U.S. patent application number 14/035066 was filed with the patent office on 2014-01-23 for ophthalmic and otorhinolaryngological device materials containing an alkylphenol ethoxylate.
The applicant listed for this patent is Novartis AG. Invention is credited to Walter R. Laredo, Douglas C. Schlueter.
Application Number | 20140024777 14/035066 |
Document ID | / |
Family ID | 39885236 |
Filed Date | 2014-01-23 |
United States Patent
Application |
20140024777 |
Kind Code |
A1 |
Laredo; Walter R. ; et
al. |
January 23, 2014 |
Ophthalmic And Otorhinolaryngological Device Materials Containing
An Alkylphenol Ethoxylate
Abstract
Disclosed are soft, high refractive index, acrylic device
materials. The materials contain a functionalized alkylphenol
ethoxylate to reduce glistenings.
Inventors: |
Laredo; Walter R.; (Fort
Worth, TX) ; Schlueter; Douglas C.; (Azle,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Family ID: |
39885236 |
Appl. No.: |
14/035066 |
Filed: |
September 24, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12243046 |
Oct 1, 2008 |
8574292 |
|
|
14035066 |
|
|
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|
60976980 |
Oct 2, 2007 |
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Current U.S.
Class: |
525/55 ; 526/301;
526/313 |
Current CPC
Class: |
A61L 2430/16 20130101;
A61L 27/16 20130101; A61L 27/50 20130101; A61L 31/048 20130101 |
Class at
Publication: |
525/55 ; 526/313;
526/301 |
International
Class: |
A61L 31/04 20060101
A61L031/04 |
Claims
1. A polymeric ophthalmic or otorhinolaryngological device material
comprising a) 75 to 97% (w/w) of a monofunctional acrylate or
methacrylate monomer of formula [1]: ##STR00010## wherein
B=O(CH.sub.2).sub.n, NH(CH.sub.2).sub.n, or
NCH.sub.3(CH.sub.2).sub.n; R.sup.1=H, CH.sub.3, CH.sub.2CH.sub.3,
or CH.sub.2OH; n=0-12; A=C.sub.6H.sub.5 or
O(CH.sub.2).sub.mC.sub.6H.sub.5, where the C.sub.6H.sub.5 group is
optionally substituted with --(CH.sub.2).sub.nH,
--O(CH.sub.2).sub.nH, --CH(CH.sub.3).sub.2, --C.sub.6H.sub.5,
--OC.sub.6H.sub.5, --CH.sub.2C.sub.6H.sub.5, F, Cl, Br, or I; and
m=0-22; b) a difunctional acrylate or methacrylate cross-linking
monomer of formula [2]: ##STR00011## wherein R.sup.2, R.sup.3
independently=H, CH.sub.3, CH.sub.2CH.sub.3, or CH.sub.2OH; W, W'
independently=O(CH.sub.2).sub.d, NH(CH.sub.2).sub.d,
NCH.sub.3(CH.sub.2).sub.d, O(CH.sub.2).sub.dC.sub.6H.sub.4,
O(CH.sub.2CH.sub.2O).sub.dCH.sub.2,
O(CH.sub.2CH.sub.2CH.sub.2O).sub.dCH.sub.2,
O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.dCH.sub.2, or nothing;
J=(CH.sub.2).sub.a, O(CH.sub.2CH.sub.2O).sub.b, O, or nothing,
provided that if W and W'=nothing, then J.noteq.nothing; d=0-12;
a=1-12; and b=1-24; and c) 1 to 20% (w/w) of an alkylphenol
ethoxylate monomer of formula [3]: ##STR00012## wherein:
T=C.sub.8H.sub.17 or C.sub.9H.sub.19; e=1-100; ##STR00013##
R.sup.4=H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OH; and
R.sup.5=CH.sub.2CH.sub.2OC(.dbd.O)C(CH.sub.3).dbd.CH.sub.2 or
##STR00014##
2. The polymeric device material of claim 1 wherein
B=O(CH.sub.2).sub.n; R.sup.1=H or CH.sub.3; n=1-4; and
A=C.sub.6H.sub.5.
3. The polymeric device material of claim 1 wherein R.sup.2,
R.sup.3 independently=H or CH.sub.3; W, W'
independently=O(CH.sub.2).sub.d, O(CH.sub.2).sub.dC.sub.6H.sub.4,
or nothing; J=O(CH.sub.2CH.sub.2O).sub.b or nothing, provided that
if W and W'=nothing, then J.noteq.nothing; d=0-6; and b=1-10.
4. The polymeric device material of claim 1 wherein:
T=C.sub.8H.sub.17 or C.sub.9H.sub.19; e=8-50; ##STR00015## and
R.sup.4=H or CH.sub.3.
5. The polymeric device material of claim 4 wherein:
T=2,4,4-trimethylpentan-2-yl alkyl or 3-ethyl-4-methylhexan-2-yl
alkyl; e=15-40; ##STR00016## and R.sup.4=H or CH.sub.3.
6. The polymeric device material of claim 1 wherein the monomer of
formula [1] is selected from the group consisting of benzyl
methacrylate; 2-phenylethyl methacrylate; 3-phenylpropyl
methacrylate; 4-phenylbutyl methacrylate; 5-phenylpentyl
methacrylate; 2-phenoxyethyl methacrylate; 2-(2-phenoxyethoxy)ethyl
methacrylate; 2-benzyloxyethyl methacrylate;
2-(2-(benzyloxy)ethoxy)ethyl methacrylate; 3-benzyloxypropyl
methacrylate; benzyl acrylate; 2-phenylethyl acrylate;
3-phenylpropyl acrylate; 4-phenylbutyl acrylate; 5-phenylpentyl
acrylate; 2-phenoxyethyl acrylate; 2-(2-phenoxyethoxy)ethyl
acrylate; 2-benzyloxyethyl acrylate; 2-(2-(benzyloxy)ethoxy)ethyl
acrylate; and 3-benzyloxypropyl acrylate.
