U.S. patent application number 10/723680 was filed with the patent office on 2004-06-17 for stabilization of poly(oxyalkylene) containing polymeric materials.
Invention is credited to Devlin, Brian Gerrard, Medina, Arturo Norberto, Perreault, Stephen Raymond, Sentell, Karen Belinda, Tena, Mireille.
Application Number | 20040116564 10/723680 |
Document ID | / |
Family ID | 32397213 |
Filed Date | 2004-06-17 |
United States Patent
Application |
20040116564 |
Kind Code |
A1 |
Devlin, Brian Gerrard ; et
al. |
June 17, 2004 |
Stabilization of poly(oxyalkylene) containing polymeric
materials
Abstract
The present invention provides a method for producing a medical
device, preferably an ophthalmic device, more preferably a contact
lens, made of a stabilized poly(oxyalkylene)-containing polymeric
material. The method of the invention comprises the steps of:
curing, in a mold, a composition comprising (a) a prepolymer having
at least one poly(oxyalkylene) unit, (b) a biocompatible organic
multi-acid or biocompatible salt thereof in an amount sufficient to
improve the stability of the poly(oxyalkylene)-containing polymer
made from the composition, (c) optionally a photoinitiator or a
thermal initiator, and (d) optionally one or more vinylic monomers,
to form the medical device being less susceptible to oxidative
degradation; and removing the medical device from the mold.
Inventors: |
Devlin, Brian Gerrard;
(Suwanee, GA) ; Medina, Arturo Norberto; (Duluth,
GA) ; Sentell, Karen Belinda; (Alpharetta, GA)
; Perreault, Stephen Raymond; (Norcross, GA) ;
Tena, Mireille; (Alpharetta, GA) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS, CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
32397213 |
Appl. No.: |
10/723680 |
Filed: |
November 25, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60429719 |
Nov 27, 2002 |
|
|
|
60512591 |
Oct 17, 2003 |
|
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Current U.S.
Class: |
524/241 ;
264/1.32; 264/1.36; 264/2.6; 524/284 |
Current CPC
Class: |
A61L 27/18 20130101;
C08K 5/098 20130101; C08K 3/32 20130101; C08G 2120/00 20130101;
C08G 18/6685 20130101; C08K 5/098 20130101; C08G 18/71 20130101;
C08K 5/175 20130101; C08L 71/02 20130101; C08K 5/092 20130101; C08L
71/02 20130101; C08L 75/14 20130101; A61L 27/18 20130101; C08G
18/5024 20130101; C08L 2203/02 20130101; C08L 71/02 20130101; C08L
71/02 20130101; C08L 2666/04 20130101 |
Class at
Publication: |
524/241 ;
264/001.32; 264/001.36; 264/002.6; 524/284 |
International
Class: |
B29D 011/00; C08K
005/09 |
Claims
What is claimed is:
1. A medical device comprising: a poly(oxyalkylene)-containing
polymeric material and a biocompatible organic multi-acid or
biocompatible salt thereof, wherein the
poly(oxyalkylene)-containing polymeric material has a polymer
network having at least one unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I) wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.4-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000; wherein the
biocompatible organic multi-acid or biocompatible salt thereof is
distributed within the poly(oxyalkylene)-containing polymeric
material but not crosslinked to the polymer network, and wherein
the biocompatible organic multi-acid or biocompatible salt thereof
is present in an amount effective to improve the stability of the
medical device so that the medical device has a decreased
susceptibility to oxidative degradation, characterized by having at
least an 1.5-fold reduction of the amount of detectable formic acid
and optionally other degradation by-products.
2. A medical device of claim 1, wherein the medical device is an
ophthalmic device.
3. A medical device of claim 1, wherein the biocompatible organic
multi-acid is selected from the group consisting of hydroxy
diacids, hydroxy triacids, and amino acids.
4. A medical device of claim 3, wherein the biocompatible organic
multi-acid is an .alpha.-oxo-multi-acid.
5. A medical device of claim 4, wherein the .alpha.-oxo-multi-acid
is selected from the group consisting of citric acid,
2-ketoglutaric acid, and malic acid.
6. A medical device of claim 5, wherein the medical device of the
invention is a copolymerization product of a composition comprising
(a) a prepolymer containing ethylenically unsaturated groups and at
least one poly(oxyalkylene) unit of formula (I); (b) a
water-soluble and biocompatible organic multi-acid or biocompatible
salt thereof in an amount sufficient to improve the stability of a
poly(oxyalkylene)-contain- ing polymeric material made from the
composition; (c) optionally a photoinitiator or a thermal
initiator; and (d) optionally one or more vinylic monomers.
7. A medical device of claim 6, wherein the prepolymer is a
crosslinkable polyurea.
8. A medical device of claim 6, wherein the prepolymer is a
crosslinkable polyurethane.
9. A medical device of claim 6, wherein the medical device is an
ophthalmic device.
10. A medical device of claim 5, wherein the biocompatible organic
multi-acid or biocompatible salt thereof is impregnated within the
poly(oxyalkylene)-containing polymeric material, wherein the
poly(oxyalkylene)-containing polymeric material is a polymerization
product of a reactive mixture comprising (a) a monomer or
prepolymer having at least one poly(oxyalkylene) unit of formula
(I) and functional groups which are amino, hydroxyl or isocyanato
groups, and (b) an organic diamine, an organic polyamine, an
organic diol, an organic polyol, an organic diisocyante, or organic
polyisocyanate, provided that components (a) and (b) react with
each other to form a polyurea and/or polyurethane network.
11. A medical device of claim 10, wherein the medical device is an
ophthalmic device.
12. A method for producing a medical device, comprising the steps
of: (1) obtaining a polymerizable fluid composition comprising (a)
a prepolymer having ethylenically unsaturated groups and at least
one poly(oxyalkylene) unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--- O).sub.m--(R.sub.3--O).sub.p--
(I) wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.4-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, (b) a biocompatible
organic multi-acid or biocompatible salt thereof, (c) optionally a
photoinitiator or a thermal initiator, and (d) optionally one or
more vinylic monomers; (2) introducing an amount of the
polymerizable fluid composition in a mold for making the medical
device; and (3) actinically or thermally polymerizing the
polymerizable fluid composition in the mold to form the medical
device having a polymer network having at least one unit of formula
(I) and the biocompatible organic multi-acid or biocompatible salt
thereof which is not crosslinked to the polymer network, wherein
the biocompatible organic multi-acid or biocompatible salt thereof
is present in an amount effective to improve the stability of the
medical device so that the medical device has a decreased
susceptibility to oxidative degradation characterized by having at
least an 1.5-fold reduction of the amount of detectable formic acid
and optionally other degradation by-products.
13. The method of claim 12, wherein the medical device is an
ophthalmic device.
14. The method of claim 13, wherein the biocompatible organic
multi-acid is selected from the group consisting of hydroxy
diacids, hydroxy triacids, olefinic diacids, olefinic tri-acids,
and amino acids.
15. The method of claim 14, wherein the biocompatible organic
multi-acid is an .alpha.-oxo-multi-acid.
16. The method of claim 15, wherein the .alpha.-oxo-multi-acid is
selected from the group consisting of citric acid, 2-ketoglutaric
acid, and malic acid.
17. The method of claim 15, wherein the prepolymer is a
crosslinkable polyurea
18. The method of claim 15, wherein the prepolymer is a
crosslinkable polyurethane.
19. The method of claim 16, further comprising the steps of
removing the medical device from the mold and hydrating the medical
device in an aqueous solution containing the .alpha.-oxo-multi-acid
or biocompatible salt thereof.
20. The method of claim 19, wherein the aqueous solution has an
osmolarity of about 200 to 450 milli-osmole in 1000 ml (unit:
mOsm/ml).
21. The method of claim 15, further comprising a step of
sterilizing the medical device in an aqueous solution containing
the .alpha.-oxo-multi-acid or biocompatible salt thereof.
22. The method of claim 21, wherein the aqueous solution has an
osmolarity of about 200 to 450 milli-osmole in 1000 ml (unit:
mOsm/ml).
23. A method for producing a medical device, comprising the steps
of: (1) introducing a reactive mixture into a mold by using a
Reaction Injection Molding (RIM) process to form the medical
device, wherein the reactive mixture comprises (a) a monomer or
prepolymer having functional groups and at least one
poly(oxyalkylene) unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I) in which R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.4-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, wherein the
functional groups are amino, carboxy, hydroxy or isocyanato groups,
and (b) an organic diamine, an organic polyamine, an organic
diacid, an organic polyacid, an organic diol, an organic polyol, an
organic diisocyante, or organic polyisocyanate, provided that
components (a) and (b) react with each other to form a polyurea
and/or polyurethane network; (2) removing the medical device from
the mold; and (3) impregnating the medical device with a
biocompatible organic multi-acid or biocompatible salt thereof in
an amount effective to improve the stability of the medical device
so that the medical device has a decreased susceptibility to
oxidative degradation characterized by having at least an 1.5-fold
reduction of the amount of detectable formic acid and optionally
other degradation by-products.
24. The method of claim 23, wherein the medical device is an
ophthalmic device.
25. The method of claim 24, wherein the biocompatible organic
multi-acid is an .alpha.-oxo-multi-acid.
26. The method of claim 25, wherein the impregnating step is
achieved by immersing the medical device for a period of time in an
aqueous solution containing the .alpha.-oxo-multi-acid or
biocompatible salt thereof.
27. The method of claim 24, wherein the reactive mixture further
comprises one or more prepolymers having ethylenically unsaturated
groups or one or more vinylic monomers to form a different polymer
network which interpenetrates the polyurea and/or polyurethane
network.
28. A stabilized poly(oxyalkylene)-containing polymeric material,
comprising: (a) a polymer network having at least one unit of
formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I) wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.6-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000; and (b) a
biocompatible organic multi-acid or biocompatible salt thereof
present in an amount sufficient to improve the stability of the
poly(oxyalkylene)-containing polymeric material, which is
distributed within the polymeric material but not crosslinked to
the polymer network.
29. The stabilized poly(oxyalkylene)-containing polymeric material
of claim 28, wherein the biocompatible organic multi-acid is
selected from the group consisting of hydroxy diacids, hydroxy
triacids, and amino acids.
30. The stabilized poly(oxyalkylene)-containing polymeric material
of claim 28, wherein the biocompatible organic multi-acid is an
.alpha.-oxo-multi-acid.
31. The stabilized poly(oxyalkylene)-containing polymeric material
of claim 30, wherein the .alpha.-oxo-multi-acid is selected from
the group consisting of citric acid, 2-ketoglutaric acid, and malic
acid.
32. The stabilized poly(oxyalkylene)-containing polymeric material
of claim 30, wherein the stabilized poly(oxyalkylene)-containing
polymeric material is a copolymerization product of a composition
comprising: (a) a prepolymer containing ethylenically unsaturated
groups and at least one unit of formula (I); and (b) the
.alpha.-oxo-multi-acid or biocompatible salt thereof in an amount
effective to improve the stability of the medical device so that
the medical device has a decreased susceptibility to oxidative
degradation characterized by having at least an 1.5-fold reduction
of the amount of detectable formic acid and optionally other
degradation by-products.
33. The stabilized poly(oxyalkylene)-containing polymeric material
of claim 30, wherein the stabilized poly(oxyalkylene)-containing
polymeric material is a poly(oxyalkylene)-containing polymeric
material impregnated with the .alpha.-oxo-multi-acid or
biocompatible salt thereof in an amount effective to improve the
stability of the medical device so that the medical device has a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products, wherein
the poly(oxyalkylene)-containing polymeric material is a
copolymerization product of a composition comprising: (a) a
prepolymer containing ethylenically unsaturated groups and at least
one unit of formula (I) and (b) optionally one or more vinylic
monomers.
