Note: Descriptions are shown in the official language in which they were submitted.
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STERILE PHOTOCHROMIC HYDROPHILIC CONTACT LENSES
Cross Reference to Related Application
This application is based on, and claims benefit
of, of Provisional Application 60/161,132 filed
October 22, 1999, which is incorporated herein by
reference.
Field of the Invention
The present invention relates to photochromic
contact lenses, and, more particularly, is directed
to normally clear, soft water-containing hydrophilic
contact lenses that have reduced visible light
transmittance while exposed to sunlight.
Background of the Invention
A wide variety of photochromic products are
known, including hard plastic lenses for framed
eyeglasses, which can reversibly reduce their degree
of light transmission when exposed to sunlight (which
contains the ultraviolet wavelengths responsible for
the activation of the photochromic effect).
Typically, photochromic plastic eyeglass lenses are
not completely clear in their most transmissive
state, but can darken significantly to protect the
wearer from bright sunlight. Such plastic
photochromic eyeglass lenses can return to a
relatively clear, deactivated state after a period of
time in the absence of activating UV exposure. Such
hard plastic lenses are generally exposed to direct
sunlight because they are prominently worn by the
user, and accordingly can receive the unshaded
intensity of ambient sunlight (including off-axis
light not in the imaging line-of-sight) to initiate
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or activate a useful level of reduction in lens
transparency. "Activation" and cognate terms as used
herein means to become absorbing in the visible light
range (to become darkened). "Deactivation" means the
reversible loss of absorption in the visible range
(to return to the molecular ground state of the
photochromic compound).
There are a variety of organic photochromic
compounds for use in such products as described, for
example, in "Photochromism" by G. H. Brown (Ed), Vol.
III of the Weissberger series "Techniques of Organic
Chemistry", Wiley Interscience, New York (1971) and ,
in "Photochromism: Molecules and Systems", by H. Durr
and H. Bouas-Laurent (Ed), Vol. 40 of the series
"Studies in Organic Chemistry", Elsevier (1990).
Photochromic spiro-oxazines, spiro-pyrans, including
napthopyrans, spiro-indolino-oxazines, spiro
(indolene) napthoxazines, and benzopyrans, and
chromenes are examples of active photochromic
materials, such as described in U.S. Pat. Nos.
5,055,576, 5,110,922, 3,567,605, 5,066,818,
5,238,981, 5,274,132, 5,369,158, 5,384,077,5,391,327,
5,405,958, 5,411,679, 5,429,774, 5,451,344,
5,458,814, 5,458,815, 5,464,567, 5,466,398,
5,565,147, 5,573,712, 5,578,252, 5,585,042,
5,624,757, 5,637,262, 5,645,767, 5,650,098,
5,651,923, 5,656,206, 5,658,500, 5,658,501,
5,674,432, 5,723,072, 5,278,758, 5,744,070,
5,770,115, 5,783,116, 5,808,063, 5,811,034,
5,869,658, 5,879,592, 5,891,368, 5,936,016,
5,955,520, 5,961,892, 5,965,680, 5,973,093,
5,976,422, 5,981,634, 6,019,914, 6,022,495 and
6,022,497,(which are incorporated herein by
reference). The photochromic materials can be used
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alone to provide a specific color, or can be mixed to
provide a broader range of transmittance reduction
across the visible spectrum. A blend of photochromic
colors is useful in providing neutral shades such as
green, brown and gray; such as described in U.S.
Patent 5,753,146 and references there cited, which
are incorporated herein by reference. Spiro-
indolino-oxazines are useful in view of their good
coloring characteristics and fatigue resistance,
typically for photochromic blue and red colors.
Chromenes or spiropyrans are also useful. The use of
chromenes or spiropyrans to provide photochromic
yellows and oranges is described in U.S. Pat. Nos.
5,066,818, 4,931,221 and 5,543,533, and 4,816,584,
all of which are incorporated herein by reference.
However, while photochromic framed plastic
eyeglasses are a conventional and popular commercial
product, hydrophilic photochromic contact lenses have
not been conventionally commercially available. For
example, while the preparation of plastic contact
lenses is described in the patent literature (e. g.,
various of the above cited patents, and PCT 97/41468,
EP Patent 277,639, and U.S. Patent Nos. 4,929,693 and
5,166,345), photochromic contact lenses, particularly
hydrophilic, oxygen-transmitting contact lenses, have
not reached substantial commercial status. There are
a number of significant problems adversely affecting
the development of photochromic hydrophilic contact
lenses, which contain up to 50 weight percent or more
of free water. First, the photochromic materials
tend to be relatively unstable, particularly in
oxygen. They also tend to have reduced performance
with increased temperatures in their use, and reduced
stability at elevated temperatures. While such
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characteristics may be tolerated in solid plastic
eyeglass lenses when the inert matrix composition of
the plastic lens or its coating may protect and
isolate the photochromic materials, they pose
substantial difficulties for use in hydrated
hydrophilic contact lenses. Hydrophilic contact
lenses are purposefully designed to have high gas
permeability for supplying the cornea with oxygen and
for removing carbon dioxide. The gas permeability
generally increases with water content, so lenses
with high water content in the range of from about 38
to about 80 percent are preferred. However, the
aqueous, oxygenated environment of the hydrophilic
contact lens tends to exacerbate the instability of
the photochromic material. Unfortunately, the
requirement for oxygenation of the eye is
incompatible with a principal degradation mechanism
for photochromic materials, which can be brought
about by the combined action of oxygen and light on
the colored form of the materials.
There are some additional problems specific to
contact lens use. Because the surface of the eye is
warm, photochromic activity may be reduced. Also,
because contact lenses are partially shielded from
direct overhead sunlight by the physical structures
of the wearer's brow and eye socket structures (and
the periodic blinking of the user's eyelids), the
amount of activating UV energy available to produce
an effective photochromic response is much lower than
for conventional eyeglass lenses continuously exposed
to the direct rays of the sun. It is estimated that
the reflected, UV-containing sunlight typically
incident upon contact lenses is only about one fifth
of that which may typically be incident upon eyeglass
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lenses. Accordingly, a relatively higher
photochromic effect is required for useful contact
lenses than plastic eyeglass lenses.
The manufacturing procedures used for
hydrophilic contact lenses from hydrophilic monomers
also present problems for the incorporation of the
relatively unstable photochromic materials in the
contact lenses. Hydrophilic contact lens manufacture
is typically carried out by polymerizing the monomers
at elevated temperatures with free radical initiators
for extended time periods, and may also include
treatment with ultraviolet light to facilitate the
polymerization. Unfortunately, conditions of heat,
free radicals (particularly peroxide free radicals)
and ultraviolet light may be destructive to the
relatively chemically unstable photochromic
materials.
It is also necessary to sterilize the
hydrophilic contact lenses after their manufacture
for use by the consumer. This is typically carried
out by hermetically sealing the lens in an aqueous
lens sterilization solution in a suitable container,
and heating the packaged lens in the aqueous solution
to a high sterilization temperature for a period of
time sufficient to assure sterility of the packaged
lens. Unfortunately, the aqueous sterilization
procedure can be destructive to photochromic
compounds included in the hydrated contact lens
compositions. Thus, while there are commercially
successful photochromic eyeglass lenses available to
consumers, there are currently no commercially
available photochromic hydrophilic contact lenses.
Fortunately, for a variety of reasons,
hydrophilic contact lenses can be made as products
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which may be worn for up to several weeks, and then
replaced. If hydrated hydrophilic contact lenses
could be formulated, manufactured and sterilized
which would retain a high photochromatic activity in
use at the warm eye surface for an extended period of
up to several weeks, the commercial need for
photochromic contact lens products would be met.
Accordingly, it is an object of the present
invention to provide packaged, sterilized
photochromic hydrophilic contact lenses that retain
their photochromic capacity for an extended period of
time. It is a further object to provide methods for
manufacturing and sterilizing hydrated photochromic
hydrophilic contact lenses while retaining effective
photochromic activity. These and other objects of
the invention will be more apparent from the
following detailed description and the accompanying
drawings.
