon or another
non-reactive gas.
[0043] In an embodiment, the oxygen in the atmosphere is reduced by
replacing some of the atmosphere in contact with the wetted
hydrophilic coating with an alternative gas, such as nitrogen,
carbon dioxide, argon or another non-reactive gas. The atmosphere
replacement may be performed by simply inserting the alternative
gas into a gas impermeable package prior to sealing the gas
impermeable package. Inserting the alternative gas at a pressure
above atmospheric pressure is desirable, but care should be taken
not to insert the alternative gas at too high of pressure or the
wetted hydrophilic coating may be affected. For example, some of
the wetting agent that has wetted the hydrophilic coating may be
inadvertently removed by the high pressure insertion of an
alternative gas. Similarly, removal of the oxygen in the atmosphere
by a vacuum is also possible, but care should be taken to operate
the vacuum to not inadvertently affect the wetted hydrophilic
coating detrimentally. Of course, some gasses other than oxygen may
be removed when inserting an alternative gas or using a vacuum, for
instance if the original atmosphere is air, but reducing the amount
of oxygen in an atmosphere in contact with the wetted hydrophilic
coating is achieved if the amount of oxygen is less than prior to
carrying out the step.
[0044] In an embodiment, the oxygen in the atmosphere is reduced by
incorporating an oxygen scavenging packaging component. An oxygen
scavenging packaging component may be an item inside a gas
impermeable packaging or part of the gas impermeable packaging
itself.
[0045] Accordingly, in a further embodiment, an oxygen scavenging
packaging component is included in the form of an oxygen scavenging
packet. For example, the oxygen scavenging packet may be a
gas-permeable package containing an oxygen scavenger. The oxygen
scavenging packet may be secured or otherwise included inside a gas
impermeable packaging. Preferably, such an oxygen scavenging packet
is held out of contact with the wetted hydrophilic coating.
[0046] The use of such oxygen scavenging packets allows for oxygen
scavengers contained within the packet that are not necessarily
biocompatible or dissolvable in a wetted hydrophilic coating. For
example, the oxygen scavenger in the oxygen scavenging packet may
be iron powder, zinc powder, manganese powder, vitamin C, or sodium
thiosulfate. Commercial examples of oxygen scavenging packets that
are satchets containing an oxygen scavenger are Ageless from
Mitsubisihi Gas and Chemical Co., Japan, ATCO products from Emco
Packaging Systems, UK, and Standa Industries, France, Freshilizers
series from Toppan Printing, Japan, FreshPax.RTM. and FreshMax.RTM.
from Multisorb Technologies, Inc. USA, Bioka oxygen absorbing
satchets from Bioka Ltd. Finland, and Oxyguard from Toyo Seikan
Kaisha, Japan. In an embodiment, the oxygen scavenging packet is
water-activated.
[0047] In an embodiment, the oxygen scavenging packaging component
is an oxygen scavenging surface. Such oxygen scavenging surfaces
are known from, for example U.S. Pat. No. 6,406,766 and U.S. Pat.
No. 6,346,308, assigned to BP Corporation of North America, and
US20080206500, assigned to DSM IP Assets BV, each hereby
incorporated by reference in its entirety. Such an oxygen
scavenging surface may be formed from a co-extruded plastic. Oxygen
scavenging surfaces are available commercially, for example as
Cryovac.RTM. OS Films--Active Barrier Films.
[0048] Such an oxygen scavenging surface may be present as an
internal surface of an outer packaging or as a separate packaging
component within an outer packaging. In an embodiment, the oxygen
scavenging packaging component is a sleeve comprising an oxygen
scavenging surface that is placed around an article inside an outer
packaging. Such a sleeve may have the added benefit of providing a
surface with which the article may be handled without touching a
surface of the article immediately prior to use. In an embodiment,
the sleeve is gas impermeable.