34. The stabilized poly(oxyalkylene)-containing polymeric material
of claim 30, wherein the stabilized poly(oxyalkylene)-containing
polymeric material is a poly(oxyalkylene)-containing polymeric
material impregnated with the .alpha.-oxo-multi-acid or
biocompatible salt thereof in an amount effective to improve the
stability of the medical device so that the medical device has a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products, wherein
the poly(oxyalkylene)-containing polymeric material is
polymerization product of a reactive mixture, wherein the reactive
mixture comprises (a) a monomer or prepolymer having at least one
poly(oxyalkylene) unit of formula (I) and functional groups which
are amino, carboxy, hydroxyl or isocyanato groups and (b) an
organic diamine, an organic polyamine, an organic diacid, an
organic polyacid, an organic diol, an organic polyol, an organic
diisocyante, or organic polyisocyanate, provided that components
(a) and (b) react with each other to form a polyurea and/or
polyurethane network.
35. A method for sterilizing a medical device having a core
material and/or a coating, wherein the core material and the
coating, independently of each other, are made of a
poly(oxyalkylene)-containing polymeric material, the method
comprising: autoclaving the medical device in a solution containing
a water-soluble and biocompatible organic multi-acid or
biocompatible salt thereof in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material,
so that the poly(oxyalkylene)-containing polymeric material has a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
36. The method of claim 35, wherein wherein the biocompatible
organic multi-acid is selected from the group consisting of hydroxy
diacids, hydroxy triacids, olefinic diacids, olefinic tri-acids,
and amino acids.
37. The method of claim 36, wherein the biocompatible organic
multi-acid is an .alpha.-oxo-multi-acid.
38. The method of claim 37, wherein the .alpha.-oxo-multi-acid is
selected from the group consisting of citric acid, 2-ketoglutaric
acid, and malic acid.
39. The method of claim 38, wherein the solution has an osmolarity
of from about 200 to 450 milli-osmole in 1000 ml (unit:
mOsm/ml).
40. An aqueous solution for sterilizing and/or storing an
ophthalmic device, wherein the ophthalmic device is made of a
poly(oxyalkylene)-containing polymeric material, the aqueous
solution having: a biocompatible organic multi-acid or
biocompatible salt thereof in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material;
an osmolarity of about 200 to 450 milli-osmole in 1000 ml (unit:
mOsm/ml), wherein the aqueous solution is capable of improving the
stability of the poly(oxyalkylene)-containing polymeric material,
so that the poly(oxyalkylene)-containing polymeric material has a
reduced susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
41. The aqueous solution of claim 40, wherein the osmolarity of the
aqueous solution is from about 250 to 350 mOsm/l.
Description
[0001] This application claims the benefits under 35 USC .sctn. 119
(e) of U.S. provisional application Nos. 60/429,719 filed Nov. 27,
2002 and 60/512,591 filed Oct. 17, 2003, incorporated by reference
in their entireties.
[0002] The present invention relates to stabilization of
poly(oxyalkylene)-containing polymeric materials. More
specifically, the present invention relates to a method for
stabilizing a poly(oxyalkylene)-containing polymeric material; a
method for making a medical device, preferably an ophthalmic
device, containing a stabilized poly(oxyalkylene)-containing
polymeric material; a method for sterilizing a medical device
having a core and/or a coating made of a
poly(oxyalkylene)-containing polymeric material, wherein the method
is characterized by having an improved stability of the
poly(oxyalkylene)-containing polymeric material. In addition, the
present invention relates to a stabilized
poly(oxyalkylene)-containing polymeric material; a medical device
comprising a core or a coating made of a stabilized
poly(oxyalkylene)-containing polymeric material; and a solution for
sterilizing and/or storing a medical device having a core or a
coating made of a poly(oxyalkylene)-containing polymeric material,
wherein the solution is capable of stabilizing the
poly(oxyalkylene)-containing polymeric material.
BACKGROUND OF THE INVENTION
[0003] Because of the biocompatibility of poly(alkyleneglycols),
also known as polyalkyl ethers or poly(alkylene oxide),
poly(oxyalkylene)-containing polymers can find use in various
fields, in particular in biomedical fields, such as, for example,
carriers for drug-delivery, artificial tissues, dentifrices,
contact lenses, intraocular lenses, and other biomedical devices.
(For a recent review of applications see the ACS Symposium Series
680, "Poly(ethyleneglycol): Chemistry and Biological Applications",
1997, Harris and Zalipsky, eds.) However,
poly(oxyalkylene)-containing polymers may be susceptible to
degradation, in particular, oxidative degradation of its
poly(oxyalkylene) chains under aerobic conditions. Oxidative
degradation may cause changes in the properties of an article made
from the poly(oxyalkylene)-containing polymers and limit the
applications of poly(oxyalkylene)-containing polymers.
[0004] Susceptibility to oxidative degradation of a
poly(oxyalkylene)-containing polymer can be effected by the method
used in preparation and purification, post-manufacturing process
(e.g., sterilization with autoclave, or the like), storage, and
use. It is generally believed that, under aerobic conditions, a
poly(oxyalkylene)-containing polymer may be degraded according to
the mechanism of a free-radical chain reaction involving an
oxidation step (see "Stability of the Polyoxyethylene Chain",
Donbrow, Max. Surfactant Sci. Ser. (1987), 23 (Nonionic
Surfactants), 1011-1072, and references contained therein). First,
homolytic degradation of the alkylene glycol chain in a
poly(oxyalkylene)-containing polymer is initiated photochemically,
thermally, or chemically (e.g., by actinic radiation including UV
radiation, ionizing radiation, or microwave, at elevated
temperatures, or with free-radical initiators, etc.), producing an
alkylene glycol radical. This radical undergoes spontaneous
oxidation under aerobic conditions to form peroxides and
hydroperoxides. The resulting peroxides and hydroperoxides may then
undergo a variety of subsequent reactions to yield by-products such
as formic acid, lower alcohols, and the like. For a contact lens
made from a poly(oxyalkylene)-containing polymer, the
poly(oxyalkylene) chain of the poly(oxyalkylene)-containing polymer
may be susceptible to oxidative degradation, leading to formation
of by-products such as formic acid and others. These by-products,
especially formic acid which can have irritating effects, are not
desirable, and thus need to be eliminated or minimized. Moreover, a
medical device made from a poly(oxyalkylene)-conta- ining polymer
may have a shorter shelf life because of oxidative degradation of
the poly(oxyalkylene)-containing polymer.
[0005] There have been attempts to stabilize
poly(oxyalkylene)-containing materials used for medical devices by
using antioxidants. For example, see U.S. Pat. Nos. 5,290,585,
5,160,790, 5,179,186, 5,367,001, 4,886,866 and 5,175,229, and EP
0333899B1. The antioxidants disclosed in those patents are hindered
phenolic compounds, such as butylated hydroxytoluene, tris
(3,5-di-t-butyl-4- hydroxy benzyl) isocyanurate, 2,2'-methylenebis
(4-methyl-6-t-lutyl phenol), 1,3,5-Trimethyl-2,4,6-tris
(3,5-di-t-butyl-4-hydroxybenzyl) benzene, octadecyl 3,5,
di-t-butyl-4-hydroxyhydrocinnamate, 4,4 methylenebis
(2,6-di-t-butylphenol), p,p-dioctyl diphenylamine,
1,1,3-tris-(2-methyl-4-hydroxy-5-t-butylphenyl) butane, Irganox
(Ciba Geigy), and Santonox (Monsanto Corp.). However, there are
some disadvantages associated with those antioxidants in the prior
art for stabilizing poly(oxyalkylene)-containing materials. Those
antioxidants may not be suitable for applications where the device
is remain in contact with living tissues for long periods of times
due to their cytotoxicity, or are water insoluble so that they can
not be used in a water-base formulation for making the
poly(oxyalkylene)-containing materials. Furthermore, those
antioxidants may not be efficient in stabilizing
poly(oxyalkylene)-containing materials and/or reducing the levels
of by-products such as formic acid, in case where the
poly(oxyalkylene)-containing materials are used to make contact
lenses or other medical devices.
[0006] Accordingly, there is still a need for a method for
stabilizing poly(oxyalkylene)-containing polymeric materials using
a biocompatible material. Such stabilized
poly(oxyalkylene)-containing polymeric materials can find
particular use in making a medical device which are in contact with
living cells or tissues.
SUMMARY OF THE INVENTION
[0007] One object of the invention is to provide a method for
stabilizing a poly(oxyalkylene)-containing polymeric material using
one or more biocompatible materials.
[0008] Another object of the invention is to provide a method for
producing a stabilized poly(oxyalkylene)-containing polymeric
material.
[0009] Still another object of the invention is to provide a method
or a composition for making a medical device from a stabilized
poly(oxyalkylene)-containing polymeric material.
[0010] A further object of the invention is to provide a stabilized
poly(oxyalkylene)-containing polymeric material and a medical
device made from a stabilized poly(oxyalkylene)-containing
polymeric material.
[0011] A still further object of the invention is to provide a
method for sterilizing a medical device made of a
poly(oxyalkylene)-containing polymeric material while improving the
stability of the poly(oxyalkylene)-containing polymeric
material.
[0012] These and other objects of the invention are met by the
various aspects of the invention described herein.
[0013] In accomplishing the foregoing, there is provided, in
accordance with one aspect of the present invention, a stabilized
poly(oxyalkylene)-containing polymeric material, which comprises:
(a) a polymer network having at least one unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I)
[0014] wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.6-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, preferably 5 to 500,
more preferably 5 to 200, even more preferably 8 to 120; and (b) a
biocompatible organic multi-acid or biocompatible salt thereof
present in an amount sufficient to improve the stability of the
poly(oxyalkylene)-containing polymeric material, wherein the
biocompatible organic multi-acid or biocompatible salt thereof is
distributed within the polymeric material but not crosslinked to
the polymer network. Preferably, the biocompatible organic
multi-acid or biocompatible salt thereof is present in an amount
effective to impart to the medical device a decreased
susceptibility to oxidative degradation characterized by having at
least an 1.5-fold reduction of the amount of detectable formic acid
and optionally other degradation by-products.
[0015] In another aspect, the present invention provides a medical
device comprising a poly(oxyalkylene)-containing polymeric material
and a biocompatible organic multi-acid or biocompatible salt
thereof present in an amount sufficient to improve the stability of
the poly(oxyalkylene)-containing polymeric material, wherein the
poly(oxyalkylene)-containing polymeric material has a polymer
network having at least one unit of formula (I), and wherein the
biocompatible organic multi-acid or biocompatible salt thereof is
distributed within the poly(oxyalkylene)-containing polymeric
material but not crosslinked to the polymer network. Preferably,
the biocompatible organic multi-acid or biocompatible salt thereof
is present in an amount effective to impart to the medical device a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
[0016] In still another aspect, the present invention provides a
method for producing a medical device, preferably an ophthalmic
device, more preferably a contact lens, made of a stabilized
poly(oxyalkylene)-contain- ing polymeric material, the method
comprising the steps of: (1) obtaining a polymerizable fluid
composition comprising (a) a prepolymer having at least one
poly(oxyalkylene) unit of formula (I) and ethylenically unsaturated
groups, (b) a biocompatible organic multi-acid or biocompatible
salt thereof, (c) optionally a photoinitiator or a thermal
initiator, and (d) optionally one or more vinylic monomers; (2)
introducing an amount of the polymerizable fluid composition in a
mold for making the medical device; and (3) actinically or
thermally polymerizing the polymerizable fluid composition in the
mold to form the medical device having a polymer network having at
least one unit of formula (I) and the biocompatible organic
multi-acid or biocompatible salt thereof which is not crosslinked
to the polymer network, wherein the biocompatible organic
multi-acid or biocompatible salt thereof is present in an amount
effective to improve the stability of the medical device so that
the medical device has a decreased susceptibility to oxidative
degradation characterized by having at least an 1.5-fold reduction
of the amount of detectable formic acid and optionally other
degradation by-products.