Description of the Drawings
FIGURE 1 is a cross-sectional side view of a
hydrophilic contact lens polymerization mold;
FIGURE 2a is a perspective view of a
hermetically sealed blister package containing a
sterilized photochromic hydrophilic contact lens;
FIGURE 2b is a cross-sectional side view,
through line 2-2, of a contact lens immersed in
aqueous packaging solution, within the hermetically
sealed bacteria-impervious packaging material of the
blister package of FIGURE 2a;
FIGURE 3a is a graphical plot of the
transmittance of a hydrophilic contact lens in
accordance with the present disclosure, upon initial
exposure to a specific treatment with ultraviolet
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light, and after specified time periods after such
exposure. The FIGURE illustrates both the
sensitivity of the photochromic activation, and rapid
deactivation of the photochromic response with
consequently rapid return of the lens toward clarity
in the absence of photoactivating stimulus; and
FIGURE 3b is a graphical plot of the
transmittance of a hydrophilic contact lens in
accordance with the present disclosure, after having
been subjected to 48 repeated half-hour cycles of
strong UV stimulus and relaxation. Like FIGURE 3a,
FIGURE 3b shows the reduction in visible
transmittance upon exposure to a specific treatment
of ultraviolet light, and the rapid return toward
clarity after cessation of such exposure. The FIGURE
illustrates relatively low fatigue (permanent loss of
photochromic response) as a result of the 48 cycles
of UV pretreatment, while retaining rapid reversible
photochromic activation and deactivation.
Summary of the Invention
Generally, the present invention is directed to
sterile, hydrated, hydrophilic contact lenses which
are substantially clear, but can reversibly reduce
their transmission in sunlight when worn by the user,
as well as to methods for manufacturing such
hydrophilic photochromic contact lenses.
In accordance with such methods, a substantially
acid-free, cross-linkable hydrophilic monomer mixture
is copolymerized with one or more photochromic
comonomers to produce a cross-linked hydrophilic
polymer gel incorporating the photochromic material
and optionally a hindered amine. Desirably, the
hydrophilic monomer mixture may include a light
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stabilizing comonomer, and optionally a W absorbing
dye, which is also preferably a comonomer. The
copolymerization mixture, including the monomer
mixture, the photochromic copolymer and desirably the
light stabilizer comonomer and/or the UV absorbing
dye, is polymerized under relatively mild free-
radical initiation conditions. Preferably, the
copolymerization is carried out in bulk, without the
addition of substantial amounts of inert solvent, at
a temperature of less than about 80° C., in suitable
molds, to form the contact lenses directly, or under
equivalent time-temperature conditions. For example,
it may be desirable to conduct the polymerization at
high temperature (e. g., 120° C.) for short thermal
exposure time of less than about a half hour down to
the order of seconds. Less than 25 minutes is
contemplated, preferably 15 minutes or less, most
preferably 10 minutes or less. The shorter times are
preferred when it is desired to decrease the time of
manufacturing individual lenses in molds.
The polymerized contact lens containing the
copolymerized photochromic material and stabilizer is
subsequently hydrated in an aqueous hydration
solution to a hydration level of at least about 38%
by weight water, and preferably in the range of from
about 50% to about 80% by weight water, based on the
total weight of the hydrated contact lens. The
hydrated lens may then be hermetically sealed in a
sterilization package in an aqueous packaging
solution having a pH of at least about 7.4, and
preferably from about 7.5 to about 8.2 and heated to
a sterilization temperature of at least about 121° C.
for a period of time, typically from about 20 minutes
to about 25 minutes, or equivalent time-temperature
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conditions adequate to fully sterilize the lens.
Preferably, but not necessarily, the lens is stored
in a substantially oxygen-free atmosphere during
sterilization (such as a nitrogen atmosphere) and is
sterilized in the dark. Upon cooling after the
sterilization treatment, the sterilized, hydrated
photochromic hydrophilic contact lenses are provided
in a hermetically sealed, bacteria-impervious
package.
The packaged, sterilized, hydrophilic contact
lenses will contain at least about 38 and preferably
at least about 50 weight percent water, based on the
total weight of the contact lens, and will have an
oxygen transmission coefficient Dk of at least about
9x10-11 (cc OZ mm) / (cm2 sec mm Hg) . The sterilized,
fully hydrated contact lenses are substantially clear
under non-activated conditions, but are capable of
reversibly reducing their transmittance at a.max by at
least about 20 percentage p.s.i, and preferably at
least about 40 percent under conditions of intended
use. By "conditions of intended use" is meant a 20
seconds or longer exposure to a UV light irradiance
of 0.010 to 0.30 mW/cm2, which simulates outdoor
exposure to sunlight which reaches the contact lens.
By "substantially clear" is meant that the contact
lenses transmit at least about 80% at, and preferably
at least about 900, of incident, visible light
through the central zone of the lens in their fully
hydrated condition, averaged across 380 to 780 nm.
Also contemplated is the use of a small amount
of a permanent color in the contact lenses. Thus use
of one or more tinting components, for example vat
dyes, in the lenses in such an amount that results in
an average percent transmittance over the range of
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380 to 780 nm of about 70°s transmittance or greater
when a photochrome, when present, is in its
unactivated state. In such an embodiment, the
presence of the photochromic compound then causes a
switch from at least about 70o transmittance at a.max
when the photochrome is in the unactivated state that
drops to at least about 40 o transmittance at 7~,",aX when
the photochrome is in its activated state.
The hydrated hydrophilic contact lenses also
have an effective photochromic response at both room
temperature (23° C.) and at eye-surface temperature
(nominally
35° C.). The sterilized hydrophilic, water-
containing contact lenses desirably have an initial
photochromic activity (0Y) of at least about 20°s at
23° C. Substantial activity should be retained at
35° C., the nominal temperature of the surface of the
eye.
The photochromic activity (0Y) is defined as the
difference in luminous transmittance (Y) between the
activated state and the fully faded state. The
quantity Y represents the transmission value as
perceived by the standard observer, according to ASTM
E-308 Color in CIE 193 System. The hydrophilic,
sterilized, hydrated contact lenses also have a
relatively rapid reversion to a substantially clear
state.
Detailed Description of the Invention
As indicated, the present invention is
directed to sterile, hydrated, photochromic
hydrophilic contact lenses which are substantially
clear in the unactivated state, but which can
reversibly reduce their visible light transmission
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when exposed to sunlight when worn by the user. The
present invention is also directed to methods for
manufacturing such sterile, hydrated, photochromic
hydrophilic contact lenses, as well as to specific
photochromic contact lens compositions.
In accordance with such manufacturing methods, a
hydrophilic, cross-linkable monomer mixture is
copolymerized with a photochromic comonomer. The
polymerization mixture desirably includes a light
stabilizer comonomer which is incorporated in the
hydrophilic polymerized gel of the contact lens to be
completed. The polymerization mixture composition
will typically comprise:
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Component Weight Percent
Cross linkable hydrophilic contact 80-98
lens monomer mixture
Photochromic comonomer component 1-7
Light stabilizer component 0.25-4
Free radical initiator 0.05 - .25
Cross Linkable Hydrophilic Monomer Mixture - The
cross linkable hydrophilic monomer mixture is the
predominant component of the copolymerization
mixture, typically comprising at least about 90
weight percent of the cross-linkable monomer
polymerization mixture on a non-solvent basis. The
crosslinkable hydrophilic monomer mixture will
generally comprise a hydrophilic monomer component
and a crosslinking component. A wide variety of
vinyl-polymerizable and allyl-polymerizable
hydrophilic monomers and crosslinking agents for
contact lens compositions are known, and may be used
in the production of photochromic contact lenses,
provided that the compositions are substantially free
of acid components.
In this regard, acidic monomers such as acrylic
acid and methacrylic acid are typical components of
hydrophilic contact lens formulations, in view of
their positive contribution to hydrophilic contact
lens properties. Such acids can also be present a.s
impurities in other conventional monomer components
such as acrylic and methacrylic esters. However, in
providing the hydrophilic lenses of the present
invention in an embodiment using spiro-oxazines, it
is preferred that the comonomer mixture be
substantially free of acid components, including
carboxylic acid components. By "substantially free"
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is meant that acidic monomers represent less than
0.25 and preferably less than 0.05 weight percent of
the total monomer mixture (dry basis).
Particularly preferred hydrophilic monomers are
acrylamide and methacrylamides, N-vinyl monomers,
hydroxy-alkyl acrylates and methacrylates, and
acrylic and methacrylic alkoxyesters, as are known in
the art.