[0049] In an embodiment of the invention, a method of sterilizing a
packaged article is provided comprising the step of sterilizing
with radiation a package comprising an article and a gas
impermeable packaging enclosing the article, the article comprising
a wetted hydrophilic coating, the wetted hydrophilic coating
comprising water, and the package comprising an amount of oxygen
that is less than an amount of oxygen that would have been present
in the package if oxygen scavengers that may be present in the
wetted hydrophilic coating were alone acting on ambient air at the
time of packaging within the gas impermeable packaging, wherein the
wetted hydrophilic coating comprises at least 70 wt %, or more
preferably at least 90 wt % water, based on the total weight of the
wetted hydrophilic coating.
[0050] By ambient air at the time of packaging it is meant the
composition of the surrounding gasses present at the time of
packaging that contain a sufficient amount of oxygen for a human to
function normally for an extended period of time without the aid of
a breathing apparatus. Ambient air at the time of packaging
generally has a percentage of oxygen that is similar to the
atmosphere of earth (approximately 20.9% oxygen) at a pressure of 1
atm and may be controlled in some way. For example, ambient air at
the time of packaging may be controlled by controlling the
temperature and/or humidity of the ambient air at the time of
packaging. The situation of packaging an article in an environment
comprising an amount of oxygen that is not a sufficient amount of
oxygen for a human to function normally for an extended period of
time without the aid of a breathing apparatus would not be
considered packaging in ambient air, but would rather be a step of
reducing the amount of oxygen in an atmosphere in contact with the
wetted hydrophilic coating in addition to any reduction in oxygen
provided by oxygen scavengers that may be present in the wetted
hydrophilic coating.
[0051] A further embodiment of the invention is a method of
packaging an article comprising the steps of providing an article
comprising a hydrophilic coating; wetting the hydrophilic coating
with a wetting agent comprising water, thereby forming a wetted
hydrophilic coating, wherein the wetted hydrophilic coating
comprises at least 70 wt %, or more preferably at least 90 wt %
water, based on the total weight of the wetted hydrophilic coating;
reducing the amount of oxygen in an atmosphere in contact with the
wetted hydrophilic coating in addition to any reduction in oxygen
provided by oxygen scavengers that may be present in the wetted
hydrophilic coating; and enclosing the article in a gas impermeable
packaging.
[0052] An article may be enclosed in a gas impermeable packaging by
any number of common methods. For example, the article may be
enclosed in gas impermeable packaging by sealing the gas
impermeable packaging. For example, the sealing may be carried out
by activating an adhesive. Sealing could also be performed by
bonding together two surfaces of a gas impermeable packaging with
the aid of heat and/or pressure.
[0053] Another embodiment of the invention is a package comprising
an article comprising a wetted hydrophilic coating, the wetted
hydrophilic coating comprising water, wherein the wetted
hydrophilic coating comprises at least 70 wt %, or more preferably
at least 90 wt % water, based on the total weight of the wetted
hydrophilic coating, a gas impermeable packaging enclosing the
article, and an atmosphere within the gas impermeable packaging and
in contact with the wetted hydrophilic coating that has an amount
of oxygen that is less than an amount of oxygen that would have
been present if oxygen scavengers that may be present in the wetted
hydrophilic coating were alone acting on ambient air at the time of
packaging within the gas impermeable packaging.
[0054] In an embodiment, a method of reducing the deterioration of
a wetted hydrophilic coating comprising water at the time of
sterilization by radiation is provided, the method comprising the
step of reducing the amount of oxygen in an atmosphere in contact
with the wetted hydrophilic coating to an amount that is less than
an amount of oxygen that would have been present after exhausting
all oxygen scavengers that may be present in the wetted hydrophilic
coating, wherein the wetted hydrophilic coating comprises at least
70 wt %, or more preferably at least 90 wt % water, based on the
total weight of the wetted hydrophilic coating.
[0055] The following examples are used to further illustrate the
invention, but, of course, should not be construed as in any way
limiting its scope.
Examples
[0056] Hydrophilic coatings are provided on pieces of 14Fr
(external diameter of 4.667 mm) PVC tubing with a length of 40 cm.