[0017] In a further aspect, the present invention provides a method
for producing a medical device, preferably an ophthalmic device,
more preferably a contact lens, made of a stabilized
poly(oxyalkylene)-contain- ing polymeric material, the method
comprising the steps of: (1) introducing a reactive mixture into a
mold for making the medical device by using a Reaction Injection
Molding (RIM) process to form the medical device, wherein the
reactive mixture comprises (a) at least one monomer or prepolymer
having at least one poly(oxyalkylene) unit of formula (I) and
functional groups which are amino, carboxy, hydroxyl or isocyanato
groups and (b) at least one of an organic diamine, an organic
polyamine, an organic diacid, an organic polyacid, an organic diol,
an organic polyol, an organic diisocyante, and organic
polyisocyanate, provided that components (a) and (b) react with
each other to form a polyurea and/or polyurethane network; (2)
removing the medical device from the mold; and (3) impregnating the
medical device with a biocompatible organic multi-acid or
biocompatible salt thereof in an amount effective to improve the
stability of the medical device so that the medical device has a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
[0018] In another further aspect, the present invention provides a
method for sterilizing a medical device which comprises a core
material and/or a coating, wherein the core material and the
coating, independently from each other, are made of a
poly(oxyalkylene)-containing polymeric material, the method
comprising: autoclaving the medical device in an aqueous solution
containing a biocompatible organic multi-acid or biocompatible salt
thereof in an amount sufficient to improve the stability of the
poly(oxyalkylene)-containing polymeric material, so that the
poly(oxyalkylene)-containing polymeric material has a decreased
susceptibility to oxidative degradation characterized by having at
least an 1.5-fold reduction of the amount of detectable formic acid
and optionally other degradation by-products.
[0019] In still a further aspect, the present invention provides an
aqueous solution for sterilizing and/or storing an ophthalmic
device, wherein the ophthalmic device is made of a
poly(oxyalkylene)-containing polymeric material, the aqueous
solution having: a biocompatible organic multi-acid or
biocompatible salt thereof in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material;
an osmolarity of about 200 to 450 milli-osmole in 1000 ml (unit:
mOsm/ml), wherein the aqueous solution is capable of improving the
stability of the poly(oxyalkylene)-containing polymeric material,
so that the poly(oxyalkylene)-containing polymeric material has a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
[0020] These and other aspects of the invention will become
apparent from the following description of the preferred
embodiments. As would be obvious to one skilled in the art, many
variations and modifications of the invention may be effected
without departing from the spirit and scope of the novel concepts
of the disclosure.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] Reference now will be made in detail to the embodiments of
the invention. It will be apparent to those skilled in the art that
various modifications and variations can be made in the present
invention without departing from the scope or spirit of the
invention. For instance, features illustrated or described as part
of one embodiment, can be used on another embodiment to yield a
still further embodiment. Thus, it is intended that the present
invention cover such modifications and variations as come within
the scope of the appended claims and their equivalents. Other
objects, features and aspects of the present invention are
disclosed in or are obvious from the following detailed
description. It is to be understood by one of ordinary skill in the
art that the present discussion is a description of exemplary
embodiments only, and is not intended as limiting the broader
aspects of the present invention.
[0022] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs.
Generally, the nomenclature used herein and the laboratory
procedures are well known and commonly employed in the art.
Conventional methods are used for these procedures, such as those
provided in the art and various general references. Where a term is
provided in the singular, the inventors also contemplate the plural
of that term. The nomenclature used herein and the laboratory
procedures described below are those well known and commonly
employed in the art.
[0023] An "article" refers to a medical device or a mold for making
a medical device.
[0024] A "medical device", as used herein, refers to a device or a
part thereof having one or more surfaces that contact tissue,
blood, or other bodily fluids of patients in the course of their
operation or utility. Exemplary medical devices include: (1)
extracorporeal devices for use in surgery such as blood
oxygenators, blood pumps, blood sensors, tubing used to carry blood
and the like which contact blood which is then returned to the
patient; (2) prostheses implanted in a human or animal body such as
vascular grafts, stents, pacemaker leads, heart valves, and the
like that are implanted in blood vessels or in the heart; (3)
devices for temporary intravascular use such as catheters, guide
wires, and the like which are placed into blood vessels or the
heart for purposes of monitoring or repair; (4) artificial tissues
such as artificial skin for burn patients; (5) dentifrices, dental
moldings; (6) ophthalmic devices. In a preferred embodiment,
medical devices are ophthalmic devices; and (7) cases or containers
for storing ophthalmic devices or ophthalmic solutions.
[0025] An "ophthalmic device", as used herein, refers to a contact
lens (hard or soft), an intraocular lens, a corneal onlay, other
ophthalmic devices (e.g., stents, or the like) used on or about the
eye or ocular vicinity.
[0026] "Biocompatible", as used herein, refers to a material or
surface of a material, which may be in intimate contact with
tissue, blood, or other bodily fluids of a patient for an extended
period of time without significantly damaging the ocular
environment and without significant user discomfort.
[0027] "Ophthalmically compatible", as used herein, refers to a
material or surface of a material which may be in intimate contact
with the ocular environment for an extended period of time without
significantly damaging the ocular environment and without
significant user discomfort. Thus, an ophthalmically compatible
contact lens will not produce significant corneal swelling, will
adequately move on the eye with blinking to promote adequate tear
exchange, will not have substantial amounts of protein or lipid
adsorption, and will not cause substantial wearer discomfort during
the prescribed period of wear.
[0028] "Ocular environment", as used herein, refers to ocular
fluids (e.g., tear fluid) and ocular tissue (e.g., the cornea)
which may come into intimate contact with a contact lens used for
vision correction, drug delivery, wound healing, eye color
modification, or other ophthalmic applications.
[0029] A "monomer" means a low molecular weight compound that can
be polymerized. Low molecular weight typically means average
molecular weights less than 700 Daltons.
[0030] A "vinylic monomer", as used herein, refers to a low
molecular weight compound that has an ethylenically unsaturated
group and can be polymerized actinically or thermally. Low
molecular weight typically means average molecular weights less
than 700 Daltons. Exemplary ethylenically unsaturated groups
include without limitation acryloyl, methacryloyl, allyl, vinyl,
styrenyl, or other C.dbd.C containing groups.
[0031] A "hydrophilic vinylic monomer", as used herein, refers to a
vinylic monomer which as a homopolymer typically yields a polymer
that is water-soluble or can absorb at least 10 percent by weight
water.
[0032] A "hydrophobic vinylic monomer", as used herein, refers to a
vinylic monomer which as a homopolymer typically yields a polymer
that is insoluble in water and can absorb less than 10 percent by
weight water.
[0033] A "macromer" refers to a medium and high molecular weight
compound or polymer that contains functional groups capable of
undergoing further polymerizing/crosslinking reactions. Medium and
high molecular weight typically means average molecular weights
greater than 700 Daltons. Preferably, a macromer contains
ethylenically unsaturated groups and can be polymerized actinically
or thermally.
[0034] A "polymer" means a material formed by
polymerizing/crosslinking one or more monomers.
[0035] A "prepolymer" refers to a starting polymer which can be
cured (e.g., crosslinked and/or polymerized) actinically or
thermally or chemically to obtain a crosslinked and/or polymerized
polymer having a molecular weight much higher than the starting
polymer.
[0036] Preferably, a prepolymer contains ethylenically unsaturated
groups and can be polymerized actinically or thermally.
[0037] As used herein, "actinically" in reference to curing or
polymerizing of a polymerizable composition or material means that
the curing (e.g., crosslinked and/or polymerized) is performed by
actinic irradiation, such as, for example, UV irradiation, ionized
radiation (e.g. gamma ray or X-ray irradiation), and microwave
irradiation.
[0038] A "photoinitiator" refers to a chemical that initiates
radical crosslinking/polymerizing reaction by the use of light.
Suitable photoinitiators include, without limitation, benzoin
methyl ether, diethoxyacetophenone, a benzoylphosphine oxide,
1-hydroxycyclohexyl phenyl ketone, Darocure.RTM. types, and
Irgacure.RTM. types, preferably Darocure.RTM. 1173, and
Irgacure.RTM. 2959.
[0039] A "thermal initiator" refers to a chemical that initiates
radical crosslinking/polymerizing reaction by the use of heat
energy. Examples of suitable thermal initiators include, but are
not limited to, 2,2'-azobis (2,4-dimethylpentanenitrile),
2,2'-azobis (2-methylpropanenitrile), 2,2'-azobis
(2-methylbutanenitrile), peroxides such as benzoyl peroxide, and
the like. Preferably, the thermal initiator is azobisisobutyronite
(AIBN).
[0040] A "stabilized poly(oxyalkylene)-containing polymeric
material" means that a poly(oxyalkylene)-containing polymeric
material, which is prepared from a composition comprising a
stabilizer and/or subjected to a sterilization treatment in a
solution containing the stabilizer, is less susceptible to
oxidative degradation (i.e., characterized by the amount of
detectable formic acid and optionally other degradation by-products
in a stabilized poly(oxyalkylene)-containing polymeric material
being 80% or less, preferably 65% or less, more preferably 50% or
less, of that detected in a non-stabilized
poly(oxyalkylene)-containing polymeric material). A "non-stabilized
poly(oxyalkylene)-containing polymeric material" means that a
poly(oxyalkylene)-containing polymeric material, which is prepared
from a composition without the stabilizer and/or subjected to a
sterilization treatment in a solution without the stabilizer.
[0041] "Improve the stability of a poly(oxyalkylene)-containing
polymeric material" means that the susceptibility to oxidative
degradation of a poly(oxyalkylene)-containing polymeric material,
which is prepared from a composition comprising a stabilizer and/or
subjected to a sterilization treatment in a solution containing the
stabilizer, is reduced (characterized by the amount of detectable
formic acid and optionally other degradation by-products in a
stabilized poly(oxyalkylene)-containin- g polymeric material being
smaller than that detected in a non-stabilized corresponding
poly(oxyalkylene)-containing polymeric material). The amount of
detectable formic acid and optionally other degradation by-products
derived from oxidative degradation of a
poly(oxyalkylene)-containing polymeric material can be determined
by any known suitable methods, such as, for example, ion-exchange
chromatography described in Examples.
[0042] A "decreased susceptibility to oxidative degradation" in
reference to a poly(oxyalkylene)-containing polymeric material or a
medical device comprising a poly(oxyalkylene)-containing polymeric
material means that its susceptibility to oxidative degradation is
decreased by having a stabilizer therein. Typically, a decreased
susceptibility to oxidative degradation of a
poly(oxyalkylene)-containing polymeric material or a medical device
comprising a poly(oxyalkylene)-containing polymeric material is
characterized by having a stabilizer-induced reduction (preferably
at least an 1.5-fold reduction, more preferably at least a 3-fold
reduction, even more preferably at least a 5-fold reduction, most
preferably at least a 1 0-fold reduction) of the amount of
detectable formic acid and optionally other degradation by-products
derived from oxidative degradation of the
poly(oxyalkylene)-containing polymeric material. An "X-fold
reduction of the amount of detectable formic acid and optionally
other degradation by-products" means that, when comparing a
stabilized poly(oxyalkylene)-containing polymeric material (or a
stabilized medical device containing a stabilizer) with a
corresponding non-stabilized poly(oxyalkylene)-containing polymeric
material (or a non-stabilized medical device without a stabilizer),
the amount of detectable formic acid and optionally other
degradation by-products in the non-stabilized
poly(oxyalkylene)-containing polymeric material (or the
non-stabilized medical device) is at least X folds of the amount of
detectable formic acid and optionally other degradation by-products
in the stabilized poly(oxyalkylene)-containing polymeric material
(or the stabilized medical device).