Preferred hydrophilic polymer compositions may
be prepared from acrylamide and/or methacrylamide
monomers, with appropriate amounts of compatible
hydrophilic copolymers and crosslinking agents to
produce the desired water absorption. While
preferred hydrophilic polymer formulations are based
on acrylamide, other hydrophilic contact lens
formulations may also be utilized. In a preferred
version of the embodiment of the invention using
spiro-oxazine-based chromophores, the other
hydrophobic contact lens formulations are
substantially carboxylic acid-free. Glycol
monoesters of acrylic or methacrylic acid (preferably
glyceryl and hydroxyethyl methacrylate) with a minor
proportion of groups of a non-hydroxy terminated
alkoxy monomer, such as alkoxyalkyl acrylates and
methacrylates, alkylcarbitol acrylates and
methacrylates may also be used. Suitable hydrophilic
N-vinyl heterocyclic monomers include N-vinyl
pyrrolidones, N-vinyl succinimide, N-vinyl-epsilon-
caprolactam, N-vinyl pyridine and N-vinyl
glutarimide. For introduction of specialized
properties such as higher Dk values, one may also
incorporate polymerizable vinyl group (acrylate,
styryl, etc.) esters and amides containing fluorine
and siloxane substituents.
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The crosslinkable hydrophilic monomer mixture
will also include a crosslinking agent, in accordance
with conventional practice. Suitable crosslinking
agents for the acrylamide, methacrylamide and hydroxy
acrylate and methacrylate-based polymers include
polyfunctional acrylates such as ethylenediacrylate,
ethylene-dimethacrylate and/or trimethylol propane
trimethacrylate. Suitable crosslinking agents for
the N-vinyl based monomers are allyl esters derived
from the esterification of polybasic acids with allyl
alcohol, monoallyl itaconate, triallyl cyanurate and
N,N-diallylmelamine, the preferred crosslinking
monomer being diallylitaconate which contains a
polymerizable vinyl double bond in addition to two
allyl bonds. For example, water-swellable
hydrophilic contact lenses comprising N-vinyl
heterocyclic monomers, may include suitable
crosslinking agents such as polyfunctional allylic
crosslinking units containing more than one
polymerizable double bond (e. g., monoallyl itaconate,
diallyl itaconate, triallyl cyanurate, triallyl
isocyanurate, triallyl trimellitate, N,N-
diallylmelamine, and other multifunctional allyl
monomers) formed by the esterification of polybasic
acids with allyl alcohol, or mixtures thereof. The
proportions of the monomers are adjusted to give the
desired water content when the polymer is swollen to
equilibrium in an aqueous environment.
The concentration (percent by weight based on
the total weight of monomers) at which the
crosslinking monomers are used, typically range from
about 0.01% to about 2o depending on the mechanical
properties and water content desired. For high water
contents in the range of 70o-95°s, the preferred
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concentration range of crosslinking monomer is from
about 0.01% to about 0.5%. Where essentially none or
a very low amount of hydrophobic comonomer is used, a
concentration range of about 1% to 10% may be
employed, with about 5% being the preferred amount.
As indicated, the copolymerizable mixture may
also include minor amounts of compatible hydrophobic
monomers to adjust the water-absorbing capacity of
the contact lens. Suitable hydrophobic monomers are
the olefinically unsaturated alkyl esters of acrylic
and methacrylic acid, e.g., methyl, ethyl and butyl
methacrylates and acrylates. The percentage by
weight (based on the total weight of monomers
exclusive of the crosslinking monomer) of hydrophobic
monomer used, will depend on the desired water
content of the polymeric gel. 4dhen methyl
methacrylate is used as the hydrophobic monomer and
the concentration of crosslinking monomer is in the
range of 0.1 to 0.5%, about 60% is used to give a
polymeric gel of about 30% water content and about
5%-10% is used to give a polymeric gel of about 90%-
95% water content.
A UV absorbing dye which does not strongly
absorb in the entire range of activation wavelength
of the photochromic component, which is also
preferably a comonomer, may also be included in the
comonomer polymerization mixture. These UV blocking
comonomers include benzophenones and benzotriazoles
which do not block all of the UV A radiation. Their
long wavelength "cutoff" (i.e., at which the percent
transmission of shorter wavelengths decreases to
below 50 percent of the incident wavelength) is
desirably at about 360 nm.
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Photochromic Comonomer Component - As indicated,
an important component of the copolymerization
mixture is a vinyl (which is used herein to include
allyl groups) copolymerizable photochromic material,
preferably one or more photochromic chromenes,
spirooxazines, or spiropyrans having pendant
acryloyl, allyl, styryl, acenapthalene or
methacryloyl groups. By "vinyl copolymerizable" is
meant that the photochromic material has as an
integral component an unsaturated moiety, such as an
acryloyl, methacryloyl, vinyl e.g., including styryl
and acenapthalenoyl), allyl, or malefic group, which
is capable of undergoing free radical addition
reaction with a free radical polymer chain, and when
added to the free-radical chain is itself capable of
continuing the free-radical addition reaction with a
vinyl functional group.
The vinyl-polymerizable photochromic comonomer
components will typically be present in the
copolymerization mixture at a level of from about 0-.5
to about 6, and more preferably from about 1.5 to
about 4 weight percent, based on the total weight of
the copolymerization mixture. A particularly useful
vinyl-polymerizable blue photochromic comonomer is:
,CH3
H3 ~
N O
O
~N O
H3C ~ H
2
Acryloyl Photochrome Blue
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This comonomer is the D-acrylate derivative of the
Variacrol Blue A~ product of Great Lakes Chemical
Italia, S.r.i., although other vinyl-polymerizable
derivatives (including the non-methylated 2° amine
version) may also be used.
Similarly, the D-acrylate derivative of the
Variacrol Blue D~ product of Great Lakes Chemical
Italia S.r.i., or other vinyl-polymerizable
derivatives thereof (including the non-methylated 2°
amine version), are also preferred comonomers:
CH3 H3C ~CH3
N O
O
N O
CH3
H3C CH2
Dimethyl Acryloyl Photochrome Blue
The photochromic comonomer may be a single
compound having a specific absorption spectrum in the
activated state, or may be a mixture of different
vinyl-polymerizable photochromic compounds having
different absorption spectra in the activated state.
Photochromic monomers which may be utilized as
yellow and orange components in hydrophilic
photochromic contact lenses in accordance with the
present disclosure may include photochromic materials
as described in U.S. Patent No. 5,543,533, which have
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a vinyl functionality. Examples of additional
photochromic comonomers which may be blended with
other photochromic comonomers such as the photochrome
blue component to produce more neutral darkening such
as gray, brown or green colors, include:
H3C
CH3
O O
H31
CH2
Acryloyl Photochrome Red
This comonomer is an acrylic ester derivative of the
Variacrol Red PNO° product of Great Lakes Chemical
Italia S.r.i., although other vinyl-polymerizable
derivatives (including the non-methylated 2° amino
compound) may also be useful. The vinyl-
polymerizable functionality for photochromic monomers
such as the above-diagrammed Photochrome Blue(s),
Photochome Reds) and Photochrome Yellows) may, for
example, be positioned elsewhere on the napthalene
ring, on the phenyl ring, or bonded to the amine
group, e.g., as an acrylic ester or acrylamide,
preferably with a flexible intermediate chain such as
a C3 to Clo alkane, or a poly (ethylene) oxide ether
chain, joining the amine group of the merocryanine
system to the acrylic ester or acrylic amide group.
Similarly, a yellow-activatable photochromic
comonomer such as the following acryloyl photochrome
yellow in blends with other photochromic comonomers
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will assist in making the visible absorption spectrum
more uniform:
O
O
CH2
Acryloyl Photochrome Yellow
This comonomer is the L-acrylate derivative of the
Variacrol Photo L° product of Great Lakes Chemical
Italia S.r.i., although other vinyl-polymerizable
derivatives may similarly be particularly useful.
While the above-described compounds are examples
of preferred photochromic comonomers, a wide variety
of other vinyl-polymerizable comonomers may be
copolymerized into hydrophilic contact lens polymers,
and protected during sterilization in accordance with
the present disclosure. Particularly useful organic
photochromatic vinyl-polymerizable comonomers may
belong to the group of spirooxazines and
oxyspiropyranes which are derivatized with vinyl-
polymerizable functionality. Preferred organic
photochromatic compounds are those having a vinyl
polymerization functionality and a spirooxazine
moiety defined with the following general formula:
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s Ry [A)
R~ /
y ~ 3 T
Z
6\
R= ~ i O e~ ,
Ry / \ 9,
y. e.