7. The polymeric device material of claim 1 wherein the monomer of
formula [2] is selected from the group consisting of ethylene
glycol dimethacrylate; diethylene glycol dimethacrylate;
triethylene glycol dimethacrylate; 1,6-hexanediol dimethacrylate;
1,4-butanediol dimethacrylate; 1,4-benzenedimethanol
dimethacrylate; ethylene glycol diacrylate; diethylene glycol
diacrylate; triethylene glycol diacrylate; 1,6-hexanediol
diacrylate; 1,4-butanediol diacrylate; and 1,4-benzenedimethanol
diacrylate.
8. The polymeric device material of claim 1 wherein the amount of
monomer [1] is 80 to 95% (w/w).
9. The polymeric device material of claim 1 wherein the amount of
monomer [2] is 0.5 to 3% (w/w).
10. The polymeric device material of claim 1 wherein the amount of
monomer [3] is 1 to 15% (w/w).
11. The polymeric device material of claim 10 wherein the amount of
monomer [3] is 1 to 10% (w/w).
12. The polymeric device material of claim 1 further comprising an
ingredient selected from the group consisting of a polymerizable UV
absorbers and a polymerizable colorants.
13. The polymeric device material of claim 12 comprising 0.1-5%
(w/w) of a polymerizable UV absorber and 0.01-0.5% (w/w) of a
polymerizable colorant.
14. An ophthalmic or otorhinolaryngological device comprising the
device material of claim 1 wherein the ophthalmic or
otorhinolaryngological device is selected from the group consisting
of intraocular lenses; contact lenses; keratoprostheses; corneal
inlays or rings; otological ventilation tubes; and nasal
implants.
15. The ophthalmic or otorhinolaryngological device of claim 14
wherein the ophthalmic or otorhinolaryngological device is an
intraocular lens.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of U.S. patent
application Ser. No. 12/243,046 filed Oct. 1, 2008, which claims
priority to U.S. Provisional Application, U.S. Ser. No. 60/976,980
filed Oct. 2, 2007.
FIELD OF THE INVENTION
[0002] This invention is directed to improved ophthalmic and
otorhinolaryngological device materials. In particular, this
invention relates to soft, high refractive index acrylic device
materials that have improved glistening resistance.
BACKGROUND OF THE INVENTION
[0003] With the recent advances in small-incision cataract surgery,
increased emphasis has been placed on developing soft, foldable
materials suitable for use in artificial lenses. In general, these
materials fall into one of three categories: hydrogels, silicones,
and acrylics.
[0004] In general, hydrogel materials have a relatively low
refractive index, making them less desirable than other materials
because of the thicker lens optic necessary to achieve a given
refractive power. Conventional silicone materials generally have a
higher refractive index than hydrogels, but tend to unfold
explosively after being placed in the eye in a folded position.
Explosive unfolding can potentially damage the corneal endothelium
and/or rupture the natural lens capsule. Acrylic materials are
desirable because they typically have a high refractive index and
unfold more slowly or controllably than conventional silicone
materials.
[0005] U.S. Pat. No. 5,290,892 discloses high refractive index,
acrylic materials suitable for use as an intraocular lens ("IOL")
material. These acrylic materials contain, as principal components,
two aryl acrylic monomers. The IOLs made of these acrylic materials
can be rolled or folded for insertion through small incisions.
[0006] U.S. Pat. No. 5,331,073 also discloses soft acrylic IOL
materials. These materials contain as principal components, two
acrylic monomers which are defined by the properties of their
respective homopolymers. The first monomer is defined as one in
which its homopolymer has a refractive index of at least about
1.50. The second monomer is defined as one in which its homopolymer
has a glass transition temperature less than about 22.degree. C.
These IOL materials also contain a cross-linking component.
Additionally, these materials may optionally contain a fourth
constituent, different from the first three constituents, which is
derived from a hydrophilic monomer. These materials preferably have
a total of less than about 15% by weight of a hydrophilic
component.
[0007] U.S. Pat. No. 5,693,095 discloses foldable, high refractive
index ophthalmic lens materials containing at least about 90 wt. %
of only two principal components: one aryl acrylic hydrophobic
monomer and one hydrophilic monomer. The aryl acrylic hydrophobic
monomer has the formula
##STR00001##
wherein: X is H or CH.sub.3 ; [0008] m is 0-6; [0009] Y is nothing,
O, S, or NR, wherein R is H, CH.sub.3, C.sub.nH.sub.2n+1 (n=1-10),
iso-OC.sub.3H.sub.7, C.sub.6H.sub.5, or CH.sub.2C.sub.6H.sub.5; and
[0010] Ar is any aromatic ring which can be unsubstituted or
substituted with CH.sub.3, C.sub.2H.sub.5, n-C.sub.3H.sub.7,
iso-C.sub.3H.sub.7, OCH.sub.3, C.sub.6H.sub.11, Cl, Br,
C.sub.6H.sub.5, or CH.sub.2C.sub.6H.sub.5. The lens materials
described in the '095 Patent preferably have a glass-transition
temperature ("T.sub.g") between about -20 and +25.degree. C.
[0011] Flexible intraocular lenses may be folded and inserted
through a small incision. In general, a softer material may be
deformed to a greater extent so that it can be inserted through an
increasingly smaller incision. Soft acrylic or methacrylic
materials typically do not have an appropriate combination of
strength, flexibility and non-tacky surface properties to permit
IOLs to be inserted through an incision as small as that required
for silicone IOLs.
[0012] Polyethylene glycol (PEG) dimethacrylates are known to
improve glistening resistance of hydrophobic acrylic formulations.
See, for example, U.S. Pat. Nos. 5,693,095; 6,528,602; 6,653,422;
and 6,353,069. Both the concentration and molecular weight of PEG
dimethacrylates have an impact on glistening performance.