[0043] An "interpenetrating polymer network (IPN)" as used herein
refers broadly to an intimate network of two or more polymers at
least one of which is either synthesized and/or crosslinked in the
presence of the other(s). Techniques for preparing IPN are known to
one skilled in the art. For a general procedure, see U.S. Pat. Nos.
4,536,554, 4,983,702, 5,087,392, and 5,656,210, the contents of
which are all incorporated herein by reference. The polymerization
is generally carried out at temperatures ranging from about room
temperature to about 145.degree. C.
[0044] The present invention generally relates to a stabilized
poly(oxyalkylene)-containing polymeric material and methods for
making the same.
[0045] In one aspect, the present invention provides a stabilized
poly(oxyalkylene)-containing polymeric material. A stabilized
poly(oxyalkylene)-containing polymeric material of the invention
comprises: (a) a polymer network having at least one unit of
formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I)
[0046] wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.6-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, preferably 5 to 500,
more preferably 5 to 200, even more preferably 8 to 120; and (b) a
biocompatible organic multi-acid or biocompatible salt thereof
present in an amount sufficient to improve the stability of the
poly(oxyalkylene)-containing polymeric material, which is
distributed within the polymeric material but not crosslinked to
the polymer network.
[0047] In accordance with the present invention, a
poly(oxyalkylene)-conta- ining polymeric material can be any
polymer which is a reaction product of a mixture including a
poly(oxyalkylene) polymer with functional groups (e.g., amino,
hydroxyl, acid, or isocyanato groups) and at least a chemical with
functional groups (e.g., amino, hydroxyl, isocyanato, or acid
groups) which are co-reactive with the functional groups of
poly(oxyalkylene) polymer. Examples of such polymer include without
limitation: (1) a polyester obtained by esterification of the
terminal diols of a hydroxy terminated (diols)
poly(oxyalkylene)-containing polymer with organic monoacids or
diacids such as, for example, glutaric or adipic acids; (2) a
polyamide obtained by reacting an amine terminated
poly(oxyalkylene)-containing polymer with organic monoacids or
diacids acids such as, for example, glutaric or adipic acids; (3) a
polyurethane which is the copolymerization product of a mixture
comprising one or more hydroxyl (or isocyanate)-terminated
poly(oxyalkylene)-containing polymer and one or more organic di- or
polyisocyanates (or diols or polyols); (4) a polyurea which is the
copolymerization product of a mixture comprising one or more amine
(or isocyanate)-terminated poly(oxyalkylene)-containing polymer and
one or more di- or multi-isocyanates (or diamines or polyamines);
and a polyurea/polyurethane which is the copolymerization product
of a mixture comprising one or more amine or hydroxy-terminated
poly(oxyalkylene)-containing polymer, one or more di- or
multi-isocyanates and one or more organic di-or polyamines (or di-
or polyols). The above examples have been given as a means of
illustrating the aspects of the invention and are not limiting in
any way. It should be understood that a
poly(oxyalkylene)-containing polymeric material can also contain
one or more silicone and/or fluorine atoms.
[0048] In accordance with the present invention, a
poly(oxyalkylene)-conta- ining polymeric material can also be an
interpenetrating or semi-interpenetrating polymer network.
Exemplary interpenetrating polymer networks are interpenetrating
polyurea/polyacrylic networks disclosed in EP 0735097 B1. Such
interpenetrating polyurea/polyacrylic networks are formed by
polymerizing a reactive mixture comprising: (a) at least one
amine-terminated poly(alkylene glycol); (b) an organic di- or
polyisocyanate which reacts with (a) to form a polyurea network;
(c) an acrylic ester; (d) a free radical initiator to polymerize
(c) to form a polyacrylic network; and (e) a triamine to crosslink
(a).
[0049] Exemplary poly(alkylene glycol), include, but are not
limited to, a poly(ethylene glycol), a poly(1-propylene glycol), a
poly(2-propylene glycol), a poly(ethylene glycol)/poly(propylene
glycol) block polymer, a poly(ethylene glycol)/poly(propylene
glycol )/poly(butylene glycol) block polymer, a
polytetrahydrofuran, a poloxamer, and the like.
[0050] In accordance with the present invention, a stabilized
poly(oxyalkylene)-containing polymeric material has a decreased
susceptibility to oxidative degradation, characterized by having
preferably at least an 1.5-fold reduction of, more preferably at
least a 3-fold reduction, even more preferably at least a 5-fold
reduction of, most preferably at least 10-fold reduction of the
amount of detectable formic acid and optionally other degradation
by-products.
[0051] Any known suitable organic multi-acids or biocompatible
salts thereof, which are water-soluble, non-toxic, biocompatible,
and capable of stabilizing poly(oxyalkylene) chains in the presence
of UV light or free radical sources or at high temperatures.
Exemplary organic multi-acids suitable for the present invention
include, but are not limited to, hydroxy diacids, hydroxy
multi-acids, amino acids, and the like. Preferably, an organic
multi-acid of the present invention is an .alpha.-oxo-multi-acid,
such as, for example, citric acid, 2-ketoglutaric acid, or malic
acid. More preferably, an organic multi-acid is citric or malic
acid. Biocompatible (preferably ophthalmically compatible) salts of
organic multi-acids suitable for the present invention include
sodium, potassium, and ammonium salts.
[0052] As used herein, an "alpha-oxo-multiacid" refers to an acid
which has a plurality (two or more) of carboxyl groups and at least
one carbon atom which is simultaneously substituted by a carboxyl
group and an oxygen atom, i.e., O--C--COOR, wherein the oxygen
could be a carbonyl, a hydroxy, an esterified hydroxy, an ether, or
the like, and wherein the oxygen is on the carbon which is alpha to
the carboxyl group.
[0053] In accordance with the present invention, a biocompatible
organic multi-acid or biocompatible salt thereof can be introduced
into a stabilized poly(oxyalkylene)-containing polymeric material
either by adding it into a pre-polymerization composition for
making the poly(oxyalkylene)-containing polymeric material and/or
by immersing a poly(oxyalkylene)-containing polymeric material in a
solution containing the biocompatible organic multi-acid or
biocompatible salt thereof (i.e., impregnation of the
poly(oxyalkylene)-containing polymeric material with the
biocompatible organic multi-acid or biocompatible salt thereof.
[0054] The concentration of a biocompatible organic multi-acid or
biocompatible salt thereof in a pre-polymerization composition for
making a stabilized poly(oxyalkylene)-containing polymeric material
or in a solution for impregnation of the
poly(oxyalkylene)-containing polymeric material with the
biocompatible organic multi-acid or biocompatible salt thereof is
preferably from 0.001 millimolar to the solubility limit of a
particular biocompatible organic multi-acid or biocompatible salt
thereof, more preferentially from 10 to 300 millimolar. It is
understood that the weight percentages will change based on the
molecular weight of the acid employed.
[0055] In a preferred embodiment, a stabilized
poly(oxyalkylene)-containin- g polymeric material of the invention
is a copolymerization product of a composition comprising:
[0056] (a) a prepolymer containing ethylenically unsaturated groups
and at least one unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I)
[0057] wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.4-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, preferably 5 to 500,
more preferably 5 to 200, even more preferably 8 to 120;
[0058] (b) a water-soluble and biocompatible organic multi-acid or
biocompatible salt thereof in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material
made from the composition;
[0059] (c) optionally a photoinitiator or a thermal initiator;
and
[0060] (d) optionally one or more vinylic monomers.
[0061] In another preferred embodiment, a stabilized
poly(oxyalkylene)-containing polymeric material of the invention is
a poly(oxyalkylene)-containing polymeric material impregnated with
a biocompatible organic multi-acid or biocompatible salt thereof in
an amount sufficient to improve the stability of the
poly(oxyalkylene)-conta- ining polymeric material, wherein the
poly(oxyalkylene)-containing polymeric material is a
copolymerization product of a composition comprising:
[0062] (a) a prepolymer containing ethylenically unsaturated groups
and at least one unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--
(I)
[0063] wherein R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.4-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, preferably 5 to 500,
more preferably 5 to 200, even more preferably 8 to 120;
[0064] (b) optionally a photoinitiator or a thermal initiator;
and
[0065] (c) optionally one or more vinylic monomers.
[0066] Impregnation of a poly(oxyalkylene)-containing polymeric
material can be performed according to any known suitable methods,
for example, such as immersing the poly(oxyalkylene)-containing
polymeric material in a solution containing a biocompatible organic
multi-acid or biocompatible salt thereof.
[0067] A prepolymer having at least one unit of formula (I) and
ethylenically unsaturated groups can be prepared according to any
methods known to a person skilled in the art. For example,
ethylenically unsaturated groups, such as, for example, acryloyl,
methacryloyl, allyl, vinyl, styrenyl, or other C.dbd.C containing
groups, could be covalently attached to the poly(alkylene glycol)
moiety according to any method known to a person skilled in the
art.
[0068] One example of such prepolymer is a crosslinkable polyurea
polymer described in U.S. Pat. No. 6,479,587, herein incorporated
by reference in its entirety. Such crosslinkable polyurea polymer
can be prepared by introducing ethylenically unsaturated groups
into a polyurea which is the copolymerization product of a reaction
mixture including at least one amine-terminated poly(alkylene
glycol) and an organic di- or polyisocyanate.
[0069] A further example is a crosslinkable polyurethane described
in U.S. patent application Ser. No. 10/640,294 filed on Aug. 13,
2003 (herein incorporated by reference in its entirety). Such
crosslinkable polyurethane polymer can be prepared by introducing
ethylenically unsaturated groups into an isocyanate-capped
polyurethane which is the copolymerization product of a reaction
mixture including at least one hydroxy-terminated poly(alkylene
glycol) and an organic di- or polyisocyanate.
[0070] The vinylic monomer which may be additionally used for
photo-crosslinking in accordance with the invention may be
hydrophilic, hydrophobic or may be a mixture of a hydrophobic and a
hydrophilic vinylic monomer. Suitable vinylic monomers include
especially those normally used for the manufacture of contact
lenses.
[0071] It is preferable to use a hydrophobic vinylic monomer, or a
mixture of a hydrophobic vinylic monomer with a hydrophilic vinylic
monomer, whereby this mixture contains at least 50 percent by
weight of a hydrophobic vinyl monomer. In this way, the mechanical
properties of the polymer may be improved without the water content
dropping substantially. Both conventional hydrophobic vinylic
monomers and conventional hydrophilic vinylic monomers are suitable
for copolymerization with the radiation-curable prepolymers
according to the invention.