\ /
6'
R6
where: R1 and RZ independently represent a
hydrogen or halogen atom (fluorine, chlorine or
bromine) or a group chosen from: linear or branched
C1-CS alkyl or halogen-alkyl, alkoxy C1-C5, nitro or
cyano; carboxyl, carboxy alkyl, carbonyl: R3 and R4
independently represent a linear or branched C1-CS
alkyl group, phenyl or benzyl; or R3 and R4 jointly
considered at the carbon atom to which they are
linked, form a cycloalkyl CS-C$ group; RS represents a
linear or branched C1-CS alkyl group, alkyl phenyl,
benzyl or allyl alkoxy, but also may represent a
vinyl polymerizable group such as an acryloyl or
methacryolyl group forming an amide with the ring
nitrogen, or a more spaced-apart functionality such
as a methacryloyl or an acryloyl ester which forms a
tertiary amine with the ring nitrogen to which the RS
group is attached:
O
CH2=C-C- (O-CHz-CH2}n-; where n= 1 to 10
R6 represents the hydrogen atom or a linear or
branched C1-CS alkyl group, or the group -NRB, R9 where
R8 is a linear or branched C1-CS alkyl group, phenyl
or benzyl, R9 is hydrogen or has the same meaning as
Re, or R8 and R9, considered jointly at the nitrogen
atom to which they are linked, form a cyclic
structure with from 5 to 12 members, possibly
containing an additional heteroatom chosen from
CA 02386247 2002-04-02
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oxygen and nitrogen; R~ represents a hydrogen or
halogen atom (fluorine, chlorine or bromine), or a
group chosen from linear or branched C1-CS alkyl,
cyano thioalkyl, ester carboxylate with 1 to 3 carbon
atoms in the ester portion, or it represents an
aromatic or condensed heterocyclic nucleus; in one of
the positions 7', 8', 9' or 10' with the CH group
which can be substituted by N. The R~ group is a
particularly desirable position for vinyl-
polymerizable functionality because it is remote from
the ring-opening functionality of the photochromic
moiety. The R~ vinyl-polymerizable groups are
preferably acryloyl or methacryloyl ester groups,
such as previously described for particularly
preferred comonomers. R1, R2, R6 or R~ may also
desirably be a styrenyl group to provide vinyl-
polymerization functionality. At least one of the R1,
RZ, R5, R6 or R~, should have a vinyl-polymerizable
functional group.
Examples of preferred photochromic compounds
belonging to the group of spirooxazines, which may
further include a vinyl polymerizable group for use
according to the present invention are: 1,3,3,4,5 or
1,3,3,5,6-pentamethyl spiro(indoline-2,3'-(3H)-
naphtho-(2,1-b)-(1,4)-oxazine; 1,3,3-
trimethylspiro(indoline-2,3'-(3H) naphtho-(2,1-b)-
(1,4)-oxazine; 1,3,3-trimethyl spiro(indoline-6'-(1-
piperidine) -2, 3- (3H) naphtho- (2, 1-b) - (1, 4) -oxazine,
1,3,3-trimethyl spiro (indoline-6'-(1-morpholine)-
2,3'-(3H)-naphtho-(2,1-b)-(1,4)-oxazine); 1,3,3,4,5-
or 1,3,3,5,6-pentamethyl spiro (indoline-6'-(1-
piperidine) -2, 3' - (3H) -naphtho - (2, 1-b) - (1, 4) -
oxazine); and 1,3,3-trimethyl spiro (indoline-6'-(1-
21
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piperidine)-9'-(methoxy)-2,3' (3H) naphtho(2,1-b)
(1,4-oxazine).
More generally, it is also possible to provide
vinyl polymerizable groups, such as previously
discussed, on photochromic compounds belonging to the
group
of spiro-indolino-oxazines defined with the general
formula (I)
R4 R5 R6R~
R3 _ N
-.,
2 ~ J A 1
R ~ N O ~ ~
Ri R ~~-~i
where: R represents a hydrogen atom; a C1-CS alkyl
group, linear or branched; a similar C1-CS alkyl group
substituted with from 1 to 5 halogen atoms chosen
from fluorine, chlorine, bromine or iodine, hydroxy
groups, C1-CS alkoxy groups, C1-CS carboxy alkyl
groups, cyano groups; a Cz-CS alkenyl group; a phenyl
group; a styrenyl or acenapthyl (vinyl-polymerizable)
group or benzyl group; or a vinyl-polymerizable group
such as an acryloyl or methacryloyl ester or amide
group, with or without a bridging group such as an
alkoxy, polyalkoxy or aliphatic chain.
R1 to R4 may, for example, be either the same or
different, as a hydrogen atom; a C1-CS alkyl group,
linear or branched; a similar C1-CS alkyl group
substituted with from 1 to 5 atoms of halogen chosen
from fluorine, chlorine, bromine and iodine, hydroxy
groups, C1-CS alkoxy groups, C1-CS carboxy alkyl
groups, cyano groups; a CZ-CS alkenyl group; a benzyl
group; a halogen atom chosen from fluorine, chlorine,
bromine and iodine; a hydroxy group; a C1-CS alkoxy or
polyalkoxy group; an amino group; a monoalkyl (C1-CS)
22
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amino group; a di-alkyl (C1-CS) amino group; a cyclo-
alkyl (C3- Clo) amino group; a piperidine, piperazine
or morpholine group; a carboxyl group; a carboxy
alkyl (C1-CS) group; a carboxy alkenyl C1-CS group; a
carboxy amidic group; a substituted carboxy amidic N-
alkyl (C1-CS) group, a substituted carboxy amidic N,N-
dialkyl (C1-CS) group; a cyano group; a nitro group; a
sulfonic group; a (C1 -CS) alkyl sulfonic group; an
aryl sulfonic group chosen from benzene sulfonic, p-
toluene sulfonic, p-chlorotoluene sulfonic groups; an
aryl group chosen from phenyl, styrenyl, biphenyl,
naphthyl groups;
RS and R6, either the same or different, each
represent independently an alkyl group (C1-CS), linear
or branched; a phenyl or styrenyl group; or RS and R6,
together with the carbon atom to which they are
connected, jointly represent a cycloalkyl (C4-C-,)
group;
R-, represents a hydrogen atom; a linear or
branched alkyl (C1-CS) group; a phenyl or styrenyl
group; a halogen atom chosen from fluorine, chlorine
or bromine; an alkoxy (C1 -CS) group; or a phenoxy
group;
A represents an arenic, monocyclic or polycyclic
group, containing at least one carboxylic function
(C--O) on the nucleus or in the side chain, chosen
from those which can be defined with formulae (II),
(III), (IV), (V) or (VI) shown below:
23
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Rle nu
RII R9
Re
R
Rls O
Rlo O Rn (111)
RII ~~ Rle
R ~Rls
Rls O RI~
Rlo Rls Ov)
RII Rs
RI Re
Rls R~~ O
Rlo Rls O RI9 M
RII ~) Rle
RI RI7
Ru Rl a Rls
RIO Ru (VI)
Rli Ris
RI g0
RIs
py Rle
Rt Rn
R71
where: R8 represents a hydrogen atom; a halogen
atom chosen from chlorine and bromine; a linear or
branched alkyl ( C1-C5 ) group ; an alkenyl ( CZ-CS ) group ;
a monocyclic or polycyclic aryl group, or a
heteroaryl group chosen from phenyl, naphthyl,
anthracyl, furanyl, pyrrolyl, thiophenyl, quinolyl
and pyrrolyl; or a similar aryl or heteroaryl group
substituted with from 1 to 4 groups chosen from
halogen atoms (fluorine, chlorine and bromine),
linear or branched alkyl (C1-CS) groups, hydroxy
groups, alkoxy C1-CS groups, nitro groups, cyano
groups, amino, mono-alkyl (C1-CS) amino groups, di-
alkyl(C1-CS) amino groups, piperidine groups,
piperazine groups or morpholine groups;
two contiguous points from Rlo to R13 represent
the condensation position with the oxazinic nucleus
in the general formula (I) and the others have the
same meaning as R1 - R4 ;
R9 and from R14 to Rl9 have the same meaning as Rl
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_R4 Preferably, in formula (I)
R represents a methyl, ethyl, benzyl, 2-allyl,
2-hydroxyethyl or 2-carboxymethylethyl group;
from R1 and R4, either the .same or different,
each represent independently the hydrogen atom, a
fluorine, chlorine or bromine atom, or a methyl,
isopropyl, trifluoromethyl, hydroxymethyl, benzyl,
hydroxy, methoxy, amino, piperidino, morpholino,
carboxyl, carboxymethyl, N,N-dimethylcarboxyamide,
cyano, nitro or phenyl group;
RS and R6, either the same or different, each
represent independently a methyl or phenyl group, or
together with the carbon atom to which they are
connected, jointly represent the cyclohexyl group;
R-, represents the hydrogen atom, the chlorine
atom or a phenyl, methyl or methoxy group;
A is one of the groups with formula from (II) to
(VI) where:
R8 represents the hydrogen atom, or a methyl,
isopropyl, phenyl, p-N,N-dimethyl amino phenyl, p-
cyano phenyl, p-nitro phenyl, p-methoxy phenyl,
naphthyl, 2-thiophenyl, 2-furanyl or 4-pyridyl group;
two contiguous points from Rlo to R13 represent
the condensation position with the oxazinic nucleus
in general formula (I) and the others each represent
independently the hydrogen atom, a fluorine, chlorine
or bromine atom, or a methyl, isopropyl,
trifluoromethyl, hydroxymethyl, benzyl, hydroxy,
methoxy, amino, piperidino, morpholino, carboxyl,
carboxymethyl, N,N-dimethylcarboxyamido, cyano, nitro
or phenyl group;
R9 from R14 to R19 each represent independently
the hydrogen atom, a fluorine, chlorine or bromine
atom or a methyl, isopropyl, trifluoromethyl,
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hydroxymethyl, benzyl, hydroxy, methoxy, amino,
piperidino, morpholino, carboxyl, carboxymethyl, N,N-
dimethylcarboxyamido, cyano, nitro or phenyl group.