Generally, use of higher molecular weight PEG dimethacrylates (1000
MW) yield copolymers with improved glistening performance at low
PEG concentrations (10-15 wt %), as compared to lower molecular
weight PEG dimethacrylates (<1000 MW). However, low PEG
dimethacrylate concentrations are desirable to maintain a high
refractive index copolymer. Addition of PEG dimethacrylates also
tends to decrease the modulus and tensile strength of the resulting
copolymer. Also, higher molecular weight PEG dimethacrylates are
generally not miscible with hydrophobic acrylic monomers.
SUMMARY OF THE INVENTION
[0013] Improved soft, foldable acrylic device materials which are
particularly suited for use as IOLs, but which are also useful as
other ophthalmic or otorhinolaryngological devices, such as contact
lenses, keratoprostheses, corneal rings or inlays, otological
ventilation tubes and nasal implants, have been discovered. These
polymeric materials comprise an alkylphenol ethoxylate monomer.
[0014] Among other factors, the present invention is based on the
finding that use of alkylphenol ethoxylate monomers in acrylic
intraocular lens formulations reduces or eliminates
temperature-induced glistening formation in hydrophobic acrylic
copolymers. The subject monomers allow synthesis of glistening
resistant, low equilibrium water content, high refractive index
IOLs.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Unless indicated otherwise, all component amounts are
presented on a % (w/w) basis ("wt. %").
[0016] The device materials of the present invention are copolymers
comprising a) a monofunctional acrylate or methacrylate monomer
[1], b) a difunctional acrylate or methacrylate cross-linker [2],
and c) a functionalized alkylphenol ethoxylate [3]. The device
materials may contain more than one monomer [1], more than one
monomer [2], and more than one monomer [3]. Unless indicated
otherwise, references to each ingredient are intended to encompass
multiple monomers of the same formula and references to amounts are
intended to refer to the total amount of all monomers of each
formula.
##STR00002##
wherein [0017] B=O(CH.sub.2).sub.n, NH(CH.sub.2).sub.n, or
NCH.sub.3(CH.sub.2).sub.n; [0018] R.sup.1=H, CH.sub.3,
CH.sub.2CH.sub.3, or CH.sub.2OH; [0019] n=0-12; [0020]
A=C.sub.6H.sub.5 or O(CH.sub.2).sub.mC.sub.6H.sub.5, where the
C.sub.6H.sub.5 group is optionally substituted with
--(CH.sub.2).sub.nH, --O(CH.sub.2).sub.nH, --CH(CH.sub.3).sub.2,
--C.sub.6H.sub.5, --OC.sub.6H.sub.5, --CH.sub.2C.sub.6H.sub.5, F,
Cl, Br, or I; and [0021] m=0-22;
##STR00003##
[0021] wherein [0022] R.sup.2, R.sup.3 independently=H, CH.sub.3,
CH.sub.2CH.sub.3, or CH.sub.2OH; [0023] W, W'
independently=O(CH.sub.2).sub.d, NH(CH.sub.2).sub.d,
NCH.sub.3(CH.sub.2).sub.d, O(CH.sub.2).sub.dC.sub.6H.sub.4,
O(CH.sub.2CH.sub.2O).sub.dCH.sub.2,
O(CH.sub.2CH.sub.2CH.sub.2O).sub.dCH.sub.2,
O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.dCH.sub.2, or nothing;
[0024] J=(CH.sub.2).sub.a, O(CH.sub.2CH.sub.2O).sub.b, O, or
nothing, provided that if W and W'=nothing, then J.noteq.nothing;
[0025] d=0-12; [0026] a=1-12; [0027] b=1-24;
##STR00004##
[0027] wherein: [0028] T=C.sub.8H.sub.17 or C.sub.9H.sub.19; [0029]
e=1-100;
[0029] ##STR00005## [0030] R.sup.4=H, CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2OH; and [0031]
R.sup.5=CH.sub.2CH.sub.2OC(.dbd.O)C(CH.sub.3).dbd.CH.sub.2 or
##STR00006##
[0031] Preferred monomers of formula [1] are those wherein: [0032]
B=O(CH.sub.2)n; [0033] R.sup.1=H or CH.sub.3; [0034] n=1-4; and
[0035] A=C.sub.6H.sub.5. Preferred monomers of formula [2] are
those wherein: [0036] R.sup.2, R.sup.3 independently=H or CH.sub.3;
[0037] W, W' independently=O(CH.sub.2).sub.d,
O(CH.sub.2).sub.dC.sub.6H.sub.4, or nothing; [0038]
J=O(CH.sub.2CH.sub.2O).sub.b or nothing, provided that if W and W'
=nothing, then J.noteq.nothing; [0039] d=0-6; and [0040] b=1-10.
Preferred monomers of formula [3] are those wherein: [0041]
e=8-50;
[0041] ##STR00007## [0042] and [0043] R.sup.4=H or CH.sub.3. Most
preferred monomers of formulas [3] are those wherein [0044]
T=2,4,4-trimethylpentan-2-yl alkyl or 3-ethyl-4-methylhexan-2-yl
alkyl; [0045] e=15-40;
[0045] ##STR00008## [0046] and [0047] R.sup.4=H or CH.sub.3.
Representative monomers of formula [3] include:
##STR00009##
[0048] Monomers of formula [1] are known and can be made by known
methods. See, for example, U.S. Pat. Nos. 5,331,073 and 5,290,892.
Many monomers of formula [1] are commercially available from a
variety of sources. Preferred monomers of formula [1] include
benzyl methacrylate; 2-phenylethyl methacrylate; 3-phenylpropyl
methacrylate; 4-phenylbutyl methacrylate; 5-phenylpentyl
methacrylate; 2-phenoxyethyl methacrylate; 2-(2-phenoxyethoxy)ethyl
methacrylate; 2-benzyloxyethyl methacrylate;
2-(2-(benzyloxy)ethoxy)ethyl methacrylate; and 3-benzyloxypropyl
methacrylate; and their corresponding acrylates.