[0072] Suitable hydrophobic vinylic monomers include, without
limitation; C.sub.1-C.sub.18-alkylacrylates and -methacrylates,
C.sub.3-C.sub.18 alkylacrylamides and -methacrylamides,
acrylonitrile, methacrylonitrile,
vinyl-C.sub.1-C.sub.18-alkanoates, C.sub.2-C.sub.18-alkenes,
C.sub.2-C.sub.18-halo-alkenes, styrene,
C.sub.1-C.sub.6-alkylstyrene, vinylalkylethers in which the alkyl
moiety has 1 to 6 carbon atoms,
C.sub.2-C.sub.10-perfluoralkyl-acrylates and -methacrylates or
correspondingly partially fluorinated acrylates and methacrylates,
C.sub.3-C.sub.12-perfluoralkyl-ethyl-thiocarbonylaminoethyl-acrylates
and -methacrylates, acryloxy and methacryloxy-alkylsiloxanes,
N-vinylcarbazole, C.sub.1-C.sub.12-alkylesters of maleic acid,
fumaric acid, itaconic acid, mesaconic acid and the like.
Preference is given e.g. to C.sub.1-C.sub.4-alkylesters of
vinylically unsaturated carboxylic acids with 3 to 5 carbon atoms
or vinylesters of carboxylic acids with up to 5 carbon atoms.
[0073] Examples of suitable hydrophobic vinylic monomers include
methylacrylate, ethyl-acrylate, propylacrylate, isopropylacrylate,
cyclohexylacrylate, 2-ethylhexylacrylate, methylmethacrylate,
ethylmethacrylate, propylmethacrylate, vinyl acetate, vinyl
propionate, vinyl butyrate, vinyl valerate, styrene, chloroprene,
vinyl chloride, vinylidene chloride, acrylonitrile, 1-butene,
butadiene, methacrylonitrile, vinyl toluene, vinyl ethyl ether,
perfluorohexylethyl-thio-carbonyl-aminoethyl-methacrylate,
isobornyl methacrylate, trifluoroethyl methacrylate,
hexafluoro-isopropyl methacrylate, hexafluorobutyl methacrylate,
tris-trimethylsilyloxy-silyl-- propyl methacrylate,
3-methacryloxypropyl-pentamethyl-disiloxane and
bis(methacryloxypropyl)-tetramethyl-disiloxane.
[0074] Suitable hydrophilic vinylic monomers include, without
limitation, hydroxy-substituted lower alkylacrylates and
-methacrylates, acrylamide, methacrylamide, lower alkyl-acrylamides
and -methacrylamides, ethoxylated acrylates and methacrylates,
hydroxy-substituted lower alkyl-acrylamides and -methacrylamides,
hydroxy-substituted lower alkylvinyl-ethers, sodium ethylene
sulphonate, sodium styrene sulphonate, 2-acrylamido-2-methyl-pro-
pane-sulphonic acid, N-vinyl pyrrole, N-vinyl succinimide, N-vinyl
pyrrolidone, 2- or 4-vinyl pyridine, acrylic acid, methacrylic
acid, amino- (whereby the term "amino" also includes quaternary
ammonium), mono-lower-alkylamino- or
di-lower-alkylamino-lower-alkyl-acrylates and -methacrylates, allyl
alcohol and the like. Preference is given e.g. to
hydroxy-substituted C.sub.2-C.sub.4-alkyl(meth)acrylates, five- to
seven-membered N-vinyl-lactams,
N,N-di-C.sub.1-C.sub.4-alkyl-methacrylami- des and vinylically
unsaturated carboxylic acids with a total of 3 to 5 carbon
atoms.
[0075] Examples of suitable hydrophilic vinylic monomers include
hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylamide,
methacrylamide, dimethylacrylamide, allyl alcohol, vinyl pyridine,
vinyl pyrrolidone, glycerol methacrylate,
N-(1,1-dimethyl-3-oxobutyl)acrylamide- , and the like.
[0076] Preferred hydrophobic vinylic monomers are methyl
methacrylate and vinyl acetate. Preferred hydrophilic vinylic
monomers are 2-hydroxyethyl methacrylate, N-vinyl pyrrolidone and
acrylamide.
[0077] A photo-initiator or thermal initiator is advantageously
added to a composition of the invention. The amount of
photo-initiator may be selected from a wide range, whereby an
amount of up to 0.05 g/g polymer and especially up to 0.003 g/g
polymer has proved favorable.
[0078] A composition of the invention can further comprise a color
additive which is capable of creating a light colored visibility
tint. Such tint can facilitate the handling of ophthalmic lenses.
Any known suitable color additives can be used. Preferably, copper
phthalocyanin is used as a color additive which is capable of
creating a light blue or light green or other light color
visibility tint.
[0079] A composition of the invention can optionally comprise other
additives, such as, for example, a crosslinking agent, an
antimicrobial agents, and/or the like.
[0080] Preferably, a composition of the invention is a water-based
composition.
[0081] Optionally a solvent may be present in a composition of the
invention. Any known suitable solvents can be used. Exemplary
solvents include, but are not limited to, alcohols, such as lower
alkanols, for example ethanol or methanol, and furthermore
carboxylic acid amides, such as dimethylformamide, dipolar aprotic
solvents, such as dimethyl sulfoxide or methyl ethyl ketone,
ketones, for example acteone or cyclohexanone, hydrocarbons, for
example toluene, ethers, for example THF, dimethoxyethane or
dioxane, and halogenated hydrocarbons, for example trichloroethane,
and also mixtures of suitable solvents, for example mixtures of
water with an alcohol, for example a water/ethanol or a
water/methanol mixture. A person skilled in the art will know how
to select a solvent.
[0082] A composition of the invention for preparing a stabilized
poly(oxyalkylene)-containing polymeric material can find use in
making a medical device, preferably an ophthalmic device, more
preferably a contact lens.
[0083] In another aspect, the present invention provides a method
for producing a medical device, preferably an ophthalmic device,
more preferably a contact lens, made of a stabilized
poly(oxyalkylene)-contain- ing polymeric material, the method
comprising the steps of: (1) obtaining a polymerizable fluid
composition comprising (a) a prepolymer having at least one
poly(oxyalkylene) unit of formula (I) and ethylenically unsaturated
groups, (b) a biocompatible organic multi-acid or biocompatible
salt thereof, (c) optionally a photoinitiator or a thermal
initiator, and (d) optionally one or more vinylic monomers; (2)
introducing an amount of the polymerizable fluid composition in a
mold for making the medical device; and (3) actinically or
thermally polymerizing the polymerizable fluid composition in the
mold to form the medical device having a polymer network having at
least one unit of formula (I) and the biocompatible organic
multi-acid or biocompatible salt thereof which is not crosslinked
to the polymer network, wherein the biocompatible organic
multi-acid or biocompatible salt thereof is present in an amount
effective to improve the stability of the medical device so that
the medical device has a decreased susceptibility to oxidative
degradation characterized by having at least an 1.5-fold reduction
of the amount of detectable formic acid and optionally other
degradation by-products.
[0084] The polymerizable fluid composition can be introduced into a
mold by methods known per se, especially conventional dispensing,
e.g. dropwise addition in a desired quantity.
[0085] Appropriate disposable molds are made, for example, from
polypropylene. Suitable materials for re-usable mounds are e.g.
quartz, sapphire glass or metals.
[0086] If the molded articles to be produced are contact lenses,
these may be produced in a manner known per se, e.g. in a
conventional "spin-casting mold", as described for example in U.S.
Pat. No. 3,408,429, or by the so-called full mold process in a
static form, as described e.g. in U.S. Pat. Nos. 4,347,198,
5,508,317, 5,583,463, 5,789,464, and 5,849,810.
[0087] Crosslinking/polymerizing of the composition may be
initiated in the mold actinically (e.g. by means of actinic
radiation, such as UV irradiation, gamma or X-ray irradiation) or
thermally.
[0088] Opening of the mold so that the molded article can be
removed from the mold may take place in a manner known per se.
[0089] If the molded article produced according to the invention is
a contact lens which is produced solvent-free from an already
purified crosslinkable prepolymer in the absence of vinylic
monomers according to the invention, then after removal of the
molded article, it is not normally necessary to follow up with
purification steps such as extraction. This is because the
prepolymers employed do not contain any undesired constituents of
low molecular weight; consequently, the crosslinked product is also
free or substantially free from such constituents and subsequent
extraction can be dispensed with. Accordingly, the contact lens can
be directly transformed in the usual way, by hydration, into a
ready-to-use contact lens. Appropriate embodiments of hydration are
known to the person skilled in the art, whereby ready-to-use
contact lenses with very varied water content may be obtained. The
contact lens (in particular, a hydrogel contact lens) is expanded,
for example, in water, in an aqueous salt solution, especially an
aqueous salt solution having an osmolarity of about 200 to 450
milli-osmole in 1000 ml (unit: mOsm/ml), preferably about 250 to
350 mOsm/l and especially about 300 mOsm/l, or in a mixture of
water or an aqueous salt solution with a physiologically compatible
polar organic solvent, e.g. glycerol. Preference is given to
expansions of the article in water or in aqueous salt
solutions.
[0090] The aqueous salt solutions used for hydration are
advantageously solutions of physiologically compatible salts, such
as buffer salts conventionally used in the field of contact lens
care, e.g. phosphate salts, or isotonizing agents conventionally
used in the field of contact lens care, such as in particular
alkali halides, e.g. sodium chloride, or solutions of mixtures
thereof. One example of an especially suitable salt solution is an
artificial, preferably buffered lachrymal fluid, which is adapted
to natural lachrymal fluid as regards pH value and osmolarity, e.g.
an unbuffered or preferably buffered common salt solution, for
example buffered by phosphate buffer, whose osmolarity and pH value
correspond to the osmolarity and pH value of human lachrymal
fluid.
[0091] The aqueous salt solutions used for hydration preferably
contain biocompatible organic multi-acids or biocompatible salts
thereof in an amount sufficient to improve the stability of the
poly(oxyalkylene)-conta- ining polymer made from the
composition.
[0092] The above-defined hydration fluids are preferably at least
substantially free from undesired constituents. This is most
preferably pure water or an artificial lachrymal fluid as described
above.
[0093] If the molded article produced according to the invention is
a contact lens which is produced from an aqueous solution of an
already purified crosslinkable prepolymer in the absence of vinylic
monomers according to the invention, then the crosslinked product
is likely not to contain any impurities. It is therefore not
necessary to carry out subsequent extraction. Since crosslinking is
carried out in an essentially aqueous solution, it is additionally
unnecessary to carry out subsequent hydration. The contact lenses
obtained by this process are therefore notable, according to an
advantageous embodiment, for the fact that they are suitable for
their intended usage without extraction. By intended usage is
understood, in this context, that the contact lenses can be used in
the human eye.
[0094] The contact lenses obtained according to the invention have
a low susceptibility to oxidative degradation, characterized by
having a reduced amount of formic acid and/or other degradation
by-products detected in the contact lenses. They may have a longer
shelf life. Moreover, because of reduction in the formation of
formic acid, the contact lenses obtained according to the invention
may not cause irritation to the eyes of a wearer.
[0095] Of course, all the above-mentioned advantages apply not only
to contact lenses, but also to other molded articles according to
the invention, for example, an implantable medical device obtained
according to the invention. The total of the different advantageous
aspects during production of the molded articles according to the
invention leads to the suitability of the molded articles in
particular as mass-produced articles, for example, as contact
lenses which are for daily use and/or for weekly use.