Examples of photochromic compounds that may be
derivatized with vinyl-polymerizable functional
groups are:
1,3,3-trimethyl-8'-oxyphenyl-spiro-indolino-
[2 .3' ] (3H) -naphtho [2, 1-b] -1, 4-oxazine;
1,3,3-trimethyl-spiro-indolino-[2.3'](3H)-benzo
(a-)anthracen-(7',12')-dione-[3,4-b]-1,4-oxazine; and
1,3,3-trimethyl-8'-oxyphenyl-6'-piperidinyl-
spiro-indolino- [2.3' ] (3H) -naphtho- [2, 1-b] -1, 4-
oxazine.
Other photochromic compounds which may be
provided with a polymerizable vinyl group for
copolymerization in hydrophilic contact lens
formulations include those belonging to the group of
spiro-oxazepin-oxazines described in Italian patent
application No. 22.659 a/89 filed on Dec. 12, 1989,
definable with the general formula:
Rs R6
Ra
R; O ~ R~
R1 ~ N Ra
R~ R \
O X
R» ~ R9
Ril Rio
where: X represents the nitrogen atom or CH
group; R represents a hydrogen atom; a linear or
branched alkyl group; a similar alkyl C1-CS group
substituted with from 1 to 5 halogen atoms chosen
from fluorine, chlorine, bromine and iodine; an
alkoxy C1-CS group; a carboxyalkyl C1-CS group; a cyano
26
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group; an alkenyl Cz-C6 group; a phenyl group; or a
benzyl from R1 to Rlz, either the same or different,
each represent independently a hydrogen atom; a
linear or branched alkyl C1-CS group; an alkenyl Cz-CS
group; a benzyl group; a halogen atom chosen from
fluorine, chlorine, bromine and iodine; a hydroxy
group; an alkoxy Cz-CS group; an amino group; a mono-
alkyl (C1-CS) amino group; a di-alkyl (Cz_CS) amino
group; a cyclo-alkyl (C3-C7) amino group; a carboxyl
group; a carboxyalkyl C1-CS group; a carboxyamidic
group; a substituted carboxyamidic N-alkyl (C1-CS), or
substituted N,N-dialkyl (C1-CS) group; a cyano group
or a nitro group; or two contiguous points between R9,
Rio, Rll and Rlz j ointly represent a condensed benzenic
nucleus without any substituents or carrying from 1
to 3 substituents chosen from those described for R1 -
Rlz .
Preferably, in formula (VII), R represents the
hydrogen atom or the methyl radical; from R1 to R8
each represent independently the hydrogen atom or the
methyl radical, from R9 to Rlz each represent
independently the hydrogen atom, the methoxy radical
or the nitro radical; or two adjacent points jointly
represent a condensed benzenic nucleus without any
substituents or carrying from 1 to 3 substituents
chosen from the methoxy, nitro and carboxymethyl
groups. At least one of the groups R and R1-Rlo
should be a vinyl-polymerizable functional group such
as a methacryloyl or acryloyl ester or amide group, a
styrenyl or acenapthalene group, as previously
discussed.
Specific examples of preferred photochromic
compounds which may be provided with vinyl
polymerization functionality are:
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10-methyl spiro dibenzo (b, f)-1,4-oxazepin-
11, 3' - (11h) naphtho (2, 1-b) - (1, 4-oxazine) .
10-methyl-8'-methoxy-6'nitro spiro dibenzo(b,-
f)-1,4-oxazepin-11,2'-(llh)benzo(2,1-b) (3H) pyrano;
10-methyl-8'-methoxy spiro dibenzo (b, f)-1,4-
oxazepin-11,3'-(llh)naphtho(2,1-b)-(1,4-oxazine); and
the formic acid esters of these spiro dibenzo
compounds.
Similarly, other useful copolymerizable
photochromic materials which can be copolymerized
under basic pH conditions to manufacture packaged,
sterile photochromic hydrophilic lenses, include
substituted or unsubstituted benzopyrano-fused
napthopyrans such as:
R
Rz
;2
R
R2
;2
28
R, R,
R,
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R
R2
2
R~
and
R
R2
" K2
where at least one of R, R1 or RZ (preferably R)
comprises an additional polymerizable group such as
an acryloyl, methacryloyl, vinyl (including
styrenyl)or allyl group, which may be directly or
indirectly (via an intermediate moiety which does not
prevent copolymerization with contact lens
comonomers) attached to the photochromic moiety, as
indicated. The benzopyrano-fused[2,1-b]naphthopyrans
may be prepared as described in U.S. Patent No.
6,022,495 and have a variety of substituents, for
example, at a position ortho to the oxygen atom of
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the naphthopyran ring, such as 2,10-
dihydro [2] benzopyrano
[4',3':3,4]naphtho-[2,1-b]-pyrans, as well as 3,8-
dihydro [ 2 ] benzopyrano [ 3 ' , 4 ' : 5 , 6 ] -naphtho [ 2 , 1-
b]pyrans. The R and/or R1 groups may together form a
ring such as an oxo group, may each be hydrogen, C1-C6
alkyl, C3-C-, cycloalkyl, allyl, phenyl, mono- and di-
substituted phenyl, benzyl or mono-substituted
benzyl. Each of the phenyl and benzyl group
substituents may be C1-C6 alkyl or C1-C6 alkoxy.
Preferably, Rl and R2 (when not an addition
polymerizable moiety) may be hydrogen, C1-C4 alkyl,
C3-C6 cycloalkyl, phenyl, mono- or di-substituted
phenyl, benzyl and mono-substituted benzyl. Each of
the preferred phenyl and benzyl group substituents
may be C1-C4 alkyl, C1-C4 alkoxy, chloro or fluoro.
The R2 substituents may be unsubstituted, mono-,
di- and tri-substituted aryl groups, phenyl and
naphthyl; unsubstituted, mono- and di-substituted
heteroaromatic groups pyridyl, furanyl, benzofuran-2-
yl, benzofuran-3-yl, thienyl, benzothien-2-yl,
benzothien-3-yl, each of the aryl and heteroaromatic
substituents being phenyl, phenyl (C1-C3) alkyl, di (C1-
C6)alkylamino, piperidino, morpholino, pyrryl, C1-C6
alkyl, C1-C6 chloroalkyl, C1-C6 fluoroalkyl, C1-C6
alkoxy, mono (C1-C6) alkoxy (Cl-C4) alkyl, acryloxy,
methacryloxy, chloro or fluoro.
Substituted or unsubstituted addition
copolymerizable indeno-fused napthopyrans are
photochromes, shown below, which may desirably have
yellow to orange colors, and which may also be
utilized as photochromic comonomers.