[0049] Monomers of formula [2] are known and can be made by known
methods, and are commercially available. Preferred monomers of
formula [2] include ethylene glycol dimethacrylate ("EGDMA");
diethylene glycol dimethacrylate; triethylene glycol
dimethacrylate; 1,6-hexanediol dimethacrylate; 1,4-butanediol
dimethacrylate; 1,4-benzenedimethanol dimethacrylate; and their
corresponding acrylates. Most preferred is 1,4-butanediol
diacrylate.
[0050] Monomers of formula [3] can be made by known methods. For
example, such monomers may be made by esterification reactions
involving, for example, the alkylphenol ethoxylate alcohol and
suitable carboxylic acids, acyl halides, or carboxylic acid
anhydrides. For example, the alkylphenol ethoxylate can be heated
with a carboxylic acid or carboxylic acid alkyl ester in the
presence of a catalyst to form the desired ester, with water or low
boiling alcohol as a byproduct which can be removed to drive the
reaction to completion. The alkylphenol ethoxylate can also be
treated with an acyl halide in the presence of a base such as
triethylamine which serves as a hydrohalide acceptor. The
alkylphenol ethoxylate can also be treated with a carboxylic acid
anhydride in the presence of a base such as triethylamine or
pyridine which catalyzes the reaction and neutralizes the acid
formed.
[0051] The copolymeric materials of the present invention contain a
total amount of monomer [1] from 75 to 97%, preferably from 80 to
95%, and most preferably from 80-93%. The difunctional cross-linker
[2] concentration is generally present in an amount from 0.5-3%,
and preferably 1-2%.
[0052] The materials of the present invention have at least one
monomer [3]. The total amount of monomer [3] depends on the desired
physical properties for the device materials. The copolymeric
materials of the present invention contain a total of at least 1%
and can contain as much as 20% of monomer [3]. Preferably, the
copolymeric device materials will contain from 1 to 15% of monomer
[3]. Most preferably, the device materials will contain from 1 to
10% of monomer [3].
[0053] The copolymeric device material of the present invention
optionally contains one or more ingredients selected from the group
consisting of a polymerizable UV absorber and a polymerizable
colorant. Preferably, the device material of the present invention
contains no other ingredients besides the monomers of formulas [1]
and [2], the monomer [3], and the optional polymerizable UV
absorbers and colorants.
[0054] The device material of the present invention optionally
contains reactive UV absorbers or reactive colorants. Many reactive
UV absorbers are known. A preferred reactive UV absorber is
2-(2'-hydroxy-3'-methallyl-5'-methylphenyl)benzotriazole,
commercially available as o-Methallyl Tinuvin P ("oMTP") from
Polysciences, Inc., Warrington, Pa. UV absorbers are typically
present in an amount from about 0.1-5%. Suitable reactive
blue-light absorbing compounds include those described in U.S. Pat.
No. 5,470,932. Blue-light absorbers are typically present in an
amount from about 0.01-0.5%. When used to make IOLs, the device
materials of the present invention preferably contain both a
reactive UV absorber and a reactive colorant.
[0055] In order to form the device material of the present
invention, the chosen ingredients [1], [2], and [3], along with any
of the optional ingredients, are combined and polymerized using a
radical initiator to initiate polymerization by the action of
either heat or radiation. The device material is preferably
polymerized in de-gassed polypropylene molds under nitrogen or in
glass molds.
[0056] Suitable polymerization initiators include thermal
initiators and photoinitiators. Preferred thermal initiators
include peroxy free-radical initiators, such as t-butyl
(peroxy-2-ethyl)hexanoate and di-(tert-butylcyclohexyl)
peroxydicarbonate (commercially available as Perkadox.RTM. 16 from
Akzo Chemicals Inc., Chicago, Ill.). Particularly in cases where
the materials of the present invention do not contain a blue-light
absorbing chromophore, preferred photoinitiators include
benzoylphosphine oxide initiators, such as
2,4,6-trimethyl-benzoyldiphenyl-phosphine oxide, commercially
available as Lucirin.RTM. TPO from BASF Corporation (Charlotte,
N.C.). Initiators are typically present in an amount equal to about
5% or less of the total formulation weight, and more preferably
less than 2% of the total formulation. As is customary for purposes
of calculating component amounts, the initiator weight is not
included in the formulation weight % calculation.
[0057] The particular combination of the ingredients described
above and the identity and amount of any additional components are
determined by the desired properties of the finished device
material. In a preferred embodiment, the device materials of the
present invention are used to make IOLs having an optic diameter of
5.5 or 6 mm that are designed to be compressed or stretched and
inserted through surgical incision sizes of 2 mm or less. For
example, the monomer [3] is combined with at least one
mono-functional acrylate or methacrylate monomer [1] and a
multifunctional acrylate or methacrylate cross-linker [2] and
copolymerized using a radical initiator in a suitable lens
mold.
[0058] The device material preferably has a refractive index in the
hydrated state of at least about 1.50, and more preferably at least
about 1.53, as measured by an Abbe' refractometer at 589 nm (Na
light source) and 25.degree. C. Optics made from materials having a
refractive index lower than 1.50 are necessarily thicker than
optics of the same power which are made from materials having a
higher refractive index. As such, IOL optics made from materials
with comparable mechanical properties and a refractive index lower
than about 1.50 generally require relatively larger incisions for
IOL implantation.
[0059] The proportions of the monomers to be included in the
copolymers of the present invention should be chosen so that the
copolymer has a glass transition temperature (T.sub.g) not greater
than about 37.degree. C., which is normal human body temperature.