[0096] In still another aspect, the present invention provides a
method for producing a medical device, preferably an ophthalmic
device, more preferably a contact lens, made of a stabilized
poly(oxyalkylene)-contain- ing polymeric material, the method
comprising the steps of: (1) introducing a reactive mixture into a
mold for making the medical device by using a Reaction Injection
Molding (RIM) process to form the medical device, wherein the
reactive mixture comprises (a) a monomer or prepolymer having at
least one poly(oxyalkylene) unit of formula (I) and functional
groups which are amino, carboxy, hydroxyl or isocyanato groups and
(b) an organic diamine, an organic polyamine, an organic diacid, an
organic polyacid, an organic diol, an organic polyol, an organic
diisocyante, or organic polyisocyanate, provided that components
(a) and (b) react with each other to form a polyurea and/or
polyurethane network; (2) removing the medical device from the
mold; and (3) impregnating the medical device with a biocompatible
organic multi-acid or biocompatible salt thereof in an amount
effective to improve the stability of the medical device so that
the medical device has a decreased susceptibility to oxidative
degradation characterized by having at least an 1.5-fold reduction
of the amount of detectable formic acid and optionally other
degradation by-products.
[0097] The RIM process is a known molding process wherein two or
more streams of monomers react in the mold to form a polymer; and
is well described by L. T. Manzione in The Encyclopedia of Polymer
Science and Engineering; 2nd Edition Vol 14, pg. 72, herein
incorporated by reference in its entirety.
[0098] In a preferred embodiment, the reactive mixture can further
comprise one or more prepolymers having ethylenically unsaturated
groups or one or more vinylic monomers to form a different polymer
network which interpenetrate with the polyurea and/or polyurethane
network.
[0099] In a further aspect, the present invention provides a
medical device comprising a poly(oxyalkylene)-containing polymeric
material and a biocompatible organic multi-acid or biocompatible
salt thereof present in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material,
wherein the poly(oxyalkylene)-containing polymeric material has a
polymer network having at least one unit of formula (I)
--O--(R.sub.1--O).sub.n--(R.sub.2--O).sub.m--(R.sub.3--O).sub.p--(I)
[0100] in which R.sub.1, R.sub.2, and R.sub.3, independently of one
other, are each linear or branched C.sub.2-C.sub.6-alkylene, and n,
m and p, independently of one another, are each a number from 0 to
100, wherein the sum of (n+m+p) is 5 to 1000, preferably 5 to 500,
more preferably 5 to 200, even more preferably 8 to 120, and
wherein the biocompatible organic multi-acid or biocompatible salt
thereof is distributed within the poly(oxyalkylene)-containing
polymeric material but not crosslinked to the polymer network. The
biocompatible organic multi-acid or biocompatible salt thereof is
present in an amount effective to improve the stability of the
medical device so that the medical device has a decreased
susceptibility to oxidative degradation characterized by having
preferably at least an 1.5-fold reduction of, more preferably at
least a 3-fold reduction of, even more preferably at least a 5-fold
reduction, most preferably at least a 10-fold reduction of the
amount of detectable formic acid and optionally other degradation
by-products.
[0101] In a preferred embodiment, the medical device of the
invention is a polymerization product of a composition comprising
(a) a prepolymer containing ethylenically unsaturated groups and at
least one poly(oxyalkylene) unit of formula (I); (b) a
water-soluble and biocompatible organic multi-acid or biocompatible
salt thereof in an amount sufficient to improve the stability of a
poly(oxyalkylene)-contain- ing polymeric material made from the
composition; (c) optionally a photoinitiator or a thermal
initiator; and (d) optionally one or more vinylic monomers.
[0102] In another preferred embodiment, the biocompatible organic
multi-acid or biocompatible salt thereof is impregnated within the
poly(oxyalkylene)-containing polymeric material, wherein the
poly(oxyalkylene)-containing polymeric material is a polymerization
product of a reactive mixture comprising (a) at least one monomer
or prepolymer having at least one poly(oxyalkylene) unit of formula
(I) and functional groups which are amino, carboxy, hydroxyl or
isocyanato groups, and (b) at least one of an organic diamine, an
organic polyamine, an organic diacid, an organic polyacid, an
organic diol, an organic polyol, an organic diisocyante, and
organic polyisocyanate, provided that components (a) and (b) react
with each other to form a polyurea and/or polyurethane network.
More preferably, the reactive mixture further comprises one or more
vinylic monomers or prepolymer with ethylenically unsaturated
groups. Those monomers or prepolymers can form upon actinical
irradiation a different polymer network which interpenetrates the
polyurea and/or polyurethane network.
[0103] In another further aspect, the present invention provides a
method for sterilizing a medical device which comprises a core
material and/or a coating, wherein the core material and the
coating, independently of each other, are made of a
poly(oxyalkylene)-containing polymeric material, the method
comprising: autoclaving the medical device in a solution containing
a water-soluble and biocompatible organic multi-acid or
biocompatible salt thereof in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material,
so that the poly(oxyalkylene)-containing polymeric material has a
decreased susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
[0104] A medical device can be coated with a
poly(oxyalkylene)-containing material according to any methods
known to a person skilled in the art. Exemplary coating techniques
include, but are not limited to, dip coating, spraying coating,
painting, knife-coating, and printing.
[0105] In still a further aspect, the present invention provides an
aqueous solution for sterilizing and/or storing an ophthalmic
device, wherein the ophthalmic device is made of a
poly(oxyalkylene)-containing polymeric material, the aqueous
solution having: a biocompatible organic multi-acid or
biocompatible salt thereof in an amount sufficient to improve the
stability of the poly(oxyalkylene)-containing polymeric material;
an osmolarity of about 200 to 450 milli-osmole in 1000 ml (unit:
mOsm/ml), wherein the aqueous solution is capable of improving the
stability of the poly(oxyalkylene)-containing polymeric material,
so that the poly(oxyalkylene)-containing polymeric material has a
reduced susceptibility to oxidative degradation characterized by
having at least an 1.5-fold reduction of the amount of detectable
formic acid and optionally other degradation by-products.
[0106] An aqueous solution of the invention has an osmolarity of,
preferably from about 250 to 350 mOsm/l, more preferably about 300
mOsm/l. An aqueous solution of the invention can comprise
physiologically compatible salts, such as buffer salts
conventionally used in the field of contact lens care, e.g.
phosphate salts, or isotonizing agents conventionally used in the
field of contact lens care, such as in particular alkali halides,
e.g. sodium chloride. An aqueous solution of the invention can
further comprise a physiologically compatible polar organic
solvent, e.g. glycerol.
[0107] The previous disclosure will enable one having ordinary
skill in the art to practice the invention. In order to better
enable the reader to understand specific embodiments and the
advantages thereof, reference to the following non-limiting
examples is suggested. However, the following examples should not
be read to limit the scope of the invention.
EXAMPLE 1
[0108] 68.63 g of Jeffamine XTJ-501, 16.04 g of Jeffamine XTJ-502
(both from Huntsman Corporation), and 2.14 g of diethylene triamine
(Aldrich Chemicals) were weighed in a jacketed 1-L reactor. 370 g
of tetrahydrofuran (Aldrich) and 200 g of deionized water were
added to the reactor and the contents were stirred to be dissolved.
A sample was taken for titration (0.332 mAeq/g vs. 0.335 by
theory). The reactor was then chilled to 0.degree. C. with stirring
under nitrogen. 21.74 g of isophorone diisocyanate (Aldrich
Chemicals, used as received) was then dissolved in 35 g of THF and
added dropwise over 45 minutes. The solution was stirred at
temperature for one hour, and then a sample was withdrawn and
titrated (0.033 mAeq/g vs. 0.035 theory). 3.5 g of
cyclohexylisocyanate (Aldrich Chemicals, used as received) was then
added in one portion, and the reactor was stirred at 0.degree. C.
for one hour. The product was then decanted to a 2-L flask, and the
reactor was chased with 400 mL of water. The combined products were
concentrated on a rotary evaporator at 53.degree. C./80 mBar
ultimate vacuum to yield a solution essentially free of
tetrahydrofuran. This solution was then ultrafiltered with 20 L of
water using a 3-kilodalton membrane. The resulting purified
solution was then concentrated to 50% solids on a rotary
evaporator.
EXAMPLE 2
[0109] 70 g of Poly(ethylene glycol) with a molecular weight of
approximately 2000, available from Aldrich Chemicals, was dissolved
in 70 g of water.
EXAMPLE 3
[0110] 2.00 g of Sodium Ascorbate (Aldrich) was dissolved in 20 g
with water. pH was adjusted to 6.92 by addition of 100 .mu.L of 10%
Ascorbic acid in water (Aldrich Chemicals). 1.00 g of
Irgacure.RTM.-2959
(2-Hydroxy-4'-(2-hydroxyethyl)-2-methylpropiophenone, available
from Ciba Specialty Chemicals) was mixed with 8.83 g of the
ascorbate buffer, and then diluted to 100 g with water. The mixture
was dissolved with gentle heating and agitation to provide a clear
solution.
EXAMPLE 4
[0111] 2.00 g of Sodium Citrate Dihydrate (Aldrich) was dissolved
in 20 g with water. pH was adjusted to 7.04 by addition of
.about.300 .mu.L of sodium dihydrogencitrate (Aldrich Chemicals)
which was 10% in water. 1.00 g of Irgacure.RTM.-2959 was mixed with
13.11 g of the citrate buffer, and then diluted to 100 g with
water. The mixture was dissolved with gentle heating and agitation
to provide a clear solution.
EXAMPLE 5
[0112] 2.00 g of sorbitol (Aldrich Chemicals) was dissolved in 20 g
with water. 1.00 g of Irgacure.RTM.-2959 was mixed with 8.12 g of
the sorbitol solution, and then diluted to 100 g with water. The
mixture was dissolved with gentle heating and agitation to provide
a clear solution.
EXAMPLE 6
[0113] 1.875 g of 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, free
radical (hereafter, 4-hydroxy-TEMPO) was dissolved in 25 mL of
water.
EXAMPLE 7
[0114] 1.00 g of Irgacure 2959 (Ciba Specialty Chemicals) was
dissolved in 99.00 g of water.
EXAMPLE 8
[0115] 10.00 g of polymer from Example 2 was mixed with 0.7425 of
the solution from Example 7 and diluted to 12.00 g with water to
afford a PEG/Irgacure.RTM. mixture at a ratio of 100:0.15.
EXAMPLE 9
[0116] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of
the solution from Example 7 and diluted to 12.00 g with water to
afford a PEG/Irgacure.RTM. mixture.
EXAMPLE 10
[0117] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of
the solution from Example 3 and diluted to 12.00 g with water to
afford a PEG/Irgacure.RTM. mixture containing ascorbate.
EXAMPLE 11
[0118] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of
the solution from Example 4 and diluted to 12.00 g with water to
afford a PEG/Irgacure.RTM. mixture containing citrate.
EXAMPLE 12
[0119] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of
the solution from Example 5 and diluted to 12.00 g with water to
afford a PEG/Irgacure.RTM. mixture containing sorbitol.
EXAMPLE 13
[0120] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of
the solution from Example 6 and diluted to 12.00 g with water to
afford a PEG/Irgacure.RTM. mixture containing 4-hydroxy-TEMPO.
EXAMPLE 14
[0121] 10.00 g of polymer from Example 1 was mixed with 0.7425 of
the solution from Example 7 and diluted to 12.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture at a ratio of 100:0.15.
EXAMPLE 15
[0122] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of
the solution from Example 7 and diluted to 12.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture.
EXAMPLE 16
[0123] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of
the solution from Example 3 and diluted to 12.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture containing ascorbate.
EXAMPLE 17
[0124] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of
the solution from Example 4 and diluted to 12.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture containing citrate.
EXAMPLE 18
[0125] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of
the solution from Example 5 and diluted to 12.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture containing sorbitol.
EXAMPLE 19
[0126] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of
the solution from Example 6 and diluted to 12.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture containing
4-hydroxy-TEMPO.