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~1
Similarly, substituted or unsubstituted addition
copolymerizable fluorenapthenopyrans, shown below,
are photochromic compounds that may be utilized as
photochromic comonomers alone or in combination with
other photochromes in a sterilized hydrophilic
contact lens:
R
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Other substituted copolymerizable napthopyrans
generally include compounds such as:
a_
~1
R
and
R~
R~
where at least one of R or Rz is a vinyl or allyl
group which can undergo copolymerization with vinyl-
polymerizable hydrophilic contact lens monomers such
as hydroxyethyl methacrylate and acrylamide, and the
32
R R
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various R, Rl.and Rz groups may be as previously
described.
Hindered Amine Liqht Stabilizer Comonomer -
Further in accordance with the present invention, a
vinyl-copolymerizable, sterically hindered amine
light stabilizer for the photochromic component is
also desirably provided in the copolymerization
mixture. Particularly desirable sterically light
stabilizer comonomers are hindered cyclic tertiary
amines having acrylic or methacrylic functionality,
such as the methacryloyl ester hindered cyclic
tertiary amine derivative of Uvacryl 80T"' (Great Lakes
Chemical Italia S.r.i.):
H3(
i
CH3
Methacryloyl Hindered Amine Comonomer
Other suitable hindered amine stabilizers typically
referred to as HALS may be prepared as vinyl-
copolymerizable comonomers, and may also be suitable
for copolymerization in the lenses of the present
disclosure, such as a similar hindered amine which
may be prepared by esterification of the hindered
tertiary piperidine moiety with malefic acid:
33
H3C /CH2
O O
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CHg CH3
HsC CH3
O O
HgC-N O O N-CHg
H C ~CH3
CHg CHg
Malefic ester hindered amine comonomer
The vinyl-polymerizable sterically hindered
amine light stabilizer component will typically be
present in the copolymerization mixture at a level of
from about 0.25 to about 4 weight percent, and more
preferably from about 1 to about 2 weight percent,
based on the amount of the total monomer mixture on a
dry basis. Various other vinyl-polymerizable
sterically hindered amines (HALS) may be utilized.
Other photochromic fatigue stabilizers may also
be copolymerized in the manufacture of sterilized
photochromic contact lenses. In this regard, small
amounts of vinyl-polymerizable ultraviolet light
and/or hindered phenolic antioxidants may be utilized
in the lens compositions. For example, vinyl-
copolymerizable hindered antioxidant compounds and/or
asymmetric diaryloxalimide UV absorbing compounds
such as the following may be provided, where R groups
may, for example, be in accordance with U.S. Patent
R
HO
O
R R 0I \CH2
No. 5,770,115:
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R R
R
N
H
However, the amounts of these materials, if any,
should be relatively small. Even sterically hindered
phenol antioxidants can interfere with the
polymerization reaction, and the amount and
absorption wavelength spectrum of any UV absorption
components should not substantially interfere with
the UV photochromic activation of the lenses) in use
by the wearer.
Copolymerization Procedure - As indicated, the
copolymerization mixture is polymerized under
relatively mild copolymerization conditions. In this
regard, relatively mild free radical generators such
as azoisobutylnitrile (AIBN) and 2,2'-azobis (2,4-
dimethylvalero nitrile (e. g., the Vazo 52~ mild free
radical initiator product of DuPont) may be used at
relatively low levels, in the substantial absence of
peroxide free-radical initiators.
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The copolymerization is preferably carried out
in bulk, without additional solvent, in order to
maximize the effectiveness of the free-radical
initiator and minimize the amount of free-radical
initiator required. Other, mild, non-oxidizing free-
radical generators may be utilized, such as mild
redox systems and free-radical generators using
visible light sensitizers.
It is preferable that the copolymerization be
carried out in a substantially oxygen-free or reduced
oxygen environment, such as a nitrogen atmosphere
with at least 95o nitrogen and less than 5 weight
percent oxygen. It may also be desirable to carry
out the polymerization, at least partially, in the
dark (a UV and visible light-free environment) in
order to protect the photochrome material. The
copolymerization may desirably be carried out in
individual contact lens molds such as illustrated in
FIGURE 1 (see U.S. Patent No. 5,316,700), although
the polymerization may also be carried out in a
cylinder or other container to produce shapes such as
solid rods which can be sliced and shaped into
contact lenses in accordance with conventional
practice. For individual molded contact lenses,
typically the polymerization may be carried out at a
temperature in the range of from about 50° C. to
about 90° C. for a time period of 2 to 5 hours.
Typically, for solid rod polymerization, the
copolymerization may be carried out at a temperature
in the range of from about 30 to about 45~ C., using
from about 0.03 to about 0.10 weight percent of AIBN,
Vazo 52 or other mild non-peroxide, free-radical
based on the total weight of the monomer (dry basis).
The polymerization time may typically be in the range
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of from about 6 to about 48 hours. As indicated, at
high temperature-short time cures, the polymerization
times will be less than 10 minutes at temperatures of
120° C. or more.
Hydration and Sterilization Procedures - The
formed polymerized contact lens containing the
copolymerized photochromic material and stabilizer is
hydrated in an aqueous hydrating solution to a
hydration level of at least about 38% by weight
water, and preferably in the range of from about 50%
to about 80°s by weight water, based on the total
weight of the hydrated contact lens. The hydration
solution may also serve the function of leaching any
water-soluble components from the lens. The
temperature at which the lenses are hydrated is
preferably less than about 80° C. and typically in the
range of from about 15 to about 30° C. The hydration
of the lens may typically take from about 10 to about
200 minutes. The hydration and leaching solution is
predominantly water, but generally contains small
amounts of additional materials such as
bacteriostats, and buffers such as sodium or
potassium carbonates, phosphates, bicarbonates,
and/or borates. The hydration solution will
desirably have a pH in the range of from about 7.0 to
about 9.0, preferably in the range of from about 7.0
to about 8.2, and more preferably in the range of
from about 7.0 to about 7.8.
The hydrated lens is subsequently hermetically
sealed in a sterilization package in an aqueous
packaging solution for sterilization having a pH of
at least about 7.2 and preferably in the range of
from about 7.5 to about 8.2. The pH of the packaging
solution may be adjusted with physiologically
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acceptable alkali or alkaline earth bicarbonates,
borates and/or phosphates, such as sodium or
potassium bicarbonates, borates and/or phosphates or
mixtures thereof, and/or ethylenediamine tetraacetate
(EDTA, e.g., disodium salt) or
tris(hydroxymethyl)aminomethane ("Tris") as necessary
or appropriate, and heated to a sterilization
temperature of at least about 121° F. for a period of
time adequate to fully sterilize the lens. V~Ihile the
hydration solution used to hydrate the contact lens
may be used in the sterilization procedure, it is
preferred that the hydrated contact lenses be removed
or separated from the aqueous hydration fluid, and
reintroduced into a separate aqueous sterilization
packaging solution having a pH of at least about 7.2,
and preferably in the range of from about 7.2 to 8.5.
The hydrated lenses and the packaging solution are
then hermetically sealed in a suitable sterilization
package. In this regard, for example, the lenses may
be sterilized in a sealed blister package, which
protects the lens and maintains its sterility until
it is first opened by the consumer. The high pH
packaging solution may be placed with the lenses in
the cup-like receptacles of a contact lens blister
package 20 such as illustrated in FIGURES 2a and 2b.
The blister pack 20 may be a conventional contact
lens package such as illustrated in U.S. Design
patent 352,237, and used by Wesley Jessen Corporation
for packaging of its FreshLookTM contact lens
products. In the packaging and sterilization
procedure, the high pH aqueous packaging solution 21
is placed in the packaging receptacle 22 formed in a
thermoplastic plastic film, with the hydrated contact
lens 23. A sealing layer 24, which may comprise a
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thermoplastic film and an aluminum foil with
appropriate adhesive sealant, may be placed and
sealed on the carrier receptacle 22 to secure the
contact lens 23 and the aqueous sterilization
solution within a hermetically sealed chamber 25 in
accordance with conventional practice. The contact
lens blister package 20 itself may be sealed in a
bacteria-impervious plastic package containing
another contact lens.