Copolymers having glass transition temperatures higher than
37.degree. C. are not suitable for use in foldable IOLs; such
lenses could only be rolled or folded at temperatures above
37.degree. C. and would not unroll or unfold at normal body
temperature. It is preferred to use copolymers having a glass
transition temperature somewhat below normal body temperature and
no greater than normal room temperature, e.g., about 20-25.degree.
C., in order that IOLs made of such copolymers can be rolled or
folded conveniently at room temperature. T.sub.g is measured by
differential scanning calorimetry at 10.degree. C./min., and is
determined at the midpoint of the transition of the heat flux
curve.
[0060] For IOLs and other applications, the materials of the
present invention must exhibit sufficient strength to allow devices
made of them to be folded or manipulated without fracturing. Thus
the copolymers of the present invention will have an elongation of
at least 80%, preferably at least 100%, and most preferably between
110 and 200%. This property indicates that lenses made of such
materials generally will not crack, tear or split when folded.
Elongation of polymer samples is determined on dumbbell shaped
tension test specimens with a 20 mm total length, length in the
grip area of 4.88 mm, overall width of 2.49 mm, 0.833 mm width of
the narrow section, a fillet radius of 8.83 mm, and a thickness of
0.9 mm. Testing is performed on samples at ambient conditions using
an Instron Material Tester (Model No. 4442 or equivalent) with a 50
Newton load cell. The grip distance is set at 14 mm and a crosshead
speed is set at 500 mm/minute and the sample is pulled until
failure. The elongation (strain) is reported as a fraction of the
displacement at failure to the original grip distance. Since the
materials to be tested are essentially soft elastomers, loading
them into the Instron machine tends to make them buckle. To remove
the slack in the material sample a pre-load is placed upon the
sample. This helps to reduce the slack and provide a more
consistent reading. Once the sample is pre-loaded to a desired
value (typically 0.03 to 0.05 N) the strain is set to zero and the
test begun. The modulus is calculated as the instantaneous slope of
the stress-strain curve at 0% strain ("Young's modulus"), 25%
strain ("25% modulus") and 100% strain ("100% modulus).
[0061] IOLs made of the ophthalmic device materials of the present
invention are more resistant to glistenings than other materials.
Glistenings are measured according to the following test. The
presence of glistenings is measured by placement of a lens or disk
sample into a vial or sealed glass chamber and adding deionized
water or a balanced salt solution. The vial or glass chamber is
then placed into a water bath preheated to 41.degree. C. Samples
are to be maintained in the bath for a minimum of 16 hours and
preferably 24.+-.2 hours. The vial or glass chamber is then
immediately placed in a water bath preheated to 35.degree. C. and
allowed to equilibrate at 35.degree. C. for a minimum of 30 minutes
and preferably 30 to 60 minutes. The sample is inspected visually
in various on angle or off angle lighting to evaluate clarity while
at 35.degree. C. Visualization of glistenings is carried out at
35.degree. C. with light microscopy using a magnification of 50 to
200.times.. A sample is judged to have many glistenings if, at
50-200.times. magnification, there are approximately 50 to 100% as
many glistenings as observed in control samples based on 65 weight
% PEA, 30 weight % PEMA, 3.2 weight % BDDA, and 1.8 weight % OMTP.
Similarly, a sample is judged to have few glistenings if there are
approximately 10% or more glistenings relative to the quantity
observed in control samples. A sample is judged to have very few
glistenings if there are approximately 1% or more glistenings
relative to a control sample. A sample is judged to be free of
glistenings if the number of glistenings detected in the eyepiece
is zero. A sample is judged to be substantially free of glistenings
if the number of glistenings detected in the eyepiece is less than
about 2/mm.sup.3. It is often very difficult to detect glistenings,
especially at surfaces and edges where more defects and debris have
formed, so the sample is rastered throughout the entire volume of
the lens, varying the magnification levels (50-200.times.), the
aperture iris diaphragm, and the field conditions (using both
bright field and dark field conditions) in an attempt to detect the
presence of glistenings.
[0062] The copolymers of the present invention preferably have an
equilibrium water content (EWC) of 0.5 to 3 weight %. EWC is
measured by placing one rectangular 0.9.times.10.times.20 mm slab
in a 20 ml scintillation vial filled with deionized water and
subsequently heating in a 35.degree. C. water bath for a minimum of
20 hours and preferably 48.+-.8 hours. The slab is blotted dry with
lens paper and the % water content is calculated as follows:
% water content = ( wet weight - dry weight ) wet weight .times.
100 ##EQU00001##
[0063] IOLs constructed of the device materials of the present
invention can be of any design capable of being stretched or
compressed into a small cross section that can fit through a 2-mm
incision. For example, the IOLs can be of what is known as a
one-piece or multi-piece design, and comprise optic and haptic
components. The optic is that portion which serves as the lens and
the haptics are attached to the optic and are like arms that hold
the optic in its proper place in the eye. The optic and haptic(s)
can be of the same or different material. A multi-piece lens is so
called because the optic and the haptic(s) are made separately and
then the haptics are attached to the optic. In a single piece lens,
the optic and the haptics are formed out of one piece of material.
Depending on the material, the haptics are then cut, or lathed, out
of the material to produce the IOL.
[0064] In addition to IOLs, the materials of the present invention
are also suitable for use as other ophthalmic or
otorhinolaryngological devices such as contact lenses,
keratoprostheses, corneal inlays or rings, otological ventilation
tubes and nasal implants.
[0065] The invention will be further illustrated by the following
examples, which are intended to be illustrative, but not
limiting.