The tubing is useful for intermittent catheter products.
Coating and Curing Process
[0057] The primer composition was P41001, a primer composition
available from DSM Biomedical, Inc. P41001 comprises a hydrophilic
polymer comprising reactive groups, a further hydrophilic polymer,
a photoinitiator and greater than 90 wt % of solvent, based on the
total weight of the primer composition. The hydrophilic coating
composition was TC43005, a UV-curable hydrophilic coating
composition available from DSM Biomedical, Inc. TC43005 comprises a
hydrophilic polymer, a polyelectrolyte hydrophilic polymer, a
photoinitiator, and greater than 90 wt % of solvent, based on the
total weight of the hydrophilic coating composition.
[0058] A metal mandrel was inserted into the end of a piece of PVC
tubing and subsequently attached into the device holder of a
Harland PCX coater. The dip length for the primer composition was
35 cm. The dip length for the hydrophilic coating composition was
34 cm.
[0059] Pieces of PVC tubing were dip coated and cured using the
Harland PCX coater. Extraction speed of the coated tubing was 1
cm/s for both the primer and hydrophilic coating formation. Cure
took place directly after application of the hydrophilic coating
composition. Intensity of the lamps was on average 60 mW/cm2 and
was measured using 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. The instruction manual of
International Light was applied, which is available on the
internet: www.intl-light.com. UV dose was approximately 0.9 J/cm2
for the primer and 21.6 J/cm2 for the hydrophilic coating. The
primer composition was coated and cured first, and then the
hydrophilic coating composition was coated and cured. After curing,
a coated tubing comprising a hydrophilic coating was obtained.
Preparation of a Wetted Hydrophilic Coating
[0060] A wetting agent is formed by weighing the components of the
wetting agent and simply mixing together the components in a glass
bottle. The compositions of the wetting agents are shown in the
below Table 3 in weight percent, based on the total amount of
wetting agent. The water was demineralized water. Shortly after
preparing the wetting agent, the hydrophilic coatings on the pieces
of coated tubing formed above are wetted by immersion for one
minute in the wetting agent, thereby forming pieces of coated
tubing comprising a wetted hydrophilic coating.
Packaging
[0061] A gas impermeable, heat sealable packaging with an external
surface of an aluminum foil and an internal surface of polyethylene
foil were obtained from Steripack (U/P Pouch 70*505 mm SO5198). 2.5
ml of wetting agent was inserted into each gas impermeable
packaging prior to placing the coated tubing comprising a wetted
hydrophilic coating in the gas impermeable packaging. Each piece of
coated tubing comprising a wetted hydrophilic coating was then
individually placed in a gas impermeable package and the package
was sealed by applying heat, thereby forming a package.
Atmosphere Replacement
[0062] In the case that the specific package was subject to an
atmosphere replacement before sealing of the package, the
atmosphere replacement was performed by injecting argon at a
pressure of 0.5 bar. After approximately 30 seconds, the package
was sealed such that a significant quantity of argon was contained
within the package.
Sterilization
[0063] The packages were sterilized by exposing them to 45 kGy of
.gamma.-radiation.
Lubricity and Durability
[0064] After sterilization, the pieces of coated tubing comprising
a wetted hydrophilic coating are tested for lubricity and
durability. The sterilized package was opened shortly before
testing. The tests were performed using a Harland FTS5000 Friction
Tester (HFT). The lubricity and durability measurements are
performed in water. The protocol was as indicated in the following
table:
TABLE-US-00001 TABLE 1 HFT settings transport movement (cm) 10
clamp force (g) 300 pull speed (cm/s) 1 acceleration time (sec) 2
number of rubs 25
[0065] Friction tester pads from Harland Medical Systems were used:
P/N 102692, FTS5000 Friction Tester Pads, 0.125''0.5''0.125''60
durometer. A metal mandrel was inserted into a piece of coated
tubing comprising a wetted hydrophilic coating and the test
started.