Both the contact lens blister package 20 and any
surrounding packaging may desirably each provide a
hermetic seal against contact with the external
atmosphere and bacteria. An inert gas such as
nitrogen may desirably be used in the packaging of
the contact lenses in the contact lens carrier and in
the hermetically sealed package. The atmosphere
surrounding the contact lenses in the contract lens
carrier may be less than 5 weight percent oxygen, and
at least 95 percent nitrogen, to reduce the amount of
oxygen present during the sterilization step. A
physiologically acceptable oxidation inhibitor such
as ascorbic acid (e. g., the sodium or potassium salt
thereof) may also be included in the packaging
solution, which may serve to increase the shelf-life
of the packaged lens.
As indicated, it is important that the aqueous
sterilization solution have a pH of at least about
7.4 at ambient storage temperature (about 20°C), and
preferably in the range of from about 7.4 to about
8.2 or more. The sterilization solution is
predominantly water, also containing a suitable
alkaline buffering agent such as alkali carbonates,
bicarbonates, phosphates, borates or mixtures
thereof. Sodium and potassium carbonates or
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bicarbonates, and tris(hydroxymethyl)aminomethane
("Tris")are particularly preferred pH adjusting
agents.
Triethylamine has been tested as a pH
adjusting agent by addition of to by weight of
triethylamine to the aqueous sterilization solution;
however, greater discoloration resulted from the
sterilization procedure with the triethylamine
additive than sodium bicarbonate additive.
Bacteriostatic agents, water soluble polymers and
other typical hydrophilic lens storage components
such as sodium borate may be present in small
quantities, provided they do not reduce the pH below
7.12, or adversely affect the photochromic properties
of the lens during sterilization. Typically, the
aqueous sterilization solution will contain from
about 0.05 to about 0.20 weight percent of the
buffering agent, which is sufficient to provide the
desired pH in equilibrium with the hydrated contact
lens.
~nlhen sterilizing a photochromic contact lens at
a relatively high pH, such as above a pH about 7.8,
it may be desirable to provide for a reduction in the
pH within the hermetically sealed package after the
sterilization procedure. For example, when using an
alkali carbonate or bicarbonate packaging solution
with a pH of 8.2, it may be desirable to reduce the
pH of the packaging solution to a pH in the range of
from 7.12 to 7.8 after sterilization for storage,
shipping and ultimate use by the consumer. In this
regard, for example, it may be desirable to form at
least part of the sealed contact lens package from a
plastic sheet or film which has a limited degree of
permeability to carbon dioxide, and to store the
CA 02386247 2002-04-02
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sealed, sterilized contact lens packages in a carbon
dioxide atmosphere until the pH of the solution is,
for example, within the range of 7.12 to 8.5,
preferably 7.12 to 7.8.
It may be desirable for maintaining the
photochromic shelf-stability of the sealed,
sterilized contact lenses, that they be retained in
the package in an aqueous solution having a pH of
more than 7.2. The packaging may desirably filter
out W radiation such as by incorporating a W
absorber in the packaging film. Preferably, the
packaging of the hermetically sealed, sterilized
contact lens will absorb at least 95 percent of
incident UVA and UvB radiation (which would otherwise
be transmitted to the lens) integrated over the
entire package.
Sterilization Procedure - The hermetically
sealed contact lenses in the aqueous sterilization
solution having a pH above about 7.4 are subsequently
sterilized in an autoclave at a temperature of at
least about 121°C. for a time of at least about 25
minutes, or equivalent time-temperature conditions,
in order to fully sterilize the lenses. Because
elevated temperatures are destructive to the
photochromic materials, however, time-temperature
sterilization treatment in excess of the minimum
necessary to provide adequate sterilization
(including an appropriate process safety factor)
should best not be carried out. It may also be
desirable that the sterilization be carried out in
the dark to minimize the degradation of the
photochrome material.
As indicated, the sterilized contact lens is
substantially clear (e. g., containing a tint level
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only sufficient to act as a "handling tint") under
non-activated conditions, but is capable of
reversibly reducing its transmittance over the
visible spectrum by at least about 30 percent under
conditions of intended use. These conditions include
an aqueous environment at a temperature of about 35°
C. which is shielded from direct, overhead sunlight
with a maximum incident UV flux of about 1/5th that
of direct sunlight.
The hydrophilic, water-containing contact lens
will desirably have an initial photochromic activity
of at least about 30%, at room temperature (23° C.)
under conditions of outside use. The hydrophilic,
water-containing contact lens should also have a
fatigue resistance suitable for extended use of at
least two (2) weeks, characterized by retaining a
photochromic activity of at least 250 over 70 hours
of use in sunlight.
Having generally described various aspects of
the present invention, it will now be described with
respect to the following illustrated examples.
Example 1
A series of hydrophilic photochromic contact
lens formulations is prepared by mixing a solventless
blend of hydrophilic lens monomers, a functional
acrylic-based photochromic compound, and a functional
vinyl-polymerizable, acrylic-based light stabilizer
stabilizing agent, in the following proportions:
Composition of Photochromic Test Lenses
Run Run Run Run Run Run Run Run
#1 #2 #3 #4 #5 #6 #7 #8
DMA (Dimethyl0.53050.57190.55790.55010.53030.56600.57610.5302
ac lamide
MMA (Methyl 0.37940.38120.39850.40730.43320.39040.39740.4332
methac late)
EGDMA (Ethylene0.04790.01810.01580.01510.01000.01500.01530.0100
GI col Dimethac
late
Vazo~ 64,AIBNfree0.00370.00240.00100.00050.00010.00000.00000.0003
radical initiation
product
of DuPont
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Vazo~ 52, 0.00000.00000.00000.00000.00000.00050.00000.0000
low temp.
free radical
initiator
roduct of
DuPont
Esperox 33, 0.00000.00000.00000.00000.00000.00000.00200.0000
peroxide
initiator
Acryloyl Photochrome0.01910.01950.01980.02000.01930.02020.00200.0193
Blue (supra
Uvacryl 80 0.01940.00690.00700.00710.00700.00790.00720.0070
product of
Great Lakes
Chemical
Italia S,r,l.
methacryloyl
hindered tertiary
amine,
(su ra)
Polymerization Procedure - The monomer mixture,
including a crosslinker, vinyl-polymerizable
photochromic compound, vinyl-polymerizable light
stabilizer stabilizer and initiator were weighed in a
flask and mixed. Approximately 0.2 ml of the mixture
was dispensed into the concave mold half of a contact
lens casting cup. The convex mold half was press-
fitted into the concave half, leaving the monomer
sandwiched between the optical surfaces of the
casting cup. The lens was cured in an oven for 3
hours at 75° C. under a nitrogen atmosphere. The
casting cup was removed and its halves separated. By
deforming the mold, the lens was removed. It was
placed in about 10 ml of hydration solution for 45
minutes. During this time it swells, forming a
hydrogel with water content of about 57-62% by
weight, based on the latest weight of the hydrated
lens. The hydrated lens is removed from the
hydration solution and placed in a vial containing
about 5 ml of standard packaging solution. Ten drops
of saturated aqueous sodium bicarbonate solution are
added. The bottle is sealed with a rubber stopper
held in place by a crimped aluminum cap. The lens is
sterilized by placing the vial in an aluminum block
heater at a temperature of 125° C. for twenty
minutes. The vial fits into a cavity in the block,
so heat transfer to the vial is very rapid. Vials
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are then removed and cooled by running cold tap water
over them.
Photochromic properties of lenses made in
accordance with Run 8 were determined by recording
the UV-visible spectra at 23° C. of the deactivated
and activated forms, with a Hewlett Packard HP8452A
spectrophotometer (activation for 60 seconds of
radiation with a UVA lamp having an irradiance at the
lens surface of 1.5 mW/cm2.
A first hydrated photochromic contact lens made
in accordance with Run 8 of Example 1 and having a
thickness of about 0.09 mm at its central zone is
placed in a quartz cuvette, and the transmittance of
the central zone was tested in the spectrophotometer.