[0066] The following abbreviations are used throughout the Examples
and have the following meanings. [0067] PEA 2-phenylethyl acrylate
[0068] PEMA 2-phenylethyl methacrylate [0069] BzMA benzyl
methacrylate [0070] BDDA 1,4-butanediol diacrylate [0071] IEMA
2-isocyanatoethyl methacrylate [0072] THF tetrahydrofuran [0073]
AIBN azobisisobutyronitrile [0074] OMTP
2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-methyl-6-(2-methylallyl)phenol
[0075] TMI 3-isopropenyl-alpha,alpha-dimethylbenzyl isocyanate
[0076] MEHQ methyl hydroquinone or 4-methoxyphenol [0077]
TergNP4-MA Reacted adduct of Tergitol.TM. NP-4 surfactant and
methacrylic anhydride or methacryloyl chloride or IEMA [0078]
TergNP6-MA Reacted adduct of Tergitol.TM. NP-6 surfactant and
methacrylic anhydride or methacryloyl chloride or IEMA [0079]
TergNP9-MA Reacted adduct of Tergitol.TM. NP-9 surfactant and
methacrylic anhydride or methacryloyl chloride or IEMA [0080]
TergNP11-MA Reacted adduct of Tergitol.TM. NP-11 surfactant and
methacrylic anhydride or methacryloyl chloride or IEMA [0081]
TergNP15-MA Reacted adduct of Tergitol.TM. NP-15 surfactant and
methacrylic anhydride or methacryloyl chloride or IEMA [0082]
TergNP40-MA Reacted adduct of Tergitol.TM. NP-40 surfactant and
methacrylic anhydride [0083] TergNP4-TMI Reacted adduct of
Tergitol.TM. NP-4 surfactant and TMI [0084] TergNP6-TMI Reacted
adduct of Tergitol.TM. NP-6 surfactant and TMI [0085] TergNP9-TMI
Reacted adduct of Tergitol.TM. NP-9 surfactant and TMI [0086]
TergNP11-TMI Reacted adduct of Tergitol.TM. NP-11 surfactant and
TMI [0087] TergNP15-TMI Reacted adduct of Tergitol.TM. NP-15
surfactant and TMI [0088] TritX15-MA Reacted adduct of Triton.TM.
X-15 surfactant and methacrylic anhydride or methacryloyl chloride
or IEMA [0089] TritX35-MA Reacted adduct of Triton.TM. X-35
surfactant and methacrylic anhydride or methacryloyl chloride or
IEMA [0090] TritX114-MA Reacted adduct of Triton.TM. X-114
surfactant and methacrylic anhydride or methacryloyl chloride or
IEMA [0091] TritX102-MA Reacted adduct of Triton.TM. X-102
surfactant and methacrylic anhydride or methacryloyl chloride or
IEMA
Example 1
[0092] TritonX15-MA. 51.2 g (176 mmol based on equivalent
weight=291) of Triton.TM. X-15 (Dow/Union Carbide) and 20 mg MEHQ
(Aldrich, Milwaukee, Wis.) were dissolved in 300 ml anhydrous THF
(Aldrich) in a 1 liter round bottom flask equipped with magnetic
stirrer and nitrogen inlet. 27.6 g (178 mmol) of 2-isocyanatoethyl
methacrylate (IEMA) (Aldrich) and 20 mg stannous octoate (Aldrich)
were added and the reaction mixture was heated to 60.degree. C. for
20 hours. The solvent was removed via rotary evaporation and the
resulting liquid was further dried under vacuum (.about.0.1 mm Hg)
for 40 hours.
Example 2
[0093] TritX35-MA. The reaction was carried out as in Example 1
using 53.6 g (169 mmol based on equivalent weight=317) of
Triton.TM. X-35 (Dow/Union Carbide) and 20 mg MEHQ (Aldrich,
Milwaukee, Wis.) and 24.3 g (157 mmol) of 2-isocyanatoethyl
methacrylate (IEMA) (Aldrich) resulting in a liquid which was
further dried under vacuum (.about.0.1 mm Hg) for 40 hours.
Example 3
[0094] TritX102-MA. The reaction was carried out as in Example 1
using 49.5 g (66.9 mmol based on equivalent weight=740) of
Triton.TM. X-102 (Dow/Union Carbide) and 11.3 g (72.8 mmol) of
2-isocyanatoethyl methacrylate (IEMA) (Aldrich) resulting in a
liquid which was further dried under vacuum (.about.0.1 mm Hg) for
40 hours.
Example 4
[0095] TritX114-MA. The reaction was carried out as in Example 1
using 51.5 g (96.3 mmol based on equivalent weight=535) of
Triton.TM. X-114 (Dow/Union Carbide) and 17.1 g (110.2) of
2-isocyanatoethyl methacrylate (IEMA) (Aldrich) resulting in a
liquid which was further dried under vacuum (.about.0.1 mm Hg) for
40 hours.
Example 5
[0096] TergNP4-MA. The reaction was carried out as in Example 1
using 49.7 g (117 mmol based on equivalent weight=424) of
Tergitol.TM. NP-4 (Dow/Union Carbide) and 19.4 g (125 mmol) of
2-isocyanatoethyl methacrylate (IEMA) (Aldrich) resulting in a
liquid which was further dried under vacuum (.about.0.1 mm Hg) for
40 hours.
Example 6
[0097] TergNP11-MA. The reaction was carried out as in Example 1
using 51.2 g (70.6 mmol based on equivalent weight=725) of
Tergitol.TM. NP-11 (Dow/Union Carbide) and 16.1 g (104 mmol) of
2-isocyanatoethyl methacrylate (IEMA) (Aldrich) resulting in a
liquid which was further dried under vacuum (.about.0.1 mm Hg) for
40 hours.
Example 7
[0098] TergNP15-MA. The reaction was carried out as in Example 1
using 50.9 g (55.0 mmol based on equivalent weight=926) of
Tergitol.TM. NP-15 (Dow/Union Carbide) and 9.72 g (62.6 mmol) of
2-isocyanatoethyl methacrylate (IEMA) (Aldrich) resulting in a
viscous liquid which was further dried under vacuum (.about.0.1 mm
Hg) for 40 hours.
