CA2386247A1 - Sterile photochromic hydrophilic contact lenses - Google Patents

Abstract

Sterile, hydrophilic photochromic contact lenses, and methods for manufacturing such lenses, utilizing an alkaline sterilization solution.</SD OAB>

Description

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 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 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 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 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 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 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 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 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 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 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:

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"

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.

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 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.

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

Acryloyl Photochrome Blue 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

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 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:

O O

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 will assist in making the visible absorption spectrum more uniform:
O
O

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:

s Ry [A) R~ /
y ~ 3 T
Z
6\
R= ~ i O e~ , Ry / \ 9, y. e.
\ /
6' 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 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-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) 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:

Rle nu 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 Ru Rl a Rls RIO Ru (VI) Rli Ris RI g0 RIs py Rle Rt Rn 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 _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, 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 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:

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

;2 R, R, R, R

R~
and R

" 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 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.

~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

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 R R

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 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:

O O

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:

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.

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 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 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 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 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 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 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 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 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 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 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:

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 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) 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 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.

Claims (10)

WHAT IS CLAIMED IS:

1. A method for manufacturing sterile, hydrated, hydrophilic contact lenses which are substantially clear, but can reversibly reduce their transmission in sunlight when worn by the user, comprising the steps of: copolymerizing a cross-linkable hydrophilic contact lens monomer mixture, and one or more vinyl-polymerizable photochromic comonomers under mild free-radical initiation conditions to produce a cross-linked hydrophilic polymer gel integrally incorporating the one or more photochromic comonomers;
hydrating the contact lens containing the copolymerized one or more photochromic comonomers in an aqueous hydration solution to a hydration level of at least about 38% by weight water, based on the total weight of the hydrated contact lens, hermetically sealing the hydrated contact lens in a sterilization package in an aqueous sterilization solution containing a protective alkaline buffering agent in effective amount and having a pH of at least about 7.2, and heating the hydrated contact lens in the aqueous sterilization solution in the sterilization package to a sterilization temperature for a period of time adequate to fully sterilize the lens in the sterilization package, and cooling the hydrated contact lens in the sterilization solution to provide a sterilized, hydrated photochromic hydrophilic contact lens in a hermetically sealed, bacteria-impervious package.

2. The method in accordance with Claim 1 wherein said photochromic comonomer is a chromene, spirooxazine, spiropyran, benzopyran, napthopyran, or mixture thereof, and wherein the pH of the sterilization solution is in the range of from about 7.8 to about 8.4.

3. The method in accordance with Claim 1 wherein said copolymerization step further includes copolymerization of said contact lens monomer mixture and said one or more vinyl-polymerizable photochromic comonomers with one or more vinyl-polymerizable light stabilizer stabilizers for the one or more photochromic comonomers, and wherein the alkali buffering agent comprises sodium or potassium carbonate, borate, bicarbonate or phosphate.

4. The method in accordance with Claim 1 wherein said monomer mixture comprises dimethylacrylamide, methylmethacrylate, and ethylene dimethacrylate, and wherein copolymerization is carried out at a temperature of less than about 80°c using an azobisisobutylnitrile free radical initiator without a substantial excess of free radical initiator over the amount necessary to substantially fully polymerize the contact lens monomer mixture, in a suitable mold to directly form the contact lenses.

5. The method in accordance with Claim 2 wherein the pH of the sterilization solution is in the range of from about 7.6 to about 8.5.

6. A packaged, sterilized, hydrophilic contact lens comprising a lens-shaped, cross-linked vinyl-polymer hydrogel and one or more vinyl-copolymerized photochromic monomers integrally copolymerized in the hydrogel, said hydrogel comprising at least about 38 to about 74 weight percent water, based on the total weight of the contact lens, and having a transmittance under non-activated conditions of at least about 80% of incident, visible light through the central zone of the lens averaged across the visible spectrum of 400-700 nm, and being capable of reversibly reducing its transmittance over the visible spectrum by at least about 40 percent upon a 60 second exposure to a UV light irradiance of 0.3 mW/cm2 simulating outdoor exposure to sunlight.

7. The packaged, sterilized, hydrophilic contact lens in accordance with Claim 6 having a fatigue resistance suitable for extended use of at least two weeks, characterized by retaining at least half of the initial photochromic activity after 70 hours of outdoor use.

8. The packaged, sterilized, hydrophilic contact lens in accordance with Claim 6 wherein said hydrogel comprises a copolymerized dimethylacrylamide, methylmethacrylate and ethylene dimethacrylate copolymer and wherein the lens is hermetically sealed in a package in an aqueous solution having a pH in the range of from about 7.6 to about 8.2.

9. The packaged, sterilized, hydrophilic photochromic contact lens in accordance with Claim 6 wherein said lens is packaged in contact with an alkaline sterilization solution having a pH in the range of from about 7.5 to about 8.5.

10. The packaged, sterilized hydrophilic photochromic contact lens in accordance with Claim 8 wherein the sterilization solution comprises a potassium bicarbonate and/or Tris buffering component.