This lens had been stored in the dark at ambient
temperature, and not previously been exposed to UV
radiation. The transmissivity of the lens at its
central zone was first measured prior to UVA
exposure, to provide a transmissivity baseline Curve
32 as ("no activation") shown on FIGURE 3a. The lens
was then subjected to 60 seconds of exposure to UV
radiation from a UVA lamp. The visible light
transmissivity spectrum measured immediately after 60
seconds of exposure to UVA radiation at an irradiance
of 1.5 mW/cm2 is shown as Curve 34 (T zero) in FIGURE
3a. The absorption peak at approximately 610 nm
shows a transmissivity of less than 20%, which was
reduced to this level by the 60 second UVA exposure,
from a transmissivity of greater than 90% at the
baseline 32. The transmissivity of the lens was
again measured after 10 seconds without any further
UVA exposure, and the transmissivity data is
presented at Curve 36 (10 sec). The transmissivity
of the lens was again measured after an additional 10
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seconds without further UVA exposure, and the
transmissivity after 20 seconds from UVA activation
is presented by Curve 38 (20 sec). Similarly, the
transmissivity was again measured 30 seconds after
the activating UVA exposure, and the transmissivity
data is presented at Curve 40. The data of Curves
32, 34, 36 and 38 illustrates the initial
photochromic sensitivity, and the relatively rapid
deactivation of the photochromic hydrophilic contact
lenses of Run 8 of the Example.
A second hydrated photochromic contact lens made
in accordance with Run 8 of Example 1 and having a
central zone thickness of about 0.09 millimeters, was
pretreated by exposure to 48 cycles of UVA radiation
before measuring its activation and deactivation
response. The lens was subjected to 48 one-half hour
cycles of 15 minutes of irradiation from a model XX-
15L UVA lamp (UVP, Inc., San Gabriel, CA) at an
irradiance of about 1.98 milliwatts/square
centimeter, followed by 15 minutes without such
radiation. This 24 hour UV treatment thus subjected
the lens to a total of 12 "on" hours of UVA radiation
during which the lens was being activated, with 12
total "off" hours during which the lens was
undergoing deactivation. The pretreated lens was
subsequently placed in a quartz cuvette, and tested
in the spectrophotometer in the same manner as the
lens used for the tests of FIGURE 3a. The
transmissivity of the lens was measured prior to UVA
exposure, to provide a transmissivity baseline as
("no activation") shown on FIGURE 3a. The visible
light transmissivity spectrum measured immediately
after 60 seconds of exposure to UVA radiation at 1.5
mW/cm2 is shown as Curve T zero in FIGURE 3b. The
CA 02386247 2002-04-02
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absorption peak at approximately 610 nm shows a
transmissivity of about 200, which is only slightly
more than that of the lens of FIGURE 3a, indicating
good fatigue resistance. The transmissivity of the
lens was again measured after 10 seconds (without any
further UVA exposure), and the transmissivity data is
presented at Curve 36. The transmissivity of the
lens was again measured after an additional 10
seconds without further UVA exposure; the
transmissivity after 20 seconds from UVA activation
is presented by Curve 38. Similarly, the
transmissivity was again measured 30 seconds after
the activating UVA exposure, and the transmissivity
data is presented at Curve 40. This data further
illustrates the relatively rapid deactivation of the
photochromic hydrophilic contact lenses of Run 8 of
the Example, the rapid deactivation and the fatigue
resistance of the lens formulation.
Example 2
Yellow Photochrome - Lenses containing the
yellow vinyl-polymerizable photochrome have been made
and sterilized as set forth in Example 1. No
discoloration was noticed after the sterilization,
and photochromic response was intact.
Example 3
A series of seven hydrophilic photochromic
contact lens formulations is prepared by mixing a
solventless blend of substantially acid free
hydrophilic lens monomers, a blend of copolymerizable
acrylic-based photochromic compounds having different
absorption characteristics across the visible light
region, and a functional vinyl-polymerizable,
acrylic-based hindered amine stabilizing agent, in
proportions as follows:
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Composition of Photochromic Test Lenses
Run Run Run Run Run Run Run
#1 #2 #3 #4 #5 #6 #7
DMA (Dimethyl0.50820.50820.50820.50820.50820.50820.5082
ac lamide
MMA (Methyl 0.41520.41520.41520.41520.41520.41520.4152
methac late)
EGDMA (Ethylene0.00950.00950.00950.00950.00950.00950.0095
Glycol Dimethacrylate
VazoO 64,AIBNfree0.00040.00040.00040.00040.00040.00040.0004
radical initiation
product
of DuPont
Acryloyl Photochrome0.02000.03000.00000.03000.01500.03000.0150
Blue or dimethyl
acryloyl
photochrome
blue
(supra)
Acryloyl Photochrome0.02000.00000.03000.03000.03000.01500.0150
Yellow (su
ra
Acryloyl Photochrome0.02000.03000.03000.00000.01500.01500.0300
Red (supra)
Methacryloyl 0.00670.00670.00670.00670.00670.00670.0067
hindered
tertia amine,
(supra)
The polymerization mixture of each of Runs 1-7,
including the EGDMA crosslinker, the vinyl-
polymerizable photochromic compound mixture, the
vinyl-polymerizable hindered amine stabilizer and the
Vazo 64~ mild free-radical initiator are weighed in a
flask and mixed.
Approximately 0.2 ml of each mixture of Runs 1-7
is dispensed into the concave mold half of a contact
lens casting cup, such as that illustrated in FIGURE
1. The convex mold half is press-fitted into the
concave half, leaving the monomer sandwiched between
the optical surfaces of the casting cup. The lens is
cured in an oven for 3 hours at 75° C. under a
nitrogen atmosphere. The casting cup was removed and
its halves separated and the lens was removed. It is
placed in about 10 ml of aqueous hydration solution
for 45 minutes. During this time it swells, forming
a hydrogel with water content of about 55-65% by
weight, based on the total weight of the hydrated
lens. The hydrated lens is removed from the
hydration solution and placed in a vial containing
about 5 ml of standard packaging solution. Ten drops
of saturated aqueous sodium bicarbonate solution are
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added. The bottle is sealed with a rubber stopper
held in place by a crimped aluminum cap. The lens is
sterilized by placing the vial in an aluminum block
heater at a temperature of 125° C. for twenty
minutes. The vial fits into a cavity in the block,
so heat transfer to the vial is very rapid. The
vials are then removed and cooled with running cold
tap water over them.
The lenses of Runs 1-7 have a photochromic
response, and a relatively more neutral color in the
activated state, than a lens using any one
photochrome alone.
Example 4
Photochromic lenses were prepared [as in Example
1 having a composition of Dimethylacrylamide
(0.5082), Methylmethacrylate (0.4152), Ethylene
Glycol Dimethacrylate (0.0095), Vazo~ 64 (DuPont;
0.0004), Photochrome D (0.0600), and amine-
derivatized UvacrylT"" 80 (Great Lakes Chemical Italia
S.r.I.; 0.0067). Five identically prepared lenses
were hydrated as in Example 1, and after hydration of
the dry lenses, they were respectively transferred to
each of the following solutions:
A. 0.2M sodium bicarbonate, added sodium
carbonate to pH 8.19
B. 0.2M tris(hydroxymethyl)aminomethane, added
HCl to pH 8.19
C. Sodium tetraborate (--0.18M boron) added HC1
to pH 8.17
D. 0.2M Na2HP04, added HC1 to pH 8.14
E. Standard packaging solution, nominally pH
7.4 (very low bicarbonate concentration)
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The lenses in solutions A, B, C, and D were
autoclaved at a temperature of 121°C for 25 minutes,
while the lens in solution E was not autoclaved. The
resulting pH values of the solutions containing the
lenses were measured as follows:
A. 8.36
B. 8.26
C. 8.24
D. 8.21
E. 7.72
The o transmission values at 620 nm after 120
sec of 400 uW/cm2 UVA were measured for each of the
Runs A-E, for initial values, and after storage for
11 weeks at room temperature and after 11 weeks at a
refrigeration temperature of 4°~. '
Initial 11 weeks Room Temp. 11 weeks refrigerated
A. 32 44 55
B. 31 48 55
C. 47 42 53
D. 43 42 52
E. 32 31 50
NOTE: except for sample "B", the 11-week oT
numerical values are somewhat misleading because of
the haze present in some lenses.
Physical appearance of lenses after 11 weeks:
most contained a haze that could not be removed by
cleaning the surface. Observations:
Room temp storage Refrigerated storage
A. cloudy clear
B. clear clear
C. cloudy clear
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D. some cloudiness very little cloudiness
E. very hazy very hazy
From these tests, the sodium bicarbonate, sodium
tetraborate and Tris buffers appear to be effective
in protecting the photochromic lenses, with the Tris
buffer having the best performance. A variety of
related biological buffers may similarly be used.
While the present invention has been described
with respect to particular embodiments of apparatus
and methods, it will be appreciated that various
modifications and adaptations may be made based on
the present disclosure and are intended to be within
the scope of the accompanying claims.