[0127] Each of the above parent samples from Examples 8-19 were
then divided into four. Samples with the above example numbers with
no suffix(e.g., Example-11) were simply held under refrigeration.
Samples with the above lot numbers suffixed with "T" (e.g.,
Example-11-T) were autoclaved in the dark at 121.degree. C./30
minutes. Samples with the above lot numbers suffixed with "P"
(e.g., Example-11-P) were subjected to 25 minute exposure to UV
light. Samples of the above lot numbers suffixed with "PA" (e.g.,
Example-11-PA) were subjected to 25 minute exposure to UV light,
followed by autoclave at 121.degree. C./30 minutes.
[0128] UV light exposure was accomplished using a Macam Lamp with a
Phillips HPA 400/30 S Sunlamp bulb. The output of the lamp was
captured by an EFOS.RTM. Liquid Light Guide and focused on a
cylindrical cell quartz cuvette available from Aldrich Chemicals as
part number Z27696-0. The cuvette was filled with test substance
and placed atop an assembly directly under the liquid light guide.
Lamp intensity was ca. 1.8 mW/cm.sup.2, and exposure time was 25
minutes, implying exposure dose of 2.7 J/cm.sup.2.
[0129] The above-described samples were analyzed by Ion-Exchange
Chromatography. The column used was an ICSep ICE-ORH-801
(0.65.times.300 mm) Transgenomic, P/N ICE-99-9754. The mobile phase
was 10 mN H.sub.2SO.sub.4 at a flow rate of 0.8 mL/min. UV
detection (.lambda.=205 nm) was used to quantitate formic acid and
total unknowns; Refractive Index detection was used to quantitate
formaldehyde (sensitivity=512 mv). Injection volume was 100 .mu.L
and run time was 240 minutes.
1TABLE 1 Sample Polymer Amendment Treatment HCOOH HC(O)H IC
Unknowns Example 8 PEG-2000 0.15% Initiator Nitrogen 300 1579
3387845 Example 8 P PEG-2000 LS-1 UV 284 226 4089917 Example 8 T
PEG-2000 Autoclaved 56 247 1460 1600472 Example 8 PA PEG-2000
autoclaved + LS-1 UV 319 165 234 3387845 Example 9 PEG-2000 0.38%
Initiator Nitrogen ND 276 4019 1561001 Example 9 P PEG-2000 LS-1 UV
ND 308 466 9413559 Example 9 T PEG-2000 Autoclaved 156 272 3786
1625876 Example 9 PA PEG-2000 autoclaved + LS-1 UV 219 217 442
8508847 Example 10 PEG-2000 Ascorbate Buffer Nitrogen 291 4146
1759608 Example 10 P PEG-2000 LS-1 UV 337 136 21333767 Example 10 T
PEG-2000 Autoclaved 51 301 3822 1451887 Example 10 PA PEG-2000
autoclaved + LS-1 UV 250 380 19728127 Example 11 PEG-2000 Citrate
Buffer Nitrogen 317 3825 1799368 Example 11 P PEG-2000 LS-1 UV 339
482 8699143 Example 11 T PEG-2000 Autoclaved 339 3747 1425557
Example 11 PA PEG-2000 autoclaved + LS-1 UV 290 554 8110747 Example
12 PEG-2000 Sorbitol Nitrogen 299 3967 1679516 Example 12 P
PEG-2000 LS-1 UV 243 375 7442590 Example 12 T PEG-2000 Autoclaved
188 228 3723 1421715 Example 12 PA PEG-2000 autoclaved + LS-1 UV
240 193 432 7803607 Example 13 PEG-2000 TEMPO Nitrogen 286 3586
1715501 Example 13 P PEG-2000 LS-1 UV 306 466 9072232 Example 13 T
PEG-2000 Autoclaved 302 2885 1155402 Example 13 PA PEG-2000
autoclaved + LS-1 UV 156 266 692 9481513 IC stands for Irgacure
.RTM. initiator.
[0130] Table 1 shows results of ion-exchange chromatography of
samples generated in Examples 11-16. All results expressed in
parts-per-million (.mu.g/mL). A blank entry means that the analyte
concentration was below the detection limit (50 ppm for formic
acid)
2TABLE 2 Sample Polymer Amendment Treatment HCOOH HC(O)H Irgacure
Unknowns Example 14 PEG-Urea 0.15% Irgacure Nitrogen 989 626725
Example 14 P PEG-Urea LS-1 UV 78 202 1205303 Example 14 T PEG-Urea
Autoclaved 1364 1021780 Example 14 PA PEG-Urea autoclaved + LS-1 UV
195 243 869404 Example 15 PEG-Urea 0.38% Irgacure Nitrogen 2842
448187 Example 15 P PEG-Urea LS-1 UV 533 7932312 Example 15 T
PEG-Urea Autoclaved 4690 475180 Example 15 PA PEG-Urea autoclaved +
LS-1 UV 136 868 7232686 Example 16 PEG-Urea Ascorbate Buffer
Nitrogen 3593 697009 Example 16 P PEG-Urea LS-1 UV 69 165 21371459
Example 16 T PEG-Urea Autoclaved 4235 799883 Example 16 PA PEG-Urea
autoclaved + LS-1 UV 60 380 16135664 Example 17 PEG-Urea Citrate
Buffer Nitrogen 3170 535949 Example 17 P PEG-Urea LS-1 UV 662
7178992 Example 17 T PEG-Urea Autoclaved 3919 669291 Example 17 PA
PEG-Urea autoclaved + LS-1 UV 74 521 5752951 Example 18 PEG-Urea
Sorbitol Nitrogen 3238 614870 Example 18 P PEG-Urea LS-1 UV 746
7979709 Example 18 T PEG-Urea Autoclaved 4499 629794 Example 18 PA
PEG-Urea autoclaved + LS-1 UV 124 551 5327765 Example 19 PEG-Urea
TEMPO Nitrogen 3178 499934 Example 19 P PEG-Urea LS-1 UV 439
4215228 Example 19 T PEG-Urea Autoclaved 5232 504369 Example 19 PA
autoclaved + LS-1 UV 104 595 5215616
[0131] Table 2 shows results of ion-exchange chromatography of
samples generated in Examples 14-19. All results expressed in
parts-per-million (.mu.g/mL). A blank entry means that the analyte
concentration was below the detection limit.
[0132] As can be seen from the tables, the levels of formic acid in
the irradiated and autoclaved samples were highest for any given
family of samples. Furthermore, a second by-product of degradation,
formaldehyde, was present in PEG materials of Examples 8-13,
whereas formaldehyde was not detected in any PEG-urea polymers in
Examples 14-19 (Table 2). The nature of the amendment added to the
formulation had dramatic effects on by-product generation during
the curing/autoclaving steps. As can be seen, sorbitol, whose
hydroxyl groups should act as chain transfer agents, had very
little efficacy as a stabilizer. The free-radical scavenger TEMPO
had a modest effect on lowering the amount of detectable
by-products, reducing them by approximately 25%. But the ascorbate
and citrate buffered formulations had little or no detectable
formic acid in any of the samples, indicating a large stabilizing
effect brought by these materials. The efficacy of these two
stabilizers versus the more conventional stabilizers sorbitol and
TEMPO was unexpected.
[0133] There is a difference between the two buffers in terms of
side effects. This was conveniently quantified by monitoring the
"total unknowns" in the chromatograms. These unknowns have been
partially characterized in that they are known to represent
Irgacure decomposition products, high-molecular weight fragments of
degraded polymer, and the like. In general, non-irradiated samples
had total unknowns on the order of 2.times.10.sup.6 counts; on
irradiation, the unknowns increased to about 9.times.10.sup.6
counts. Citrate-buffered PEG followed this trend with
1.8.times.10.sup.6 counts before irradiation and 8.7.times.10.sup.6
counts after irradiation and autoclave. Ascorbate buffered
polyethylene glycol, however, showed an unknowns level of
1.8.times.10.sup.6 counts before irradiation and
21.3.times.10.sup.6 counts after, a ten-fold increase. All of the
trends observed for the PEG were observed for the PEG Urea. There
was thus a large and unexpected stabilization of PEG and PEG-Urea
in the presence of an organic multi-acid of the present
invention.
EXAMPLE 20
[0134] 2.45 g of Pyruvic Acid Sodium Salt (Aldrich) were diluted to
100 g with water. The pH of this solution was adjusted to 7.2 by
addition of 15% aqueous sodium hydroxide. 0.5 g of
Irgacure.RTM.-2959 was dissolved in 49.5 g of this mixture. 5.00 g
of polymer from Example 1 was mixed with 0.75 g of this initiator
solution and diluted to 6.00 g with water to afford a
PEG-Urea/Irgacure.RTM. mixture containing pyruvate.
EXAMPLE 21
[0135] 3.75 g of 2-Ketoglutaric Acid Monosodium Salt (Aldrich) were
diluted to 100 g with water. The pH of this solution was adjusted
to 7.2 by addition of 15% aqueous sodium hydroxide. 0.5 g of
Irgacure.RTM.-2959 was dissolved in 49.5 g of this mixture. 5.00 g
of polymer from Example 1 was mixed with 0.75 g of this initiator
solution and diluted to 6.00 g with water to afford a
PEG-Urea/Irgacure.RTM. mixture containing 2-ketoglutarate.
EXAMPLE 22
[0136] 2.99 g of Malic Acid (Aldrich) were diluted to 100 g with
water. 2.99 g of Malic Acid Disodium Salt (Aldrich) were diluted to
100 g with water. The pH of this Malic Acid Disodium Salt solution
was adjusted to 7.2 by addition of a small amount of the Malic Acid
solution. 0.5 g of Irgacure.RTM.-2959 was dissolved in 49.5 g of
this mixture. 5.00 g of polymer from Example 1 was mixed with 0.75
g of this initiator solution and diluted to 6.00 g with water to
afford a PEG-Urea/Irgacure.RTM. mixture containing malate
buffer.
[0137] Samples of the above Examples 20, 21, and 22 were subjected
to 25-minute exposure to UV light, followed by autoclave at
121.degree. C./30 minutes. UV light exposure was accomplished using
a Macam Lamp with a Phillips HPA 400/30 S Sunlamp bulb directed by
an EFOS.RTM. Liquid Light Guide and focused on a cylindrical cell
quartz cuvette as described above. Lamp intensity was ca. 1.8
mW/cm.sup.2, and exposure time was 25 minutes, implying exposure
dose of 2.7 J/cm.sup.2.
[0138] The samples were subjected to Ion Exchange Chromatography
with the following results:
3 Sample Treatment HCOOH HC(O)H Irgacure Unknowns Example Pyruvate
200 115 4481172 20 Example Ketoglutarate 286 2567220 21 Example
Malate 187 713127 22
[0139] A blank entry in the above table means that the analyte
concentration was below detection limits. It can thus be seen from
the above examples that .alpha.-oxo-diacids have unexpected,
beneficial results in regard to PEG stabilization which are not
realized in the case of the an .alpha.-oxo monoacid.
EXAMPLE 23
[0140] 74.26 g of Jeffamine XTJ-501 (from Huntsman Corporation),
and 3.1 g of diethylene triamine (Aldrich Chemicals) were weighed
into a jacketed 1-L reactor. 450 g of tetrahydrofuran (Aldrich) and
250 g of deionized water were added to the reactor and the contents
were stirred to dissolve. The reactor was then chilled to 0.degree.