[0066] The lubricity of the wetted hydrophilic coating is defined
as the friction force measured after the first cycle. A friction
force of less than 15 gram is considered to be very good. The
durability of the wetted hydrophilic coating is defined as the
difference between the friction force measured after the 25.sup.th
cycle and the friction force measured after the first cycle. The
durability is a measure of the adhesion of the wetted hydrophilic
coating on a surface and coating integrity. A durability of less
than 5 grams is considered to be very good.
[0067] A typical lubricity value for unsterilized coated tubing
with a wetted hydrophilic coating wetted with 100% water is 5-10
grams. A typical value for durability of such unsterilized coated
tubing is less than 5 gram.
Characterization of Deterioration
[0068] Deterioration is characterized by loss of lubricity and
durability in the friction tester. The amount of deterioration is
also assessed by comparison to the lubricity of an unsterilized
wetted hydrophilic coating with 100 wt % water as the wetting agent
by gentle rubbing of the wetted coated tubing between the pointer
finger and the thumb immediately after removal from the sterilized
package. Deterioration of the wetted hydrophilic coating was
assessed using the criteria in table 2, below.
TABLE-US-00002 TABLE 2 Deterioration Level Description 0 No
deterioration observed 1 Deterioration is observed, but the
lubricity is not significantly affected. Thinning of the wetted
hydrophilic coating is observed. 2 Deterioration is observed and
the lubricity of the wetted hydrophilic coating is somewhat
adversely affected. 3 Significant improvement over a wetting agent
comprising 100 wt % of water, but significant deterioration is
still observed. 4 Very little improvement over a wetting agent
comprising 100 wt % of water, significant deterioration is
observed. 5 Baseline level of deterioration for the case when the
wetting agent comprises 100 wt % water.
[0069] The pre-sterilization lubricity of each sample was about 5
to 10 g. Results of the experiment are reported in Table 3
below.
TABLE-US-00003 TABLE 3 Deterio- Atmosphere Lubricity Durability
ration Ex. Wetting agent replacement (g) (g) level 1 100 wt % water
no >>100 >50 gr after 5 2.sup.nd cycle 2 100 wt % water
Yes, argon 13 0 2 3 99 wt % water + no >>100 >50 after 5 1
wt % vitamin C 2.sup.nd cycle 4 99 wt % water + Yes, argon 5 0 0 1
wt % vitamin C
Discussion of Results
[0070] Example 1 and 2 show the influence of atmosphere replacement
in the packaging by the inert gas argon. After the sterilization in
air (Example 1) the wetted hydrophilic coating performance has
deteriorated completely. After replacement of the air with argon
(Example 2) the lubricity increased slightly (.about.3-8 grams)
from an unsterilized case while the durability remained similar to
the unsterilized case.
[0071] Example 3 and 4 show the additional benefit of a radical and
oxygen scavenger in the wetting agent. Without atmosphere
replacement with argon (Example 3), a complete deterioration of
wetted hydrophilic coating was observed despite the presence of
vitamin C. The presence of vitamin C further improved the wetted
hydrophilic coating performance after atmosphere replacement with
argon (Example 4), such that no deterioration is observed.
[0072] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference were individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein.
[0073] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention (especially in
the context of the following claims) are to be construed to cover
both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context. The terms "comprising,"
"having," "including," and "containing" are to be construed as
open-ended terms (i.e., meaning "including, but not limited to,")
unless otherwise noted. Recitation of ranges of values herein are
merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range,
unless otherwise indicated herein, and each separate value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein, is
intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise
claimed. No language in the specification should be construed as
indicating any non-claimed element as essential to the practice of
the invention.
[0074] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Variations of those preferred embodiments may
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. While
certain embodiments detail certain optional features as further
embodiments of the invention, the description is meant to encompass
and specifically disclose all combinations of these features unless
specifically indicated otherwise or physically impossible.
* * * * *
References