Example 8
[0099] TergNP40-MA. 76.7 g (38.7 mmol based on equivalent
weight=1983) of Tergitol NP-40 (Dow/Union Carbide) was dissolved in
176 g anhydrous pyridine. 20 mg MEHQ and 50 mg dibutyltin dilaurate
(Aldrich) were added followed by 12.4 g methacrylic anhydride (Alfa
Aesar, 94%). The reaction mixture was heated at 50.degree. C. for
20 hours and the solid isolated by precipitation in cold diethyl
ether 3 times to give 56 g (71%) of a white solid which was dried
under vacuum (.about.0.1 mm Hg) for 72 hours.
Example 9
[0100] TergNP4-TMI. 5.11 g (12.1 mmol) of Tergitol.TM. NP-4 and 10
mg MEHQ (Aldrich, Milwaukee, Wis.) were dissolved in 100 ml
anhydrous THF (Aldrich) in a 250 ml round bottom flask equipped
with magnetic stirrer and nitrogen inlet. 2.54 g (12.6 mmol) of
3-isopropenyl-alpha,alpha-dimethylbenzyl isocyanate (TMI) (Aldrich)
and 10 mg dibutyltin dilaurate (Aldrich) were added and the
reaction mixture was heated to 60.degree. C. for 20 hours under a
nitrogen blanket. The solvent was removed via rotary evaporation
and the resulting liquid was further dried under vacuum (.about.0.1
mm Hg) for 20 hours.
Example 10
[0101] TergNP6-TMI. The reaction was carried out as in Example 9
using 5.00 g (9.84 mmol) of Tergitol.TM. NP-6 and 2.28 g (1.14
mmol) of TMI resulting in a liquid which was further dried under
vacuum (.about.0.1 mm Hg) for 20 hours.
Example 11
[0102] TergNP9-TMI. The reaction was carried out as in Example 9
using 5.16 g (7.84 mmol) of Tergitol.TM. NP-9 and 1.70 g (8.29
mmol) of TMI resulting in a liquid which was further dried under
vacuum (.about.0.1 mm Hg) for 20 hours.
Example 12
[0103] TergNP15-TMI. The reaction was carried out as in Example 9
using 4.56 g (4.92 mmol) of Tergitol.TM. NP-15 and 1.00 g (4.98
mmol) of TMI resulting in a liquid which was further dried under
vacuum (.about.0.1 mm Hg) for 20 hours.
[0104] The refractive index values and molecular weights of the
starting alkyllphenol ethoxylate alcohols were measured prior to
functionalizing with reactive groups as shown in Table 1.
Refractive index values were measured at 35.degree. C. GPC number
average molecular weights were measured in THF relative to
polystyrene standards. Number average molecular weight values were
also estimated using a Bruker 400 MHz NMR spectrometer using
CD.sub.2Cl.sub.2 as solvent. Equivalent weights were determined
using a modified hydroxyl number (OH#) test method in which 2-3
grams of alkylphenol ethoxylate were treated with acetic anhydride
in pyridine to give a mixture of the alkylphenol ethoxylate acetate
and acetic acid. The mixture was then titrated with a solution of
1.0 N potassium hydroxide to a basic endpoint using phenolphthalein
indicator. A blank containing acetic anhydride and pyridine was
also titrated and the equivalence points of sample and blank were
used to calculate the hydroxyl number (OH#=mg KOH/g sample) and
corresponding equivalent weight using the following equation:
Equivalent Weight=56,100/OH#.
TABLE-US-00001 TABLE 1 Average Equiv- Number alent Of Weight
Alkylphenol Ethylene Mn Mn (from Ethoxylate Oxide Units R.I. (GPC)
(.sup.1H NMR) OH#) Triton .TM. X-15 1.5 1.506 279 282 291 Triton
.TM. X-35 3 1.502 330 317 317 Triton .TM. X-114 7.5 1.502 632 555
535 Triton .TM. X-102 12 1.484 891 729 740 Tergitol .TM. NP-4 4
1.495 456 404 424 Tergitol .TM. NP-6 6 1.490 576 497 508 Tergitol
.TM. NP-9 9 1.485 795 645 658 Tergitol .TM. NP-11 11 1.484 870 689
725 Tergitol .TM. NP-15 15 1.482 1100 843 926 Tergitol .TM. NP-40
40 -- -- -- 1983
Example 13
Lens Materials
[0105] The reaction components listed in Tables 2-4, except for
AIBN, were mixed together with stirring or shaking for at least 30
minutes at 23.degree. C., until all components were dissolved. The
AIBN was subsequently added and the reaction mixture was stirred
for a minimum of 5 minutes, until the initiator was dissolved. The
reactive components are reported in grams.
[0106] The reactive components were purged for approximately 15
minutes using N.sub.2 and placed inside a low humidity N.sub.2
purged glove box.
[0107] The reactive components were syringed or pipetted onto clean
polypropylene mold halves containing 1.times.10.times.20 mm
rectangular wells and then covered with the complementary flat
polypropylene mold halves. The mold halves were compressed using
binder clips and the mixtures were cured at 70.degree. C. for 16
hours using a Yamato DKN400 constant temperature oven. The molds
were allowed to cool to room temperature. The top mold halves were
removed and the rectangular polymer slabs were removed from the
wells with tweezers and placed individually in 38.times.8 mm Histo
Plas tissue processing capsules (Bio Plas Inc., San Rafael,
Calif.). The slabs were extracted in acetone for a minimum of 16
hours and then air dried at ambient temperature for 20 hours,
followed by high vacuum (.about.0.1 mm Hg) at ambient temperature
for 20 hours, and high vacuum at 70.degree. C. for 20 hours.