C. with stirring under nitrogen. 23.34 g of isophorone diisocyanate
(Aldrich Chemicals, used as received) was then dissolved in 50 g of
THF and added dropwise over 45 minutes. The solution was stirred at
temperature for one. 20 g of 20% aqueous Sodium Carbonate (Aldrich)
were added to the reactor and stirred to mix. 2.8 g of acryloyl
chloride (Aldrich Chemicals, used as received) was then added in
one portion, and the reactor was stirred at 0.degree. C. for 30
minutes. Treatment of the reaction mixture with 20 g 20% sodium
carbonate, followed by 2.8 g of acryloyl chloride, was repeated
twice more at 30 minute intervals. The product was then decanted to
a 2-L flask, and the reactor was chased with 400 mL of water. The
mixture was filtered with a 40 .mu.m sintered glass filter. The
product was then concentrated on a rotary evaporator at 53.degree.
C./80 mBar ultimate vacuum to yield a solution essentially free of
tetrahydrofuran. This solution was then ultrafiltered with 10 L of
water using a 1-kilodalton membrane. The resulting purified
solution was then concentrated to 25.33% solids on a rotary
evaporator.
EXAMPLE 24
[0141] 11.76 g of Sodium Citrate Dihydrate (Aldrich) was diluted to
1.0 L with water in a volumetric flask. 0.8564 g of Sodium
Dihydrogencitrate (Aldrich) was diluted to 100 mL with water in a
100 mL volumetric. Both solutions were thus 40 mM of citrate. The
Sodium Citrate Dihydrate solution was pH-adjusted to 7.2 by adding
the Sodium Dihydrogencitrate solution. 8.2 g of sodium chloride was
then weighed into a 1-L volumetric and diluted to the mark with the
citrate buffer.
EXAMPLE 25
[0142] 4.76 g of Disodium Phosphate (Aldrich), 0.77 g of Sodium
Phosphate (Aldrich), and 8.2 g of sodium chloride were weighed into
a 1-L volumetric and diluted to the mark with water.
EXAMPLE 26
[0143] 47.37 g of the 25.33% solids solution of Example 23 were
weighed into a rotary evaporator flask. 19.77 g of water were
removed at 55.degree. C./70-100 mBar. 2.4 g of initiator solution
from Example 7 were added and the mixture was agitated to
homogenize.
EXAMPLE 27
[0144] 44 mg of the material afforded by Example 26 was dosed into
a quartz mold and the mold was closed. The mold was then exposed to
UV light using a Macam Lamp with a Phillips HPA 400/30 S Sunlamp
bulb. The output of the lamp was captured by an EFOS.RTM. Liquid
Light Guide and focused into the mold. The intensity of the lamp
was 1.85 mW/cm.sup.2 and the exposure time was 20 s, implying an
exposure energy of 37 mJ/cm.sup.2. The molds were opened and the
resulting contact lens was rinsed off. Five lenses made in this way
were placed in autoclave vials which contained 2.5 mL of the
buffered saline of Example 24. The lenses were then subjected to 5
autoclave cycles (121.degree. C./30 minutes). The salines were then
combined and analyzed by ion-exclusion chromatography. The saline
was found to have 9 ppm of formic acid, a value below the
Occupational Safety and Health Administration's Short-Term Exposure
Limit (STEL) of 10 ppm.
EXAMPLE 28
[0145] 44 mg of the material afforded by Example 26 was dosed into
a quartz mold and the mold was closed. The mold was then exposed to
UV light using a Macam Lamp with a Phillips HPA 400/30 S Sunlamp
bulb. The output of the lamp was captured by an EFOS.RTM. Liquid
Light Guide and focused into the mold. The intensity of the lamp
was 1.85 mW/cm.sup.2 and the exposure time was 20 s, implying an
exposure energy of 37 mJ/cm.sup.2. The molds were opened and the
resulting contact lens was rinsed off.
[0146] Five lenses made in this way were placed in autoclave vials
which contained 2.5 mL of the buffered saline of Example 25. The
lenses were then subjected to 5 autoclave cycles (121.degree. C./30
minutes). The salines were then combined and analyzed by
ion-exclusion chromatography. The saline was found to have 36 ppm
of formic acid. This value is well above the Occupational Safety
and Health Administration's Short-Term Exposure Limit (STEL) of 10
ppm, rendering the lenses unfit for use.
[0147] The utility of the organic multi-acids of the present
invention was thus unexpectedly equivalent regardless of where in
the processing the organic multi-acids is employed.
EXAMPLE 29
[0148] Preparation of Acrylamide-Capped Polyurea
[0149] Place 2017 grams of tetrahydrofuran (THF), 1257 grams of
water, 420 amine group milliequilvalents (meq) of Jeffamine.RTM.
XTJ501 (Hunstman Chemicals), 250 amine group meq of Jeffamines.RTM.
XTJ502 (Hunstman Chemicals), 134 amine group meq of
bis-hexamethylenetriamine (Aldrich Chemicals) into a jacketed 5 L
reactor. At a temperature of approximately from 0 to 5.degree. C.,
add a solution of 500 isocyanate group meq of isophorone
diisocyanate (Aldrich Chemicals), 134 isocyanate group meq of
VESTANAT.RTM. T1890/100 (Degussa Chemicals) and about 370 grams of
THF drop wise with intensive stirring over about 30 minutes. Keep
the solution temperature at approximately 0 to 5.degree. C. for
approximately 25 minutes. Add approximately 108 grams of a 20%
sodium carbonate aqueous solution, followed by 17 grams of acryloyl
chloride (Aldrich Chemicals) to the solution. After 30 minutes, add
a second aliquot of 108 grams of sodium carbonate solution followed
by 17 grams of acryloyl chloride. Discontinue cooling after the
second addition. After 30 minutes, add a third aliquot of 108 grams
of sodium carbonate solution followed by 3.4 grams of acryloyl
chloride. Thirty minutes after the final addition, drain the
reaction mixture from the reactor, then rinse the reactor with a
small amount of THF or water. Filter the mixture through a 17 .mu.m
sintered glass filter under vacuum. Concentrate the solution under
vacuum using a rotary evaporator to yield a solution essentially
free of THF. Ultrafilter this solution with approximately 31 L of
water using a 1-kilodalton membrane. Further purify the solution by
passing the solution through a 0.45 um Teflon membrane under
pressure. Stabilize the macromer solution with 50 ppm of
hydroxyl-TEMPO (versus the polymer). Concentrate the solution to
approximately 49% solids under vacuum using a rotary
evaporator.
EXAMPLE 30
[0150] Dissolve 1.875 g of
4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, free radical
(hereafter, 4-hydroxy-TEMPO) in 25 mL of water.
EXAMPLE 31
[0151] Preparation of Formulation. Mix 19.47 grams of the polymer
solution from Example 29 (49.3% polymer), 0.0576 grams of the
solution from Example 30, 1.92 grams of the solution from Example
7, 7.67 grams of D.I. water, and 1.58 grams of visitint solution.
Place the formulation containing 32% polymer, 80 ppm of
4-hydroxy-TEMPO, 0.2% Irgacure and 42 ppm of visitint into 5 mL
syringes and centrifuge for 15 minutes at 4500 rpm.
EXAMPLE 32
[0152] Preparation of Formulation containing CBS. Mix 6.49 grams of
the polymer solution from Example 29, 0.0192 grams of the solution
from Example 30, 0.64 grams of the solution from Example 7, 2.69
grams of 60 mM CBS described in Example 37, and 0.158 grams of
visitint solution. Place the formulation containing 32% polymer, 80
ppm of 4-hydroxy-TEMPO, 0.2% Irgacure, 16 mM of CBS, and 42 ppm of
visitint into 5 mL syringes and centrifuge for 15 minutes at 4500
rpm.
EXAMPLE 33
[0153] Preparation of Contact Lenses. Place about 2 drops of the
formulation from Example 31 (or Example 32) into a quartz mold
(-1.0 diopters). Irradiate the formulation with 17 mJ of energy
using the Macam lamp described in Examples 19. Place the resulting
lenses into 0.85 mL of various buffer solutions. Use fifteen lenses
for each buffer solution. Autoclave five lenses with buffer
solution once, five lenses 3 times and five lenses 5 times. Each
autoclave cycle is 121.degree. C. for 30 minutes.
EXAMPLE 34
[0154] Preparation of 20 mM Citrate Buffered Saline CBS. Weigh 5.88
grams of sodium citrate dihydrate (Aldrich Chemicals), 0.060 grams
of Sodium Dihydrogencitrate (Aldrich), and 7.70 grams of sodium
chloride into a 1-L volumetric flask and dilute to the mark with
D.I. water. The pH of the solution is 7.05 and the osmolarity is
300 mOsm.
EXAMPLE 35
[0155] Preparation of 40 mM Citrate Buffered Saline CBS. Weigh
11.76 grams of sodium citrate dihydrate (Aldrich Chemicals), 0.121
grams of Sodium Dihydrogencitrate (Aldrich), and 5.90 grams of
sodium chloride into a 1-L volumetric flask and dilute to the mark
with D.I. water. The pH of the solution is 7.08 and the osmolarity
is 302 mOsm.
EXAMPLE 36
[0156] Preparation of 40 mM Citrate Buffered Saline CBS at low pH.
Weigh 0.420 grams of citric acid monohydrate (Aldrich Chemicals),
0.428 grams of Sodium Dihydrogencitrate (Aldrich), and 0.70 grams
of sodium chloride into a 100 mL volumetric flask and dilute to the
mark with D.I. water. The pH of the solution is 3.67 and the
osmolarity is 292 mOsm.
EXAMPLE 37
[0157] Preparation of 60 mM Citrate Buffered Saline CBS. Weigh
17.64 grams of sodium citrate dihydrate (Aldrich Chemicals), 0.182
grams of Sodium Dihydrogencitrate (Aldrich), and 4.20 grams of
sodium chloride into a 1-L volumetric flask and dilute to the mark
with D.I. water. The pH of the solution is 7.10 and the osmolarity
is 306 mOsm.
EXAMPLE 38
[0158] Measurement of formic acid concentration. Combine the buffer
solution of 2 lenses from each condition and test for formic acid
using the method described in Example 18. Table 4 lists the average
amount of formic acid in ppm from 2 different samples. The
detection limit of the instrument is 0.3 ppm
4 40 mM Number 40 mM w/CBS 40 mM of auto- 20 CBS 40 in 60 40 CBS
clave mM with mM formu- mM mM with no cycles CBS low pH CBS lation
CBS PBS water lens 1 <0.3 <0.3 <0.3 0.6 <0.3 4.7 7.0
<0.3 3 1.1 3.5 2.9 8.8 6.8 135 17.0 0.6 5 5.0 5.0 8.4 14.8 14.3
191 106.0 3.6
[0159] The addition of citrate buffered saline at all
concentrations used reduces the amount of formic acid formed by the
lenses versus water and PBS. The effect is most obvious at 5
autoclave cycles where the formic acid concentration is more than
an order of magnitude higher in water or PBS than in 40 mM CBS. CBS
also functions to reduce the formation of formic acid during the at
low pH (3.67) using similar conditions. CBS concentrations of 20,
40 and 60 mM are all acceptable. Having CBS in the formulation
during the UV cure does not further reduce the concentration of
formic acid after 5 autoclave cycles versus 60 mM CBS.
[0160] Although various embodiments of the invention have been
described using specific terms, devices, and methods, such
description is for illustrative purposes only. The words used are
words of description rather than of limitation. It is to be
understood that changes and variations may be made by those skilled
in the art without departing from the spirit or scope of the
present invention, which is set forth in the following claims. In
addition, it should be understood that aspects of the various
embodiments may be interchanged either in whole or in part.
Therefore, the spirit and scope of the appended claims should not
be limited to the description of the preferred versions contained
therein.
* * * * *