TABLE-US-00002 TABLE 2 Example % (w/w) Component 13A 13B 13C 13D Ex
1 0 0 0 15.0 Ex 2 0 0 14.8 0 Ex 3 11.9 0 0 0 Ex 4 0 12.4 0 0 PEA
57.0 56.7 55.1 55.1 PEMA 26.8 26.6 26.0 25.4 BDDA 2.7 2.7 2.7 3.0
OMTP 1.5 1.5 1.5 1.5 AIBN 0.45 0.46 0.45 0.45
TABLE-US-00003 TABLE 3 Example % (w/w) Component 13E 13F 13G 13H
13I 13J Ex 5 13.1 0 0 0 0 0 Ex 6 0 12.1 0 0 0 0 Ex 7 0 0 11.6 0 0 0
Ex 9 0 0 0 14.3 0 0 Ex 10 0 0 0 0 13.4 0 Ex 11 0 0 0 0 0 12.9 PEA
56.3 56.9 57.3 55.5 56.0 56.4 PEMA 26.0 26.3 26.4 25.7 25.9 26.1
BDDA 3.1 3.1 3.1 3.0 3.1 3.1 OMTP 1.6 1.6 1.6 1.5 1.6 1.6 AIBN 0.48
0.45 0.45 0.40 0.44 0.44
TABLE-US-00004 TABLE 4 Example % (w/w) Component 13K 13L 13M 13N
13O 13P Ex 8 0 0 0 0 6.1 5.9 Ex 12 9.8 7.4 4.9 2.6 0 0 PEA 58.7
60.3 61.9 63.3 48.1 63.1 PEMA 27.0 27.8 28.5 29.3 43.8 7.3 BzMA 0 0
0 0 0 21.7 BDDA 2.81 2.9 3.0 3.0 1.9 2.0 OMTP 1.6 1.7 1.7 1.8 0 0
AIBN 0.58 0.59 0.63 0.52 0.53 0.55
The % extractables were calculated as follows:
% extractables = ( non - extracted weight - extracted weight ) non
- extracted weight .times. 100 ##EQU00002##
The equilibrium water content (EWC) was measured by placing one
slab in a 20 ml scintillation vial filled with deionized water and
subsequently heating in a 35.degree. C. water bath for a minimum of
20 hours. The slab was blotted dry with lens paper and the % water
content was calculated as follows:
% water content = ( wet weight - dry weight ) wet weight .times.
100 ##EQU00003##
The refractive index values of hydrated samples were measured using
a Bausch & Lomb refractometer (catalog #33.46.10) at 35.degree.
C.
[0108] The extent of glistening formation was evaluated by carrying
out a 41.degree. C. to 35.degree. C. change in temperature
(.DELTA.T) test. In brief, samples were first placed in 20 ml
scintillation vials containing deionized water and heated at
41.degree. C. for a minimum of 20 hours. The entire cross section
(.about.200 mm.sup.2) of samples was examined for glistening
formation approximately 30 to 60 minutes after cooling to ambient
temperature using an Olympus BX60 microscope equipped with a
10.times. objective. The number of glistening was counted visually
at 3 different points along the slab, typically in the center and
approximately 2, 5, and 7 mm from the left edge. The samples were
also visually inspected for haze after the .DELTA.T test.
[0109] The refractive index (R.I.), % extractables, appearance of
haze, and glistening results are shown in Table 5.
TABLE-US-00005 TABLE 5 Clarity % (during Relative Ex. Extract-
glistening glistening # R.I. ables test) formation 13A 1.546 6.2
clear many 13B 1.545 5.9 haze many 13C 1.546 7.0 haze many 13D
1.548 3.5 haze many 13E 1.546 3.6 clear many 13F 1.546 3.7 clear
few 13G 1.545 4.8 clear many 13H 1.546 3.9 clear many 13I 1.543 6.2
clear few 13J 1.544 4.9 clear very few 13K 1.551 3.8 clear very few
13L 1.550 3.5 clear very few 13M 1.550 2.8 clear very few 13N 1.550
2.0 clear very few 13O 1.548 1.9 clear 0 13P 1.545 2.1 clear 0
[0110] The results of Examples 13A through 13P show that the
reaction mixture components and their amounts may be varied. All
materials were clear and showed low haze prior to contact with
water. Examples 13B through 13D showed noticeable haze after
equilibrating in deionized water at 41.degree. C. followed by
cooling to 35.degree. C.
[0111] The refractive index values were generally high, between
1.54 and 1.55 for all examples.
[0112] The equilibrium water contents (EWCs) at 35.degree. C. were
less than 1.0% for Examples 13A through 13N, which contained
functionalized alkylphenol ethoxylates with between 1 and 15
ethylene oxide repeat units. EWC values of 1.5% were observed for
Examples 13O and 13P, which contained functionalized alkylphenol
ethoxylates with an average of 40 ethylene oxide repeat units.
[0113] In general, fewer glistenings were observed when higher
molecular weight alkylphenol ethoxylates were used. The ethylene
oxide content of select nonylphenol ethoxylates are shown in Table
6 Further, increased loadings of the lower molecular weight
functionalized alkylphenol ethoxylates of up to 20 weight % also
reduced or completely eliminated glistening formation.
TABLE-US-00006 TABLE 6 Molecular Ethylene Alkylphenol Weight Oxide
.sup.aGlistening ethoxylate (Mn) Wt. % Formation Tergitol .TM. NP-4
424 52 High Tergitol .TM. NP-6 508 60 High Tergitol .TM. NP-9 658
69 Medium Tergitol .TM. NP-11 725 72 Medium Tergitol .TM. NP-15 926
78 Low Tergitol .TM. NP-40 1983 89 0 .sup.aTypical loading of 5-10
weight %
[0114] The materials from Examples 13O and 13P, which showed zero
glistenings under the conditions studied, were analyzed to
determine their tensile properties. The results are shown in Table
7, below.
TABLE-US-00007 TABLE 7 25% 100% Stress at Young's Secant Secant Ex.
Break Strain at Modulus Modulus Modulus # (MPa) Break (%) (MPa)
(MPa) (MPa) 13O 8.7 140 46.5 9.3 4.8 13P 7.1 145 20 4.6 3.1
[0115] This invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its special or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *